bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multicentre randomised controlled trial: protocol for Plasma-Lyte Usage and Assessment of Kidney Transplant Outcomes in Children (PLUTO)
Authors: Hayes Wesley , Laing Emma , Foley Claire , Pankhurst Laura , Thomas Helen , Hume-Smith Helen , Marks Stephen , Kessaris Nicos , Bryant William A , Spiridou Anastassia , Wray Jo , Peters Mark J 
Published: March 2022

IntroductionAcute electrolyte and acid–base imbalance is experienced by many children following kidney transplantation. When severe, this can lead to complications including seizures, cerebral oedema and death. Relatively large volumes of intravenous fluid are administered to children perioperatively in order to establish perfusion to the donor kidney, the majority of which are from living and deceased adult donors. Hypotonic intravenous fluid is commonly used in the post-transplant period due to clinicians’ concerns about the sodium, chloride and potassium content of isotonic alternatives when administered in large volumes.Plasma-Lyte 148 is an isotonic, balanced intravenous fluid that contains sodium, chloride, potassium and magnesium with concentrations equivalent to those of plasma. There is a physiological basis to expect that Plasma-Lyte 148 will reduce the incidence of clinically significant electrolyte and acid–base abnormalities in children following kidney transplantation compared with current practice.The aim of the PLUTO trial is to determine whether the incidence of clinically significantly abnormal plasma electrolyte levels in paediatric kidney transplant recipients will be different with the use of Plasma-Lyte-148 compared to intravenous fluid currently administered.Methods and analysisPLUTO is a pragmatic, open-label, randomised controlled trial comparing Plasma-Lyte 148 to current care in paediatric kidney transplant recipients, conducted in nine UK paediatric kidney transplant centres.A total of 144 children receiving kidney transplants will be randomised to receive either Plasma-Lyte 148 (the intervention) intraoperatively and postoperatively, or current fluid. Apart from intravenous fluid composition, all participants will receive standard clinical transplant care.The primary outcome measure is acute hyponatraemia in the first 72 hours post-transplant, defined as laboratory plasma sodium concentration of <135 mmol/L. Secondary outcomes include symptoms of acute hyponatraemia, other electrolyte and acid–base imbalances and transplant kidney function.The primary outcome will be analysed using a logistic regression model adjusting for donor type (living vs deceased donor), patient weight (<20 kg vs ≥20 kg pretransplant) and transplant centre as a random effect.Ethics and disseminationThe trial received Health Research Authority approval on 20 January 2020. Findings will be presented to academic groups via national and international conferences and peer-reviewed journals. The patient and public involvement group will play an important part in disseminating the study findings to the public domain.Trial registration numbers2019-003025-22 and 16586164.
AKATSUKI study: a prospective, multicentre, phase IV study evaluating the safety of emicizumab under and immediately after immune tolerance induction therapy in persons with congenital haemophilia A with factor VIII inhibitors
Authors: Matsushita Tadashi , Suzuki Nobuaki , Nagao Azusa , Nagae Chiai , Yamaguchi-Suita Haruko , Kyogoku Yui , Ioka Akiko , Nogami Keiji 
Published: March 2022

IntroductionFor persons with haemophilia A with factor (F) VIII inhibitors (PwHAwI), immune tolerance induction (ITI) therapy is indicated for inhibitor eradication; however, since PwHAwI on ITI were excluded from the emicizumab clinical development programme, there are limited safety data for emicizumab treatment under/immediately after ITI in PwHAwI. Accordingly, there is a need to collect safety and efficacy data on this concomitant treatment strategy. The AKATSUKI study aims to evaluate the safety of emicizumab under/immediately after ITI in PwHAwI; here we report details of the study protocol.Methods and analysisAKATSUKI is an open-label, non-randomised, interventional, multicentre study. Twenty participants with congenital HA with FVIII inhibitors will be enrolled from 17 sites across Japan. Emicizumab will be administered subcutaneously, with an initial loading dose of 3 mg/kg once per week (QW) for the first 4 weeks, followed by a maintenance dose of 1.5 mg/kg QW, 3 mg/kg once every 2 weeks or 6 mg/kg once every 4 weeks. For ITI therapy, 50 IU/kg FVIII will be administered three times per week. For extended half-life FVIII, a dosing frequency of twice per week will be permitted. The primary endpoint is a comprehensive safety evaluation of adverse events (mainly thromboembolic events) and abnormal laboratory values over time. Secondary endpoints are the number of bleeds requiring coagulation factor treatment, the number of participants achieving a partially successful ITI response, FVIII inhibitor titres under/immediately after ITI, quality of life and time to achieve a negative FVIII inhibitor result (<0.6 BU/mL) and partial success in PwHAwI starting ITI after study enrolment.ConclusionsAKATSUKI will evaluate the safety of emicizumab administered under/immediately after ITI, providing reference data to inform treatment strategies in PwHAwI.Ethics and disseminationThe results of this study will be published in a peer-reviewed international journal and presented at national and/or international medical scientific conferences; the major findings of this study will be published on the jRCT registry website (https://jrct.niph.go.jp).Trial registration numberjRCTs041200037.
Association between sustained opioid prescription and frequent emergency department use: a cohort study
Authors: Racine-Hemmings François , Vanasse Alain , Lacasse Anaïs , Chiu Yohann , Courteau Josiane , Dépelteau Andréa , Hudon Catherine 
Published: March 2022

