bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost effectiveness of nusinersen for patients with infantile-onset spinal muscular atrophy in US
Authors: Thokala Praveen , Stevenson Matt , Kumar Varun M. , Ren Shijie , Ellis Alexandra G. , Chapman Richard H. 
Published: October 2020

Abstract
Background
Patients with infantile-onset spinal muscular atrophy (SMA), a rare, genetic neuromuscular disease, do not achieve key motor function milestones (e.g., sitting) and have short life expectancy in the absence of treatment. Nusinersen is a disease-modifying therapy for patients with SMA.

Objective
The aim of this study was to estimate the cost-effectiveness of nusinersen compared to best supportive care (BSC) in patients diagnosed with infantile-onset SMA in the US.

Methods
A de novo economic model was developed with the following health states: “permanent ventilation”, “not sitting”, “sitting”, “walking”, and “death”. Short-term data were sourced from the pivotal clinical trials and studies of nusinersen (ENDEAR and SHINE). Motor function milestones achieved at the end of follow-up in the clinical trials were assumed to be sustained until death. Mortality risks were based on survival modelling of relevant published Kaplan–Meier data. Costs, life years (LYs), and quality-adjusted life years (QALYs) were discounted at 3% per annum, and the analyses were performed from a US health care sector perspective. Scenario analyses and sensitivity analyses were conducted to assess the robustness of the results to key parameters.

Results
In our base-case analysis, nusinersen treatment achieves greater QALYs and more LYs (3.24 and 7.64, respectively) compared with BSC (0.46 QALYs and 2.40 LYs, respectively), resulting in an incremental cost per QALY gained of approximately $1,112,000 and an incremental cost per LY gained of $590,000 for nusinersen compared to BSC. The incremental cost effectiveness ratios did not fall below $990,000 per QALY gained in scenario and sensitivity analyses. Results were most sensitive to the length of survival, background health care costs, and utility in the “not sitting” and “sitting” health states.

Conclusions
The estimated incremental cost-effectiveness of nusinersen from a US health care sector perspective exceeded traditional cost-effectiveness thresholds. Cost-effectiveness was dependent on assumptions made regarding survival, costs, utilities, and whether the motor function milestones were sustained over lifetime. Given the relatively short-term effectiveness data available for the treatment, a registry to collect long-term data of infantile-onset SMA patients is recommended.
H. pylori modulates DC functions via T4SS/TNFα/p38-dependent SOCS3 expression
Authors: Sarajlic Muamera , Neuper Theresa , Vetter Julia , Schaller Susanne , Klicznik Maria M. , Gratz Iris K. , Wessler Silja , Posselt Gernot , Horejs-Hoeck Jutta 
Published: October 2020

AbstractBackgroundHelicobacter pylori(H. pylori) is a gram-negative bacterium that chronically infects approximately 50% of the world’s human population. While in most cases the infection remains asymptomatic, 10% of infected individuals develop gastric pathologies and 1–3% progress to gastric cancer. AlthoughH. pyloriinduces severe inflammatory responses, the host’s immune system fails to clear the pathogen andH. pylorican persist in the human stomach for decades. As suppressor of cytokine signaling (SOCS) proteins are important feedback regulators limiting inflammatory responses, we hypothesized thatH. pyloricould modulate the host’s immune responses by inducing SOCS expression.MethodsThe phenotype of human monocyte-derived DCs (moDCs) infected withH. pyloriwas analyzed by flow cytometry and multiplex technology. SOCS expression levels were monitored by qPCR and signaling studies were conducted by means of Western blot. For functional studies, RNA interference-based silencing ofSOCS1–3and co-cultures with CD4+T cells were performed.ResultsWe show thatH. pyloripositive gastritis patients express significantly higherSOCS3, but notSOCS1andSOCS2, levels compared toH. pylorinegative patients. Moreover, infection of human moDCs withH. pylorirapidly inducesSOCS3expression, which requires the type IV secretion system (T4SS), release of TNFα, and signaling via the MAP kinase p38, but appears to be independent of TLR2, TLR4, MEK1/2 and STAT proteins. Silencing ofSOCS3expression in moDCs prior toH. pyloriinfection resulted in increased release of both pro- and anti-inflammatory cytokines, upregulation of PD-L1, and decreased T-cell proliferation.ConclusionsThis study shows thatH. pyloriinduces SOCS3 via an autocrine loop involving the T4SS and TNFα and p38 signaling. Moreover, we demonstrate that high levels of SOCS3 in DCs dampen PD-L1 expression on DCs, which in turn drives T-cell proliferation.
Zero problems with compositional data of physical behaviors: a comparison of three zero replacement methods
Authors: Rasmussen Charlotte Lund , Palarea-Albaladejo Javier , Johansson Melker Staffan , Crowley Patrick , Stevens Matthew Leigh , Gupta Nidhi , Karstad Kristina , Holtermann Andreas 
Published: October 2020

