Given the leading role school nurses occupy within the school setting, they are often the most suited health care professionals to lead asthma programs. However, most school-based asthma programs have been conducted by researchers outside the school setting. Thus, we aim to determine what is currently known about the type of school nurse-led asthma intervention programs and their impact on children’s asthma-related outcomes. This article describes published literature on school nurse-led asthma intervention programs for the school-aged population using Arksey and O’Malley’s scoping review framework. A search strategy was developed and implemented in six electronic databases from 1980 to 2020. Results showed that school nurse-led asthma programs were predominantly educational interventions. Yet given the positive outcomes of school nurse-led asthma interventions reported across the articles reviewed, it is important to emphasize the leadership role school nurses assume in asthma programs, to promote more positive asthma-related outcomes in school children. Asthma is the most common chronic condition among children, with more than a million children in the United Kingdom  and moreThe National Association of School Nurses (NASN) defines school nursing as a specialized public health nursing field that protects and promotes student health, enables normal development, and promotes academic success . In the The impact of asthma intervention programs on children’s health outcomes using various interventions has been consistently reported in the literature . These iImplementing school nurse-led asthma intervention programs outside of the hospital setting enables students with asthma to learn about their condition, develop asthma self-management skills, and reduce school absence and missed class time . HoweverDescribe the types of school nurse-led asthma intervention programs that have been reported for the school-aged population, their impact on children’s asthma-related outcomes, and the role of school nurses in each program.Identify the research gaps in existing literature concerning aspects of school nurse-led asthma intervention programs, particularly educational interventions.Scoping reviews aim to identify and map the existing evidence in a specific area of research. Furthermore, they have a broader question and aim to identify research gaps in existing literature . As suchThe population, exposure, and outcomes framework was employed to guide the selection of included studies and can be seen in Six electronic databases were searched: Cumulative Index of Nursing and Allied Health Literature (CINAHL), PsychINFO, MEDLINE, Educational Resources Information Centre (ERIC), EMBASE, and Applied Social Sciences Index and Abstracts (ASSIA). The search was limited to articles published in the English language. The reference lists of the retrieved articles were examined but the manual search did not uncover additional eligible studies. The search was carried out between June and August 2020.Search terms related to “asthma,” “school,” and “nurses” were adapted to maximize results from each database. These terms were combined with the Boolean operator (AND). The search strategy was designed in the CINAHL database and translated to other databases see .N = 5) and were not a school nurse-led intervention (N = 7). Overall, seven studies were included in the review. There were no disagreements between the evaluators when selecting and extracting the data. The third step was to review the bibliography of the identified articles; no additional articles were identified.The literature review search was conducted in consultation with the university librarian. Data from the included studies were extracted into an evidence table that included author, year, country, aim, design, population/sample, nature of the intervention, outcome assessed, results, and measurement tools see .The purpose of this review was to identify the current evidence on the impact of school nurse-led asthma intervention programs. The school nurse’s role in the included studies varied between providing educational interventions for asthmatic children , superviN = 7) discussed an asthma program led by a school nurse  and the control group (N = 18). Both groups had a preintervention appointment where they received a physical examination and pulmonary function test by a pediatrician. However, the intervention group received education sessions by the school nurse, while the control group received no education. There were two data collection points, at baseline and immediately following the 8-week session.The participating school nurses in Similarly, N = 37) or usual care (control N = 36). The intervention group received a school nurse-led asthma group session over 6 weeks. Topics covered were (1) pathophysiology, (2) PFM, (3) symptom identification and asthma action plans, (4) medication and delivery devices, (5) triggers identification and prevention as well as breathing exercises, and (6) individualized discussion and self-management strategies. To improve class interaction, researchers utilized hands-on practice, problem-based learning, case studies, storytelling, role-plays, and class discussions. The treatment group received a PFM with a personal peak flowchart and a spacer. The control group received usual care, which refers to receiving their medication according to the action plan prescribed by the child’s doctor. Data collection took place three times: at baseline, 6 weeks, and 12 weeks.N = 21) and its impact on asthma-related health outcomes. The school nurse administered a daily dose of the inhaled corticosteroids (ICS) every morning at school to those assigned to the intervention group (n = 18). The clinician prescribed administration of ICS at home every evening of a school day, and every morning and evening during holidays. Parents did home medication administration. For the control group (n = 25), the ICS doses were prescribed to be administered daily by parents at home every morning and evening for the 2-month study period. There were two data collection points: at baseline and 60 days after enrolment. Structured telephone follow-up interviews were conducted with parents to assess ICS doses and parental reported asthma symptoms and disability during the study period.Two studies examined school nurse-supervised asthma therapy . In an RSimilarly, The focus of this scoping review is to discuss the available evidence in relation to the impact of school nurse-led asthma programs on children’s health-related outcomes. The measurement of different outcomes varied and was complex due to the incomplete data reported by some papers. The outcomes reported included: medication use, inhaler technique, and PFM use, symptoms, school absence, QoL, health care utilization, and asthma knowledge.p < .001). p = .89) or daily ICS use (p = .60) following the implementation of a school nurse-led asthma program.Three studies evaluated medication usage among asthmatics in a school setting after a school nurse-led asthma program . Trivedip = .03). Two studies assessed the inhaler technique among students with asthma . D. M. Cp = .36) between the groups.There was a lack of PFM assessment in the included studies with only two studies highlighting this outcome . Persaudp = .42) for the intervention group (adolescents) attending a school nurse asthma clinic, p < .001).Two studies assessed the impact of school nurse-led asthma programs on symptom frequency . While SThe outcome of school absenteeism was measured using school records or self-reported data in six of the included studies . Overallp = .179), yet the treatment group missed fewer school days.p = .63).In our review, three studies examined QoL as an outcome . SalisbuThe study by p = .04), required adjustment to family life (p = .03), and sleep loss due to asthma (p = .04) after the school nurse-supervised asthma therapy. Overall, there was a statistically significant difference in QoL in the treatment group compared to the control group (p < .001).N = 9) than the intervention group . When the age of onset was controlled, however, the association between the number of ER visits per child and the educational intervention was not statistically significant.The impact of school nurse-led asthma programs on health care use includes ER visits, unscheduled visits to physicians, and/or hospitalization. Out of the seven included studies, three studies explored the impact of a nurse-led asthma program on the number of ER visits . Persaudp < .001). Asthma-related hospital admission showed a significant decline as well from a preintervention mean of 0.3 admissions to a postintervention mean of 0 admissions (p < .001). Contrastingly, p = .9) and their parents (p = .54) after program implementation. This was the only study that addressed parent’s knowledge alongside children’s knowledge. In contrast, p = .001).Only two studies in this review assessed the knowledge of children after an asthma program was delivered by a school nurse . PersaudAs has been illustrated, nurses play a leading role in the school setting, placing them in an optimal position to lead programs in asthma management. However, most school-based asthma programs were conducted by researchers outside the school setting; thus, highlighting a gap in the literature. We, therefore, aimed to determine what is currently known about the type of school nurse-led asthma intervention programs and their impact on children’s asthma-related outcomes by conducting a scoping review.Our scoping review found that school nurse-led asthma programs had a positive impact on children’s asthma health-related outcomes, which include medication use, reduction in school absenteeism, reduction in health care utilization, improved asthma knowledge, and QoL. The review findings are consistent with previous non-nurse-led intervention studies, which found that school-based asthma programs improved health outcomes and prevented complications . HoweverThe review highlighted a positive impact on medication adherence and, therefore, symptom frequency among children. This positive impact was not significantly prominent among adolescents in The frequency and accuracy of medication administration through medication delivery devices to either prevent symptoms or for quick episode relief are important indicators of asthma management. The review reported a weakening of inhaler technique skills as early as 1 month after receiving education on best practice inhaler technique skills. This illustrates how improper inhaler technique is a major problem among asthmatic children . SuwannaAs asthma is strongly linked to school absenteeism, studies supported school nurses’ role in reducing school absence among students with chronic conditions . The AmeAddressing asthma knowledge among children and their parents is an important determining factor of asthma management. Our results demonstrated that educating parents and children was a major component of school nurse-led asthma interventions. The National Heart, Lung, and Blood Institute highlights the importance of involving children and their parents in asthma management . HoweverIt could be argued from our review that the consistency and sustainability of the intervention is a challenge. Our review highlighted supervised asthma medication administration in school settings as a form of a school nurse-led asthma intervention. Many studies described school-based interventions targeting children, and these interventions showed improvement in asthma outcomes . HoweverThe NASN framework for 21st Century School Nursing Practice includes leadership as one of the domains. Through school nurse-led interventions, school nurses contribute to the health and well-being of the students  as well In summary, different school nurse-led asthma interventions carried out in schools can improve child health outcomes. Training of school nurses specifically support positive practice sustainability at a reduced cost Overall, this scoping review found that school nurse-led asthma intervention programs had a positive impact on children’s asthma-related outcomes. Several limitations identified in this review should be considered when planning a school nurse-led asthma program in the future. First, the included studies did not explore the effect a school nurse-led asthma program had on several other outcomes such as the number of exacerbations and asthma severity. Second, the dearth of evaluation strategies of school nurse-led programs requires investigation. It is not possible to draw a firm conclusion on the impact of a school nurse-led asthma program without an in-depth evaluation of such outcomes and a longer follow-up period of each outcome. Third, the wide variations in sample size, measurement tools, and the nature of school nurse-led asthma programs in the studies reviewed require a more rigorous type of research designed to better illustrate how nurse-led asthma programs are beneficial in reducing asthma-related outcomes. Most interventions included in our review were short-term, individual programs that lasted 1 year or consisted of four or less sessions. This reduced the impact of school nurse-led interventions or limited the opportunity to reinforce the instructions. Finally, the sustainability of interventions is influenced by the degree to which school nursing services are available, as the partnership between the clinical system  and the public system (school setting) promotes long-term asthma outcomes sustainability. Thus, the school nurse, as a member of an interprofessional team, can act as a linkage between the health sector and the educational sector. This provides an important insight that should be further explored in future research. Taken together, the findings highlighted in this review provide important practical implications in terms of ensuring the effectiveness of school nurse-led intervention programs addressing asthma among school-aged children. Thus, these insights can guide the future development and implementation of such programs, led by nurses, which will ensure positive asthma-related outcomes.


