bluuebunny/crossref_metadata_2025_split huggingface dataset:
C3aR costimulation enhances the antitumor efficacy of CAR-T cell therapy through Th17 expansion and memory T cell induction
Authors: Lai Peilong , Chen Xiaomei , Wang Yulian , Wang Jinghua , Zhang Yuchen , Geng Suxia , Li Peng , Du Xin , Weng Jianyu , Pei Duanqing 
Published: May 2022

AbstractAlthough chimeric antigen receptor (CAR)-modified adoptive T cell therapy is a promising immunotherapy for hematological malignancies, the efficacy improvement in relapsed/refractory acute lymphoblastic leukemia (ALL) with extramedullary infiltration and in multiple myeloma (MM) is still warranted. Since C3aR activation can promote the expansion of tumor-killing Th17 cells, we hypothesized that incorporating C3aR as a costimulatory domain would augment the antitumor activity of CAR-T. In this study, we introduced the C3aR domain into a CAR and generated BB-ζ-C3aR CAR-T targeting CD19 or BCMA. These new CAR-T exhibited a potent cytolytic ability to eradicate tumor cells expressing CD19 or BCMA in vitro. When administered intravenously to ALL or MM xenograft mouse models, BB-ζ-C3aR CAR-T reduced the tumor burden and improved the survival rate. Of note, these CAR-T could effectively eradicate subcutaneous CD19+ tumor cells, highlighting the therapeutic potential in extramedullary leukemia. Mechanistically, BB-ζ-C3aR CAR-T tended to exhibit a Th17 phenotype favoring tumor killing and suppressed Tregs. In addition, the induction of memory T cell in the BB-ζ-C3aR CAR-T cells indicated their long-term effects. Together, our findings suggest that the application of C3aR costimulation boosts the ability of CAR-T to eradicate aggressive tumor cells via Th17 expansion and memory T cell induction.
Clinical picture and long-term symptoms of SARS-CoV-2 infection in an Italian pediatric population
Authors: Bloise Silvia , Isoldi Sara , Marcellino Alessia , De Luca Enrica , Dilillo Anna , Mallardo Saverio , Martucci Vanessa , Sanseviero Mariateresa , Del Giudice Emanuela , Iorfida Donatella , Leone Rita , Testa Alessia , Frasacco Beatrice , Gizzone Pietro , Proietti Ciolli Claudia , Sinceri Alessandro , Zuliani Francesca , Zanardi Elena , Gambarotto Anna , Lisa Grandinetti Anna , Ventriglia Flavia , Lubrano Riccardo 
Published: May 2022

Abstract
Background
SARS-CoV-2 infection in the pediatric age group has a milder course than in adults, but in some cases even children may present with severe forms or develop long-term consequences. The aim of this study was to analyze the clinical features, long-term effects, lifestyle changes and psychological effects of SARS-CoV-2 infection in a pediatric sample of the Italian population.

Methods
We conducted a telephone survey among 3075 children infected with SARS-CoV-2 in the Latina Local Health Authority. Outcomes included: clinical features of infection, long-term symptoms, lifestyle changes and emotional symptoms during the illness. The information obtained was automatically linked to a spreadsheet and analyzed.

Results
One thousand four hundred thirteen children agreed to participate in the study; the mean age was 112.8 ± 21.9 months. Children were infected mainly inside familial clusters (59.6%; n = 842); 99% (n = 1399) of children were asymptomatic or exhibited mild symptoms. 20% (n = 259) of children experienced long-term symptoms; risk factors were: older age, higher body mass index and longer duration of infection.
Throughout the period of infection, children spent most of the time on devices like tv-video, social media and mobile phone for non-educational activities. 58.8% (n = 620) of parents expressed a negative opinion about distance learning. Finally, we observed that 49,6% (n = 532) of children experienced psychological symptoms during quarantine period.

