bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systematic review of diagnostic methods for acute respiratory distress syndrome
Authors: Hagens Laura A. , Heijnen Nanon F.L. , Smit Marry R. , Schultz Marcus J. , Bergmans Dennis C.J.J. , Schnabel Ronny M. , Bos Lieuwe D.J. 
Published: October 2020

Rationale
Acute respiratory distress syndrome (ARDS) is currently diagnosed by the Berlin definition, which does not include a direct measure of pulmonary oedema, endothelial permeability or pulmonary inflammation. We hypothesised that biomarkers of these processes have good diagnostic accuracy for ARDS.

Methods
Medline and Scopus were searched for original diagnostic studies using minimally invasive testing. Primary outcome was the diagnostic accuracy per test and was categorised by control group. The methodological quality was assessed with QUADAS-2 tool. Biomarkers that had an area under the receiver operating characteristic curve (AUROCC) of >0.75 and were studied with minimal bias against an unselected control group were considered to be promising.

Results
Forty-four articles were included. The median AUROCC for all evaluated tests was 0.80 (25th to 75th percentile: 0.72�0.88). The type of control group influenced the diagnostic accuracy (p=0.0095). Higher risk of bias was associated with higher diagnostic accuracy (AUROCC 0.75 for low-bias, 0.77 for intermediate-bias and 0.84 for high-bias studies; p=0.0023). Club cell protein 16 and soluble receptor for advanced glycation end-products in plasma and two panels with biomarkers of oxidative stress in breath showed good diagnostic accuracy in low-bias studies that compared ARDS patients to an unselected intensive care unit (ICU) population.

Conclusion
This systematic review revealed only four diagnostic tests fulfilling stringent criteria for a promising biomarker in a low-bias setting. For implementation into the clinical setting, prospective studies in a general unselected ICU population with good methodological quality are needed.
High-sensitivity troponin I for risk stratification in normotensive pulmonary embolism
Authors: Ebner Matthias , Guddat Niklas , Keller Karsten , Merten Marie Christine , Lerchbaumer Markus H. , Hasenfuß Gerd , Konstantinides Stavros V. , Lankeit Mareike 
Published: October 2020

While numerous studies have confirmed the prognostic role of high-sensitivity troponin T (hsTnT) in pulmonary embolism (PE), high-sensitivity troponin I (hsTnI) is inappropriately studied. This study aimed to investigate the prognostic relevance of hsTnI in normotensive PE, establish the optimal cut-off value for risk stratification and to compare the prognostic performances of hsTnI and hsTnT.Based on data from 459 consecutive PE patients enrolled in a single-centre registry, receiver operating characteristic analysis was used to identify an optimal hsTnI cut-off value for prediction of in-hospital adverse outcomes (PE-related death, cardiopulmonary resuscitation or vasopressor treatment) and all-cause mortality.Patients who suffered an in-hospital adverse outcome (4.8%) had higher hsTnI concentrations compared with those with a favourable clinical course (57 (interquartile range (IQR) 22–197)versus15 (IQR 10–86) pg·mL−1, p=0.03). A hsTnI cut-off value of 16 ng·mL−1provided optimal prognostic performance and predicted in-hospital adverse outcomes (OR 6.5, 95% CI 1.9–22.4) and all-cause mortality (OR 3.7, 95% CI 1.0–13.3). Between female and male patients, no relevant differences in hsTnI concentrations (17 (IQR 10–97)versus17 (IQR 10–92) pg·mL−1, p=0.79) or optimised cut-off values were observed. Risk stratification according to the 2019 European Society of Cardiology algorithm revealed no differences if calculated based on either hsTnI or hsTnT (p=0.68).Our findings confirm the prognostic role of hsTnI in normotensive PE. HsTnI concentrations >16 pg·mL−1predicted in-hospital adverse outcome and all-cause mortality; sex-specific cut-off values do not seem necessary. Importantly, our results suggest that hsTnI and hsTnT can be used interchangeably for risk stratification.
Lower urinary tract symptoms in men: challenges to early hospital presentation in a resource-poor health system
Authors: Nnabugwu Ikenna I. , Okoronkwo Ijeoma L. , Nnabugwu Chinwe A. 
Published: October 2020

Abstract

Background
The point at which men seek medical care for lower urinary tract symptoms (LUTS) varies between individuals. Presentation to hospital with complications beyond LUTS appears prevalent in our setting. The aim of this survey is to assess from the community perspective in southeast Nigeria, the challenges to early presentation for medical evaluation for LUTS by men.