Hepatic manifestations of Epstein-Barr virus (EBV) infection are relatively common, mild, and self-limiting. Although fulminant hepatic failure has been reported in a few cases, the contributing factors are unclear. This report discusses a pediatric case of EBV-associated acute liver failure that required urgent liver transplantation; however, liver damage continued to progress post-liver replacement. Monoclonal CD8+ T cells that preferentially infiltrated the native and transplanted liver were positive for EBV-encoded small RNA, suggesting a pathophysiology similar to that of EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection. Therefore, subsequent chemotherapy and hematopoietic cell transplantation was conducted, which led to cure. This is the first case of EBV-associated acute liver failure that relapsed post-liver transplant. As such, it sheds light on an under-recognized clinical entity: liver-restricted hyperinflammation caused by EBV-infected monoclonal CD8+ T cells. This phenomenon needs to be recognized and differentiated from hepatitis/hepatic failure caused by EBV-infected B cells, which has a relatively benign clinical course. Epstein-Barr virus (EBV), a member of the herpes virus family, causes a self-limiting infectious mononucleosis. The pathogenesis of infectious mononucleosis is driven by T cells specific for EBV-infected B cells, which results in the triad of fever, pharyngitis, and lymphadenopathy, and often accompanied by mild liver enzyme elevations . OccasioHere, we describe a pediatric case that presented initially with presumed acute liver failure. Liver biopsy revealed predominant infiltration of the liver by EBV-infected CD8+ T cells. Liver transplant was conducted as the definitive treatment; however, several days later, relapse of EBV-hepatitis was observed in the donor liver. Although extra-hepatic involvement was scarce, chemotherapy and subsequent bone marrow transplant were attempted in accordance with EBV-LPD. The patient’s liver was free of EBV 2 months after the bone marrow transplant. Our report is the first to imply that acute liver failure caused by EBV-infected T cells might require HCT as the definitive therapy in addition to liver transplantation.A previously healthy 2-year-old boy was referred to our hospital with a 2-day history of fever, jaundice, and abdominal pain. Blood tests revealed elevated transaminases , total-bilirubin (6.9 mg/dL), direct-bilirubin (5.6mg/dL), and a prolonged PT-INR of 3.77, all of which were compatible with pediatric acute liver failure (ALF). In addition, a hyperinflammatory state was suggested by sIL-2R  and ferritin . Liver biopsy revealed fulminant hepatitis, with portal lymphocyte infiltration and massive necrosis E. There+ T cells, along with portal inflammation and endotheliitis, which are compatible with acute cellular rejection. FDG-PET/CT did not reveal any systemic lesions, and abnormal uptake was confined to the liver  5. Follow-up liver biopsy on POD 10 revealed re-infiltration by EBER-positive CD8he liver Figure 22 twice per week) led to sustained normalization of liver function and a gradual decrease in the EBV viral load in the peripheral blood and liver. However, the attempt to extend etoposide infusion intervals from POD 80 caused the EBV viral load and transaminase levels to increase. The patient was considered refractory to chemotherapy and underwent HCT from a HLA-full matched unrelated donor with reduced-intensity conditioning  ’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.KN wrote the case report and prepared the figures. EH was the attending physician of this patient and the director of the whole writing process. HN, KK, YH, KI, and TY performed the diagnostic evaluation of the patient. EO, MS, TO, and HO performed liver transplant surgery. NK, IK, and JT were responsible for the bone marrow transplant procedure. All authors contributed to the article and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: Perfusion strategies and aortic clamping techniques for right mini-thoracotomy mitral valve (MV) surgery have evolved over time and remarkable short- and long-term results have been reported. However, some concerns have raised about the adequacy of myocardial protection during the minimally invasive approach, particularly with the endo-aortic clamp (EAC). Aim of this study was to compare the efficacy, in terms of myocardial preservation, of the EAC with the trans-thoracic aortic clamp (TTC) in patients undergoing right mini-thoracotomy MV surgery.Methods: A single center, prospective observational study was performed on patients undergoing right mini-thoracotomy MV surgery with retrograde arterial perfusion and EAC or TTC. A propensity matched analysis was performed to compare the two groups. Primary outcome was the comparison between cardiac troponin T levels measured at different time-points after surgery.Results: Eighty EAC patients were compared with 37 TTC patients. No cases of myocardial infarction or low cardiac-output syndrome were overall reported. No differences were recorded in terms of stroke, peri-operative mortality, and in the release of myocardial markers, lactates levels and need for inotropic support at different time-points after surgery. CK-MB peak levels were significantly lower in the EAC group.Conclusion: Despite concerns arising about the EAC, this prospective study shows equivalence in terms of myocardial preservation of the EAC compared with the TTC in patients undergoing right mini-thoracotomy MV surgery. Perfusion strategies and aortic clamping techniques for right mini-thoracotomy mitral valve (MV) surgery have evolved over time and remarkable short- and long-term results have been reported all over the world –5. HowevThe standard right mini-thoracotomy set-up is based on retrograde arterial perfusion (RAP) through the femoral artery and endo-aortic clamp (EAC) or trans-thoracic aortic clamp (TTC). In the former, aortic occlusion is obtained with a balloon catheter inserted through the femoral cannula, and cardioplegia is delivered through the tip of the catheter; in the latter, aortic occlusion is obtained with a trans-thoracic direct clamping and a separate line into the ascending aorta is used for cardioplegia delivery. Efficacy of the EAC setting on myocardial preservation is definitely more debated due to several factors, including the higher risk of instability and possible migration or tearing of the balloon, and the more challenging learning curve for the surgeon .Aim of this prospective observational study was to compare the effectiveness, in terms of myocardial protection, of the EAC vs. the TTC setting in patients undergoing right mini-thoracotomy MV surgery.A single-institution prospective observational study was performed at the University of Turin, Cardio-thoracic Department, between June 2014 and June 2018. The study protocol was reviewed and approved by the Institutional Ethics Committee (protocol number 0095187). Inclusion criteria were diagnosis of MV regurgitation, planned surgery through the right mini-thoracotomy and RAP. Exclusion criteria were non-elective surgery, cardiac ejection fraction lower than 40%, more than mild aortic regurgitation, previous coronary artery bypass grafts, coronary artery disease, severe peripheral vascular disease, and concomitant procedures for atrial fibrillation ablation. Patients admitted at our Department during the study period underwent a full preoperative work-up based upon clinical history and analysis of the vascular anatomy with the aim to be allocated to the most appropriate setting: RAP with EAC, RAP with TTC, or antegrade arterial perfusion with TTC (Primary outcome was the comparison between cardiac troponin T (cTn-T) levels measured at different time-points after surgery; secondary outcomes were peri-operative myocardial infarction, creatinine kinase-myocardial band (CK-MB) and lactates levels at different time-points after surgery, the occurrence of low cardiac output syndrome, and the need for post-operative inotropic support.Peri-operative myocardial infarction was recorded in the case of cTn-T value >10 times the 99th percentile of the upper reference limit during the first 48 h with electrocardiographic (ECG) abnormalities and/or angiographic or imaging evidence of new myocardial ischemia/new loss of myocardial viability  in the absence of hypovolemia (Low cardiac-output syndrome was defined as cardiac index lower than 2 L/min/movolemia .2. Vasoactive-inotropic score (VIS) indicates the amount of cardiovascular support by various inotropes or vasopressors in the first 24 h after the surgical procedure. The VIS was calculated as: dopamine dose (mg/kg/min) + dobutamine dose (mg/kg/min) + 100 × epinephrine dose (mg/kg/min) + 10 × milrinone dose (mg/kg/min) + 10.000 × vasopressin dose (unit/kg/min) + 100 × norepinephrine dose (mg/kg/min)  .Peri-operative mortality was defined as all deaths occurring during hospitalization or within 30 days of the procedure. Post-operative stroke was defined as a new, permanent neurological disability or deficit.Right mini-thoracotomy approach with perfusion strategies and aortic clamping techniques used in our Department has been previously described , 9. AfteTM, Hospira Inc., Lake Forest, Illinois, USA) or Bretschneider solution (Custodiol®). At the end of the procedure air venting was obtained, in the EAC group, with the balloon inflated, through the cardioplegia line, while in the TTC group through the aortic line.In the EAC setting, clamping and cardioplegia delivery were obtained through a balloon catheter  inserted through the sidearm of the arterial cannula; in the TTC setting, a Chitwood clamp, inserted through a first intercostal space port  was used and the cardioplegia was delivered through a 7F cardioplegia needle  placed into the ascending aorta. Antegrade myocardial protection was performed using St Thomas hospital solution 