bluuebunny/crossref_metadata_2025_split huggingface dataset:
Visual detection of porcine epidemic diarrhea virus by recombinase polymerase amplification combined with lateral flow dipstrip
Authors: Ma Lei , Lian Kaiqi , Zhu Mengjie , Tang Yajie , Zhang Mingliang 
Published: April 2022

Abstract
Background
Porcine epidemic diarrhea virus (PEDV) is one of the most important enteric viruses causing diarrhea in pigs. The establishment of a rapid detection method applicable in field conditions will be conducive to early detection of pathogen and implementation of relevant treatment. A novel nucleic acid amplification method, recombinase polymerase amplification (RPA), has been widely used for infectious disease diagnosis.

Results
In the present study, a reverse transcription (RT)-RPA assay combined with lateral flow dipstrip (LFD) was established for the visual detection of PEDV by targeting the N gene. The RT-RPA-LFD assay detected as low as 102 copies/µL of PEDV genomic RNA standard. Moreover, the novel RT-RPA-LFD assay did not show cross-reactivity with common swine pathogens, demonstrating high specificity. The performance of the assay for detection of clinical samples was also evaluated. A total number of 86 clinical samples were tested by RT-RPA-LFD and RT-PCR. The detection results of RT-RPA-LFD were compared with those of RT-PCR, with a coincidence rate of 96.5%.

Conclusion
The newly established RT-RPA-LFD assay in our study had high sensitivity and specificity, with a potential to use in resource-limited areas and countries.
Identification of two novel pathogenic variants of the NR1H4 gene in intrahepatic cholestasis of pregnancy patients
Authors: Lai Hua , Liu Xianxian , Xin Siming , Zheng Jiusheng , Liu Huai , Ouyang Yu , Yang Huoxiu , Zeng Yang , Zou Yang , Zeng Xiaoming 
Published: April 2022

AbstractBackgroundIntrahepatic cholestasis of pregnancy (ICP) can cause adverse pregnancy outcomes, such as spontaneous preterm delivery and stillbirth. It is a complex disease influenced by multiple factors, including genetics and the environment. Previous studies have reported that functioning nuclear receptor subfamily 1 group H member 4 (NR1H4) plays an essential role in bile acid (BA) homeostasis. However, some novel variants and their pathogenesis have not been fully elucidated. Therefore, this research aimed to investigate the genetic characteristics of theNR1H4gene in ICP.MethodsIn this study, we sequenced the entire coding region ofNR1H4in 197 pregnant women with ICP disease. SIFT and PolyPhen2 were used to predict protein changes. Protein structure modelling and comparisons between NR1H4 reference and modified protein structures were performed by SWISS-MODEL and Chimera 1.14rc, respectively. T-tests were used to analyse the potential significant differences betweenNR1H4mutations and wild types for 29 clinical features. Fisher’s test was conducted to test the significance of differences in mutation frequencies between ICP and the three databases.ResultsWe identified four mutations: two novel missense mutations, p.S145F and p.M185L; rs180957965 (A230S); and rs147030757 (N275N). The two novel missense mutations were absent in 1029 controls and three databases, including the 1000 Genomes Project (1000G_ALL), Exome Aggregation Consortium (ExAC) and ChinaMAP. Two web-available tools, SIFT and PolyPhen2, predicted that these mutations are harmful to the function of the protein. Moreover, compared to the wild-type protein structure, theNR1H4p.S145F and p.M185L protein structure showed a slight change in the chemical bond in two zinc finger structures. Combined clinical data indicate that the mutation group had higher levels of total bile acid (TBA) than the wild-type group. Therefore, we hypothesized that these two mutations altered the protein structure ofNR1H4, which impaired the function ofNR1H4itself and its target gene and caused an increase in TBA.ConclusionsTo our knowledge, this is the first study to identify the novel p.S145F and p.M185L mutations in 197 ICP patients. Our present study provides new insights into the genetic architecture of ICP involving the two novelNR1H4mutations.
Bilirubin as an indicator of cardiometabolic health: a cross-sectional analysis in the UK Biobank
Authors: Seyed Khoei Nazlisadat , Wagner Karl-Heinz , Sedlmeier Anja M. , Gunter Marc J. , Murphy Neil , Freisling Heinz 
Published: April 2022

