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Chimeric antigen receptor (CAR) T cell therapy in glioblastoma faces many challenges including insufficient CAR T cell abundance and antigen-negative tumor cells evading targeting. Unfortunately, preclinical studies evaluating CAR T cells in glioblastoma focus on tumor models that express a single antigen, use immunocompromised animals, and/or pre-treat with lymphodepleting agents. While lymphodepletion enhances CAR T cell efficacy, it diminishes the endogenous immune system that has the potential for tumor eradication. Here, we engineered CAR T cells to express IL7 and/or Flt3L in 50% EGFRvIII-positive and -negative orthotopic tumors pre-conditioned with non-lymphodepleting irradiation. IL7 and IL7 Flt3L CAR T cells increased intratumoral CAR T cell abundance seven days after treatment. IL7 co-expression with Flt3L modestly increased conventional dendritic cells as well as the CD103+XCR1+ population known to have migratory and antigen cross-presenting capabilities. Treatment with IL7 or IL7 Flt3L CAR T cells improved overall survival to 67% and 50%, respectively, compared to 9% survival with conventional or Flt3L CAR T cells. We concluded that CAR T cells modified to express IL7 enhanced CAR T cell abundance and improved overall survival in EGFRvIII heterogeneous tumors pre-conditioned with non-lymphodepleting irradiation. Potentially IL7 or IL7 Flt3L CAR T cells can provide new opportunities to combine CAR T cells with other immunotherapies for the treatment of glioblastoma.

Background In Ireland, over 53,000 older adults are supported in their community by formal home support, amounting to an estimated 19 million care hours annually. There is a growing need to move beyond care, to more proactive approaches to maintain physical function. In a feasibility study, we delivered the ‘Care to Move’ (CTM) programme through existing home support services. The aim of the present qualitative study was to explore the experience and perceptions of Health Care Assistants (HCAs), who were trained in, and delivered the CTM programme. Methods We conducted semi-structured telephone interviews with 22 HCAs involved in the delivery of the programme among older adults [n = 35, mean age 82.8 (7.8) years]. Interview transcripts were coded and analysed thematically to capture barriers and facilitators to programme delivery. Results Barriers and facilitators were identified under three main themes i) the programme ii) the care setting, iii) the clients. Overall, there was a positive perception of the programme’s focus on ‘movement prompts and motivators’, the ‘fit’ within home support services, and the training provided. Practical challenges of limited time and the task-orientation nature of home support were reported as recurring barriers for CTM. Many HCAs commented on the value and perceived positive benefits of the programme for their clients. Though negative perceptions of older adult’s motivation or ability to engage with physical activity also emerged. Risk, such as injury or pain, was identified but was not a dominant theme. Conclusion Our preliminary findings suggest that embedding physical activity initiatives within home support services could be feasible. Restructuring of services, engaging HCAs, and moving beyond traditional ‘task-oriented' care models to more personalised proactive approaches may facilitate this initiative and support ageing in place.

Background Physical activity programmes have been shown to improve older adults’ functional capacity, independence and quality of life. Research around structured exercise programmes has been completed in different groups of community-dwelling older people, however few studies have focused on the older population receiving formal home care. In a feasibility study, we embedded physical activity within older adults existing home care services through the ‘Care to Move’ (CTM) programme. The aim of this qualitative study is to explore older adults’ experiences of the CTM programme. Methods We conducted semi-structured telephone interviews with 13 older adults and one carer. Topics covered included participants overall experiences of the CTM programme, changes to their overall activity and participation, aspects of the programme that they liked or found valuable and issues that they found challenging. Interview transcripts were coded and analysed thematically to capture barriers and facilitators to programme delivery. Results Four themes emerged: i) ‘I’m feeling good about it’, ii) ‘safety and security is the name of the game’, iii) ‘we’re a team as it stands’, iv) ‘it’s [COVID] depressing for everybody at the moment’. Older adults identified benefits of CTM participation including improvements in physical and psychological wellbeing. However, frailty and multimorbidity influenced overall engagement. Participants expressed concerns around the logistics of programme delivery and competing healthcare assistant (HCA) interests. The broader role of HCA’s in supporting the CTM programme was highlighted as well as the emotional support that HCAs provided to older adults. HCA continuity was identified as a barrier to ongoing programme engagement. The impact of COVID on older adults physical and mental health negatively impacted programme delivery. Conclusion Our findings suggest that embedding the CTM programme within home support services is feasible. Restructuring of services, addressing HCA continuity, and adopting individual approaches to programme delivery may enhance the implementation of services.

