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ImportanceThe administration of a high fraction of oxygen following return of spontaneous circulation in out-of-hospital cardiac arrest may increase reperfusion brain injury.ObjectiveTo determine whether targeting a lower oxygen saturation in the early phase of postresuscitation care for out-of-hospital cardiac arrest improves survival at hospital discharge.Design, Setting, and ParticipantsThis multicenter, parallel-group, randomized clinical trial included unconscious adults with return of spontaneous circulation and a peripheral oxygen saturation (Spo2) of at least 95% while receiving 100% oxygen. The trial was conducted in 2 emergency medical services and 15 hospitals in Victoria and South Australia, Australia, between December 11, 2017, and August 11, 2020, with data collection from ambulance and hospital medical records (final follow-up date, August 25, 2021). The trial enrolled 428 of a planned 1416 patients.InterventionsPatients were randomized by paramedics to receive oxygen titration to achieve an oxygen saturation of either 90% to 94% (intervention; n = 216) or 98% to 100% (standard care; n = 212) until arrival in the intensive care unit.Main Outcomes and MeasuresThe primary outcome was survival to hospital discharge. There were 9 secondary outcomes collected, including hypoxic episodes (Spo2 ResultsThe trial was stopped early due to the COVID-19 pandemic. Of the 428 patients who were randomized, 425 were included in the primary analysis (median age, 65.5 years; 100 [23.5%] women) and all completed the trial. Overall, 82 of 214 patients (38.3%) in the intervention group survived to hospital discharge compared with 101 of 211 (47.9%) in the standard care group (difference, −9.6% [95% CI, −18.9% to −0.2%]; unadjusted odds ratio, 0.68 [95% CI, 0.46-1.00]; P = .05). Of the 9 prespecified secondary outcomes collected during hospital stay, 8 showed no significant difference. A hypoxic episode prior to intensive care was observed in 31.3% (n = 67) of participants in the intervention group and 16.1% (n = 34) in the standard care group (difference, 15.2% [95% CI, 7.2%-23.1%]; OR, 2.37 [95% CI, 1.49-3.79]; P Conclusions and RelevanceAmong patients achieving return of spontaneous circulation after out-of-hospital cardiac arrest, targeting an oxygen saturation of 90% to 94%, compared with 98% to 100%, until admission to the intensive care unit did not significantly improve survival to hospital discharge. Although the trial is limited by early termination due to the COVID-19 pandemic, the findings do not support use of an oxygen saturation target of 90% to 94% in the out-of-hospital setting after resuscitation from cardiac arrest.Trial RegistrationClinicalTrials.gov Identifier: NCT03138005

BACKGROUND In March 2020, New Zealand was plunged into its first nationwide lockdown to halt the spread of COVID-19. Our team rapidly adapted our existing chatbot platform to create Aroha - a wellbeing chatbot intended to address the stress experienced by young people aged 13-24 in the early phase of the pandemic. Aroha was made available nationally within two weeks of the lockdown and continued to be available throughout 2020. OBJECTIVE To evaluate the acceptability and relevance of the chatbot format and Aroha’s content in young adults and to identify areas for improvement. METHODS We conducted qualitative in-depth and semi-structured interviews with young adults, as well as in situ demonstrations of Aroha to elicit immediate feedback. Interviews were recorded transcribed and analyzed using thematic analysis assisted by NVivo. RESULTS 15 young adults (median age 20 years, M = 20.07, SD = 3.17; 13 female, two male; all tertiary students) were interviewed in person. Participants spoke of the challenges of living through the lockdown, including social isolation, loss of motivation, and the demands of remote work/study – though some were able to find silver linings. Aroha was well liked for sounding like a ‘real person’ and peer with its friendly, local ‘Kiwi’ communication style, rather than an authoritative adult or counselor. The chatbot was praised for including content that went beyond traditional mental health advice. Participants particularly enjoyed the modules on gratitude, getting active, anger management, job-seeking, and how to deal with alcohol and drugs. Aroha was described as being more accessible than traditional mental health counselling and resources. It was an appealing option for those who did not want to talk to someone in person for fear of the stigma associated with mental health. On the other hand, participants dislike software bugs. They also wanted a more sophisticated conversational interface where they could express themselves and “vent” in free text. There were several suggestions for how to make Aroha more relevant to a diverse range of users, including developing content on navigating relationships and diverse chatbot avatars. CONCLUSIONS Chatbots are an acceptable format to scale up the delivery of public mental health and wellbeing-enhancing strategies. We make the following recommendations for others interested in designing and rolling out mental health chatbots to better support young people: 1) Make the chatbot relatable to its target audience by working with them to develop an authentic and relevant communication style; 2) Consider including holistic health and lifestyle content beyond traditional “mental health”; 3) Focus on developing features that make users feel heard, understood, and empowered CLINICALTRIAL