Abstract
Background
Mildly elevated bilirubin, a by-product of hemoglobin breakdown, might mitigate cardiometabolic risk factors including adiposity, dyslipidemia, and high blood pressure (BP). We investigated the cross-sectional relationship between (total) bilirubin and baseline cardiometabolic risk factors in 467,519 UK Biobank study participants.

Methods
We used multivariable-adjusted linear regression to estimate associations between bilirubin levels and risk factors of cardiometabolic diseases including body mass index (BMI), waist and hip circumferences (WC, HC), waist-to-hip ratio (WHR), fat mass (FM), and trunk FM, and the blood lipids: apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), apoB/apoA-I, lipoprotein (a), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), LDL/HDL, TC/HDL, triglycerides (TG). Log-transformed bilirubin was modelled with restricted cubic splines and predicted mean values with 99% confidence intervals (CI) for each risk marker were estimated, separately. Second, we applied principal component analysis (PCA) for dimension reduction to in turn six anthropometric traits (height, weight, BMI, WC, HC, and WHR) and all above lipids. Last, we estimated associations (99%CI) between bilirubin and three components of the metabolic syndrome, i.e. WC, TG, and BP using logistic regression.

Results
After multivariable adjustments, higher levels of bilirubin were inversely associated with indicators of general adiposity (BMI and FM) and of body fat distribution (WC, HC, WHR, and trunk FM) in both men and women. For example, women with mildly elevated bilirubin (95th percentile equal to 15.0 µmol/L), compared to women with low bilirubin (5th percentile equal to 4.5 µmol/L), had on average a 2.0 kg/m2 (99% CI 1.9–2.1) lower BMI. Inverse associations were also observed with dyslipidemia among men and women. For example, mildly elevated bilirubin among men (95th percentile equal to 19.4 µmol/L) compared to low levels of bilirubin (5th percentile equal to 5.5 µmol/L) were associated with approx. 0.55 mmol/L (99% CI 0.53–0.56) lower TG levels, with similar inverse associations among women. Multiple-trait analyses using PCA confirmed single-trait analyses. Men and women with mildly elevated bilirubin levels ≥ 17.1 µmol/L, compared to low-normal bilirubin < 10 µmol/L had 13% (99% CI 8%–18%) and 11% (99% CI 4%–17%) lower odds of exceeding systolic BP levels of ≥ 130 mm Hg, respectively.

Conclusions
Higher levels of bilirubin were inversely associated with cardiometabolic risk factors including adiposity, dyslipidemia, and hypertension.
Whole-genome analysis of coxsackievirus B3 reflects its genetic diversity in China and worldwide
Authors: Yang Qian , Yan Dongmei , Song Yang , Zhu Shuangli , He Yun , Han Zhenzhi , Wang Dongyan , Ji Tianjiao , Zhang Yong , Xu Wenbo 
Published: April 2022

Abstract
Background
Coxsackievirus B3 (CVB3) has emerged as an active pathogen in myocarditis, aseptic meningitis, hand, foot, and mouth disease (HFMD), and pancreatitis, and is a heavy burden on public health. However, CVB3 has not been systematically analyzed with regard to whole-genome diversity and recombination. Therefore, this study was undertaken to systematically examine the genetic characteristics of CVB3 based on its whole genome.

Methods
We combined CVB3 isolates from our national HFMD surveillance and global sequences retrieved from GenBank. Phylogenetic analysis was performed to examine the whole genome variety and recombination forms of CVB3 in China and worldwide.