DNA topoisomerases regulate the topological state of DNA, relaxing DNA supercoils and resolving catenanes and knots that result from biologic processes, such as transcription and replication. DNA topoisomerase II (TOP2) enzymes achieve this by binding DNA and introducing an enzyme-bridged DNA double-strand break (DSB) where each protomer of the dimeric enzyme is covalently attached to the 5' end of the cleaved DNA via an active site tyrosine phosphodiester linkage. The enzyme then passes a second DNA duplex through the DNA break, before religation and release of the enzyme. However, this activity is potentially hazardous to the cell, as failure to complete religation leads to persistent TOP2 protein-DNA covalent complexes, which are cytotoxic. Indeed, this property of topoisomerase has been exploited in cancer therapy in the form of topoisomerase poisons which block the religation stage of the reaction cycle, leading to an accumulation of topoisomerase-DNA adducts. A number of parallel cellular processes have been identified that lead to removal of these covalent TOP2-DNA complexes, facilitating repair of the resulting protein-free DSB by standard DNA repair pathways. These pathways presumably arose to repair spontaneous stalled or poisoned TOP2-DNA complexes, but understanding their mechanisms also has implications for cancer therapy, particularly resistance to anti-cancer TOP2 poisons and the genotoxic side effects of these drugs. Here, we review recent progress in the understanding of the processing of TOP2 DNA covalent complexes, the basic components and mechanisms, as well as the additional layer of complexity posed by the post-translational modifications that modulate these pathways. SIGNIFICANCE STATEMENT: Multiple pathways have been reported for removal and repair of TOP2-DNA covalent complexes to ensure the timely and efficient repair of TOP2-DNA covalent adducts to protect the genome. Post-translational modifications, such as ubiquitination and SUMOylation, are involved in the regulation of TOP2-DNA complex repair. Small molecule inhibitors of these post-translational modifications may help to improve outcomes of TOP2 poison chemotherapy, for example by increasing TOP2 poison cytotoxicity and reducing genotoxicity, but this remains to be determined.

ImportanceThe use of nonphysician practitioners (NPPs) in the emergency department (ED) continues to expand, yet little is known about associations between NPPs and ED imaging use.ObjectiveTo investigate whether the state share of ED visits for which an NPP was the clinician of record is associated with imaging studies ordered, given that state NPP share is associated with state-level NPP scopes of practice.Design, Setting, and ParticipantsThis cross-sectional study compared diagnostic imaging ordering patterns associated with ED visits based on 2005-2020 Medicare claims for a nationally representative 5% sample of fee-for-service beneficiaries. For all 50 states and the District of Columbia, the state NPP share of ED visits by year was used to represent state-specific practice patterns for NPPs and physicians and how those patterns have evolved over time. The analysis controlled for patient demographic characteristics, Charlson Comorbidity Index scores, ED visit severity, year, and principal diagnosis.ExposuresThe share of ED visits in each state in each year (state share) for which an NPP was the evaluation and management clinician.Main Outcomes and MeasuresThe main outcomes were the number and modality of imaging studies associated with ED visits. Analyses were by logistic regression and generalized linear model with γ-distribution and log-link function.ResultsAmong 16 922 274 ED visits, 60.0% involved women, and patients’ mean (SD) age was 70.3 (16.1) years. The share of all ED visits with an NPP as the clinician increased from 6.1% in 2005 to 16.6% in 2020. Compared with no NPPs, the presence of NPPs in the ED was associated with 5.3% (95% CI, 5.1%-5.5%) more imaging studies per ED visit, including a 3.4% (95% CI, 3.2%-3.5%) greater likelihood of any imaging order per ED visit and 2.2% (95% CI, 2.0%-2.3%) more imaging studies ordered per visit involving imaging.Conclusions and RelevanceIn this study, use of NPPs in the ED was associated with higher imaging use compared with the use of only physicians in the ED. Although expanded use of NPPs in the ED may improve patient access, the costs and radiation exposure associated with more imaging warrants additional study.