1  in order to remove the crystalloid solution or underwent hemofiltration during cardiopulmonary bypass. No additional topical cooling, nor retrograde cardioplegia through the coronary sinus were used; aortic clamp was released above 33°C in all the patients.After the surgical procedure, all patients were investigated for ECG abnormalities and for new hypokinetic or akinetic area by echocardiography.Blood samples for biochemical examination were collected immediately after the surgical procedure and at 6, 12, and 24 h post-operatively. Upper reference limit for CK-MB and for cTn-T were 5 ng/mL and 50 ng/L, respectively.t-test or Wilcoxon-Mann-Whitney according to distribution type. Categorical variables were compared with the use of the Chi-square test or Fisher exact test, when appropriate.Continuous data are presented as mean and standard deviation (SD) or median and interquartile range (IQR) depending on data distribution, while categorical data are presented as rate and proportion. In univariate analysis continuous variables were compared using unpaired To reduce possible differences between patients receiving EAC or TTC and obtain unbiased estimation of the treatment effect, a matched analysis using propensity score was performed. The propensity score of receiving EAC or TTC was estimated using a multivariable logistic regression analysis with the type of clamping as dependent variable. The priori selected variables were: age, gender, body mass index, pre-operative creatinine, peripheral vasculopathy, EuroSCORE II, previous cardiac surgery, ejection fraction, type of MV disease, length of aortic clamping, type of cardioplegia, and mean pressure during CPB.The genetic matching method without replacement was used to match patients undergoing surgery with EAC or TTC –15. Stanp-values of 0.05 or less were considered statistically significant and were conducted using the following software packages: Stata , R  and SAS .A mixed-linear regression model for repeated measures was used to examine the temporal effect across groups (EAC and TTC) during the 24-h observation period after surgery. Statistical tests were two-sided, and A receiver operating characteristic curve  with peak cTn-T and CK-MB levels was performed. The results were expressed by providing the value of the AUC and relative interval at a 95% confidence level.Five-hundred and sixty-six patients underwent right mini-thoracotomy MV surgery at our Department during the study period. One-hundred and eighty-nine patients met the study inclusion criteria. Of these, 81 underwent surgery with the EAC setting and 106 with the TTC setting; two patients did not undergo myocardial protection analysis due to conversion to median sternotomy before CPB onset. Groups were not comparable with respect to age, pre-operative creatinine level, peripheral vascular disease, EuroSCORE II, previous cardiac surgery, and type of MV regurgitation . After mNo cases of EAC tearing or dislodgement were overall reported. No cases of myocardial infarction or low cardiac-output syndrome were observed. No ECG abnormalities or new hypokinetic or akinetic area were highlighted at the post-operative echocardiogram. No differences were recorded in terms of stroke, intensive care unit and hospital length of stay, and peri-operative mortality . Two patp = 0.030), while no differences were found in the release of myocardial markers, lactates levels and need for inotropic support at different time-points after surgery . The area under the curve for cTn-T has demonstrated excellent linear relationship with the mass of myocardial injury; the area under the curve for CK-MB is also good, although clearly inferior to cTn-T  the TTC setting was predominantly used; in case of aorto-iliac-femoral arteries disease, an antegrade arterial perfusion with TTC was preferred , 19, 20.Results of the present study are in contrast with reports of other centers showing superiority of the TTC. Mazine et al., in a retrospective analysis on 243 patients undergoing right mini-thoracotomy MV surgery and EAC or TTC concluded that the TTC setting results in better myocardial protection . Howeverp = 0.05)  . The impThe single-center non-randomized study design is clearly the main limitation. However, the reason for not performing a prospective randomized clinical trial was driven by our consolidated practice in minimally invasive surgery based on a tailored approach for each patient. Moreover, the propensity matched analysis reached a suboptimal balance between groups regarding age, previous cardiac surgery, and mean pressure during CPB. Standardized difference for these variables widely reduced after matching, even if it still remains above 0.2: this can be explain considering that in our every-day clinical practice the EAC is the preferred setting in redo cases and in young patients without atheromatous disease. Furthermore, with the EAC setting the mean pressure during CPB is more accurately verified and persistently kept low than 60–65 mmHg because it is one of the determinant factors in maintaining the right position of the balloon during the clamping time; this gives reasons for the different mean CPB pressure recorded between the two groups. It must be said that, from a clinical point of view, there are no differences between 60 and 62 mmHg.Despite concerns arising about the EAC, this prospective study shows equivalence in terms of myocardial protection of the EAC compared with the TTC in patients undergoing right mini-thoracotomy MV surgery.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Institutional Ethics Committee Città della Salute e della Scienza - Torino (protocol number 0095187). The patients/participants provided their written informed consent to participate in this study.CB and MR: conceptualization. CB and DR: methodology. CF: software. MR, MB, MP, and GM: validation. CB and CF: formal analysis. ES, CC, and VS: investigation and data curation. CB: writing-original draft preparation and writing-review and editing. MR: supervision and project administration. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Joint replacement surgeries are one of the most frequent medical interventions globally. Infections of prosthetic joints are a major health challenge and typically require prolonged or even indefinite antibiotic treatment. As multidrug-resistant pathogens continue to rise globally, novel diagnostics are critical to ensure appropriate treatment and help with prosthetic joint infections (PJI) management. To this end, recent studies have shown the potential of molecular methods such as next-generation sequencing to complement established phenotypic, culture-based methods. Together with advanced bioinformatics approaches, next-generation sequencing can provide comprehensive information on pathogen identity as well as antimicrobial susceptibility, potentially enabling rapid diagnosis and targeted therapy of PJIs. In this review, we summarize current developments in next generation sequencing based predictive antibiotic susceptibility testing and discuss potential and limitations for common PJI pathogens. The number of prosthetic joints implanted increases as people live longer and have greater aspirations for maintaining mobility . In GermWith the evolution and increased accessibility of next-generation sequencing (NGS), infectious disease testing using NGS-based methods is becoming a viable option in clinical settings for a variety of applications ,8. NGS eIn this review, we discuss current approaches towards NGS based predictive AST, exemplified on common PJI pathogens, and the potential and limitations of sequencing-based methods for the management of PJIs.Symptoms of PJI are often unspecific and potentially hard to distinguish from aseptic prosthesis failure . ClinicaResistance status is typically determined via AST by microbiology culture using broth microdilution or disk diffusion, which are considered the standard reference methods . Both me® PCR cartridge on 97 patients with aseptic or septic, hip or knee revision surgery, and obtained an overall accuracy of 91.8% [® Bone and Joint Infection was evaluated by Graue et al. on 1544 patient samples and the obtained overall sensitivity was 90.2% and specificity was 99.8% [®, that uses a combined approach of PCR and sequencing for infection diagnosis and management for periprosthetic joint infection [To help with the situation, PCR-based methods targeting known antimicrobial resistance (AMR) marker genes are increasingly used in diagnostic settings. While limited in their applicability by the number of resistance-related genes targeted by the PCR panel, performance for well-defined use cases has been encouraging. PCR-based techniques are independent from bacterial culture and operate directly on patient samples, decreasing turn-around times to a few hours ,16. Lausof 91.8% . BioFireas 99.8% . Recentlnfection .Streptococcus pneumoniae [With the falling cost of genome sequencing, NGS-based diagnostics are becoming attractive, that may be able to address limitations of current AST and PCR techniques . Specieseumoniae ,24. In ceumoniae .To shorten turn-around-time by circumventing microbial culture, NGS-based identification and predictive AST (pAST) might also be performed directly on native patient material. While direct sequencing of native patient samples may suffer from high human background compared to isolated microbial DNA, enrichment methods prior to sequencing  can reduce the host background. A capture enrichment panel, for example, includes a selection of probes that target sequences such as AMR markers and the library size can be several orders of magnitude higher compared to PCR panels, allowing for more information to be captured, e.g., for pAST ,27. EnriOf note, with recent technologies such as the Oxford Nanopore Technology (ONT) platform, that sequence single DNA or RNA molecules with minimal sample