Methods
A questionnaire-based cross-sectional survey of randomly-selected men ≥40 years. The questionnaire captured respondent’s age; presence, duration and severity of LUTS; access to health information; wealth-index; and when (and why) medical care for LUTS was sought. Analysis was with SPSS® version 20.

Results
In all, responses from 1319 men (mean age 54.2 ± 10.2 years) are analysed. Of these, 267 report LUTS: 58.4% (156) report moderate to severe LUTS and 51.7% (138) are yet to seek medical care. As regards seeking medical care, all the men reporting LUTS of 3 months, 35.7% of 126 men reporting moderate LUTS, and 20.0% of 30 men reporting severe LUTS are yet to seek medical care. LUTS being non-bothersome (not financial constraint) is the most prevalent reason for not seeking medical care early. Delay is encouraged by limited access to health information (OR 3.10; p < 0.001), but discouraged by literacy (OR 0.86; p < 0.001) and aging (OR 0.93; p = 0.002).

Conclusion
From the community perspective, the prevalent challenge to seeking medical care for LUTS early is absence of bother. Empowering men through formal education and researched health information will influence positively the time that LUTS in men is appreciated as bothersome.
Determining the cost-effectiveness requirements of an exoskeleton preventing second hip fractures using value of information
Authors: Manetti Stefania , Turchetti Giuseppe , Fusco Francesco 
Published: October 2020

Abstract
Background
Falls may lead to hip fractures, which have a detrimental effect on the prognosis of patients as well as a considerable impact on healthcare expenditures. Since a secondary hip fracture (SHF) may lead to even higher costs than primary fractures, the development of innovative services is crucial to limit falls and curb costs in high-risk patients. An early economic evaluation assessed which patients with a second hip fracture could benefit most from an exoskeleton preventing falls and whether its development is feasible.

Methods
The life-course of hip fractured patients presenting with dementia or cardiovascular diseases was simulated using a Markov model relying on the United Kingdom administrative data and complemented by published literature. A group of experts provided the exoskeleton parameters. Secondary analyses included a threshold analysis to identify the exoskeleton requirements (e.g. minimum impact of the exoskeleton on patients’ quality of life) leading to a reimbursable incremental cost-effectiveness ratio. Similarly, the uncertainty around these requirements was modelled by varying their standard errors and represented alongside population Expected Value of Perfect Information (EVPI).

Results
Our base-case found the exoskeleton cost-effective when providing a statistically significant reduction in SHF risk. The secondary analyses identified 286 cost-effective combinations of the exoskeleton requirements. The uncertainty around these requirements was explored producing further 22,880 scenarios, which showed that this significant reduction in SHF risk was not necessary to support the exoskeleton adoption in clinical practice. Conversely, a significant improvement in women quality of life was crucial to obtain an acceptable population EVPI regardless of the cost of the exoskeleton.

Conclusions
Our study identified the exoskeleton requisites to be cost-effective and the value of future research. Decision-makers could use our analyses to assess not only whether the exoskeleton could be cost-effective but also how much further research and development of the exoskeleton is worth to be pursued.
The best execution of the DuoStim strategy (double stimulation in the follicular and luteal phase of the same ovarian cycle) in patients who are poor ovarian responders
Authors: Luo Yanqun , Sun Li , Dong Mei , Zhang Xiqian , Huang Li , Zhu Xiulan , Nong Yingqi , Liu Fenghua 
Published: October 2020

Abstract
Background
Patients found to be poor ovarian responders (POR) are a challenging patient population for any assisted reproduction technology. Despite attempts at various controlled ovarian stimulation schemes, reproductive outcomes in this patient population have not improved. In recent years, the DuoStim protocol (both follicular and luteal phase stimulation during the same menstrual cycle) has shown a potential for use in patients with POR.

Methods
This retrospective study reviewed the medical records of 304 women who were diagnosed as POR and underwent the DuoStim protocol. We compared follicular phase stimulation (FPS) data and luteal phase stimulation (LPS) data of the same patients. We also compared the effects of different trigger drugs including urine human chorionic gonadotropin (uHCG; 10,000 IU), recombinant human chorionic gonadotropin (rHCG; 250 μg), and gonadotropin-releasing hormone agonist (GnRH-a; 0.2 mg) at the FPS and LPS stages.

Results
POR undergoing the DuoStim protocol resulted in a significantly higher number of oocytes retrieved, normal fertilised oocytes, cleaved embryos, cryopreserved embryos, and good quality embryos at the LPS stage than at the FPS stage. Trigger drugs at the FPS stage did not affect the FPS stage data. Regardless of the stage, rHCG and GnRH-a yielded significantly more cryopreserved embryos and good quality embryos than uHCG.