Results
Phylogenetic analysis showed that CVB3 strains isolated worldwide could be classified into clusters A–E based on the sequence of the entire VP1 region. The predominant CVB3 strains in China belonged to cluster D, whereas cluster E CVB3 might be circulated globally compared to other clusters. The average nucleotide substitution rate in the P1 region of CVB3 was 4.82 × 10–3 substitutions/site/year. Myocarditis was more common with cluster A. Clusters C and D presented more cases of acute flaccid paralysis, and cluster D may be more likely to cause HFMD. Multiple recombination events were detected among CVB3 variants, and there were twenty-three recombinant lineages of CVB3 circulating worldwide.

Conclusions
Overall, this study provides full-length genomic sequences of CVB3 isolates with a wide geographic distribution over a long-term time scale in China, which will be helpful for understanding the evolution of this pathogen. Simultaneously, continuous surveillance of CVB3 is indispensable to determine its genetic diversity in China as well as worldwide.
Cross-border mobility responses to COVID-19 in Europe: new evidence from facebook data
Authors: Docquier Fredérić , Golenvaux Nicolas , Nijssen Siegfried , Schaus Pierre , Stips Felix 
Published: April 2022

Abstract
Background
Assessing the impact of government responses to Covid-19 is crucial to contain the pandemic and improve preparedness for future crises. We investigate here the impact of non-pharmaceutical interventions (NPIs) and infection threats on the daily evolution of cross-border movements of people during the Covid-19 pandemic. We use a unique database on Facebook users’ mobility, and rely on regression and machine learning models to identify the role of infection threats and containment policies. Permutation techniques allow us to compare the impact and predictive power of these two categories of variables.

Results
In contrast with studies on within-border mobility, our models point to a stronger importance of containment policies in explaining changes in cross-border traffic as compared with international travel bans and fears of being infected. The latter are proxied by the numbers of Covid-19 cases and deaths at destination. Although the ranking among coercive policies varies across modelling techniques, containment measures in the destination country (such as cancelling of events, restrictions on internal movements and public gatherings), and school closures in the origin country (influencing parental leaves) have the strongest impacts on cross-border movements.

Conclusion
While descriptive in nature, our findings have policy-relevant implications. Cross-border movements of people predominantly consist of labor commuting flows and business travels. These economic and essential flows are marginally influenced by the fear of infection and international travel bans. They are mostly governed by the stringency of internal containment policies and the ability to travel.
Current challenges and opportunities in the care of patients with fibrodysplasia ossificans progressiva (FOP): an international, multi-stakeholder perspective
Authors: Pignolo Robert J. , Bedford-Gay Christopher , Cali Amanda , Davis Michelle , Delai Patricia L. R. , Gonzales Kristi , Hixson Candace , Kent Alastair , Newport Hope , Robert Manuel , Scott Christiaan , Kaplan Frederick S. 
Published: April 2022

Abstract
Background
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, disabling genetic disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification of soft and connective tissues. Assiduous attention to the unmet needs of this patient community is crucial to prevent potential iatrogenic harm and optimize care for individuals with FOP.

Objective
To gather international expert opinion and real-world experience on the key challenges for individuals with FOP and their families, highlight critical gaps in care, communication, and research, and provide recommendations for improvement.

Methods
An international group of expert clinicians, patients and patient advocates, caregivers and representatives from the international FOP community participated in a virtual, half-day meeting on 22 March 2021 to discuss the key unmet needs of individuals with FOP.

Results
Individuals with FOP often face the frustration of long diagnostic journeys, the burden of self-advocacy and the navigation of novel care pathways. Globally, patients with FOP are also confronted with inequities in access to diagnosis and specialist care, and consequently, unequal access to registries, clinical trials, and essential support from patient associations. Organizations such as the International FOP Association, the International Clinical Council on FOP, and national FOP organizations work to provide information, facilitate access to expert clinical guidance, nurture patient empowerment, fund FOP research and/or foster meaningful collaborations with the research community. The non-profit Tin Soldiers Global FOP Patient Search program aims to identify and provide a pathway to diagnosis and care for individuals with FOP, particularly in underserved communities. Such global initiatives and the increasingly widespread use of telemedicine and digital platforms offer opportunities to improve vital access to care and research.