Study Design: Retrospective cohort study. Objective: The purpose of the study was to compare early complication, morbidity and mortality risks associated with fusion surgery crossing the cervico-thoracic junction in patients aged over 80 years undergoing combined anterior and posterior approach versus a posterior-only approach. Methods: We retrospectively identified octogenarian patients with myelopathy who underwent fusion crossing the cervico-thoracic junction. Patient demographics, Nurick score, surgical characteristics, complications, hospital course, early outcome and 90-day mortality were collected. Comorbidities were classified using the age-adjusted Charlson Comorbidity Index (AACCI). Radiographic measurements for deformity correction included the C2-C7 sagittal Cobb angle, C2-7 sagittal vertical axis and T1 slope pre- and postoperatively. Results: Out of 8,521 surgically treated patients, 12 octogenarian patients had a combined anterior and posterior approach (AP group) and 14 were treated from posterior-only (P group). Mean age was 81.4 ± 1.2 and 82.5 ± 2.7 years, respectively. There was no significant difference in Nurick scores between the groups ( P > 0.05). The major complication risk in the AP group was significantly higher, requiring PEG tube placement due to severe dysphagia in 4 patients (33%) compared to none in the P group. A greater improvement in cervical lordosis could be achieved through a combined approach. The 90-day mortality risk was 8% for the AP group and 0% for the P group. Conclusions: A combined anterior and posterior approach is associated with a significantly higher major complication rate and can result in severe dysphagia requiring PEG tube placement in one-third of patients over 80 years of age.

BACKGROUND Before the COVID-19 pandemic, adolescents with type 1 diabetes (T1D) had already experienced far greater rates of psychological distress than their peers. With the pandemic further challenging mental health and increasing the barriers to maintaining optimal diabetes self-management, it is vital that this population has access to remotely deliverable, evidence-based interventions to improve psychological and diabetes outcomes. Chatbots, defined as digital conversational agents, offer these unique advantages, as well as the ability to engage in empathetic and personalized conversations 24-7. Building on previous work developing a self-compassion program for adolescents with T1D, a self-compassion chatbot (COMPASS) was developed for adolescents with T1D to address these concerns. However, the acceptability and potential clinical usability of a chatbot to deliver self-compassion coping tools to adolescents with T1D remained unknown. OBJECTIVE This qualitative study was designed to evaluate the acceptability and potential clinical utility of COMPASS among adolescents aged 12 to 16 years with T1D and diabetes health care professionals. METHODS Potential adolescent participants were recruited from previous participant lists, and on the web and in-clinic study flyers, whereas health care professionals were recruited via clinic emails and from diabetes research special interest groups. Qualitative Zoom (Zoom Video Communications, Inc) interviews exploring views on COMPASS were conducted with 19 adolescents (in 4 focus groups) and 11 diabetes health care professionals (in 2 focus groups and 6 individual interviews) from March 2022 to April 2022. Transcripts were analyzed using directed content analysis to examine the features and content of greatest importance to both groups. RESULTS Adolescents were broadly representative of the youth population living with T1D in Aotearoa (11/19, 58% female; 13/19, 68% Aotearoa New Zealand European; and 2/19, 11% Māori). Health care professionals represented a range of disciplines, including diabetes nurse specialists (3/11, 27%), health psychologists (3/11, 27%), dieticians (3/11, 27%), and endocrinologists (2/11, 18%). The findings offer insight into what adolescents with T1D and their health care professionals see as the shared advantages of COMPASS and desired future additions, such as personalization (mentioned by all 19 adolescents), self-management support (mentioned by 13/19, 68% of adolescents), clinical utility (mentioned by all 11 health care professionals), and breadth and flexibility of tools (mentioned by 10/11, 91% of health care professionals). CONCLUSIONS Early data suggest that COMPASS is acceptable, is relevant to common difficulties, and has clinical utility during the COVID-19 pandemic. However, shared desired features among both groups, including problem-solving and integration with diabetes technology to support self-management; creating a safe peer-to-peer sense of community; and broadening the representation of cultures, lived experience stories, and diabetes challenges, could further improve the potential of the chatbot. On the basis of these findings, COMPASS is currently being improved to be tested in a feasibility study.