Conclusion
The use of GnRH-a or rHCG as the trigger drug may be better than uHCG in both the FPS and LPS stages for POR undergoing the DuoStim protocol. This will increase the number of good quality embryos at the LPS stage. We found that the LPS stage results in more oocytes (and therefore more embryos) than the FPS stage.
Connecting METTL3 and intratumoural CD33+ MDSCs in predicting clinical outcome in cervical cancer
Authors: Ni Huan-he , Zhang Lin , Huang He , Dai Shu-qin , Li Jiang 
Published: October 2020

Abstract
Background
Methyltransferase-like 3 (METTL3) is a member of the m6A methyltransferase family and acts as an oncogene in cancers. Recent studies suggest that host innate immunity is regulated by the enzymes controlling m6A epitranscriptomic changes. Here, we aim to explore the associations between the levels of METTL3 and CD33+ myeloid-derived suppressor cells (MDSCs) in tumour tissues and the survival of patients with cervical cancer (CC).

Methods
Specimens of paraffin embedded tumour from 197 CC patients were collected. The expression levels of METTL3 and CD33 were measured by immunohistochemical (IHC) staining. The clinical associations of the IHC variants were analysed by Pearson’s or Spearman’s chi-square tests. Overall survival (OS) and disease-free survival (DFS) were estimated by the Kaplan–Meier method and log-rank test. Hazard ratios (HRs) and independent significance were obtained via Cox proportional hazards models for multivariate analyses. METTL3 in CD33+ cells or CC-derived cells was knocked down by METTL3-specific siRNA, and MDSC induction in vitro was performed in a co-culture system in the presence of METTL3-siRNA and METTL3-knockdown-CC-derived cells compared with that of the corresponding controls.

Results
We found that tumour tissues displayed increased levels of METTL3 and CD33+ MDSCs compared with tumour-adjacent tissues from the same CC patients. Importantly, METTL3 expression was positively related to the density of CD33+ cells in tumour tissues (P = 0.011). We further found that the direct CD33+CD11b+HLA-DR− MDSC induction and tumour-derived MDSC induction in vitro were decreased in the absence of METTL3. The level of METTL3 in tumour microenvironments was significantly related to advanced tumour stage. The levels of METTL3 and CD33+ MDSCs in tumour tissues were notably associated with reduced DFS or OS. Cox model analysis revealed that the level of METTL3 in tumour cells was an independent factor for patient survival, specifically for DFS (HR = 3.157, P = 0.022) and OS (HR = 3.271, P = 0.012), while the CD33+ MDSC number was an independent predictor for DFS (HR: 3.958, P = 0.031). Interestingly, in patients with advanced-disease stages (II–IV), METTL3 in tumour cells was an independent factor for DFS (HR = 6.725, P = 0.010) and OS (HR = 5.140, P = 0.021), while CD33+ MDSC density was an independent factor for OS (HR = 8.802, P = 0.037).

Conclusion
Our findings suggest that CD33+ MDSC expansion is linked to high levels of METTL3 and that METTL3 and CD33+ MDSCs are independent prognostic factors in CC.
Forsythoside B attenuates memory impairment and neuroinflammation via inhibition on NF-κB signaling in Alzheimer’s disease
Authors: Kong Fan’ge , Jiang Xue , Wang Ruochen , Zhai Siyu , Zhang Yizhi , Wang Di 
Published: October 2020

Abstract
Background
Neuroinflammation is a principal element in Alzheimer’s disease (AD) pathogenesis, so anti-inflammation may be a promising therapeutic strategy. Forsythoside B (FTS•B), a phenylethanoid glycoside isolated from Forsythiae fructus, has been reported to exert anti-inflammatory effects. However, no studies have reported whether the anti-inflammatory properties of FTS•B have a neuroprotective effect in AD. In the present study, these effects of FTS•B were investigated using amyloid precursor protein/presenilin 1 (APP/PS1) mice, BV-2 cells, and HT22 cells.

Methods
APP/PS1 mice were administered FTS•B intragastrically for 36 days. Behavioral tests were then carried out to examine cognitive functions, including the Morris water maze, Y maze, and open field experiment. Immunohistochemistry was used to analyze the deposition of amyloid-beta (Aβ), the phosphorylation of tau protein, and the levels of 4-hydroxynonenal, glial fibrillary acidic protein, and ionized calcium-binding adapter molecule 1 in the hippocampus. Proteins that showed marked changes in levels related to neuroinflammation were identified using proteomics and verified using enzyme-linked immunosorbent assay and western blot. BV-2 and HT22 cells were also used to confirm the anti-neuroinflammatory effects of FTS•B.