Conclusion
Despite a lower susceptibility to COVID-19 in children, it is important to keep the focus high in children, both because of the possible long symptoms after infection and the impact on a children’s mental and physical health due to pandemic. We believe that the return to school or other extracurricular activities are important to correct some of the risk factors for the long COVID syndrome, as obesity, and to limit the cultural damage generated by distance learning and psychological effects related to restrictive measures.
A multimodal intervention to optimise antimicrobial use in residential aged care facilities (ENGAGEMENT): protocol for a stepped-wedge cluster randomised trial
Authors: Falconer Nazanin , Paterson David L. , Peel Nancye , Welch Alyssa , Freeman Christopher , Burkett Ellen , Hubbard Ruth , Comans Tracy , Hanjani Leila Shafiee , Pascoe Elaine , Hawley Carmel , Gray Leonard 
Published: May 2022

Abstract
Background
Inappropriate antibiotic use can cause harm and promote antimicrobial resistance, which has been declared a major health challenge by the World Health Organization. In Australian residential aged care facilities (RACFs), the most common indications for antibiotic prescribing are for infections of the urinary tract, respiratory tract and skin and soft tissue. Studies indicate that a high proportion of these prescriptions are non-compliant with best prescribing guidelines. To date, a variety of interventions have been reported to address inappropriate prescribing and overuse of antibiotics but with mixed outcomes. This study aims to identify the impact of a set of sustainable, multimodal interventions in residential aged care targeting three common infection types.

Methods
This protocol details a 20-month stepped-wedge cluster-randomised trial conducted across 18 RACFs (as 18 clusters). A multimodal multi-disciplinary set of interventions, the ‘AMS ENGAGEMENT bundle’, will be tailored to meet the identified needs of participating RACFs. The key elements of the intervention bundle include education for nurses and general practitioners, telehealth support and formation of an antimicrobial stewardship team in each facility. Prior to the randomised sequential introduction of the intervention, each site will act as its own control in relation to usual care processes for antibiotic use and stewardship.
The primary outcome for this study will be antibiotic consumption measured using defined daily doses (DDDs). Cluster-level rates will be calculated using total occupied bed numbers within each RACF during the observation period as the denominator. Results will be expressed as rates per 1000 occupied bed days. An economic analysis will be conducted to compare the costs associated with the intervention to that of usual care. A comprehensive process evaluation will be conducted using the REAIM Framework, to enable learnings from the trial to inform sustainable improvements in this field.

Discussion
A structured AMS model of care, incorporating targeted interventions to optimise antimicrobial use in the RACF setting, is urgently needed and will be delivered by our trial. The trial will aim to empower clinicians, residents and families by providing a robust AMS programme to improve antibiotic-related health outcomes.

Trial registration
US National Library of Medicine Clinical Trials.gov (NCT04705259). Prospectively registered in 12th of January 2021.
The impact of COVID-19 on pragmatic clinical trials: lessons learned from the NIH Health Care Systems Research Collaboratory
Authors: O’Brien Emily C. , Sugarman Jeremy , Weinfurt Kevin P. , Larson Eric B. , Heagerty Patrick J. , Hernandez Adrian F. , Curtis Lesley H. 
Published: May 2022

Abstract
Background
The COVID-19 pandemic has considerably disrupted nearly all aspects of daily life, including healthcare delivery and clinical research. Because pragmatic clinical trials are often embedded within healthcare delivery systems, they may be at high risk of disruption due to the dual impacts on the conduct of both care and research.

Methods
We collected qualitative data using multiple methods to characterize the impact of COVID-19 on the research activities of 14 active pragmatic clinical trials in the National Institutes of Health (NIH) Health Care Systems Research Collaboratory. A COVID-19 impact questionnaire was administered electronically to principal investigators in June 2020. Text responses were analyzed thematically, and qualitative summaries were subsequently reviewed by five independent reviewers, who made iterative revisions. Additional COVID-19-related impacts were identified during virtual meetings with trial teams during April–July 2020 and combined with questionnaire responses for analysis.

Results
Impacts of the pandemic were broadly classified into two main types: healthcare operations and social distancing. In some instances, trial delays created statistical challenges, particularly with trials using stepped-wedge designs, and necessitated changing data collection strategies or modifying interventions. The majority of projects used existing stakeholder-driven approaches to adapt interventions. Several benefits of these adaptions were identified, including expanded outreach capabilities and ability to study virtual intervention delivery. All trial teams were able to adapt to pandemic-related modifications.