Background Sarcopenia, frailty, and malnutrition are known determinants of adverse health outcomes. Adults of advanced age, with functional dependency, socioeconomic disadvantage, or a need for home care, are expected to be at high risk of these conditions yet are likely to be underrepresented in research. We aimed to examine the feasibility and preliminary outcomes of conducting home-based assessments in this group. Methods Home-based health assessments were conducted among older adults (n= 31), in receipt of state-funded home care. Assessments included probable sarcopenia [hand-grip strength (HGS), chair rise-test and SARC-F case-finding tool] in line with the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) guidelines, the Mini Nutritional Assessment (MNA), and the Clinical Frailty Scale (CFS). Results The study group was of mean age 83.2 ± 8.2 years, 74% female, 23% lived in socioeconomically disadvantaged areas, had comorbidities (n=30, 97%) and low physical activity (71%). We found that almost all met the criteria for probable sarcopenia (94%, 29/31), most were frail or vulnerable by CFA (97%, 30/31), and over a quarter were at risk of malnutrition (26%, n=8). In all participants, it was feasible to assess sarcopenia (by HGS and SARC-F, but not chair rise test), malnutrition (MNA), and frailty (CFS). Notably, in-home assessments required additional time, the adaptation of assessment tools, responsibility to address issues arising, including signposting to health services (36%, n=11), and navigating complex psychosocial environments; the latter was commonly observed in areas of socioeconomic disadvantage. Conclusion Assessing sarcopenia, frailty, and malnutrition in community-dwelling dependant older adults in-home was feasible, once potential challenges were considered. Moreover, our findings suggest that most participants were at risk of both sarcopenia and frailty, and over a quarter were at risk of malnutrition. This highlights a need for further research and proactive evidence-based multi-modal community interventions to support ageing in place.

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) can cause the life-threatening acute respiratory disease called COVID-19 (Coronavirus Disease 2019) as well as debilitating multiorgan dysfunction that persists after the initial viral phase has resolved. Long COVID or Post-Acute Sequelae of COVID-19 (PASC) is manifested by a variety of symptoms, including fatigue, dyspnea, arthralgia, myalgia, heart palpitations, and memory issues sometimes affecting between 30% and 75% of recovering COVID-19 patients. However, little is known about the mechanisms causing Long COVID and there are no widely accepted treatments or therapeutics. After introducing the clinical aspects of acute COVID-19 and Long COVID in humans, we summarize the work in animals (mice, Syrian hamsters, ferrets, and nonhuman primates (NHPs)) to model human COVID-19. The virology, pathology, immune responses, and multiorgan involvement are explored. Additionally, any studies investigating time points longer than 14 days post infection (pi) are highlighted for insight into possible long-term disease characteristics. Finally, we discuss how the models can be leveraged for treatment evaluation, including pharmacological agents that are currently in human clinical trials for treating Long COVID. The establishment of a recognized Long COVID preclinical model representing the human condition would allow the identification of mechanisms causing disease as well as serve as a vehicle for evaluating potential therapeutics.

DNA topoisomerase II (TOP2) poisons induce protein-DNA crosslinks termed TOP2-DNA covalent complexes, in which TOP2 remains covalently bound to each end of an enzyme-induced double-strand DNA break (DSB) via a 5'-phosphotyrosyl bond. Repair of the enzyme-induced DSB first requires the removal of the TOP2 protein adduct, which, among other mechanisms, can be accomplished through the proteasomal degradation of TOP2. VCP/p97 is a AAA ATPase that utilizes energy from ATP hydrolysis to unfold protein substrates, which can facilitate proteasomal degradation by extracting target proteins from certain cellular structures (such as chromatin) and/or by aiding their translocation into the proteolytic core of the proteasome. In this study, we show that inhibition of VCP/p97 leads to the prolonged accumulation of etoposide-induced TOP2A and TOP2B complexes in a manner that is epistatic with the proteasomal pathway. VCP/p97 inhibition also reduces the etoposide-induced phosphorylation of histone H2A.X, indicative of fewer DSBs. This suggests that VCP/p97 is required for the proteasomal degradation of TOP2-DNA covalent complexes and is thus likely to be an important mediator of DSB repair after treatment with a TOP2 poison. SIGNIFICANCE STATEMENT: TOP2 poisons are chemotherapeutic agents used in the treatment of a range of cancers. A better understanding of how TOP2 poison-induced DNA damage is repaired could improve therapy with TOP2 poisons by increasing TOP2 poison cytotoxicity and reducing genotoxicity. The results presented herein suggest that repair of TOP2-DNA covalent complexes involves the protein segregase VCP/p97.