Results
In APP/PS1 mice, FTS•B counteracted cognitive decline, ameliorated the deposition of Aβ and the phosphorylation of tau protein, and attenuated the activation of microglia and astrocytes in the cortex and hippocampus. FTS•B affected vital signaling, particularly by decreasing the activation of JNK-interacting protein 3/C-Jun NH2-terminal kinase and suppressing WD-repeat and FYVE-domain-containing protein 1/toll-like receptor 3 (WDFY1/TLR3), further suppressing the activation of nuclear factor-κB (NF-κB) signaling. In BV-2 and HT22 cells, FTS•B prevented lipopolysaccharide-induced neuroinflammation and reduced the microglia-mediated neurotoxicity.

Conclusions
FTS•B effectively counteracted cognitive decline by regulating neuroinflammation via NF-κB signaling in APP/PS1 mice, providing preliminary experimental evidence that FTS•B is a promising therapeutic agent in AD treatment.
A new mouse model to study restoration of interleukin-6 (IL-6) expression in a Cre-dependent manner: microglial IL-6 regulation of experimental autoimmune encephalomyelitis
Authors: Sanchis Paula , Fernández-Gayol Olaya , Comes Gemma , Aguilar Kevin , Escrig Anna , Giralt Mercedes , Palmiter Richard D. , Hidalgo Juan 
Published: October 2020

AbstractBackgroundInterleukin-6 (IL-6) is a pleiotropic cytokine that controls numerous physiological processes both in basal and neuroinflammatory conditions, including the inflammatory response to experimental autoimmune encephalomyelitis (EAE). IL-6 is produced by multiple peripheral and central cells, and until now, the putative roles of IL-6 from different cell types have been evaluated through conditional cell-specific IL-6 knockout mice. Nevertheless, these mice probably undergo compensatory responses of IL-6 from other cells, which makes it difficult to assess the role of each source of IL-6.MethodsTo give some insight into this problem, we have produced a novel mouse model: a conditional reversible IL-6 KO mouse (IL6-DIO-KO). By using double-inverted, open-reading-frame (DIO) technology, we created a mouse line with the loss ofIl6expression in all cells that can be restored by the action of Cre recombinase. Since microglia are one of the most important sources and targets of IL-6 into the central nervous system, we have recovered microglialIl6expression in IL6-DIO-KO mice through breeding toCx3cr1-CreER mice and subsequent injection of tamoxifen (TAM) when mice were 10–16 weeks old. Then, they were immunized with myelin oligodendrocyte glycoprotein 35-55 peptide (MOG35-55) 7 weeks after TAM treatment to induce EAE. Clinical symptoms and demyelination, CD3 infiltration, and gliosis in the spinal cord were evaluated.ResultsIL6-DIO-KO mice were resistant to EAE, validating the new model. Restoration of microglialIl6was sufficient to develop a mild version of EAE-related clinical symptoms and neuropathology.ConclusionsIL6-DIO-KO mouse is an excellent model to understand in detail the role of specific cellular sources of IL-6 within a recovery-of-function paradigm in EAE.
Cyclooxygenase-1 mediates neuroinflammation and neurotoxicity in a mouse model of retinitis pigmentosa
Authors: Yang Wei , Xiong Guoyin , Lin Bin 
Published: October 2020

AbstractBackgroundRetinitis pigmentosa (RP) is a group of inherited eye disorders with progressive degeneration of photoreceptors in the retina, ultimately leading to partial or complete blindness. The mechanisms underlying photoreceptor degeneration are not yet completely understood. Neuroinflammation is reported to play a pathological role in RP. However, the mechanisms that trigger neuroinflammation remain largely unknown. To address this question, we investigated the role of cyclooxygenase-1 (COX-1), a key enzyme in the conversion of arachidonic acid to proinflammatory prostaglandins, in the rd10 mouse model of RP.MethodsWe backcrossed COX-1 knockout mice (COX-1−/−) onto the rd10 mouse model of RP and investigated the impact of COX-1 deletion on neuroinflammation in the resulting COX-1−/−/rd10 mouse line, using a combination of immunocytochemistry, flow cytometry, qPCR, ELISA, and a series of simple visual tests.ResultsWe found that genetic ablation or pharmacological inhibition of COX-1 alleviated neuroinflammation and subsequently preserved retinal photoreceptor and function and visual performance in rd10 mice. Moreover, we observed that the pharmacological inhibition of the prostaglandin E2 (PGE2) EP2 receptors largely replicated the beneficial effects of COX-1 deletion, suggesting that EP2 receptor was a critical downstream effector of COX-1-mediated neurotoxicity in rd10 mice.ConclusionOur data suggest that the COX-1/PGE2/EP2 signaling pathway was partly responsible for significantly increased neuroinflammation and disease progression in rd10 mice, and that EP2 receptor could be targeted therapeutically to block the pathological activity of COX-1 without inducing any potential side effects in treating RP patients.
Harnessing the immune system to overcome cytokine storm and reduce viral load in COVID-19: a review of the phases of illness and therapeutic agents
Authors: Khadke Sumanth , Ahmed Nayla , Ahmed Nausheen , Ratts Ryan , Raju Shine , Gallogly Molly , de Lima Marcos , Sohail Muhammad Rizwan 
Published: October 2020