Management of multiple sclerosis and neuroimmunologic disorders has become increasingly complex because of the expanding number of recognized neuroimmune disorders, increased number of therapeutic options, and multidisciplinary care management needs of people with multiple sclerosis and neuroimmunologic disorders. More subspecialists are needed to optimize care of these patients, and many fellowship programs have been created or expanded to increase the subspecialty workforce. Consequently, defining the scope and standardizing fellowship training is essential to ensure that trainees receive high-quality training. A workgroup was created to develop a consensus fellowship curriculum to serve as a resource for all current and future training programs. This curriculum may also serve as a basis for future accreditation efforts.

Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host-virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population.

There is a growing awareness that many children are not developing fast and accurate retrieval-based strategies for solving single-digit addition problems. In this study we individually assessed 16...

Understanding the properties of multiplication is a critical precursor to students’ thinking algebraically. However, these properties have not been the focus of extensive rigorous research, particularly the associative property. In this study, we report on follow-up interviews with 25 year 5–6 students who had completed five items taken from an assessment of mental computational fluency. This assessment required students to reason from the perspective of a fictional student (Emma), who had applied the associative property in various ways to solve multiplication problems. In the interviews, students had to explain their understanding of Emma’s thinking. Coding of this interview data revealed distinct continuums of understanding of each of the three applications of the associative property (noticing, doubling and halving, and place value), which teachers could use to inform their planning. The findings reveal that students best understood the noticing application, closely followed by doubling and halving. By contrast, the place value application was not well understood, which we attribute to students relying on truncation procedures applied with little or no conceptual understanding.

In Australia, student under-participation and disengagement in secondary mathematics classes are persistent problems. Academic help seeking is a unique self-regulated behaviour that is important for engagement in mathematics classes and yet many students avoid seeking help from teachers and peers as they progress through secondary school. The aim of this study was to explore the relationship between students’ perceptions of the social climate of their classrooms and their avoidance of help seeking in secondary mathematics classes. Students’ perceptions of classroom social climate, along with perceptions of their own academic and social self-efficacy, self-theories of intelligence, and help-seeking goals and intentions, were assessed for a sample of 551 Australian students in 47 classes from eight secondary schools and two vocational institutes. The measurement model for social climate was reduced to four factors (Task Orientation, Teacher Support, Cooperation and Investigation) and a mediated structural equation model, informed by theory and previous empirical studies, was assessed using Mplus. Bootstrap confidence intervals were used to assess the direct and indirect effects of social climate on help-seeking avoidance. Findings indicated that Task Orientation and Cooperation had a negative effect on help-seeking avoidance, while Investigation had a positive effect. Teacher Support was not associated with help-seeking avoidance. Implications for practice are discussed.