Conclusion
In a group of 14 ongoing pragmatic clinical trials, there was significant impact of COVID-19 on trial activities. Engaging appropriate stakeholders was critical to designing and implementing trial modifications and making continued safe progress toward meeting research objectives.
Quality of care in patients with type 1 diabetes during the COVID-19 pandemic: a cohort study from Southern Brazil
Authors: Foppa Luciana , Alessi Janine , Nemetz Betina , de Matos Rosimeri , Telo Gabriela Heiden , Schaan Beatriz D. 
Published: May 2022

Abstract
Background
Optimal glycemic control is the main goal for patients with diabetes. The results of type 1 diabetes patients’ neglected demands during the pandemic can determine a long-term negative clinical, social, and economic impact, and result in worse diabetes control and a higher incidence of chronic complications. Therefore, this study aims to evaluate the impact of the COVID-19 outbreak in the quality of care of patients with type 1 diabetes in Southern Brazil.

Methods
Cohort study based on electronic medical records of patients with type 1 diabetes, with scheduled appointments between January 1st 2020, and November 6th 2020, at a university public hospital. The quality indicators used were: assessment of albuminuria and/or serum creatinine, lipid profile, thyroid-stimulating hormone, glycated hemoglobin, retinopathy, and neuropathy. McNemar test was used to analyze categorical variables and the Wilcoxon test for continuous variables.

Results
Out of 289 patients, 49.5% were women aged 40 ± 12 years old. During the pandemic, 252 patients had at least one face-to-face appointment canceled. The quality of care indicators showed a significant worsening during the COVID-19 pandemic compared to the previous year (p < 0.001). In 2019, 23.2% of the participants had all the indicators evaluated, while in 2020, during the pandemic, only 3.5% had all of them evaluated.

Conclusion
The COVID-19 pandemic hindered the offer of comprehensive and quality care to patients with type 1 diabetes.
Is there an association between COVID-19 mortality and Human development index? The case study of Nigeria and some selected countries
Authors: Ameye Sanyaolu Alani , Ojo Temitope Olumuyiwa , Adetunji Tajudin Adesegun , Awoleye Michael Olusesan 
Published: May 2022

Abstract
Objectives
We assessed Case Fatality Rate (CFR) of COVID-19 as an indicator to situate the performance of Nigeria relative to other selected countries. We obtained case fatality rates of different countries from data sets available from open-sources. The CFRs were calculated as the rate of deaths compared with total cases. The values were compared with Nigeria’s COVID-19 CFR. Other relevant statistical comparisons were also conducted.

Results
The worst performing countries with regards to CFR in descending order were Yemen (19.5%), Peru (9.0%) Mexico (7.6%), Sudan (7.4%) and Ecuador (6.3%) while the best performing nations were Bhutan (0.11%), Burundi (0.19%), Iceland (0.20%), Laos (0.21%) and Qatar (0.25%). The CFR of Nigeria was 1.39% which falls below the 50th percentile. Other comparison done showed significant difference in the CFR values between countries similar to Nigeria and countries that are dissimilar when HDI is used. (Mann–Whitney U test 126.0, p = 0.01). The trend of the CFR in Nigeria showed a steady decline and flattening of the CFR curve which does not seem to be affected by the spikes in the daily declared cases.
Identification of excretory and secretory proteins from Haemonchus contortus inducing a Th9 immune response in goats
Authors: Liang Meng , Lu Mingmin , Aleem Muhammad Tahir , Zhang Yang , Wang Mingyue , Wen Zhaohai , Song Xiaokai , Xu Lixin , Li Xiangrui , Yan Ruofeng 
Published: May 2022

AbstractTh9 cells have been shown to play crucial roles in anti-parasite immunity, pathogenic microbe infection, and allergy. Previous studies have demonstrated thatHaemonchus contortusexcretory and secretory proteins (HcESPs) induce the proliferation of Th9 cells and alter the transcriptional level of IL-9 as well as its related pathways in the Th9 immune response after infection. However, the exact molecule(s) in HcESPs inducing the Th9 immune response is not yet known. In this study, flow cytometry, co-immunoprecipitation (Co-IP) and shotgun liquid chromatography tandem-mass spectrometry (LC–MS/MS) were used, and a total of 218 proteins from HcESPs that might interact with goat Th9 cells were identified. By in vitro culture of Th9 cells with HcESPs, 40 binding proteins were identified. In vivo, 38, 47, 42 and 142 binding proteins were identified at 7, 15, 35 and 50 days post-infection (dpi), respectively. Furthermore, 2 of the 218 HcESPs, named DNA/RNA helicase domain containing protein (HcDR) and GATA transcription factor (HcGATA), were confirmed to induce the proliferation of Th9 cells and promote the expression of IL-9 when incubated with goat peripheral blood mononuclear cells (PBMCs). This study represents a proteomics-guided investigation of the interactions between Th9 cells and HcESPs. It provides a new way to explore immunostimulatory antigens among HcESPs and identifies candidates for immune-mediated prevention ofH. contortusinfection.
Relation between electrical resistance and conductance using multifarious functional equations and applications to parallel circuit
Authors: Pachaiyappan Divyakumari , Murali Ramdoss , Park Choonkil , Lee Jung Rye 
Published: May 2022