preparation, additional approaches to target enrichment and direct sequencing are becoming available. ONT also allows for live result streaming for analysis and depending on the sequencer being used, only requires little bench space. Identification and predictive AST by ONT sequencing may further reduce turn-around-time . DiffereSeveral approaches exist for the prediction of antimicrobial susceptibility profiles from genomic data. We find that it is useful to group methods by (a) their decision algorithm and (b) their internal representation of NGS data. In this section we motivate these distinctions and introduce several key concepts of pAST as well as machine learning (ML).vanHAX resistance cassette in an enterococcal isolate may cause calling of vancomycin resistance by a rule-based method, due to the known mechanistic link of the gene products with resistance [Firstly, computational methods for pAST differ fundamentally by how resistance is determined, separating methods into rule-based or model-based. For rule-based methods, a set of rules derived by expert curation is applied to each sample, ultimately yielding the predicted resistance status. Commonly used rules pertain to the presence or absence of validated AMR resistance markers ,29. For sistance .vanA gene, due to the strong association of the gene with vancomycin resistance in the training set samples. Many ML algorithms have been devised, each differing in their internal strategy for optimizing prediction accuracy [With model-based methods, a ML model is trained on a set of samples with known resistance status to learn correlations between numerical representations of the training data and resistance status. When the trained model is then applied to samples with unknown resistance status, it returns a prediction according to the correlations learned on the training sample set. As such, an ML model trained on a training set of enterococcal isolates may report high confidence of vancomycin resistance to a sample encoding the accuracy . Severalaccuracy ,32. Otheaccuracy ,33.Both rule-based and model-based pAST methods must be validated to ensure prediction accuracy. This is achieved by applying the method to test datasets not involved in method development and scoring predictions against reference AST measurements. ML methods are also commonly validated by splitting a single dataset into the training and test dataset, either once or repeatedly in a cross-validation scheme . ClinicaA second useful distinction between pAST methods is the way the input data is structured for prediction, grouping methods into gene- and sequence-centric ones. Gene-centric methods use bioinformatics tools to annotate features like protein coding sequences, rRNA and ncRNA sequences, as well as other relevant genomic aspects in the input NGS data. In the most straight-forward case, the set of features may be restricted to established AMR marker genes or single nucleotide polymorphisms (SNPs) known to cause resistance to the compound in question. Several databases such as CARD or ResFinder curate AMR marker information and several bioinformatics tools can detect known AMR markers with high sensitivity ,40. The Conversely, sequence-centric methods utilize NGS data to make predictions without prior annotation of defined biological entities like genes and intergenic regions. Instead, input NGS data is commonly represented as the presence, absence, or abundance of so-called k-mers (DNA sequences with k base pairs) . This reIn general, pAST methods must be tailored to and evaluated on a taxon- and compound-specific basis . For rulStaphylococcus aureus is the leading causative agent of PJI [t of PJI . It can t of PJI .S. aureus is a promising target for predictive AST applications. As a high-impact human pathogen responsible for a range of diseases, S. aureus pathogenicity is well-studied and many NGS datasets relating to it are published, benefitting the development of pAST techniques [S. aureus can acquire resistance mechanisms through horizontal gene transfer (HGT), leading to the emergence of highly virulent and resistant strains [chniques . The smachniques . S. aure strains . NeverthS. aureus has been demonstrated by multiple publications. In a sequence of landmark papers, Gordon et al. (2014) and Bradley et al. (2015) investigated prediction of resistance from NGS data using a curated panel of plasmid-borne resistance markers and SNPs associated with AMR [The relative ease of in-silico prediction of antimicrobial resistance for with AMR ,49. Resiwith AMR . Bradleywith AMR . Davis ewith AMR . Taken twith AMR ,51.S. aureus, and few datasets suitable for machine learning are available [S. aureus from CoNS species, but do not expand upon resistance prediction in the latter [S. aureus, marker-based pAST methods developed for S. aureus may exhibit some level of predictiveness for CoNS [Staphylococcus, and broad multi-resistance as well as resistance to second line of defense drugs such as vancomycin is common in CoNS infections [The second major group of staphylococci known to cause PJI are coagulase-negative staphylococci (CoNS). This diverse group of human commensals and opportunistic pathogens is commonly encountered both in early-onset and late-onset PJI. Significantly less is known about virulence mechanisms and epidemiology of CoNS as compared to vailable . This lie latter . As resifor CoNS . CoNS hafections . This shEscherichia coli, Klebsiella spp. and Enterobacter spp. as well as Pseudomonas spp. [Another significant group of human pathogens in the context of PJI is Gram-negative bacilli. Commonly identified causative agents include nas spp. ,56. Ciprnas spp. ,57.E. coli and Klebsiella pneumoniae isolates. This proof-of-concept study affirmed the possibility of NGS-based AST for Gram-negative bacteria, reporting excellent performance with 96% sensitivity and specificity in both species [K. pneumoniae isolates collected from a Houston hospital system, Nguyen et al. (2018) trained gradient boosting tree ML models on DNA 10-mer representations of assembled genomes [Despite functional similarities in resistance mechanisms, predictive performance varies substantially with pathogen species, antibiotic class and, in the case of ML-based methods, with the number of training samples. Early work by Stoesser et al. (2013) used rule-based classification by sequence alignment of assemblies to published AMR markers, followed by manual expert curation of hits to classify a small set of  species . Subsequ species ,60. Rece genomes . This me genomes . Similar genomes ,51.Pseudomonas aeruginosa is a special case among Gram-negative pathogens in the context of pAST. It is difficult to make accurate AMR predictions for relevant antibiotic compounds in this pathogen, with reported sensitivity and/or specificity metrics of around 80% for many compounds  describe a tool which matches sequence data to a database of published S. pneumoniae strains, inferring resistance from database strains most closely related to the given sample. Using this technique, 91% sensitivity and 100% specificity were achieved for five clinically relevant antimicrobial compounds [S. pneumoniae specifically [Streptococcal species most associated with PJI belong to the beta-hemolytic group B and G streptococci . Little ompounds . The extifically . The obtifically ,51.As with streptococci, enterococcal pathogens constitute a minor fraction of PJIs (<5% of PJI cases) but are likewise identified with early-onset virulent cases .vanA/B resistance gene cluster enabled both a DNA k-mer based as well as an AMR marker-based pAST approach to achieve high predictive accuracies of >98%, and performance measures were obtained for several other compounds using an AMR marker-based approach (see Overall, published performance measures of pAST applied to enterococcal pathogens are encouraging. The strong determination of vancomycin resistance by the presence of the oach see  [28,38,5Algorithmic advances and an increase in number and size of datasets linking genotype and resistance phenotypes have led to significant improvements in the performance of pAST methods over the last years. However, some challenges remain unsolved, some unique to PJI.Recently published pAST methods use machine learning to correlate resistance phenotypes with sequencing data. However, ML method development may suffer from several properties inherent to biological data . For exaS. aureus shows that, in principle, marker-based methods can enable highly accurate and generalizable pAST for compounds with clearly delineated and fully understood resistance mechanisms [Methods operating on data representations informed by biology can avoid some of the problems arising with sequence-centric methods. Depending on the chosen representation, data dimensionality can be significantly lower, reducing the impact of overfitting in the case of ML models. For rule-based methods, a small number of hand-curated AMR markers with published causal relation to the phenotype are employed in the decision process. This allows for increased confidence in the validity of predictions. Nevertheless, there are pitfalls even with rule-based pAST that rely on validated AMR determinants. Work on chanisms . Howeverchanisms . This sechanisms .Beyond algorithmic and data representation aspects, a large fraction of PJI cases is caused by organisms that cannot readily be identified by microbiology culture to begin with. Resistance calling from culture-negative and multi-species PJI cases via clinical metagenomics is thus one of the promises of predictive AST. However, most of the methods reviewed here were developed and benchmarked on NGS data derived from cultured bacterial isolates, and transferability to metagenomics data is unclear: as most pAST methods are taxon-specific, binning of sequencing reads by pathogen taxon is necessary. Several discussed methods also require