BACKGROUND The number of young people in New Zealand who experience mental health challenges is increasing. As New Zealand was going into its initial COVID-19 lockdown, an ongoing digital mental health project was adapted and underwent rapid content authoring to create the Aroha chatbot. This dynamic digital support was designed with and for young people to help manage pandemic-related worry. OBJECTIVE Aroha was developed to provide practical evidence-based tools for anxiety management using cognitive behavioral therapy, and positive psychology. The chatbot included practical ideas to maintain social and cultural connection, and to stay active and well. METHODS Stay at home orders under New Zealand’s lockdown commenced on 20 March 2020. By leveraging previously developed chatbot technology and broader existing online trial infrastructure, the Aroha chatbot was launched promptly on 7 April 2020. Dissemination of the chatbot for an open trial was via a URL, feedback on experience of the lockdown and on the experience of Aroha was gathered via online questionnaires, a focus group, and from community members. RESULTS In the two weeks following the launch of the chatbot there were 393 registrations and 238 users logged into the chatbot, of whom 127 were in the target age range (13-24 years). Feedback guided iterative and responsive content authoring to suit the dynamic situation and motivated engineering to dynamically detect and react to a range of conversational intents. CONCLUSIONS The experience of the implementation of the Aroha chatbot highlights the feasibility of providing timely event-specific digital mental health support, and the technology requirements for a flexible and enabling chatbot architectural framework.

BACKGROUND Up to 6 years after the 2011 Christchurch earthquakes, approximately one-third of parents in the Christchurch region reported difficulties managing the continuously high levels of distress their children were experiencing. In response, an app named Kākano was co-designed with parents to help them better support their children’s mental health. OBJECTIVE The objective of this study was to evaluate the acceptability, feasibility, and effectiveness of Kākano, a mobile parenting app to increase parental confidence in supporting children struggling with their mental health. METHODS A cluster-randomized delayed access controlled trial was carried out in the Christchurch region between July 2019 and January 2020. Parents were recruited through schools and block randomized to receive immediate or delayed access to Kākano. Participants were given access to the Kākano app for 4 weeks and encouraged to use it weekly. Web-based pre- and postintervention measurements were undertaken. RESULTS A total of 231 participants enrolled in the Kākano trial, with 205 (88.7%) participants completing baseline measures and being randomized (101 in the intervention group and 104 in the delayed access control group). Of these, 41 (20%) provided full outcome data, of which 19 (18.2%) were for delayed access and 21 (20.8%) were for the immediate Kākano intervention. Among those retained in the trial, there was a significant difference in the mean change between groups favoring Kākano in the brief parenting assessment (F1,39=7, P=.012) but not in the Short Warwick-Edinburgh Mental Well-being Scale (F1,39=2.9, P=.099), parenting self-efficacy (F1,39=0.1, P=.805), family cohesion (F1,39=0.4, P=.538), or parenting sense of confidence (F1,40=0.6, P=.457). Waitlisted participants who completed the app after the waitlist period showed similar trends for the outcome measures with significant changes in the brief assessment of parenting and the Short Warwick-Edinburgh Mental Well-being Scale. No relationship between the level of app usage and outcome was found. Although the app was designed with parents, the low rate of completion of the trial was disappointing. CONCLUSIONS Kākano is an app co-designed with parents to help manage their children’s mental health. There was a high rate of attrition, as is often seen in digital health interventions. However, for those who did complete the intervention, there was some indication of improved parental well-being and self-assessed parenting. Preliminary indications from this trial show that Kākano has promising acceptability, feasibility, and effectiveness, but further investigation is warranted. CLINICALTRIAL Australia New Zealand Clinical Trials Registry ACTRN12619001040156; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377824&isReview=true

