bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Direct Subjective Refraction: Unsupervised measurements of the subjective refraction using defocus waves
Authors: -Lopez Victor Rodriguez , Hernandez-Poyatos Alfonso , Dorronsoro Carlos 
Published: December 2021

AbstractWe present the Direct Subjective Refraction (DSR), a new subjective refraction method, and validate it vs the Traditional Subjective Refraction (TSR) and an unsupervised version of it (UTSR). We project an optotunable lens onto the eye to create Temporal Defocus Waves produces flicker and chromatic distortions, minimum when the mean optical power of the wave matches the spherical equivalent of the eye. 25 subjects performed the DSR visual and UTSR tasks without supervision. DSR is more repeatable than TSR and UTSR (standard deviations ±0.17D, ±0.28, and ±0.47D). The time per repetition of DSR is only 39s (almost 6 min for TSR). Cyclopegia severely affects UTSR, but not DSR, confirming that the DSR task de-activates the accommodative system. DSR is a new method to obtain the spherical equivalent that does not requires supervision and overpasses existing subjective methods in terms of accuracy, precision, and measurement time.
Engineering RNA viruses with unnatural amino acid to evoke adjustable immune response in mice
Authors: Zheng Zhetao , Wang Yu , Wu Xuesheng , Zhang Haoran , Chen Hongmin , Lin Haishuang , Shen Yuxuan , Xia Qing 
Published: December 2021

AbstractRibonucleic acid (RNA) viruses pose heavy burdens on public-health systems. Synthetic biology holds great potential for artificially controlling their replication, a strategy that could be used to attenuate infectious viruses but is still in the exploratory stage. Herein, we used the genetic-code expansion technique to convert Enterovirus 71 (EV71), a model of RNA virus, into a controllable EV71 strain carrying the unnatural amino acid (UAA) Nε-2-azidoethyloxycarbonyl-L-lysine (NAEK), which we termed an EV71-NAEK virus. EV71-NAEK could recapitulate an authentic NAEK time- and dose-dependent infection in vitro and in vivo, which could serve as a novel method to manipulate virulent viruses in conventional laboratories. We further validated the prophylactic effect of EV71-NAEK in two mouse models. In susceptible parent mice, vaccination with EV71-NAEK elicited a strong immune response and potentially protected their neonatal offspring from lethal challenge similar to that of commercial vaccines. Meanwhile, in transgenic mice harboring a PylRS-tRNAPyl pair, substantial elements of genetic-code expansion technology, EV71-NAEK evoked an adjustable neutralizing-antibody response in a strictly external NAEK dose-dependent manner. These findings suggested that EV71-NAEK could be the basis of a feasible immunization program for populations with different levels of immunity. Moreover, we expanded the strategy to generate controllable coxsackieviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for conceptual verification. In combination, these results could underlie a competent strategy for attenuating viruses and priming the immune system via artificial control, which might be a promising direction for the development of amenable vaccine candidates and be broadly applied to other RNA viruses.
Machine Learning Model for Predicting Outcomes of Biologic Therapy in Psoriasis
Authors: Du Amy X. , Ali Zarqa , Ajgeiy Kawa K. , Dalager Maiken G. , Dam Tomas N. , Egebjerg Alexander , Nissen Christoffer V. S. , Skov Lone , Thomsen Simon Francis , Emam Sepideh , Gniadecki Robert 
Published: December 2021

AbstractBackgroundBiological agents used for the therapy of psoriasis lose efficacy over time, which leads to discontinuation of the drug. Optimization of long-term biologic treatment is an area of medical need but there are currently no prediction tools for biologic drug discontinuation.ObjectiveTo compare the accuracy of the risk factor-based frequentist statistical model to machine learning to predict the 5-year probability of biologic drug discontinuation.MethodsThe national Danish psoriasis biologic therapy registry, Dermbio, comprising 6,172 treatment series with anti-TNF (Etanercept, Infliximab, Adalimumab), Ustekinumab, Guselkumab and anti-IL17 (Secukinumab and Ixekizumab) in 3,388 unique patients was used as data source. Hazard ratios (HR) were computed for all available predictive factors using Cox regression analysis. Different machine learning (ML) models for the prediction of 5-year risk of drug discontinuation were trained using the 5-fold cross validation technique and using 10 clinical features routinely assessed in psoriasis patients as input variables. Model performance was assessed using the area under the receiver operating characteristic curve (AUC).ResultsThe lowest 5-year risk of discontinuation was associated with therapy with ustekinumab or ixekizumab, male sex and no previous exposure to biologic therapy. The predictive model based on those risk factors had an AUC of 0.61. The best ML model (gradient boosted tree) had an AUC of 0.85.ConclusionsA machine learning-based approach, more than a statistical model, accurately predicts the risk of discontinuation of biologic therapy based on simple patient variables available in clinical practice. ML might be incorporated into clinical decision making.
Mitochondria-targeted antioxidant supplementation augments acute exercise-induced increases in muscle PGC1α mRNA and improves training-induced increases in peak power independent of mitochondrial content and function in untrained middle-aged men
Authors: Broome S. C. , Pham T. , Braakhuis A. J. , Narang R. , Wang H. W. , Hickey A. J. R. , Mitchell C. J. , Merry T. L. 
Published: December 2021