AbstractBackgroundResearchers applying compositional data analysis to time-use data (e.g., time spent in physical behaviors) often face the problem of zeros, that is, recordings of zero time spent in any of the studied behaviors. Zeros hinder the application of compositional data analysis because the analysis is based on log-ratios. One way to overcome this challenge is to replace the zeros with sensible small values. The aim of this study was to compare the performance of three existing replacement methods used within physical behavior time-use epidemiology: simple replacement, multiplicative replacement, and log-ratio expectation-maximization (lrEM) algorithm. Moreover, we assessed the consequence of choosing replacement values higher than the lowest observed value for a given behavior.MethodUsing a complete dataset based on accelerometer data from 1310 Danish adults as reference, multiple datasets were simulated across six scenarios of zeros (5–30% zeros in 5% increments). Moreover, four examples were produced based on real data, in which, 10 and 20% zeros were imposed and replaced using a replacement value of 0.5 min, 65% of the observation threshold, or an estimated value below the observation threshold. For the simulation study and the examples, the zeros were replaced using the three replacement methods and the degree of distortion introduced was assessed by comparison with the complete dataset.ResultsThe lrEM method outperformed the other replacement methods as it had the smallest influence on the structure of relative variation of the datasets. Both the simple and multiplicative replacements introduced higher distortion, particularly in scenarios with more than 10% zeros; although the latter, like the lrEM, does preserve the ratios between behaviors with no zeros. The examples revealed that replacing zeros with a value higher than the observation threshold severely affected the structure of relative variation.ConclusionsGiven our findings, we encourage the use of replacement methods that preserve the relative structure of physical behavior data, as achieved by the multiplicative and lrEM replacements, andto avoidsimple replacement. Moreover, we do not recommend replacing zeros with values higher than the lowest observed value for a behavior.
The optimal regimen of oral tranexamic acid administration for primary total knee/hip replacement: a meta-analysis and narrative review of a randomized controlled trial
Authors: Ye Wei , Liu Yafang , Liu Wei Feng , Li Xiao Long , Shao Jianshu 
Published: October 2020

Abstract
Background
Oral tranexamic acid (TXA) has been demonstrated to reduce the blood loss in primary total knee and hip arthroplasty, but the optimal regimen of oral TXA administration is still unknown. This study aimed to find the best number of administrations of oral TXA for primary total knee and hip arthroplasty.

Methods
The PubMed, Embase, and Cochrane Library databases were searched for relevant studies published before March 20, 2020. Studies clearly reporting a comparison of multiple administrations of oral TXA for total hip/knee replacement were included, and the total blood loss (TBL), intraoperative blood loss (IBL), decline in hemoglobin (DHB), deep vein thrombosis (DVT), intramuscular venous thrombosis (IVT), length of hospital stay (LOS), and transfusion rate were evaluated. The weighted mean differences and relative risks were calculated using a fixed effects or random effects model.

Results
Nine studies involving 1678 patients were included in this meta-analysis (TXA 1363 (one administration, 201; two administrations, 496; three administrations, 215; four administrations, 336; five administrations, 115); placebo 315); the results show that compared with placebo groups, oral TXA could significantly reduce the TBL, IBL, DHB, LOS, and transfusion rate. In addition, the incidences of IVT and DVT were similar between the TXA and placebo groups. Moreover, two administrations of oral TXA significantly reduced the TBL and DHB compared with one administration, three administrations of oral TXA were better than two administrations, and four administrations of oral TXA were better than three administrations.