Chimeric antigen receptor (CAR)-T cell therapies have promising outcomes in hematologic malignancies but limited activity in solid tumors. We used 3-dimentional (3D) in vitro human cell models of increasing complexity to investigate resistance to CAR-T cell therapy in high grade serous ovarian cancer (HGSOC), a disease with poor response to immunotherapy. We identified mucin-1 (MUC1) and TnMUC1 as target antigens in HGSOC omental metastasis and the HGSOC cell lines, OvCAR3 and G164. We then generated CAR-T cells against these targets and tested them in spheroids, collagen gels and microfluidic models. In spheroids, OvCAR3 cells were killed by CAR-T cells whereas, G164 cells were resistant to CAR-T cell cytotoxicity. RNA sequencing suggested that the impaired apoptotic signaling in G164 cells caused malignant cell-intrinsic resistance to CAR-T cell cytotoxicity. Treating G164 spheroids with birinapant, an antagonist of cellular inhibitor of apoptosis protein, induced CAR-T cell cytotoxicity. Moreover, when resistant cells were co-cultured as spheroids with primary omental fibroblasts from ovarian cancer patients, CAR-T cells were activated and cytotoxic. G164 spheroids cultured in fibroblast-conditioned medium also induced CAR-T cell cytotoxicity due to C-C motif chemokine ligand 2 (CCL2) produced by fibroblasts. CCL2 activated CCR2/4+ CAR-T cells to induce cytotoxicity in an antigen-dependent manner. We then investigated CAR-T cell migration and cytotoxicity in malignant cell/fibroblast co-culture collagen gels. CAR-T cell migrated into OvCAR3 gels and were cytotoxic against the malignant cells. However, a dense extracellular matrix (ECM) produced primarily by fibroblasts prevented CAR-T cell migration and cytotoxicity in G164 gels. Treating G164 gels with transforming growth factor beta (TGFβ) receptor inhibitor SB431542 reduced ECM content and altered ECM structure, thus stimulating CAR-T cell penetration and restoring cytotoxicity against G164 cells. We also developed an ovarian cancer-on-a-chip model which involved culturing cell-seeded collagen gels in vascularized tri-channel microfluidic devices. CAR-T cells successfully penetrated and killed malignant cells in co-culture collagen gels when delivered through vascularized microfluidic devices. To our knowledge, this is the first report to use microfluidic tumor models to successfully deliver CAR-T cells. Using these different human 3D in vitro models, we uncovered malignant cell-intrinsic factors and novel mechanisms involving fibroblasts which may influence CAR-T cell activity. Complex human cell models may accelerate preclinical research into CAR-T cell therapies in solid tumors. Citation Format: Joash Dominic Joy, Beatrice Malacrida, Florian Laforêts, Panoraia Kotantaki, Eleni Maniati, Sarah Hopkins, Ianire Garrobo-Calleja, Julien Gautrot, Frances Balkwill. 3D in vitro models uncover malignant cell intrinsic and extrinsic mechanisms of CAR-T cell resistance in high grade serous ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4576.

Introduction National guidelines suggest that patients in the last year of life should be identified, their prognosis and future care options discussed, with advance care planning (ACP) recorded. Goals-of-care should be discussed with hospitalised patients at risk of deteriorating or with life-limiting conditions. The stated purpose of ACP and goals-of-care discussions is to increase goal-concordant care (i.e. patients receiving treatments they would wish to receive, and not receiving those they would not want). This literature review investigates the evidence-base for these policies and outcomes. Review question What is the evidence for goals-of-care and ACP discussions with hospitalised frail older people? Methods Systematic literature review and narrative synthesis. Electronic search of MEDLINE, CINAHL, ASSIA, PsycINFO, and Embase databases from January 1990 to September 2017. An updated search until May 2019 is currently underway. Results Of 8077 unique articles identified, 17 met inclusion criteria. There is no evidence that goals-of-care discussions lead to increased goal-concordant care; there is observational evidence that they increase the accuracy of documented preferences. Currently, rates of goals-of-care discussions are variable (38-72%), and there is poor concordance between patients’ actual and documented preferences, with agreement in only 31-33% of cases. Present rates of ACP are very low (0-3%), with mixed evidence for benefits of ACP. One single-centre randomised controlled trial suggests ACP improves outcomes for patients who die within 6 months of discharge, including increased goal-concordant care and reduced family distress. There is very limited evidence concerning patients’ and family members’ experiences of these discussions, their reasons for wishing (or not) to participate in discussions, or their perceptions of the important outcomes. Most (80%) patients would like to be involved in decisions about their care; 48% consider these conversations very important. The views and experiences of healthcare professionals have been little studied. Conclusions The asserted aim of goals-of-care and ACP discussions is to increase goal-concordant care; the extent to which this reflects patients’ priorities is unknown. In younger patient populations, while 40% of patients consider goal-concordant care the most important outcome, one third of patients consider family-related outcomes to be more important. Further research is needed to understand the perspectives of frail older patients, their families and clinicians, in order to make these discussions and subsequent care truly patient-centred.