ABSTRACTThe role of mitochondrial ROS production and signalling in muscle adaptations to exercise training has not been explored in detail. Here we investigated the effect of supplementation with the mitochondria-targeted antioxidant MitoQ on a) the skeletal muscle mitochondrial and antioxidant gene transcriptional response to acute high-intensity exercise and b) skeletal muscle mitochondrial content and function following exercise training. In a randomised, double-blind, placebo-controlled, parallel design study, 23 untrained men (age: 44 ± 7 years, VO2peak: 39.6 ± 7.9 ml/kg/min) were randomised to receive either MitoQ (20 mg/d) or a placebo for 10 days before completing a bout of high-intensity interval exercise (cycle ergometer, 10 × 60 s at VO2peakworkload with 75 s rest). Blood samples and vastus lateralis muscle biopsies were collected before exercise and immediately and 3 hours after exercise. Participants then completed high-intensity interval training (HIIT; 3 sessions per week for 3 weeks) and another blood sample and muscle biopsy were collected. MitoQ supplementation augmented acute exercise-induced increases in skeletal muscle mRNA expression of the major regulator of proteins involved in mitochondrial biogenesis peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α). Despite this, training-induced increases in skeletal muscle mitochondrial content were unaffected by MitoQ supplementation. HIIT-induced increases in VO2peakand 20 km time trial performance were also unaffected by MitoQ while MitoQ augmented training-induced increases in peak power achieved during the VO2peaktest. These data suggest that MitoQ supplementation enhances the effect of training on peak power, which may be related to the augmentation of skeletal muscle PGC1α expression following acute exercise. However, this effect does not appear to be related to an effect of MitoQ supplementation on HIIT-induced mitochondrial biogenesis in skeletal muscle and may therefore be the result of other adaptations mediated by PGC1α.
Genetic factors affecting immune phenotypes in type 1 diabetes
Authors: Chu Xiaojing , Janssen Anna W.M. , Koenen Hans , Chang Linzhung , He Xuehui , Joosten Irma , Stienstra Rinke , Kuijpers Yunus , Wijmenga Cisca , Xu Cheng-Jian , Netea Mihai , Tack Cees J. , Li Yang 
Published: December 2021

AbstractLarge inter-individual variability in immunological cell composition and function determines immune responses in general and susceptibility to immune-mediated diseases in particular. While much has been learned about the genetic variants relevant for type 1 diabetes, the pathophysiological mechanisms through which these variations exert their effects are unknown. In this study, we characterize the genetic factors influencing immune responses in patients with type 1 diabetes. Genetic variants that determine susceptibility to T1D significantly affect T cell composition. Specifically, the CCR5+ regulatory T cells associate with T1D through the CCR region, suggesting a shared genetic regulation. Genome-wide quantitative trait loci (QTL) mapping analysis of immune traits revealed 15 genetic loci that influence immune responses in T1D. Among them, 12 have never been reported in healthy population studies, implying a disease-specific genetic regulation. Altogether this study provides new insights into the genetic factors that affect immunological responses in T1D.
Parental perspectives on the grief and support needs of children and young people bereaved during the Covid-19 pandemic: Qualitative findings from a national survey
Authors: Harrop Emily , Goss Silvia , Longo Mirella , Seddon Kathy , Torrens-Burton Anna , Sutton Eileen , Farnell Damian JJ , Penny Alison , Nelson Annmarie , Byrne Anthony , Selman Lucy E. 
Published: December 2021