AbstractIn this paper, we introduce a new generalized p-dimensional multifarious radical reciprocal functional equation combining three classical means: arithmetic, geometric, and harmonic. Mainly, we find its general solution and stability related to the Ulam problem in modular spaces by using the fixed point method with suitable counterexamples. Importantly, in this paper, we illustrate the geometrical interpretation and applications of the introduced Pythagorean means multifarious functional equation in connection with the parallel circuit. Furthermore, we provide a formula for finding the equivalent resistance $R_{\mathrm{eq}}$

R
eq

of parallel electrical circuit using functional equations, which relates the electrical resistances and conductances with suitable examples.
Progress in understanding the mechanisms of resistance to BCL-2 inhibitors
Authors: Xu Yilan , Ye Haige 
Published: May 2022

AbstractVenetoclax is a new type of BH3 mimetic compound that can target the binding site in the BCL-2 protein and induce apoptosis in cancer cells by stimulating the mitochondrial apoptotic pathway. Venetoclax is especially used to treat haematological malignancies. However, with the recent expansion in the applications of venetoclax, some cases of venetoclax resistance have appeared, posing a major problem in clinical treatment. In this article, we explored several common mechanisms of venetoclax resistance. Increased expression of the antiapoptotic proteins MCL-1 and BCL-XL plays a key role in conferring cellular resistance to venetoclax. These proteins can bind to the released BIM in the context of venetoclax binding to BCL-2 and thus continue to inhibit mitochondrial apoptosis. Structural mutations in BCL-2 family proteins caused by genetic instability lead to decreased affinity for venetoclax and inhibit the intrinsic apoptosis pathway. Mutation or deletion of the BAX gene renders the BAX protein unable to anchor to the outer mitochondrial membrane to form pores. In addition to changes in BCL-2 family genes, mutations in other oncogenes can also confer resistance to apoptosis induced by venetoclax. TP53 mutations and the expansion of FLT3-ITD promote the expression of antiapoptotic proteins MCL-1 and BCL-XL through multiple signalling pathways, and interfere with venetoclax-mediated apoptosis processes depending on their affinity for BH3-only proteins. Finally, the level of mitochondrial oxidative phosphorylation in venetoclax-resistant leukaemia stem cells is highly abnormal. Not only the metabolic pathways but also the levels of important metabolic components are changed, and all of these alterations antagonize the venetoclax-mediated inhibition of energy metabolism and promote the survival and proliferation of leukaemia stem cells. In addition, venetoclax can change mitochondrial morphology independent of the BCL-2 protein family, leading to mitochondrial dysfunction. However, mitochondria resistant to venetoclax antagonize this effect, forming tighter mitochondrial cristae, which provide more energy for cell survival.
The bidirectional effects of obsessive-compulsive symptoms and difficulties in emotion regulation in Chinese adults during the COVID-19 pandemic—a dynamic structural equation model
Authors: Hong Danping , Zhu Yawen , Chen Runting , Xiao Bihong , Huang Yueyi , Yu Meng 
Published: May 2022