Conclusion
Our results suggested that oral TXA could significantly reduce the blood loss and the length of hospital stay but could not increase the incidence of DVT and IVT for total joint replacement patients; additionally, the effectiveness of oral TXA administration increased as the number of administrations increased.
Long noncoding RNA RP11-757G1.5 sponges miR-139-5p and upregulates YAP1 thereby promoting the proliferation and liver, spleen metastasis of colorectal cancer
Authors: Zhu Xiaojian , Bu Fanqin , Tan Ting , Luo Qilin , Zhu Jinfeng , Lin Kang , Huang Jun , Luo Chen , Zhu Zhengming 
Published: October 2020

Abstract
Background
Accumulating evidence indicates that long non-coding RNAs (lncRNAs) acting as crucial regulators in tumorigenesis. However, its biological functions of lncRNAs in colorectal cancer (CRC) have not been systematically clarified.

Methods
An unbiased screening was performed to identify disregulated lncRNAs revealed to be implicated in CRC carcinogenesis according to an online-available data dataset. In situ hybridization (ISH), RT-qPCR and RNA fluorescence in situ hybridization (RNA-FISH) were applied to detect RP11-757G1.5 expression in CRC tissues and cell lines. The associations of RP11-757G1.5 with clinicopathological characteristics were analyzed. Their effects on prognosis were analyzed by the Kaplan-Meier analysis, Log-rank test, Univariate and Multivariate Cox regression analysis. The potential biological function of RP11-757G1.5 in CRC was investigated by Colony formation, Edu cell proliferation, Flow cytometry, Wound healing and Transwell assays. Bioinformatics binding site analysis, Luciferase reporter assay, Ago2 immunoprecipitation assays, RNA pull-down assay, RT-qPCR and Western blotting were utilized to demonstrate the mechanism of RP11-757G1.5 acts as a molecular sponge of miR-139-5p to regulate the expression of YAP1. Finally, we further explore the potential role of RP11-757G1.5 in CRC orthotopic xenografts in vivo.

Results
We discovered a novel oncogenic lncRNA RP11-757G1.5, that was overexpressed in CRC tissues, especially in aggressive cases. Moreover, up-regulation of RP11-757G1.5 strongly correlated with poor clinical outcomes of patients with CRC. Functional analyses revealed that RP11-757G1.5 promoted cell proliferation in vitro and in vivo. Furthermore, RP11-757G1.5 stimulated cell migration and invasion in vitro and in vivo. Mechanistic studies illustrated that RP11-757G1.5 regulated the expression of YAP1 through sponging miR-139-5p and inhibiting its activity thereby promoting CRC progression and development.

Conclusions
Altogether, these results reveal a novel RP11-757G1.5/miR-139-5p/YAP1 regulatory axis that participates in CRC carcinogenesis and progression.
FPIES in exclusively breastfed infants: two case reports and review of the literature
Authors: Baldo Francesco , Bevacqua Martina , Corrado Cristiana , Nisticò Daniela , Cesca Laura , Declich Valentina , Dall’Amico Roberto , Barbi Egidio 
Published: October 2020

Abstract
Background
Food Protein-Induced Enterocolitis Syndrome (FPIES) is a non IgE-mediated food allergy that generally affects children in the first year of life. Usually symptoms break out when formula milk or solid foods are introduced for the first time but they might also appear in exclusively breastfed infants, since the trigger elements, especially cow’s milk proteins, can be conveyed by maternal milk as well. FPIES in exclusively breastfed babies is a very rare clinical condition and only few cases have been reported in the medical literature.

Case presentation
We describe two cases of FPIES in exclusively breastfed babies. The first one is a two-month-old infant with a brief history of vomit and diarrhea that presented to the Emergency Department in septic-like conditions. The main laboratory finding was a significant increase in methemoglobin (13%). Clinically, we noted that, when breastfeeding was suspended, diarrhea drastically improved, and vice versa when maternal milk was reintroduced. An amino acid-based formula allowed a complete normalization of the symptoms. The second one is a three-month-old infant admitted for a 3 days history of persistent vomit and diarrhea. Blood tests showed a raised level of methemoglobin (7%). An esophagogastroduodenoscopy was performed and biopsies showed an eosinophilic infiltration of the duodenal mucosa. A maternal exclusion diet and an amino acid-based formula allowed a rapid regularization of the bowel function.