AbstractBackgroundDuring the Covid-19 pandemic, many children and young people have experienced the death of close family members, whilst also facing unprecedented disruption to their lives. This study aimed to investigate the experiences and support needs of bereaved children and young people from the perspective of their parents and guardians.MethodsWe analysed cross-sectional qualitative free-text data from a survey of adults bereaved in the UK during the pandemic. Participants were recruited via media, social media, national associations and community/charitable organisations. Thematic analysis was conducted on free text data collected from parent/guardian participants in response to a survey question on the bereavement experiences and support needs of their children.ResultsFree-text data from 104 parent and grandparent participants was included. Three main themes were identified: the pandemic-related challenges and struggles experienced by children and young people; family support and coping; and support from schools and services. Pandemic-related challenges include the impacts of being separated from the relative prior to their death, isolation from peers and other family members, and disruption to daily routines and wider support networks. Examples were given of effective family coping and communication, but also of difficulties relating to parental grief and children’s existing mental health problems. Schools and bereavement organisations’ provision of specialist support was valued, but there was evidence of unmet need, with some participants reporting a lack of access to specialist grief or mental health support.ConclusionChildren and young people have faced additional strains and challenges associated with pandemic bereavement. We recommend resources and initiatives that facilitate supportive communication within family and school settings, adequate resourcing of school and community-based specialist bereavement/mental health services, and increased information and signposting to the support that is available.
Pharmacokinetics of ß-d-N4-hydroxycytidine, the parent nucleoside of prodrug molnupiravir, in non-plasma compartments of patients with SARS-CoV-2 infection
Authors: FitzGerald Richard , Dickinson Laura , Else Laura , Fletcher Thomas , Hale Colin , Amara Alieu , Walker Lauren , Penchala Sujan Dilly , Lyon Rebecca , Shaw Victoria , Greenhalf William , Bullock Katie , Lavelle-Langham Lara , Reynolds Helen , Painter Wendy , Holman Wayne , Ewings Sean , Griffiths Gareth , Khoo Saye 
Published: December 2021

ABSTRACTß-d-N4-hydroxycytidine (NHC), the parent nucleoside of molnupiravir, a COVID-19 antiviral, was quantified at sites of SARS-CoV-2 transmission in twelve patients enrolled in AGILE CST-2 (NCT04746183). Saliva, nasal and tear concentrations were 3, 21 and 22% that of plasma. Saliva and nasal NHC concentrations were significantly correlated with plasma (p<0.0001).
Deeply-Dyed Nanobead System Based Lateral Flow Assay for Rapid Point-of-Care Drug Testing
Authors: Fan Lingzhi , Wu Jianbing , Yang Jing , Li Fugang , Yan Wannian , Tan Fei , Zhang Madeline , Draz Mohamed S. , Han Huanxing , Zhang Pengfei 
Published: December 2021

AbstractPoint-of-care test (POCT), which allows for rapid and sensitive screening of drugs abuse, is essential and can significantly reduce the clinical, economic and social impact of the opioid crisis worldwide. However, the traditional gold nanoparticle-based lateral flow immunoassay strip is not sensitive enough for detection of trace drugs in hair sample. Herein, we aimed to develop a more specific system using a composite polymer-based nanobead that is deeply dyed with phthalocyanine or similar oil soluble dyes, and termed as deeply dyed nanobead (DDNB). The prepared composite nanobeads displayed a clear core-shell structure and the core/shell ratios were readily controlled by polymer/dye feeding ratios. The absorbance stable nanobeads capped with carboxyl groups were covalently conjugated with antibodies, and were employed for preparation of lateral flow immunoassay strips for sensitive detection of drugs in hair with naked eye. The developed platform allows the detection of drugs such as morphine and methamphetamine in hair samples within 13 min (including hair sample processing ∼5 min). The cut-off value of DDNB strip for methamphetamine detection with naked eye is down to concentration of 8.0 ng/mL, which is about 3.1 times more sensitive than the traditional gold nanoparticles based lateral flow immunoassay. Moreover, the colorful DDNB system has the potential for multiplexing detection of analytes at point-of-care settings and with low cost.
Likely community transmission of COVID-19 infections between neighboring, persistent hotspots in Ontario, Canada
Authors: Mucaki Eliseos J. , Shirley Ben C. , Rogan Peter K. 
Published: December 2021