[Background] Irrespective of initial treatment for congenital heart disease (CHD) in childhood, CHD is a lifelong condition, leaving patients at risk for complications. To support uninterrupted, age- and development-based care for young persons with CHD, guidelines and consensus papers emphasise the need for formal transition programmes, including transfer to adult CHD (ACHD) clinics. Here, we surveyed existing transfer and transition programmes in European ACHD centres. Our aims were to provide a contemporary view of transitional care for patients with CHD and to evaluate progress over the last decade., [Methods] We conducted a descriptive, cross-sectional survey in 96 ACHD centres in Europe. A specific survey form was developed that sampled the practices of transfer and/or transition. We used a transfer-transition index to quantify adherence to quality indicators of successful transfer and transition., [Results] Of the 96 ACHD centres, 40 (41.7%) offered a formal transition, and 85 (88.5%) had structured transfer from paediatric to ACHD care. Although 31% of the centres performed at a ‘good’ level on the transfer-transition index, only 4 (4.2%) satisfied all criteria. Most centres with a transition programme offered education and support through a dedicated transition specialist, who was a master's-prepared nurse in most centres. A minority of the ACHD centres offered a flexible transition process, starting at least two years before transfer., [Conclusions] Nearly half of the included ACHD centres offered a formal transition programme, and almost 90% offered structured transfer. Despite some improvements since 2009, most of the programmes lacked an age- and development-based approach., This work was supported by the ESC Working Group on Grown-Up Congenital Heart Disease www.escardio.org/Working-groups/Working-Group-on-Adult-Congenital-Heart-Disease/About

Value co-creation for service innovations involves integrating inputs from multiple actors within service ecosystems. Traditionally, value co-creation has been considered in light of business-to-consumer (B2C) interactions. The emergence of digital information platforms allowing consumer-to-consumer (C2C) communications is changing how service ecosystems establish and create value for service innovations. In this paper, we develop a Digital Information Flow Continuum that includes B2C, external provider and consumer co-created (B2C/C2C combined) and C2C digital communications. Using Service-Dominant Logic (SDL), we assess the impact digital information flow elements have on the perceptions and usage likelihood for telemedicine (TM) services. We use structural equation modeling to analyze online survey results from 827 health consumers collected as part of a healthcare organization’s TM launch. The results demonstrate that the Digital Information Flow Continuum impacts the acceptance of the TM innovation directly, and indirectly through value perceptions of comparable service quality relative to alternatives and ease of access to care.

BackgroundPatients with Fontan circulation are known to be at high risk for developing atrial tachyarrhythmias (AAs). Our objective was to examine the efficacy and safety of amiodarone in the management of ATs in adult Fontan patients.MethodsPrimary outcomes of this single-centre, retrospective study included freedom from AAs and incidence of adverse effects of amiodarone on Fontan patients. Heart failure (HF) events and composite outcomes of death from any cause, Fontan revision and heart transplantation were evaluated as secondary outcomes. Predictors of HF and discontinuing amiodarone were also evaluated.ResultsA total of 61 patients (mean age 31.6±11.3 years, 40.9% female), who were treated with amiodarone in between 1995 and 2018, were included. AAs free survival at 1, 3 and 5 years were 76.2%, 56.9% and 30.6%, respectively. During a median follow-up of 50.5 months, 34 (55.7%) patients developed side effects, and 20 (32.8%) patients discontinued amiodarone due to side effects. Thyroid dysfunction was the most common side effect (n=26, 76.5%), amiodarone-induced thyrotoxicosis (AIT) (n=16, 27.1%) being most common thyroid dysfunction. Young age (age ConclusionsShort-term efficacy of amiodarone in Fontan physiology is acceptable. However, long-term administration is associated with a reduction of efficacy and a significant prevalence of non-cardiac side effects. AIT is associated with exacerbation of HF. The judicious use of amiodarone administration should be considered in this population.

Family studies can provide a wealth of information regarding risk factors in psychological disorders. No studies have compared the trauma experiences and coping strategies of problem gamblers with those of their first-degree relatives. Therefore, in this study, childhood trauma and coping strategies were investigated among participants with gambling disorder, their first-degree biological relatives, and community controls. Participants completed diagnostic interviews and symptom severity assessments. Participants also completed the Childhood Trauma Questionnaire (CTQ) which assesses history of abuse and neglect, and the Coping Inventory for Stressful Situations (CISS) which assesses task, emotion, and avoidance oriented coping strategies. Analysis of variance showed that there was a significant effect for group, but not gender, on the CTQ. Multivariate analysis of variance revealed a significant effect for group on coping style. Post-hoc tests showed that probands and relatives were less likely to use task-oriented coping compared to controls, but probands and relatives did not differ from each other on task-oriented coping. Mediation analysis showed that task-oriented coping did not mediate the relation between childhood trauma and gambling severity. By using a family study design, this study was able for the first time to delineate familial and disease-specific effects associated with childhood trauma and coping strategies in gambling disorder.