input data to be assembled into draft genomes. De novo assembly from metagenomic sequencing data however requires significantly higher read depth than assembly from isolate sequencing and introduces a host of additional biases . Even meStaphylococcus aureus, pAST can achieve overall performance congruent with FDA guidelines for AST testing devices, using well-understood AMR marker-based methods. For several other groups of pathogens, including the most impactful enterococci and Gram-negative bacilli, several relevant resistance phenotypes can be resolved by pAST. Pseudomonas aeruginosa is an outlier in the Gram-negative group, likely requiring significant additional theoretical groundwork to enable accuracies approaching FDA guidelines. Finally, for coagulase-negative staphylococci and beta-hemolytic streptococci, no conclusive statements can be made due to a lack of published data relating to the effectiveness of pAST.Compiling and contrasting pAST performances for common PJI pathogens, we find notable performance variance across species, compounds, and computational approaches. For With the increasing availability of NGS technology for species identification in the clinic, we expect that rule-based pAST methods targeting staphylococci may be among the first to enter clinical practice for PJI pathogens. Methods targeting most other organisms will likely require broader sampling of representative training data sets to improve and validate ML models, as well as additional study of resistance mechanisms to complement AMR marker databases.


The five-year survival rate of childhood cancer has increased substantially over the past 50 yr; however, racial/ethnic disparities in health outcomes of survival have not been systematically reviewed. This scoping review summarized health disparities between racial/ethnic minorities  and non-Hispanic White childhood cancer survivors, and elucidated factors that may explain disparities in health outcomes. We used the terms “race”, “ethnicity”, “childhood cancer”, “pediatric cancer”, and “survivor” to search the title and abstract for the articles published in PubMed and Scopus from inception to February 2021. After removing duplicates, 189 articles were screened, and 23 empirical articles were included in this review study. All study populations were from North America, and the mean distribution of race/ethnicity was 6.9% for non-Hispanic Black and 4.5% for Hispanic. Health outcomes were categorized as healthcare utilization, patient-reported outcomes, chronic health conditions, and survival status. We found robust evidence of racial/ethnic disparities over four domains of health outcomes. However, health disparities were explained by clinical factors , demographic , individual-level socioeconomic status , family-level SES , neighborhood-level SES , and lifestyle health risk  in some but not all articles. We discuss the importance of collecting comprehensive social determinants of racial/ethnic disparities inclusive of individual-level, family-level, and neighborhood-level SES. We suggest integrating these variables into healthcare systems , and utilizing information technology and analytics to better understand the disparity gap for racial/ethnic minorities of childhood cancer survivors. Furthermore, we suggest national and local efforts to close the gap through improving health insurance access, education and transportation aid, racial-culture-specific social learning interventions, and diversity informed training. The shifting racial/ethnic makeup of the population indicates that in as early as 2045 the United States (US) will become a “minority majority population” country . By 2060Health equity is considered one of the four basic human rights , yet detper se  is a stronger determinant of health outcomes than race per se . Others per se  or populper se  contribuper se . Disadvaper se .The main objective of this study was to summarize the evidence of racial/ethnic disparities in health outcomes for survivors of childhood cancer based on a scoping review of previously published literature. We focused on race/ethnicity as the primary variable determining disparities in health outcomes, and viewed SES factors as confounding or mediating variables that explain the associations between race/ethnicity and health outcomes. This is because the vast majority of the studies selected are based on the cross-sectional design, and the true effect of SES factors on health outcomes cannot be determined . Specifically, we aimed to elucidate the role that personal/family/community-level SES factors alongside other demographic and clinical factors might play to explain the associations between race/ethnicity and health outcomes. Based on these findings, we made recommendations toward improving health disparities for minority childhood cancer survivors, especially by identifying modifiable social determinants of health using information technology, integrating social determinant information into healthcare systems, and suggesting potential interventions for health outcomes improvement.In line with our aims, a scoping review was performed to aggregate evidence from empirical studies. Scoping reviews are particularly useful for complex/diverse issues  such as We performed a literature search process according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) . Two indTwo independent investigators screened the articles for inclusion if these articles included the following criteria: health disparity (i.e. difference in outcome based on race/ethnicity), health outcomes/late effects, and any age range of the survivorship stage. We excluded articles if they met the following criteria: not reporting health outcomes/late effects (90 articles), race/ethnicity listed but only in descriptive statistics (64 articles), no full-text available (4 articles), and absence of IRB approval or otherwise proof of rigor . In addition, two Swiss articles were removed from subsequent review because they did not include non-Hispanic Black or Hispanic survivors. We included two articles that use the term “non-White”  into our review.We extracted data from each article according to the study design, race/ethnicity, health outcomes, and risk modulators of racial/ethnic disparity in health outcomes. We focused on marginalized/minoritized . US cateWe classified health outcomes of childhood cancer survivors by four distinct categories: (1) healthcare utilization, (2) patient-reported outcomes, (3) chronic health conditions, and (4) survival rates. For counting health outcomes of interest, if studies reported outcomes in more than one category, these studies were listed in different, separate outcome categories. Healthcare utilization outcomes included the concept of healthcare self-efficacy, initial and follow-up care visits, contact with general or cancer-specific healthcare providers, and use of hospital services. Patient-reported outcomes included the concept of health-related quality of life, symptom presence or severity, adaptive functioning, and post-traumatic stress. Chronic health conditions represented individual health conditions  or organ system-based condition groups . Survival outcomes were categorized as all-cause or condition-specific survival rates. In addition, we reported the factors used to explain racial/ethnic disparities in health outcomes per the rationale of the articles or statistical modeling process .Five articles reported racial/ethnic disparities in healthcare utilization . The typIn two articles, inclusion of individual characteristics and individual-/family-level SES in multivariable modeling attenuated the statistical significance for racial/ethnic disparities in healthcare utilization. Specifically, in an odds-ratio model, inclusion of individual-level and family-level SES and individual characteristics (cancer diagnosis and age at the time of study) removed statistical significance of the disparity in general medical contact among non-Hispanic Black male survivors . SimilarNine articles have reported racial/ethnic disparities in patient-reported outcomes . The typIn two articles, inclusion of individual characteristics and SES in multivariable modeling attenuated the significance for racial/ethnic disparities in patient-reported outcomes. Specifically, inclusion of cancer diagnosis, individual-level SES and age at study participation removed the significance for adverse mental health outcomes among non-Hispanic Black females . SimilarFive articles reported racial/ethnic disparities in chronic health conditions . The typIn two articles, inclusion of clinical factors, individual characteristics, and SES in the modeling attenuated the significance for racial/ethnic disparities in chronic health condition. Specifically, one article found that inclusion of clinical factors, individual characteristics, and SES factors removed the significance of disparity in subsequent neoplasms for non-Hispanic Black survivors . AnotherFive articles reported racial/ethnic disparities in survival rates . Type ofIn two articles, inclusion of clinical and SES factors attenuated the significance for racial/ethnic disparities in survival outcomes. Specifically, one article found that inclusion of census-tract  SES removed the significance of death hazard for non-Hispanic Black survivors diagnosed with astrocytoma and non-astrocytoma CNS tumor, but not acute myeloid leukemia . AnotherCompared to non-Hispanic White, non-Hispanic Black and Hispanic childhood cancer survivors suffer more from poorer health outcomes including healthcare utilization, patient-reported outcomes, chronic health conditions and survival rate. While there is an effect of race/ethnicity on health outcomes for childhood cancer survivors; there is not yet enough evidence to determine the true effect of SES across all outcomes given the cross-sectional design of previous studies. The current findings do show that