BackgroundChronic non-cancer pain (CNCP) is common among frequent emergency department (ED) users, although factors underlying this association are unclear. This study estimated the association between sustained opioid use and frequent ED use among patients with CNCP.MethodsRetrospective cohort study using a Canadian provincial health insurer database (Régie d’Assurance Maladie du Québec). The database included adults with both ≥1 chronic condition and ≥ 1 ED visit in 2012 or 2013. Inclusion in the study further required a CNCP diagnosis, public drug insurance coverage and 1-year survival after the first ED visit in 2012 or 2013 (index visit). Multivariable logistic regression was used to derive ORs of frequent ED use (≥5 visits in the year following the index visit) subsequent to sustained opioid use (≥60 days opioids prescription within 90 days preceding the index visit), adjusting for important covariables.ResultsFrom 576 688 patients in the database, 58 237 were included in the study. Of these, 4109 (7.1%) had received a sustained opioid prescription and 4735 (8.1%) were frequent ED users in the follow-up year. Sustained opioid use was not associated with frequent ED use in the multivariable model (OR: 1.06, 95% CI 0.94 to 1.19). Novel associated covariables were benzodiazepine prescription (OR: 1.21, 95% CI 1.12 to 1.30) and polypharmacy (OR: 1.23, 95% CI 1.13 to 1.34).ConclusionsDue to confounding by social and medical vulnerability, patients with CNCP with sustained opioid use appear to have a higher propensity for frequent ED use in unadjusted models. However, sustained opioid use was not associated with frequent ED use in these patients after adjustment.
Targeting CD96 overcomes PD-1 blockade resistance by enhancing CD8+ TIL function in cervical cancer
Authors: Wang Yumeng , Wang Congwen , Qiu Junjun , Qu Xinyu , Peng Jing , Lu Chong , Zhang Meng , Zhang Mingxing , Qi Xingling , Li Guiling , Hua Keqin 
Published: March 2022

BackgroundNovel therapies are needed to treat recurrent and advanced cervical cancer (CC), as their prognosis remains very poor. Although therapies targeting the programmed cell death protein 1 (PD-1) pathway have been approved for CC, a large subset of patients exhibit innate resistance. Using checkpoint inhibitors in combination could enhance their efficacy.MethodsBlood samples, tumor specimens, and peritumorous (PT) tissues were obtained from patients with CC. The inhibitory receptor expression and phenotypical analysis of CD8+ T cells in CC specimens were analyzed by flow cytometry. The ligands of CD96 expressed by tumor cells were measured by immunohistochemistry and immunofluorescence. Sensitivity to pembrolizumab was evaluated by an ex vivo treatment assay based on the single-cell culture of CC specimens. The efficacies of PD-1 and/or CD96 blockades were explored using an ex vivo treatment assay and an human papillomavirus-positive TC-1 xenograft mouse model in vivo.ResultsWe found that CD96 expression was elevated on CD8+ tumor-infiltrating lymphocytes (TILs) from patients with CC who were insensitive to the PD-1 blockade. These CD96-expressing CD8+ TILs often coexpressed PD-1. The ratio of the CD96+CD8+/CD96−CD8+ T-cell gene signature from the scRNA-seq data was significantly associated with the poor survival of patients with cervical squamous cell carcinoma and endocervical adenocarcinoma. The costimulatory receptor CD226, which competes with CD96, was downregulated in tumors compared with blood and PT tissue. CD96 and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) were upregulated on intratumoral CD8+ T cells. The CD226/CD96/TIGIT signaling ligands were widely expressed in CC tumor tissues. Phenotypical profiling showed that PD-1+CD96+CD8+ TILs exhibited a terminally exhausted effector phenotype with high levels of T-cell immunoglobulin mucin receptor 3 (TIM-3) and granzyme B (GZMB) and extremely low levels of proinflammatory cytokines and cytotoxic molecules. PD-1+CD96 cells exhibited a precursor exhausted phenotype with TCF-1 positivity. CD96 was further upregulated by CD8+ TILs on PD-1 blockade. Treatment with the CD96 blockade significantly enhanced the PD-1 blockade to blunt tumor growth and improve the function of CD8+ TILs in both mouse and CC specimen models.ConclusionsOur findings showed that CD96 and PD-1 cooperatively and negatively regulate the function of CD8+ TILs, and CD96 blockade has promise for use in combination with PD-1 blockade for the treatment of CC.
T cell receptor engineering of primary NK cells to therapeutically target tumors and tumor immune evasion
Authors: Morton Laura T , Wachsmann Tassilo L A , Meeuwsen Miranda H , Wouters Anne K , Remst Dennis F G , van Loenen Marleen M , Falkenburg J H Frederik , Heemskerk Mirjam H M 
Published: March 2022