Introduction When a doctor is informed of a patient’s future care preferences if they were to lose capacity, there is an ethical and legal obligation to share this information with the treating medical team. In frail older patients, conversations about treatment preferences often occur during hospital admission. We sought to assess the communication of these preferences to the patient’s GP. Methods Retrospective chart review of consecutive discharges from acute geriatric wards across seven hospitals. Records were excluded if the patient was admitted for less than 48 hours, was under orthogeriatric care, or died in hospital. Results 339 notes were included, 41-50 from each hospital. GPs were informed of the resuscitation status of 28% of all patients. 52% of patients had an inpatient DNACPR, the GP was informed of 54% of these. 36% of patients had an inpatient ceiling of treatment documented, of which GPs were informed of 19%. 53% of hospital DNACPRs were converted into community DNACPRs on discharge: GPs were informed of only 24% of new community DNACRPs. 47% of patients discharged with a new community DNACPR lacked capacity to be involved in that decision; for just 6% of these was the GP asked to review the DNACPR order in the community. Inpatient Advance Care Planning (ACP) discussions were held for 9% of patients, of which the GP was informed in 59% of cases. 49% of ACP conversations involved the next-of-kin but not the patient. Among patients who had a new DNACPR decision made during their admission (n=124), there was documentary evidence in only 25% that the patient or next-of-kin was informed whether this was time-limited or indefinite. Conclusions Communication from hospitals to GPs about resuscitation, ceiling of care and ACP discussions is very limited. For patients who have expressed ongoing future care preferences, there is a legal obligation to share this information with the treating medical team, which on discharge is the GP. There is poor documentary evidence of discussions with patients about whether DNACPR decisions are time-limited or indefinite. Furthermore, many hospitalised frail patients lack capacity to make DNACPR decisions but they may subsequently regain capacity, particularly those with delirium. Despite this, GPs are rarely asked to review new community DNACPRs, including those made for patients without capacity.

Purpose Coeliac disease (CD) is a life-long condition requiring strict adherence to a gluten-free (GF) diet. Due to wide claims of availability and lower costs of gluten-free food (GFF) and clinical commissioning groups (CCGs) in England needing to save costs, access to prescriptions for patients with CD is being limited in England. The purpose of this paper is to investigate the availability and cost of GFF in an area where patients with CD have restricted access to prescriptions and to assess the nutritional composition of GFFs available in comparison with foods containing gluten (FCG). Design/methodology/approach Eight food categories that were representative of a range of commonly purchased GFFs were selected. Availability and cost of the cheapest and most expensive branded and non-branded GFFs and gluten containing equivalents were surveyed at physical stores (n=19) and online stores (n=8). The nutritional composition of some of the widely available GFFs identified (n=190) and comparable FCGs (n=218) were calculated using MyFitnessPal. Findings None of the budget stores or corner shops surveyed stocked any of the surveyed cereal-based GFFs. Online stores had more availability than physical stores; however, there was no significant difference in cost. GFFs cost, on average, 2.18 times more than FCG. When making nutritional comparisons with gluten-containing food, protein content was lower across 55 per cent of GFF categories. There was significantly less sugar in GF brown bread, crackers, and wholegrain pasta compared with those containing gluten (CG). Another main finding was GF ready-meals contained significantly less salt than ready-meals CG. Originality/value Limited resources and perceived wide availability of GF products resulted in reduced GF prescriptions to patients in England. The findings in this study revealed that there is no availability of cereal-based GFFs in budget stores, high cost and limited access to prescriptions can influence adherence to a GF diet and is most likely to affect patients from deprived groups. This study recommends that the prescription of GFF to patients with CD should be continued.