AbstractIntroductionThis study aimed to produce community-level geo-spatial mapping of confirmed COVID-19 cases in Ontario, Canada in near real-time to support decision-making. This was accomplished by area-to-area geostatistical analysis, space-time integration, and spatial interpolation of COVID-19 positive individuals.MethodsCOVID-19 cases and locations were curated for geostatistical analyses from March 2020 through June 2021, corresponding to the first, second, and third waves of infections. Daily cases were aggregated according to designated forward sortation area [FSA], and postal codes [PC] in municipal regions covering Hamilton, Kitchener/Waterloo, London, Ottawa, Toronto, and Windsor/Essex county. Hotspots were identified with area-to-area tests including Getis-Ord Gi*, Global Moran’s I spatial autocorrelation, and Local Moran’s I asymmetric clustering and outlier analyses. Case counts were also interpolated across geographic regions by Empirical Bayesian Kriging, which localizes high concentrations of COVID-19 positive tests, independent of FSA or PC boundaries. TheGeostatistical Disease Epidemiology Toolbox, which is freely-available software, automates the identification of these regions and produces digital maps for public health professionals to assist in pandemic management of contact tracing and distribution of other resources.Results/DiscussionThis study provided indicators in real-time of likely, community-level disease transmission through innovative geospatial analyses of COVID-19 incidence data. Municipal and provincial results were validated by comparisons with known outbreaks at long-term care and other high density residences and on farms. PC-level analyses revealed hotspots at higher geospatial resolution than public reports of FSAs, and often sooner. Results of different tests and kriging were compared to determine consistency among hotspot assignments. Concurrent or consecutive hotspots in close proximity suggested potential community transmission of COVID-19 from cluster and outlier analysis of neighboring PCs and by kriging. Results were also stratified by population based-categories (sex, age, and presence/absence of comorbidities). Earlier recognition of hotspots could reduce public health burdens of COVID-19 and expedite contact tracing.
SARS-CoV-2 attack rate and population immunity in southern New England, March 2020 - May 2021
Authors: Tran Thu Nguyen-Anh , Wikle Nathan B , Yang Fuhan , Inam Haider , Leighow Scott , Gentilesco Bethany , Chan Philip , Albert Emmy , Strong Emily R , Pritchard Justin R , Hanage William P , Hanks Ephraim M , Crawford Forrest W. , Boni Maciej F 
Published: December 2021

AbstractEstimating an infectious disease attack rate requires inference on the number of reported symptomatic cases of a disease, the number of unreported symptomatic cases, and the number of asymptomatic infections. Population-level immunity can then be estimated as the attack rate plus the number of vaccine recipients who had not been previously infected; this requires an estimate of the fraction of vaccines that were distributed to seropositive individuals. To estimate attack rates and population immunity in southern New England, we fit a validated dynamic epidemiological model to case, clinical, and death data streams reported by Rhode Island, Massachusetts, and Connecticut for the first 15 months of the COVID-19 pandemic, from March 1 2020 to May 31 2021. This period includes the initial spring 2020 wave, the major winter wave of 2020-2021, and the lagging wave of lineage B.1.1.7(Alpha) infections during March-April 2021. In autumn 2020, SARS-CoV-2 population immunity (equal to the attack rate at that point) in southern New England was still below 15%, setting the stage for a large winter wave. After the roll-out of vaccines in early 2021, population immunity in many states was expected to approach 70% by spring 2021, with more than half of this immune population coming from vaccinations. Our population immunity estimates for May 31 2021 are 73.4% (95% CrI: 72.9% - 74.1%) for Rhode Island, 64.1% (95% CrI: 64.0% - 64.4%) for Connecticut, and 66.3% (95% CrI: 65.9% - 66.9%) for Massachusetts, indicating that >33% of southern Englanders were still susceptible to infection when the Delta variant began spreading in July 2021. Despite high vaccine coverage in these states, population immunity in summer 2021 was lower than planned due to 34% (Rhode Island), 25% (Connecticut), and 28% (Massachusetts) of vaccine distribution going to seropositive individuals. Future emergency-setting vaccination planning will likely have to consider over-vaccination as a strategy to ensure that high levels of population immunity are reached during the course of an ongoing epidemic.
Vertical transmission of tissue microbiota in Caenorhabditis elegans
Authors: Zheng Jun , Meng Xin , Fan Jiahao , Yang Dong 
Published: December 2021