BackgroundT cell receptor (TCR)-engineered cells can be powerful tools in the treatment of malignancies. However, tumor resistance by Human Leukocyte antigen (HLA) class I downregulation can negatively impact the success of any TCR-mediated cell therapy. Allogeneic natural killer (NK) cells have demonstrated efficacy and safety against malignancies without inducing graft-versus-host-disease, highlighting the feasibility for an ‘off the shelf’ cellular therapeutic. Furthermore, primary NK cells can target tumors using a broad array of intrinsic activation mechanisms. In this study, we combined the antitumor effector functions of NK cells with TCR engineering (NK-TCR), creating a novel therapeutic strategy to avoid TCR-associated immune resistance.MethodsBOB1, is a transcription factor highly expressed in all healthy and malignant B cell lineages, including multiple myeloma (MM). Expression of an HLA-B*07:02 restricted BOB1-specifc TCR in peripheral blood–derived NK cells was achieved following a two-step retroviral transduction protocol. NK-TCR was then compared with TCR-negative NK cells and CD8-T cells expressing the same TCR for effector function against HLA-B*07:02+ B-cell derived lymphoblastoid cell lines (B-LCL), B-cell acute lymphoblastic leukemia and MM cell lines in vitro and in vivo.ResultsFirstly, TCR could be reproducibly expressed in NK cells isolated from the peripheral blood of multiple healthy donors generating pure NK-TCR cell products. Secondly, NK-TCR demonstrated antigen-specific effector functions against malignancies which were previously resistant to NK-mediated lysis and enhanced NK efficacy in vivo using a preclinical xenograft model of MM. Moreover, antigen-specific cytotoxicity and cytokine production of NK-TCR was comparable to CD8 T cells expressing the same TCR. Finally, in a model of HLA-class I loss, tumor cells with B2M KO were lysed by NK-TCR in an NK-mediated manner but were resistant to T-cell based killing.ConclusionNK-TCR cell therapy enhances NK cell efficacy against tumors through additional TCR-mediated lysis. Furthermore, the dual efficacy of NK-TCR permits the specific targeting of tumors and the associated TCR-associated immune resistance, making NK-TCR a unique cellular therapeutic.
PI3Kδ/γ inhibitor BR101801 extrinsically potentiates effector CD8+T cell-dependent antitumor immunity and abscopal effect after local irradiation
Authors: Yoon Yi Na , Lee Eunju , Kwon Young-Ju , Gim Jeong-An , Kim Tae-Jin , Kim Jae-Sung 
Published: March 2022