Abstract
Background
Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, previously named 2019-nCov), a novel coronavirus that emerged in China in December 2019 and was declared a global pandemic by World Health Organization by March 11th, 2020. Severe manifestations of COVID-19 are caused by a combination of direct tissue injury by viral replication and associated cytokine storm resulting in progressive organ damage.

Discussion
We reviewed published literature between January 1st, 2000 and June 30th, 2020, excluding articles focusing on pediatric or obstetric population, with a focus on virus-host interactions and immunological mechanisms responsible for virus associated cytokine release syndrome (CRS). COVID-19 illness encompasses three main phases. In phase 1, SARS-CoV-2 binds with angiotensin converting enzyme (ACE)2 receptor on alveolar macrophages and epithelial cells, triggering toll like receptor (TLR) mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ƙB) signaling. It effectively blunts an early (IFN) response allowing unchecked viral replication. Phase 2 is characterized by hypoxia and innate immunity mediated pneumocyte damage as well as capillary leak. Some patients further progress to phase 3 characterized by cytokine storm with worsening respiratory symptoms, persistent fever, and hemodynamic instability. Important cytokines involved in this phase are interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. This is typically followed by a recovery phase with production of antibodies against the virus. We summarize published data regarding virus-host interactions, key immunological mechanisms responsible for virus-associated CRS, and potential opportunities for therapeutic interventions.

Conclusion
Evidence regarding SARS-CoV-2 epidemiology and pathogenesis is rapidly evolving. A better understanding of the pathophysiology and immune system dysregulation associated with CRS and acute respiratory distress syndrome in severe COVID-19 is imperative to identify novel drug targets and other therapeutic interventions.
Diesel exhaust particle exposure reduces expression of the epithelial tight junction protein Tricellulin
Authors: Smyth Timothy , Veazey Janelle , Eliseeva Sophia , Chalupa David , Elder Alison , Georas Steve N. 
Published: October 2020

AbstractBackgroundWhile exposure to diesel exhaust particles has been linked to aberrant immune responses in allergic diseases such as asthma, little attention has been paid to their effects on the airway epithelial barrier. In this study, we sought to determine the effect of diesel exhaust exposure on airway epithelial barrier function and composition using in vitro and in vivo model systems.Methods16HBE14o- human bronchial epithelial cells were grown on collagen coated Transwell inserts and exposed to 5 to 50 μg/cm2SRM 2975 diesel particulate matter (DEP) suspended in cell culture medium or vehicle controls. Changes in barrier function were assessed by measuring transepithelial electrical resistance (TEER) and permeability to 4 kDa FITC Dextran. Neonatal BALB/c mice were exposed to aerosolized DEP (255 ± 89 μg/m3; 2 h per day for 5 days) and changes in the tight junction protein Tricellulin were assessed 2 weeks post exposure.ResultsA six-hour incubation of epithelial cells with diesel exhaust particles caused a significant concentration-dependent reduction in epithelial barrier integrity as measured by decreased TEER and increased permeability to 4 kDa FITC-Dextran. This reduction in epithelial barrier integrity corresponded to a significant reduction in expression of the tight junction protein Tricellulin. siRNA mediated knockdown of Tricellulin recapitulated changes in barrier function caused by DEP exposure. Neonatal exposure to aerosolized DEP caused a significant reduction in lung Tricellulin 2 weeks post exposure at both the protein and mRNA level.ConclusionShort term exposure to DEP causes a significant reduction in epithelial barrier integrity through a reduction in the tight junction protein Tricellulin. Neonatal exposure to aerosolized DEP caused a significant and sustained reduction in Tricellulin protein and mRNA in the lung, suggesting that early life exposure to inhaled DEP may cause lasting changes in airway epithelial barrier function.