AbstractThe past forty-five years has witnessed Caenorhabditis elegans as the most significant model animal in life science since its discovery seventy years ago1,2, as it introduced principles of gene regulated organ development, and RNA interference into biology3-5. Meanwhile, it has become one of the lab animals in gut microbiota studies as these symbionts contribute significantly to many aspects in host biology6,7. Meanwhile, the origin of gut microbiota remains debatable in human8- 11, and has not been investigated in other model animals. Here we show that the symbiont bacteria in C. elegans not only vertically transmit from the parent generation to the next, but also distributes in the worm tissues parallel with its development. We found that bacteria can enter into the embryos of C. elegans, a step associated with vitellogenin, and passed to the next generation. These vertically transmitted bacteria share global similarity, and bacterial distribution in worm tissues changes as they grow at different life stages. Antibiotic treatment of worms increased their vulnerability against pathogenic bacteria, and replenishment of tissue microbiota restored their immunity. These results not only offered a molecular basis of vertical transmission of bacteria in C. elegans, but also signal a new era for the mixed tissue cell-bacteria multi-species organism study.
Revised International Staging System (R-ISS) stage-dependent analysis uncovers oncogenes and potential immunotherapeutic targets in multiple myeloma
Authors: Zhong Ling , Yuan Xinwei , Zhang Qian , Jiang Tao , Li Huan , Xiao Jialing , Li Chenglong , Luo Lan , Shuai Ping , Wang Liang , Liu Yuping , Yu Man , Shi Yi , Zhang Wei , Zhang Yunbin , Gong Bo 
Published: December 2021

AbstractMultiple myeloma (MM), characterized by high intratumour heterogeneity, accounts for ∼10% of all haematologic malignancies. Stratified by the Revised International Staging System (R-ISS), little is known about R-ISS-related plasma cell (PC) heterogeneity, gene expression modules in cytotoxic T/NK cells and immunoregulatory ligands and receptors. Herein, we constructed a single-cell transcriptome atlas of bone marrow in normal and R-ISS-staged MM patients. Focusing on PCs, we identified and validated a subset of GZMA+ cytotoxic PCs. In addition, a malignant PC population with high proliferation capability (proliferating PCs) was associated with unfavourable prognosis and EBV infection in our collected samples. Ribonucleotide Reductase Regulatory Subunit M2 (RRM2), a specific marker of proliferating PCs, was shown to induce MM cell line proliferation and serve as a detrimental marker in MM. Subsequently, three R-ISS-dependent gene modules in cytotoxic CD8+ T and NKT cells were identified and functionally analysed. Finally, cell-cell communication between neutrophils and proliferating PCs with cytotoxic CD8+ T and NKT cells was investigated, which identified intercellular ligand receptors and potential immunotargets such as SIRPA-CD47 and TIGIT-NECTIN3. Collectively, this study provides an R-ISS-related single-cell MM atlas and reveals the clinical significance of two PC clusters, as well as potential immunotargets in MM progression.
Loss of Neutralizing Antibody Response to mRNA Vaccination against SARS-CoV-2 Variants: Differing Kinetics and Strong Boosting by Breakthrough Infection
Authors: Evans John P. , Zeng Cong , Carlin Claire , Lozanski Gerard , Saif Linda J. , Oltz Eugene M. , Gumina Richard J. , Liu Shan-Lu 
Published: December 2021

AbstractThe waning efficacy of SARS-CoV-2 vaccines combined with the continued emergence of variants resistant to vaccine-induced immunity has reignited debate over the need for booster vaccines. To address this, we examined the neutralizing antibody (nAb) response against four major SARS-CoV-2 variants—D614G, Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2)—in health care workers (HCWs) at pre-vaccination, post-first and post-second mRNA vaccine dose, and six months post-second mRNA vaccine dose. Neutralizing antibody titers against all variants, especially the Delta variant, declined dramatically from four weeks to six months post-second mRNA vaccine dose. Notably, SARS-CoV-2 infection enhanced vaccine durability, and mRNA-1273 vaccinated HCWs also exhibited ~2-fold higher nAb titers than BNT162b2 vaccinated HCWs. Together these results demonstrate possible waning of protection from infection against SARS-CoV-2 Delta variant based on decreased nAb titers, dependent on COVID-19 status and the mRNA vaccine received.