embedded in race and ethnicity are a multitude of factors at the clinical , individual , and neighborhood  levels that may explain some of the disparities and poor health outcomes. However, the magnitude of racial/ethnic disparities changed in some but not all studies after adjusting for these risk modulators. As such, we see a complex interplay among these risk factors for health disparities. Future research is warranted to elucidate the complex associations between racial/ethnic and SES factors and health outcomes for childhood cancer survivors.Potential risk modulators that explained the associations between race/ethnicity and health outcomes attempted in all articles were reviewed. Risk modulators commonly reported for healthcare utilization disparity included individual-level SES , 28. SocBhatia et al. argues that the “burden of morbidity and mortality [between races] is comparable because mortality is mitigated by SES” , 46; howIn addition to improving SES measurement for childhood cancer research, it is important to use a holistic and life-course approach to investigating risk of health disparities. Williams , 51 suggRisk modulators that substantially impact health outcomes of individual childhood cancer survivors were SES, healthcare accessibility, and health insurance. Several studies suggested that neighborhood-level SES , individOur findings highlight that individual-level factors, such as culture , 34, 37 There is an opportunity to leverage health information technology to promote health equity for minority and underserved populations , 61. EmeImproving medical informatics infrastructure within healthcare systems can facilitate the collection and assessment of social determinants of health data for cancer survivors on a regular-basis and integrate social determinant information into clinical decision-making process. Incorporating neighborhood-/community-level social determinant data into electronic health records (EHRs) will allow clinicians to provide tailored interventions that are clinically actionable based on the survivors' need and contextual influence. Given the big data stored in EHRs, the use of artificial intelligence analytics  can help identify complex social determinants for individual minority survivors. Recent evidence suggests that implementation of machine learning approaches helps identify the patterns of social determinants for impaired health outcomes with superior performance compared to the use of traditional analytics .While this scoping review provides useful information for racial/ethnic disparities in health outcomes among childhood cancer survivors, the findings should be carefully interpreted. First, race/ethnicity data from all articles were self-reported. Self-reported race/ethnicity information is often arbitrary and poorly defined . FurtherThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.JB and I-CH: concept and design. MH and LR: administrative support. TR and TM: collection and assembly of data. TR, TM, and I-CH: data analysis and interpretation. TR and I-CH: manuscript writing. All authors editing and final approval of manuscript. All authors contributed to the article and approved the submitted version.The research reported in this manuscript was supported by the National Cancer Institute under award number R01CA238368  and V-Foundation Robin Roberts Cancer Thrivership Fund under award number DT2020-014 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: The 2019 coronavirus disease (COVID-19) outbreak has put the global health system under the spotlight. As part of the medical workforce, nurses play an important role in interacting with and caring for patients; hence, patient-centered communication (PCC) has been emphasized in nursing education. Thus, it is worth investigating how future nurses perceive PCC and PCC-related factors under the special circumstances of COVID-19. For this purpose, the present study analyzed the mechanisms underlying the association between self-efficacy and nurse–patient communication tendency through learning burnout among nursing students during the COVID-19 pandemic.Methods: The general self-efficacy questionnaire, college students' learning burnout scale, and doctor–patient communication tendency scale were used to survey 2,231 nursing students in higher vocational medical colleges at the onset of the COVID-19 pandemic.Results: General self-efficacy can directly negatively correlate with the degree of nursing students' overall nurse–patient communication, including caring, sharing, and health promotion. Dejection from learning burnout partially mediated the relationships between self-efficacy and caring and between self-efficacy and sharing; it fully mediated the relationship between self-efficacy and health promotion. Reduced personal accomplishment partially mediated between self-efficacy and caring, while it fully mediated between self-efficacy and health promotion; however, it did not play a role in the sharing model.Conclusion: Self-efficacy influences nurse–patient communication through learning burnout. Specifically, dejection and reduced personal accomplishment—two aspects of learning burnout—may compromise nursing students' willingness to engage in PCC. Thus, the importance of PCC, especially during critical health situations such as pandemics, should be emphasized further in future nursing education. On March 11, 2020, the World Health Organization declared the outbreak of the 2019 coronavirus disease (COVID-19) a pandemic . To ensuIn the past decades, nurse–patient communication in China was described as patriarchal and characterized by health-worker-centered communication . PatientPCC is a type of nurse–patient communication proposed by Balint in the 1960s. It contrasts with the “illness-oriented medicine” approach, which supports the biological method in patient care . The nurSelf-efficacy is an individual's confidence in their ability to accomplish certain goals . A recenLearning burnout is a concept derived from job burnout. It refers to students' negative attitude and behavior toward learning caused by learning pressure or lack of interest . LearninMeanwhile, learning burnout may impact nursing students' attitudes toward nurse–patient communication. One study by Williams et al.  establisThis study aimed to explore the mechanisms of the relationship between self-efficacy and nurse–patient communication tendency among nursing students during the COVID-19 pandemic and further uncover the mediating role of learning burnout therein see . By consH1: Self-efficacy positively predicts nurse–patient communication tendency; that is, the higher the self-efficacy is, the stronger the PCC tendency will be, and vice versa.H2: Self-efficacy negatively predicts learning burnout; that is, the higher the self-efficacy is, the lower the learning burnout will be, and vice versa.H3: Learning burnout mediates the relationship between self-efficacy and nurse–patient communication tendency.SD = 1.51).For this study, 2,272 nursing students from a higher vocational medical college in Fujian Province were recruited. Forty-one participants were excluded due to incomplete questionnaires. The remaining 2,231 questionnaires, 119 of which were from male participants and 2,112 from female participants, were valid for data analysis. This sample consisted of 705 freshmen, 755 sophomores, and 771 juniors with a mean age of 20.49 years (www.wjx.cn). All participants completed the survey voluntarily and anonymously.The survey was distributed to the nursing students in February 2020, when the COVID-19 pandemic began to unfold in China. In compliance with the quarantine requirements, we conducted the survey online via a Chinese survey website —suggesting that common method bias was unlikely to confound the interpretations of our results .The average score for general self-efficacy was 2.74, slightly above the median level (Median = 2.5), while the results of learning burnout showed that the averages of improper behavior, dejection, and reduced personal accomplishment were below the median level (Median = 3). The results of nurse–patient communication tendency showed that the health promotion and care scores were above the median level, while those of sharing were below it (Median = 3.5). An overview of the correlation coefficients between all variables is presented in To understand how self-efficacy and learning burnout influence nurse–patient communication tendency, mediation analysis was performed for three separate dimensions  after controlling the sociodemographic variables such as gender and grades. For each mediation analysis, 5,000 bootstrap samples were created to establish a 95% bias-corrected confidence interval for the expected indirect associations.t = −12.75, P < 0.001), improper behavior , reduced personal accomplishment , and caring  and reduced personal accomplishment  had a direct predictive effect on caring. Self-efficacy indirectly predicted caring through the mediating effect of dejection  and reduced personal accomplishment . Self-efficacy had a significant direct effect on caring . However, the total effect of this model was not significant .The results showed that self-efficacy had a significant direct predictive effect on dejection , improper behavior , reduced personal accomplishment , and sharing . Self-efficacy showed a significant direct effect on sharing  and a significant indirect effect on sharing through the mediation of dejection . The total effect of this mediation model was significant .Self-efficacy had a significant direct effect on dejection , improper behavior , and reduced personal accomplishment  but no effect on health promotion  and reduced personal accomplishment  had a direct effect on health promotion. Self-efficacy showed a significant indirect effect on health promotion through the mediation of dejection  and reduced personal accomplishment . The total effect of this mediation model was significant .Self-efficacy had a significant direct effect on dejection .