Conclusions
We searched all the cases of FPIES in exclusively breastfed babies reported in the medical literature, identifying eight patients, with an average age of 3 months (range 15 days – 6 months). The majority of the cases were initially diagnosed as gastroenteritis or sepsis, five cases were characterized by an acute on chronic scenario and cow’s milk was the most frequently involved food. Methemoglobin was never tested. An oral food challenge test was performed in two patients.
FPIES in exclusively breastfed infants is a rare condition that, in the presence of compatible history and symptoms, should be considered also in exclusively breastfed babies. The evaluation of methemoglobin can simplify the diagnostic process.
Evidence of a wide gap between COVID-19 in humans and animal models: a systematic review
Authors: Ehaideb Salleh N. , Abdullah Mashan L. , Abuyassin Bisher , Bouchama Abderrezak 
Published: October 2020

Abstract
Background
Animal models of COVID-19 have been rapidly reported after the start of the pandemic. We aimed to assess whether the newly created models reproduce the full spectrum of human COVID-19.

Methods
We searched the MEDLINE, as well as BioRxiv and MedRxiv preprint servers for original research published in English from January 1 to May 20, 2020. We used the search terms (COVID-19) OR (SARS-CoV-2) AND (animal models), (hamsters), (nonhuman primates), (macaques), (rodent), (mice), (rats), (ferrets), (rabbits), (cats), and (dogs). Inclusion criteria were the establishment of animal models of COVID-19 as an endpoint. Other inclusion criteria were assessment of prophylaxis, therapies, or vaccines, using animal models of COVID-19.

Result
Thirteen peer-reviewed studies and 14 preprints met the inclusion criteria. The animals used were nonhuman primates (n = 13), mice (n = 7), ferrets (n = 4), hamsters (n = 4), and cats (n = 1). All animals supported high viral replication in the upper and lower respiratory tract associated with mild clinical manifestations, lung pathology, and full recovery. Older animals displayed relatively more severe illness than the younger ones. No animal models developed hypoxemic respiratory failure, multiple organ dysfunction, culminating in death. All species elicited a specific IgG antibodies response to the spike proteins, which were protective against a second exposure. Transient systemic inflammation was observed occasionally in nonhuman primates, hamsters, and mice. Notably, none of the animals unveiled a cytokine storm or coagulopathy.

Conclusions
Most of the animal models of COVID-19 recapitulated mild pattern of human COVID-19 with full recovery phenotype. No severe illness associated with mortality was observed, suggesting a wide gap between COVID-19 in humans and animal models.
AlphaBeta: computational inference of epimutation rates and spectra from high-throughput DNA methylation data in plants
Authors: Shahryary Yadollah , Symeonidi Aikaterini , Hazarika Rashmi R. , Denkena Johanna , Mubeen Talha , Hofmeister Brigitte , van Gurp Thomas , Colomé-Tatché Maria , Verhoeven Koen J.F. , Tuskan Gerald , Schmitz Robert J. , Johannes Frank 
Published: October 2020

AbstractStochastic changes in DNA methylation (i.e., spontaneous epimutations) contribute to methylome diversity in plants. Here, we describe AlphaBeta, a computational method for estimating the precise rate of such stochastic events using pedigree-based DNA methylation data as input. We demonstrate how AlphaBeta can be employed to study transgenerationally heritable epimutations in clonal or sexually derived mutation accumulation lines, as well as somatic epimutations in long-lived perennials. Application of our method to published and new data reveals that spontaneous epimutations accumulate neutrally at the genome-wide scale, originate mainly during somatic development and that they can be used as a molecular clock for age-dating trees.
Vectors, molecular epidemiology and phylogeny of TBEV in Kazakhstan and central Asia
Authors: Abdiyeva Karlygash , Turebekov Nurkeldi , Yegemberdiyeva Ravilya , Dmitrovskiy Andrey , Yeraliyeva Lyazzat , Shapiyeva Zhanna , Nurmakhanov Talgat , Sansyzbayev Yerlan , Froeschl Guenter , Hoelscher Michael , Zinner Josua , Essbauer Sandra , Frey Stefan 
Published: October 2020