Conclusions
This multi-stakeholder perspective highlights some of the unmet needs of individuals with FOP and their families. Regional and international organizations play an important role in improving the quality of life of those they reach in the global FOP community. However, globally, fundamental issues remain around raising awareness of FOP among healthcare professionals, identifying individuals with FOP, reducing time to diagnosis, and ensuring access to best practice in care, support, and clinical research. Medical writing support was industry-sponsored.
The involvement of rare disease patient organisations in therapeutic innovation across rare paediatric neurological conditions: a narrative review
Authors: Nguyen Christina Q. , Alba-Concepcion Kristine , Palmer Elizabeth E. , Scully Jackie L. , Millis Nicole , Farrar Michelle A. 
Published: April 2022

AbstractBackgroundThe patient voice is becoming increasingly prominent across all stages of therapeutic innovation. It pervades research domains from funding and recruitment, to translation, care, and support. Advances in genomic technologies have facilitated novel breakthrough therapies, whose global developments, regulatory approvals, and confined governmental subsidisations have stimulated renewed hope amongst rare disease patient organisations (RDPOs). With intensifying optimism characterising the therapeutic landscape, researcher-advocate partnerships have reached an inflexion point, at which stakeholders may evaluate their achievements and formulate frameworks for future refinement.Main textThrough this narrative review, we surveyed relevant literature around the roles of RDPOs catering to the rare paediatric neurological disease community. Via available literature, we considered RDPO interactions within seven domains of therapeutic development: research grant funding, industry sponsorship, study recruitment, clinical care and support, patient-reported outcome measures, and research prioritisation. In doing so, we explored practical and ethical challenges, gaps in understanding, and future directions of inquiry. Current literature highlights the increasing significance of ethical and financial challenges to patient advocacy. Biomedical venture philanthropy is gaining momentum amongst RDPOs, whose small grants can incrementally assist laboratories in research, training, and pursuits of more substantial grants. However, RDPO seed funding may encounter long-term sustainability issues and difficulties in selecting appropriate research investments. Further challenges include advocate-industry collaborations, commercial biases, and unresolved controversies regarding orphan drug subsidisation. Beyond their financial interactions, RDPOs serve instrumental roles in project promotion, participant recruitment, biobank creation, and patient registry establishment. They are communication conduits between carers, patients, and other stakeholders, but their contributions may be susceptible to bias and unrealistic expectations.ConclusionFurther insights into how RDPOs navigate practical and ethical challenges in therapeutic development may enhance cooperative efforts. They may also inform resources, whose distribution among advocates, parents, and clinicians, may assist decision-making processes around rare disease clinical trials and treatments.
Fluid resuscitation with balanced crystalloids versus normal saline in critically ill patients: a systematic review and meta-analysis
Authors: Dong Wei-Hua , Yan Wen-Qing , Song Xin , Zhou Wen-Qiang , Chen Zhi 
Published: April 2022

Abstract
Background
Intravenous fluids are used commonly for almost all intensive care unit (ICU) patients, especially for patients in need of resuscitation. The selection and use of resuscitation fluids may affect the outcomes of patients; however, the optimal resuscitative fluid remains controversial.

Methods
We systematically searched PubMed, Embase, and CENTRAL. Studies comparing balanced crystalloids and normal saline in ICU patients were selected. We used the Cochrane Collaboration tool to assess the risk of bias in studies. The primary outcome was mortality at the longest follow-up. Secondary outcomes included the incidence of acute kidney injury (AKI) and new renal replacement therapy (RRT).

Results
A total of 35,456 patients from eight studies were included. There was no significant difference between balanced crystalloid solutions and saline in mortality (risk ratio [RR]: 0.96; 95% confidence interval [CI]:0.92–1.01). The subgroup analysis with traumatic brain injury (TBI) showed lower mortality in patients receiving normal saline (RR:1.25; 95% CI 1.02–1.54). However, in patients with non-TBI, balanced crystalloid solutions achieved lower mortality than normal saline (RR: 0.94; 95% CI 0.90–0.99). There was no significant difference in moderate to severe AKI (RR: 0.96; 95% CI 0.90–1.01) or new RRT (RR: 0.94; 95% CI 0.84–1.04).