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Chimeric antigen receptor (CAR) T-cells (CAR T-cells) are a promising therapeutic approach in treating hematological malignancies. CAR T-cells represent engineered autologous T-cells, expressing a synthetic CAR, targeting tumor-associated antigens (TAAs) independent of major histocompatibility complex (MHC) presentation. The most common target is CD19 on B-cells, predominantly used for the treatment of lymphoma and acute lymphocytic leukemia (ALL), leading to approval of five different CAR T-cell therapies for clinical application. Despite encouraging clinical results, treatment of other hematological malignancies such as acute myeloid leukemia (AML) remains difficult. In this review, we focus especially on CAR T-cell application in different hematological malignancies as well as strategies for overcoming CAR T-cell dysfunction and increasing their efficacy. In cell-mediated immune responses, T-lymphocytes (T-cells) play a pivotal role in surveilling and eliminating tumor cells or pre-malignant cells. If T-cell activity is impeded, cancer can develop . Since mUntil today, CAR T-cell therapy is mainly performed in the context of hematological malignancies, but an increasing number of trials are also conducted in solid tumor patients  . In the In multiple myeloma, malignant plasma cells accumulate in the bone marrow repressing normal hematopoietic cell production and further repressing osteoblast function . This leAML is a disease of the myeloid blood cell lineage arising mostly from genetic or epigenetic changes affecting normal blood cell production in the bone marrow . BesidesAntigen recognition is a crucial point in CAR T-cell therapy since many patients experience a relapse because the tumor cells become negative to the target antigen. Conversely, off-target cross reactivity in CAR T-cell therapy is still a problem. Hence, a major challenge is to improve the antigen recognition and specificity of CAR T-cells. Bispecific CAR T-cells recognize two or more tumor associated antigens simultaneously, for example, CD19 and CD20 . FurtherFor lymphoma and ALL, CAR T-cell therapy has shown remarkable results in treating patients, but for CLL for example, results are not as promising . TherefoMonoclonal antibodies used for cancer treatment either target tumor-associated antigens to induce cytotoxicity or are used to block receptor–ligand interactions. In this regard, immune checkpoint inhibitors are antibodies that block the inhibitory T-cell receptor CTLA-4 (Ipilimumab) or PD-1 (Pembrolizumab), which leads to reactivation of silenced cancer-specific T-cells ,70. As CDrugs smaller than 500 Daltons targeting distinct molecule portions are considered as small molecule inhibitors. Due to their size they are able to pass through the cell membrane to act intracellularly, antagonizing different pathways correlated with cancer development . TyrosinOncolytic viruses target and eliminate tumor cells without damaging healthy tissue in two different ways. Firstly, through a direct attack, in which the virus infects and enters the cells, leading to cell lysis. Secondly, through expression of viral antigens in infected cancer cells, which leads to their subsequent recognition and destruction by cytolytic T-cells . This prCytokines can tremendously influence T-cell function such as expansion, persistence and effector activity. In addition to the engineered co-expression of cytokines in CAR T-cells discussed in Toxic effects frequently accompany curative effects of a CAR T-cell therapy. The most frequent side effect is the cytokine release storm (CRS), where excessive release of cytokines is triggered by CAR T-cell activation, proliferation and enhanced killing, manifesting in a broad range of clinical symptoms such as fever, tachycardia and pyrexia or even death . TocilizImmunotherapy and especially CAR T-cell therapy has demonstrated outstanding response rates in subgroups of patients with hematological malignancies, leading to emergence of CAR T-cells as a major breakthrough in cancer immunotherapy. Furthermore, the fifth CAR T-cell therapy has been approved by the FDA (Breyanzi), underlining that CAR T-cells have become a valid therapy option for refractory blood cancer and points to the promising potential of this therapy approach. However, in some hematological malignancies, response rates are low and patients still relapse. Additionally, for some hematological malignancies such as Richter syndrome, data is still very thin with only a low number of patients enrolled in clinical studies so far. In addition, adverse events frequently accompany CAR T cell therapy, showing that this therapeutic approach still needs to be optimized in regard to safety and efficacy. However, so far, four out of the five FDA-approved CAR T cell drugs target CD19  and only one targets a different antigen . Comparing these drugs with the expanding list of targets currently investigated in many clinical studies gives confidence that the number of approved CAR T constructs as well as the list of targets are still growing. This is particularly important as suitable targets for some entities such as AML are still missing. Aside from the quest for novel targets, a large panel of innovative approaches are expected to markedly improve CAR T cell therapy, which have been discussed in this review and comprise the development of bispecific CAR T cells, improved CAR constructs, genetic modification of CAR T cells and combination treatments with other drugs. Regarding all these technical possibilities, it is expected that the next generation of CAR T cells will hopefully serve as a safe and highly effective weapon to fight hematological malignancies.


Background: Cognitive impairment is one of the most prominent non-motor symptoms in Parkinson's disease (PD), due in part to known cerebellar dysfunctions. Furthermore, previous studies have reported altered cerebellar functional connectivity (FC) in PD patients. Yet whether these changes are also due to the cognitive deficits in PD remain unclear.Methods: A total of 122 non-dementia participants, including 64 patients with early PD and 58 age- and gender-matched elderly controls were stratified into four groups based on their cognitive status . Cerebellar volumetry and FC were investigated by analyzing, respectively, structural and resting-state functional MRI data among groups using quality control and quantitative measures. Correlation analysis between MRI metrics and clinical features (motor and cognitive scores) were performed.Results: Compared to healthy control subjects with no cognitive deficits, altered cerebellar FC were observed in early PD participants with both motor and cognitive deficits, but not in PD patients with normal cognition, nor elderly subjects showing signs of a cognitive impairment. Moreover, connectivity between the “motor” cerebellum and SMA was positively correlated with motor scores, while intracerebellar connectivity was positively correlated with cognitive scores in PD patients with cognitive impairment. No cerebellar volumetric difference was observed between groups.Conclusions: These findings show that altered cerebellar FC during resting state in early PD patients may be driven not solely by the motor deficits, but by cognitive deficits as well, hence highlighting the interplay between motor and cognitive functioning, and possibly reflecting compensatory mechanisms, in the early PD. Parkinson's disease (PD) is the most common neurodegenerative movement disorder characterized clinically by classical motor features including bradykinesia, rigidity, tremor, and postural instability. Yet this disease is also known to lead to a wide range of non-motor symptoms , 2. IndeNumerous studies have repeatedly suggested that the human cerebellum is not solely processing motor information but also contributes to cognitive functions , 17. TheIn the current study, cerebellar FC was thus investigated in rs-fMRI data, and both “motor” and “cognitive” cerebellar regions were defined as seeds to shed light on the contributions of motor and cognitive function to the cerebellar connectivity in a group of PD participants in their early phase of disease. We hypothesized that the change of cerebellar FC in early PD was related to both the patients' motor and cognitive deficits. To test this hypothesis, we restricted our recruitment to the early stage of PD patients without dementia, and compared their performance and FC to those of matched elderly control participants. In particular, we stratified the participants into four groups based on their cognitive status: (1) matched elderly control subjects with normal cognition (EC-NC); (2) matched elderly control subjects with evidence of cognitive impairment (EC-CI); (3) PD patients with motor deficits but normal cognitive abilities (PD-NC); and (4) PD patients with both motor and cognitive deficits (PD-CI). Cerebellar gray matter (GM) volumes and seed-to-whole brain connectivity were then, respectively, compared between normal controls and participants with either motor or cognitive deficits alone, or with both types of deficits.DSM-V)  clinical diagnostic criteria . In ordeDemographic information including date of birth, sex, educational level and cognitive scores, as well as PD clinical characteristics, was obtained. The total daily levodopa equivalent dosage was also calculated for each patient. Specifically, 11 patients were newly diagnosed and unmedicated, while the other 55 patients were either given L-DOPA monotherapy, a dopaminergic agonist, a monoamine oxidase inhibitor, L-DOPA plus entacapone, or a combination of these medications. To minimize the effects of medication on our pattern of results, all clinical measurements and MRI data in all patients were assessed or acquired while