AbstractBackgroundWith the accumulation of negative emotions brought by COVID-19-related dysfunctional beliefs, individuals adopted obsessive–compulsive (OC) symptoms (e.g., over-checking the wearing of masks) and formed difficulties in emotion regulation (DER). This study focused on the temporal dynamics of the bidirectional relation between OC symptoms and DER, which had a devastating effect on the individual's mental health. As an extension, we further explored whether OC and DER and their relationship affect sleep problems.MethodsIn February 2020, a 14-day (twice a day, of 28 measurement intervals) online questionnaire survey was conducted on 122 Chinese adults (aged 18–55 years; 63 females). Subsequently, this research applied a dynamic structural equation model with a cross-lagged relationship and a time series. Health anxiety, anxiety, and depression were controlled as covariates.ResultsBoth OC symptoms and DER had a significant autoregressive and cross-lagged effect. Comparatively speaking, DER was a stronger predictor of OC symptoms than OC’s prediction of DER. Moreover, both higher levels of OC symptoms and DER were related to the severity of sleep problems.ConclusionsMore guidance on intervening in OC symptoms and identifying emotion regulation should be added to reduce the negative impact of the COVID-19 pandemic on public mental health.
Feasibility and acceptability of high-intensity interval training and moderate-intensity continuous training in kidney transplant recipients: the PACE-KD study
Authors: Billany Roseanne E. , Smith Alice C. , Hutchinson Ganisha M. , Graham-Brown Matthew P. M. , Nixon Daniel G. D. , Bishop Nicolette C. 
Published: May 2022

Abstract
Background
Kidney transplant recipients (KTRs) exhibit unique elevated inflammation, impaired immune function, and increased cardiovascular risk. Although exercise reduces cardiovascular risk, there is limited research on this population, particularly surrounding novel high-intensity interval training (HIIT). The purpose of this pilot study was to determine the feasibility and acceptability of HIIT in KTRs.

Methods
Twenty KTRs (male 14; eGFR 58±19 mL/min/1.73 m2; age 49±11 years) were randomised and completed one of three trials: HIIT A (4-, 2-, and 1-min intervals; 80–90% watts at V̇O2peak), HIITB (4×4 min intervals; 80–90% V̇O2peak) or MICT (~40 min; 50–60% V̇O2peak) for 24 supervised sessions on a stationary bike (approx. 3x/week over 8 weeks) and followed up for 3 months. Feasibility was assessed by recruitment, retention, and intervention acceptability and adherence.

Results
Twenty participants completed the intervention, and 8 of whom achieved the required intensity based on power output (HIIT A, 0/6 [0%]; HIITB, 3/8 [38%]; MICT, 5/6 [83%]). Participants completed 92% of the 24 sessions with 105 cancelled and rescheduled sessions and an average of 10 weeks to complete the intervention. Pre-intervention versus post-intervention V̇O2peak (mL/kg-1/min-1) was 24.28±4.91 versus 27.06±4.82 in HIITA, 24.65±7.67 versus 27.48±8.23 in HIIT B, and 29.33±9.04 versus 33.05±9.90 in MICT. No adverse events were reported.

Conclusions
This is the first study to report the feasibility of HIIT in KTRs. Although participants struggled to achieve the required intensity (power), this study highlights the potential that exercise has to reduce cardiovascular risk in KTRs. HIIT and MICT performed on a cycle, with some modification, could be considered safe and feasible in KTRs. Larger scale trials are required to assess the efficacy of HIIT in KTRs and in particular identify the most appropriate intensities, recovery periods, and session duration. Some flexibility in delivery, such as incorporating home-based sessions, may need to be considered to improve recruitment and retention.

Trial registration
ISRCTN, ISRCTN17122775. Registered on 30 January 2017.
Public governance of medical artificial intelligence research in the UK: an integrated multi-scale model
Authors: McKay Francis , Williams Bethany J. , Prestwich Graham , Treanor Darren , Hallowell Nina 
Published: May 2022

AbstractThere is a growing consensus among scholars, national governments, and intergovernmental organisations of the need to involve the public in decision-making around the use of artificial intelligence (AI) in society. Focusing on the UK, this paper asks how that can be achieved for medical AI research, that is, for research involving the training of AI on data from medical research databases. Public governance of medical AI research in the UK is generally achieved in three ways, namely, via lay representation on data access committees, through patient and public involvement groups, and by means of various deliberative democratic projects such as citizens’ juries, citizen panels, citizen assemblies, etc.—what we collectively call “citizen forums”. As we will show, each of these public involvement initiatives have complementary strengths and weaknesses for providing oversight of medical AI research. As they are currently utilized, however, they are unable to realize the full potential of their complementarity due to insufficient information transfer across them. In order to synergistically build on their contributions, we offer here a multi-scale model integrating all three. In doing so we provide a unified public governance model for medical AI research, one that, we argue, could improve the trustworthiness of big data and AI related medical research in the future.