Conclusions
Compared with normal saline, balanced crystalloids may not improve the outcomes of mortality, the incidence of AKI, and the use of RRT for critically ill patients. However, balanced crystalloids reduce the risk of death in patients with non-TBI but increase the risk of death in those with TBI. Large-scale rigorous randomized trials with better designs are needed, especially for specific patient populations.
Planning a method for covariate adjustment in individually randomised trials: a practical guide
Authors: Morris Tim P. , Walker A. Sarah , Williamson Elizabeth J. , White Ian R. 
Published: April 2022

AbstractBackgroundIt has long been advised to account for baseline covariates in the analysis of confirmatory randomised trials, with the main statistical justifications being that this increases power and, when a randomisation scheme balanced covariates, permits a valid estimate of experimental error. There are various methods available to account for covariates but it is not clear how to choose among them.MethodsTaking the perspective of writing a statistical analysis plan, we consider how to choose between the three most promising broad approaches: direct adjustment, standardisation and inverse-probability-of-treatment weighting.ResultsThe three approaches are similar in being asymptotically efficient, in losing efficiency with mis-specified covariate functions and in handling designed balance. If a marginal estimand is targeted (for example, a risk difference or survival difference), then direct adjustment should be avoided because it involves fitting non-standard models that are subject to convergence issues. Convergence is most likely with IPTW. Robust standard errors used by IPTW are anti-conservative at small sample sizes. All approaches can use similar methods to handle missing covariate data. With missing outcome data, each method has its own way to estimate a treatment effect in the all-randomised population. We illustrate some issues in a reanalysis ofGetTested, a randomised trial designed to assess the effectiveness of an electonic sexually transmitted infection testing and results service.ConclusionsNo single approach is always best: the choice will depend on the trial context. We encourage trialists to consider all three methods more routinely.
The distribution of Dermacentor reticulatus in the Czech Republic re-assessed: citizen science approach to understanding the current distribution of the Babesia canis vector
Authors: Daněk Ondřej , Hrazdilová Kristýna , Kozderková Dominika , Jirků Daria , Modrý David 
Published: April 2022

Abstract
Background
The range of the ornate dog tick Dermacentorreticulatus is rapidly expanding in Europe. This tick species is the vector of canine babesiosis, caused by Babesiacanis, and also plays a role in the transmission of Theileriaequi and Babesiacaballi in equids.

Methods
The geographic range of D.reticulatus in the Czech Republic was re-assessed, and an up-to-date distribution map is presented based on material and data obtained during a nationwide citizen science campaign. Received and flagged individuals of D.reticulatus were also analysed for the presence of B.canis DNA.

Results
In striking contrast to historical records, D.reticulatus was found in all regions of the Czech Republic, with most reports coming from the southeast and northwest of the country. Between February 2018 and June 2021, the project team received 558 photo reports of ticks and 250 packages containing ticks. Of the former, 71.1% were identified as Dermacentor sp. with the remainder identified as Ixodes sp., Haemaphysalis sp., Argas sp. or Hyalomma sp. The majority of specimens in the subset of ticks that were received (N = 610) were D.reticulatus (N = 568, 93.7%), followed by Ixodesricinus and Hyalomma spp. A total of 783 adult D.reticulatus, either received (568) or collected by flagging (215), were tested for the presence of B.canis DNA using species-specific nested PCR targeting part of the 18S rRNA gene; B.canis DNA was demonstrated in 22 samples (2.81%).

Conclusions
The continuous spread of D.reticulatus in the Czech Republic was documented in this study. In addition, DNA of B.canis was also detected in a number of ticks, suggesting the establishment of B.canis in the Czech Republic. These results suggest that veterinarians need to consider the possibility of canine babesiosis even in dogs without a history of travel.

Graphical Abstract