they were “off” medication .Mood was assessed using the 17-item Hamilton Rating Scale for Depression (HAMD), and thus, no participants with signs of depression were included in this study (HAMD scores <13) . The par3 isotropic, duration = 313 s]. By contrast, resting-state fMRI data were acquired using a standard gradient-echo echo-planar sequence . During the resting-state scan, individuals were instructed to keep their eyes closed and relax, but to stay awake. All structural brain MR images were checked for quality control, and subjects exhibiting abnormal brain structures were excluded from the study.MRI scans were performed on a 3T MR scanner  with a standard 12-channel head coil. The foam padding was used to restrict head motion. High-resolution anatomic images were acquired with a 3D T1-weighted magnetization prepared rapid acquisition gradient echo (MPRAGE) scan [TR = 2,530 ms, TE = 2.98 ms, 192 sagittal slices, slice thickness = 1.0 mm, no gap, field of view (FOV) = 224 × 256 mm, voxel size of 1 mmhttp://www.fil.ion.ucl.ac.uk/spm) and running under MATLAB (R2017a) . All images were parallel-aligned to the anterior commissure–posterior commissure line and kept left-posterior-inferior orientation before segmenting the cerebellum. These high-resolution T1 images were then used to isolate the cerebellum from the rest of the brain and normalized to the SUIT template using a non-linear deformation. The outputs were visually inspected for accuracy, and manual edits as well as reprocessing were performed if needed. The gray matter volume of each cerebellar anatomic subdivision from the SUIT probabilistic atlas  correction for multiple comparisons.Image segmentation of the cerebellum was performed using the Spatially Unbiased Infratentorial Template toolbox (SUIT Version 3.3) implemented in Statistical Parametric Mapping, version 12  running under MATLAB (R2014b) (The Math-Works Inc.) (A subsample of participants from the study (43 elderly controls and 50 PD patients) completed an rs-fMRI scan and underwent resting-state functional connectivity analysis. Preprocessing and analyses of resting-state data were conducted using REST plus software  . The preks Inc.) . Visual http://www.restfmri.net), and Monte Carlo simulations were performed to control Type I error  masks were created based on the SUIT probabilistic atlas  and resampled, respectively . The timt-test and/or analysis of variance (ANOVA) for continuous variables. The threshold used for statistical significance was set with Bonferroni corrected p-value < 0.05 .To compare the demographic and clinical characteristics of the study participants, we performed chi-square test for categorical variables and two-sample Student t-test based on the cognitive (EC-CI vs. EC-NC), motor (PD-NC vs. EC-NC) or combined status with both cognitive and motor functions . To control for the potentially confounding effect of disease severity between PD patients with different levels of cognitive functioning, the disease duration and UPDRS motor scores were adjusted as covariables while comparing the cerebellar FC between PD-NC and PD-CI groups. Multiple comparisons were corrected for volumetric analyses (FDR correction) and cerebellar FC analyses (AlphaSim correction).Statistical analyses of the imaging data were carried out using the SPM12 and REST Plus software. One-way ANOVA was used to compare differences among the four study groups . Furthermore, stratification analyses were conducted using two-sample p < 0.05 (two-tailed). The effect size estimate for two-group comparisons and the correlation analyses were measured by Cohen's d, which was implemented in GPower 3.1 (https://www.psychologie.hhu.de/).ROIs/clusters that were significantly different based upon morphometric and FC analysis were extracted for correlation analyses with clinical features. Pearson correlations were thus used to explore the association between the cerebellar GM volumes and FC with cognitive (MoCA scores) and motor (UPDRS-III scores) functions. Correlation analyses were carried out using SPSS version 21 and statistical thresholds were set at After quality control measurements, structural imaging from 122 participants  and resting-state functional imaging from 86 participants  were analyzed. See There was no significant difference in overall cerebellar lobular gray matter volume between the four different participant groups after correcting for multiple comparisons . Both thThe results of the “motor” and “cognitive” cerebellum to whole-brain functional connectivity in the group of elderly controls with normal cognition are shown in F = 11.848, df = 3, p < 0.001; 59 voxels, F = 13.305, df = 3, p < 0.001; one significant cluster for CBMm FC: 101 voxels, F = 11.869, df = 3, p < 0.001). Further stratification analyses revealed that, compared to the healthy elderly control group, no significant difference in cerebellar FC was observed in groups with motor deficits alone (PD-NC vs. EC-NC) or with cognitive deficits alone (EC-CI vs. EC-NC). With combined motor and cognitive status, the PD-CI group revealed significant cerebellar functional connectivity compared to the EC-NC, EC-CI, and PD-NC groups  as well as with the right putamen and right caudate . In comparison to the EC-CI group, patients with PD-CI showed significantly greater CBMm connectivity with the right putamen and right caudate . Finally, when compared with the PD-NC, patients with PD-CI showed significantly weaker connectivity between CBMc and left cerebellar VI and VIIb regions (CBMc-LC) , and the pattern of the results remained the same while adjusted by disease duration and the motor scores.ANOVA analyses on rs-fMRI data among the four groups of participants showed significant group differences in both “motor” and “cognitive” cerebellum to whole-brain functional connectivity , but not those in the groups of early PD patients with normal cognition, nor elderly controls with cognitive impairment. These findings indicate that as assessed through activity at rest, the cerebellar FC may be involved in coping with both motor and cognitive demands, hence shedding additional light on our understanding of the pathophysiology of cognitive deficits in early-stage PD patients.No significant differences among groups were observed in cerebellar lobular GM volume, nor in the results based upon the voxel-based morphometry analysis. Previous studies between patients with PD and healthy controls have shown inconsistent results on GM volumes, partly due to factors like disease duration and clinical stage . In lineCompared to healthy controls, other researchers have reported that PD patients do reveal differences with regard to their level of cerebellar FC, ranging from no significant changes , 34 to sTwo previous studies have assessed the “motor” and “cognitive” cerebellar FC in patients with PD during resting state , 43. OneAdditionally, a meta-analysis of task-related fMRI studies has emphasized that the cerebellum plays a significant role in the level of cognitive functioning in PD . MoreoveWe found that the “motor” cerebellar-SMA connectivity was positively correlated with motor scores, while the negative intracerebellar connectivity (CBMc-LC) was positively correlated with the cognitive scores in PD patients with cognitive impairment. The latter findings suggest that the cerebellar FC may be implicated in the integration of motor and cognitive functions in the early-stage PD. However, the major pathological hallmarks of PD, α-synuclein deposition with Lewy bodies, are conspicuously absent in the cerebellum. Moreover, no significant atrophy in the cerebellum was observed in this study. Hence, we suggest that the altered cerebellar FC in PD-CI could be secondary to pathophysiology such as neurotransmitter dysfunction due to the dopaminergic depletion in early PD .per se, but are also related to cognitive deficits in this group of patients, our study contains some limitations that should be considered. First, to focus on the early PD and minimize the effect of medication, we restricted our patients with H&Y ≤ 2 and scanned in the “OFF” medication phase. Thus, the results cannot be generalized to all situations. Second, one may concern about the sample size of the current study. The Cohen's d was provided to estimate the effect size. The results demonstrated large effect size for the group comparisons and moderate effect size for the correlation analyses. However, the weak diffuse effects should also be considered and validation studies are needed in the future (Despite the fact that we demonstrate that the cerebellar/brain FC alterations observed in PD patients are not due to motor deficits e future , 48. ThiIn conclusion, the present study demonstrates the existence of cerebellar FC changes in the resting state in early PD patients with cognitive impairment, and that these alterations in cerebellar FC correlate with both the motor UPDRS and cognitive MoCA scores. Our findings suggest that these changes in cerebellar FC may constitute an underlying compensatory mechanism for cognitive deficits in PD patients, hence indicating the interplay between motor and cognitive functioning in the early stage of PD. Yet future investigations focusing of longitudinal changes in cerebellar functional connectivity during the deterioration in cognitive functioning in PD patients are needed to provide additional insights into the interplay of motor and cognitive deficits in this neurological disorder.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Ethic Review Committee of the Xuanwu Hospital of Capital Medical University. The patients/participants provided their written informed consent to participate in this study.XD, TW, and PC conceived and designed the project. JS, LG, YZ, and JM collected the data of subjects. XD and YH analyzed the data. XD, JD, TW, and PC wrote and reviewed the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.