BackgroundRadiotherapy enhances antitumor immunity. However, it also induces immunosuppressive responses, which are major hurdles for an effective treatment. Thus, targeting the immunosuppressive tumor microenvironment is essential for enhancing the antitumor immunity after radiotherapy. Retrospective studies show that a blockade of PI3Kδ and/or γ, which are abundant in leukocytes, exhibits antitumor immune response by attenuating activity of immune suppressive cells, however, the single blockade of PI3Kδ or γ is not sufficient to completely eliminate solid tumor.MethodsWe used BR101801, PI3Kδ/γ inhibitor in the CT-26 syngeneic mouse model with a subcutaneously implanted tumor. BR101801 was administered daily, and the target tumor site was locally irradiated. We monitored the tumor growth regularly and evaluated the immunological changes using flow cytometry, ELISpot, and transcriptional analysis.ResultsThis study showed that BR101801 combined with irradiation promotes systemic antitumor immunity and abscopal response by attenuating the activity of immune suppressive cells in the CT-26 tumor model. BR101801 combined with irradiation systemically reduced the proliferation of regulatory T cells (Tregs) and enhanced the number of tumor-specific CD8α+T cells in the tumor microenvironment, thereby leading to tumor regression. Furthermore, the high ratio of CD8α+T cells to Tregs was maintained for 14 days after irradiation, resulting in remote tumor regression in metastatic lesions, the so-called abscopal effect. Moreover, our transcriptomic analysis showed that BR101801 combined with irradiation promoted the immune-stimulatory tumor microenvironment, suggesting that the combined therapy converts immunologically cold tumors into hot one.ConclusionsOur data suggest the first evidence that PI3Kδ/γ inhibition combined with irradiation promotes systemic antitumor immunity against solid tumors, providing the preclinical result of the potential use of PI3Kδ/γ inhibitor as an immune-regulatory radiosensitizer.
High-precision Q-value measurement and nuclear matrix element calculations for the double-$$\beta $$ decay of $$^{98}$$Mo
Authors: Nesterenko D. A. , Jokiniemi L. , Kotila J. , Kankainen A. , Ge Z. , Eronen T. , Rinta-Antila S. , Suhonen J. 
Published: March 2022

AbstractThe $$^{98}$$

98

Mo double-beta decay Q-value has been measured, and the corresponding nuclear matrix elements of neutrinoless double-beta ($$0\nu \beta \beta $$

0
ν
β
β

) decay and the standard two-neutrino double-beta ($$2\nu \beta \beta $$

2
ν
β
β

) decay have been provided by nuclear theory. The double-beta decay Q-value has been determined as $$Q_{\beta \beta }=113.668(68)$$

Q

β
β

=
113.668

(
68
)

keV using the JYFLTRAP Penning trap mass spectrometer. It is in agreement with the literature value, $$Q_{\beta \beta }=109(6)$$

Q

β
β

=
109

(
6
)

keV, but almost 90 times more precise. Based on the measured Q-value, precise phase-space factors for $$2\nu \beta \beta $$

2
ν
β
β

decay and $$0\nu \beta \beta $$

0
ν
β
β

decay, needed in the half-life predictions, have been calculated. Furthermore, the involved nuclear matrix elements have been computed in the proton–neutron quasiparticle random-phase approximation (pnQRPA) and the microscopic interacting boson model (IBM-2) frameworks. Finally, predictions for the $$2\nu \beta \beta $$

2
ν
β
β

decay are given, suggesting a much longer half-life than for the currently observed cases.
Cordyceps Improves Obesity and its Related Inflammation via Modulation of Enterococcus cecorum Abundance and Bile Acid Metabolism
Authors: Wu Guo-Dong , Pan An , Zhang Xu , Cai Yuan-Yuan , Wang Qi , Huang Feng-Qing , Alolga Raphael N. , Li Jing , Qi Lian-Wen , Liu Qun 
Published: March 2022

Abstract: Dysbiotic gut microbiota has been identified as a primary mediator of inherent inflammation that underlies the pathogenesis of obesity. Cordyceps comprises the larval body and the stroma of Cordyceps sinensis (BerK.) Sacc. parasiting on Hepialidae larvae of moths (H. pialusoberthur) with potent metabolic regulation functions. The underlying anti-obesity mechanisms, however, remain largely unknown. Here, we demonstrate that the water extract of Cordyceps attenuates glucose and lipid metabolism disorders and its associated inflammation in high-fat diet (HFD)-fed mice. 16S rRNA gene sequencing and microbiomic analysis showed that Cordyceps reduced the amounts of Enterococcus cecorum, a bile-salt hydrolase-producing microbe to regulate the metabolism of bile acids in the gut. Importantly, E. cecorum transplantation or liver-specific knockdown of farnesoid X receptor (FXR), a bile acid receptor, diminished the protective effect of Cordyceps against HFD-induced obesity. Together, our results shed light on the mechanisms that underlie the glucose- and lipid-lowering effects of Cordyceps and suggest that targeting intestinalE. cecorum or hepatic FXR are potential anti-obesity and anti-inflammation therapeutic avenues.
Establishment of Quality Control Standard and Efficacy Evaluation of Zhiqingshu Lotion Compound Preparation
Authors: Tan Benren , Huang Yichun , Zheng Jinkun , Xu Xiaomei , Xiao Jian , Liu Yanlin 
Published: March 2022