DNA topoisomerase II (TOP2) is required for the unwinding and decatenation of DNA through the induction of an enzyme-linked double-strand break (DSB) in one DNA molecule and passage of another intact DNA duplex through the break. Anticancer drugs targeting TOP2 (TOP2 poisons) prevent religation of the DSB and stabilize a normally transient intermediate of the TOP2 reaction mechanism called the TOP2-DNA covalent complex. Subsequently, TOP2 remains covalently bound to each end of the enzyme-bridged DSB, which cannot be repaired until TOP2 is removed from the DNA. One removal mechanism involves the proteasomal degradation of the TOP2 protein, leading to the liberation of a protein-free DSB. Proteasomal degradation is often regulated by protein ubiquitination, and here we show that inhibition of ubiquitin-activating enzymes reduces the processing of TOP2A- and TOP2B-DNA complexes. Depletion or inhibition of ubiquitin-activating enzymes indicated that ubiquitination was required for the liberation of etoposide-induced protein-free DSBs and is therefore an important layer of regulation in the repair of TOP2 poison-induced DNA damage. TOP2-DNA complexes stabilized by etoposide were shown to be conjugated to ubiquitin, and this was reduced by inhibition or depletion of ubiquitin-activating enzymes. SIGNIFICANCE STATEMENT: There is currently great clinical interest in the ubiquitin-proteasome system and ongoing development of specific inhibitors. The results in this paper show that the therapeutic cytotoxicity of DNA topoisomerase II (TOP2) poisons can be enhanced through combination therapy with ubiquitin-activating enzyme inhibitors or by specific inhibition of the BMI/RING1A ubiquitin ligase, which would lead to increased cellular accumulation or persistence of TOP2-DNA complexes.

Background Pregnant women with mechanical heart valves are at significant risk of obstetric/cardiac complications. This study compares the anticoagulation management in two obstetric cardiac centres. Methods Retrospective case-note review from Chelsea and Westminster/Royal Brompton Hospitals (CR) and Erasmus Medical Centre (EMC). Main outcome measure was mechanical heart valve thrombosis. Results Nineteen pregnancies from CR and 25 pregnancies from EMC were included. Most women were on low-molecular-weight heparin (LMWH) throughout pregnancy at CR, whereas at EMC most had LMWH in the first trimester and vitamin K antagonists in subsequent trimesters. Peak anti-factor Xa were performed monthly at CR, levels 0.39–1.51 IU/mL (mean 0.82 IU/mL). Anticoagulation management peri-partum was inconsistent. Delivery was mainly by caesarean section at CR (74%) and vaginal delivery at EMC (64%). No maternal deaths and only one mechanical heart valve thrombosis at CR. Two mechanical heart valve thromboses and one maternal death at EMC. Conclusion Peri-partum anticoagulation strategies, anticoagulation monitoring and mode of delivery inconsistencies reported.

Sarcopenia is characterized by the accelerated loss of muscle strength, mass, and function in aging. The disease is a major public health issue with emerging evidence of a disproportionate burden in areas of socioeconomic disadvantage.To estimate the prevalence of probable sarcopenia overall, and according to Socioeconomic Position (SEP). To explore the association between markers of SEP and probable sarcopenia.Cross-sectional analysis of the English Longitudinal Study of Ageing data.England, United Kingdom (UK).This study comprised 6,052 older adult participants from Wave 6 of the English Longitudinal Study of Ageing (ELSA) aged 60 years and older.Probable sarcopenia was identified by the EWGSOP2 guidelines as low hand grip strength (females16kg and males27kg) or poor chair rise test performance (completion of 5 chair rises15 seconds). Socioeconomic position was defined by educational attainment and subjective social status (SSS). Weighted multivariable regression analysis was employed to identify determinants of probable sarcopenia.Over one-third of older adults met the criteria for probable sarcopenia (33.7%; weighted, 36.1%) in the study population of mean age 70.7 (SD 7.7) years. When examined by SEP, the prevalence of probable sarcopenia was over 2-fold higher in adults in the most vs the least disadvantaged SEP groups (47.0% vs 20.6%, respectively, p0.001). Multivariable regression analysis identified disadvantaged SEP, as measured by educational attainment and SSS, as independent predictors of probable sarcopenia, along with older age, physical inactivity, underweight BMI, chronic conditions, osteoarthritis, and minority group ethnicity.Disadvantaged SEP was associated with an increased likelihood of probable sarcopenia when controlled for other known risk factors. The findings suggest a need and opportunity for sarcopenia prevention and treatment strategies to address socioeconomic disadvantage in policies and practice.