AbstractBackgroundIn the South of Kazakhstan, Almaty Oblastʼ (region) is endemic for tick-borne encephalitis, with 0.16–0.32 cases/100,000 population between 2016–2018. The purpose of this study was to determine the prevalence and circulating subtypes of tick-borne encephalitis virus (TBEV) in Almaty Oblastʼ and Kyzylorda Oblastʼ.MethodsIn 2015 we investigated 2341 ticks from 7 sampling sites for the presence of TBEV. Ticks were pooled in 501 pools and isolated RNA was tested for the presence of TBEV by RT-qPCR. For the positive samples, the E gene was amplified, sequenced and a phylogenetic analysis was carried out.ResultsA total of 48 pools were TBEV-positive by the RT-qPCR. TBEV-positive ticks were only detected in three districts of Almaty Oblastʼ and not in Kyzylorda Oblastʼ. The positive TBEV pools were found withinIxodes persulcatus,Haemaphysalis punctataandDermacentor marginatus. These tick species prevailed only in Almaty Oblastʼ whereas in Kyzylorda OblastʼHyalomma asiaticumandD. marginatusare endemic. The minimum infection rates (MIR) in the sampling sites were 4.4% in Talgar, 2.8% in Tekeli and 1.1% in Yenbekshikazakh, respectively. The phylogenetic analysis of the generated sequences indicates that TBEV strains found in Almaty Oblastʼ clusters in the Siberian subtype within two different clades.ConclusionsWe provided new data about the TBEV MIR in ticks in Almaty Oblastʼ and showed that TBEV clusters in the Siberian Subtype in two different clusters at the nucleotide level. These results indicate that there are different influences on the circulating TBEV strains in south-eastern Kazakhstan. These influences might be caused by different routes of the virus spread in ticks which might bring different genetic TBEV lineages to Kazakhstan. The new data about the virus distribution and vectors provided here will contribute to an improvement of monitoring of tick-borne infections and timely anti-epidemic measures in Kazakhstan.
Cellular and molecular changes and immune response in the intestinal mucosa during Trichinella spiralis early infection in rats
Authors: Saracino María Priscila , Vila Cecilia Celeste , Cohen Melina , Gentilini María Virginia , Falduto Guido Hernán , Calcagno Marcela Adriana , Roux Estela , Venturiello Stella Maris , Malchiodi Emilio Luis 
Published: October 2020

AbstractBackground:The main targets of the host’s immune system inTrichinella spiralisinfection are the adult worms (AW), at the gut level, and the migrant or newborn larvae (NBL), at systemic and pulmonary levels. Most of the studies carried out in the gut mucosa have been performed on the Payer’s patches and/or the mesenteric lymph nodes but not on the lamina propria, therefore, knowledge on the gut immune response againstT. spiralisremains incomplete.MethodsThis study aimed at characterizing the early mucosal immune response againstT. spiralis, particularly, the events taking place between 1 and 13 dpi. For this purpose, Wistar rats were orally infected with muscle larvae ofT. spiralisand the humoral and cellular parameters of the gut immunity were analysed, including the evaluation of the ADCC mechanism exerted by lamina propria cells.ResultsA marked inflammation and structural alteration of the mucosa was found. The changes involved an increase in goblet cells, eosinophils and mast cells, and B and T lymphocytes, initially displaying a Th1 profile, characterised by the secretion of IFN-γ and IL-12, followed by a polarization towards a Th2 profile, with a marked increase in IgE, IgG1, IL-4, IL-5 and IL-13 levels, which occurred once the infection was established. In addition, the helminthotoxic activity of lamina propria cells demonstrated the role of the intestine as a place of migrant larvae destruction, indicating that not all the NBLs released in the gut will be able to reach the muscles.ConclusionsThe characterization of the immune response triggered in the gut mucosa duringT. spiralisinfection showed that not only an effector mechanism is directed toward the AW but also towards the NBL as a cytotoxic activity was observed against NBL exerted by lamina propria cells.