Objective. To establish the quality standard of Zhiqingshu lotion by high-performance liquid chromatography (HPLC). Methods. HPLC was used to determine emodin, chrysophanol, caffeic acid, and berberine hydrochloride content, key water-soluble components of rhubarb, dandelion, and Phellodendron amurense in Zhiqingshu lotion. The macrophage inflammation model was used to analyze the anti-inflammatory effects of Zhiqingshu lotion. Results. HPLC results showed that the contents of emodin, chrysophanol, caffeic acid, and berberine hydrochloride in Zhiqingshu lotion were

7.93
±
2.25

,

20.85
±
4.27

,

48.9
±
6.79

, and

58.4
±
10.3

μg/mL, respectively. Moreover, RT-qPCR results showed that different concentrations of Zhiqingshu lotion significantly reduced the expression of inflammatory factor tumor necrosis factor- (TNF-) α and interleukin- (IL-) 1β in lipopolysaccharide-induced macrophages. Conclusion. HPLC could quantitatively and qualitatively analyze and identify the main components of Zhiqingshu lotion as rhodopsin, rhodopsin, caffeic acid, and berberine hydrochloride. And Zhiqingshu lotion has an excellent anti-inflammatory effect. This method was simple and reliable and could be used for the identification of the ingredients and content of Zhiqingshu lotion, thus improving the quality control of the drug.
Modeling the Ranked Antenatal Care Visits Using Optimized Partial Least Square Regression
Authors: Sadiq Maryam , Abdulrahman Alanazi Talal , Alharbi Randa , Alnagar Dalia Kamal Fathi , Anwar Syed Masroor 
Published: March 2022

The frequency and timing of antenatal care visits are observed to be the significant factors of infant and maternal morbidity and mortality. The present research is conducted to determine the risk factors of reduced antenatal care visits using an optimized partial least square regression model. A data set collected during 2017-2018 by Pakistan Demographic and Health Surveys is used for modeling purposes. The partial least square regression model coupled with rank correlation measures are introduced for improved performance to address ranked response. The proposed models included PLS

ρ

s

, PLS

τ

A

, PLS

τ

B

, PLS

τ

C

, PLS

D

, PLS

τ

G
K

, PLS

G

, and PLS

U

. Three filter-based factor selection methods are executed, and leave-one-out cross-validation by linear discriminant analysis is measured on predicted scores of all models. Finally, the Monte Carlo simulation method with 10 iterations of repeated sampling for optimization of validation performance is applied to select the optimum model. The standard and proposed models are executed over simulated and real data sets for efficiency comparison. The PLS

ρ

s

is found to be the most appropriate proposed method to model the observed ranked data set of antenatal care visits based on validation performance. The optimal model selected 29 influential factors of inadequate use of antenatal care. The important factors of reduced antenatal care visits included women’s educational status, wealth index, total children ever born, husband’s education level, domestic violence, and history of cesarean section. The findings recommended that partial least square regression algorithms coupled with rank correlation coefficients provide more efficient estimates of ranked data in the presence of multicollinearity.
Application of the Concept of Enhanced Recovery after Surgery in Total Laparoscopic Radical Gastrectomy
Authors: Guo Wei , Li Wenyuan , Mei Xianghuang , Wang Yangyang , He Zhipeng , Su Shi , Dong Jianhong , Zhu Liping 
Published: March 2022

To explore the clinical effects of total laparoscopic radical gastrectomy under the guidance of the concept of enhanced recovery after surgery (ERAS). Fifty-five patients were perioperatively treated under the concept of ERAS (ERAS group), while the remaining 55 patients were treated under the traditional perioperative concept (control group). The operation time, intraoperative blood loss, the time of first anal exhaust and first postoperative off-bed activity, postoperative length of stay, and incidence of postoperative complications were recorded in both groups. The pain of patients was assessed using VAS system. The nausea and vomiting and abdominal distension were assessed using the NVDS and abdominal distension score, respectively, within 24 h after operation. The patient’s daily living ability was evaluated by the ADL scale at 3 d after the operation. The time of first anal exhaust, the time of first postoperative off-bed activity time, and the postoperative in-hospital time were all significantly shorter in the ERAS group than those in the control group (

P

< 0.001). The VAS score in the ERAS group was significantly lower than that in the control group at 12 h, 24 h, 48 h, and 72 h after operation (

P

< .001). The ERAS group had significantly lower NVDS score and abdominal distension score than the control group (

P

< 0.001). The postoperative ADL score in the ERAS group was significantly higher than that in the control group (

P

< 0.001). ERAS during the perioperative period of total laparoscopic radical gastrectomy can promote the postoperative rehabilitation of patients and alleviate postoperative pain and gastrointestinal reactions, which is safe and effective.