Acute flaccid myelitis (AFM) is a polio-like disease that results in paralysis in previously healthy persons. Although the definitive cause of AFM remains unconfirmed, enterovirus D68 (EV-D68) is suspected based on 2014 data demonstrating an increase in AFM cases concomitant with an EV-D68 outbreak. We examined the prevalence in children and the molecular evolution of EV-D68 for 2009–2018 in Philadelphia, Pennsylvania, USA. We detected widespread EV-D68 circulation in 2009, rare detections in 2010 and 2011, and then biennial circulation, only in even years, during 2012–2018. Prevalence of EV-D68 significantly correlated with AFM cases during this period. Finally, whole-genome sequencing revealed early detection of the B1 clade in 2009 and continued evolution of the B3 clade from 2016 to 2018. These data reinforce the need to improve surveillance programs for nonpolio enterovirus to identify possible AFM triggers and predict disease prevalence to better prepare for future outbreaks.

In this study, we investigate a program designed for young adults with intellectual disability to learn how to calculate the value of a collection of coins and notes with procedural fluency. In the first half of the paper, we establish the importance of financial literacy for people with intellectual disability and the need to address mathematical foundations using approaches that build procedural fluency. In the second half of the paper, we present findings from an analysis of pre-service teachers’ weekly reflections after having just tutored a student in the program. Using educational design research, we articulate how students build procedural fluency and what supports this type of learning. This paper will be of interest to researchers and practitioners alike who are looking to apply the latest findings on effective pedagogies to the field of inclusive education.

We have assessed the utility of 3-dimensional (3D) in vitro human cell models to understand barriers to chimeric antigen receptor (CAR)-T cell activity in high-grade serous ovarian cancer, (HGSOC) a disease with a poor response to immunotherapy. We defined mucin-1 (MUC1) as a potential target in HGSOC biopsies and the HGSOC cell lines, OvCAR3 and G164. We then generated CAR-T cells against MUC1 and tested them in spheroid and collagen gel cultures. In spheroids, although CAR-T cells killed OvCAR3 cells, G164 cells failed to induce CAR-T cell activation or cytotoxicity. However, when we added primary omental fibroblasts from ovarian cancer patients to G164 spheroids, CAR-T cells were activated and cytotoxic. Fibroblast conditioned medium also activated CAR-T cells to kill G164 cells in spheroids and this was due to their production of C-C motif chemokine ligand 2 (CCL2). Further experiments revealed that CCL2 produced by fibroblast stimulated CCR2/4 positive CAR-T cells to a higher state of activation, which enhanced the cytotoxicity of CAR-T cells against G164 cells. We then investigated CAR-T cell activity in co-cultures of OvCAR3 or G164 cells and primary fibroblasts embedded in collagen. CAR-T cells migrated into OvCAR3 gels and killed the malignant cells during a three-day period. However, CAR-T cells failed to migrate into gels with G164 cells and there was no malignant cell killing. Gels containing G164 cells had denser extracellular matrix (ECM) than OvCAR3 gels, as measured by staining for collagens and fibronectin. Previously, we showed that transforming growth factor-beta (TGFβ) secreted by HGSOC cells acted on fibroblasts to induce the production of ECM in collagen gels.1 Treating G164 gels with the TGFβ receptor inhibitor SB431542 reduced ECM density, stimulated CAR-T cell migration and restored CAR-T cell cytotoxicity against G164 cells. Using these different human 3D models we have demonstrated that malignant cell intrinsic factors can cause resistance to CAR-T cells. Sensitivity to CAR-T cell killing can be modulated both positively and negatively by fibroblasts. Targeting ECM along with CAR-T cell therapy might improve the efficiency of CAR-T cells in solid tumors. 1Delaine-Smith et al, iScience, 2021 Citation Format: Joash Dominic Joy, Beatrice Malacrida, Florian Laforêts, Panoraia Kotantaki, Eleni Maniati, Sarah Hopkins, Ianire Calleja, Sara Brett, Takis Athanasopoulos, Sadfer Ali, Peter Emery-Billcliff, Ida Ricciardelli, Charlotte Kay, Jayne Colebrook, Magda Ali, Katherine Strong, Frances Balkwill. TGFβ-mediated targeting of the extracellular matrix enhances the migration and cytotoxicity of CAR-T cells in 3D models of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 693.

Study design: Case-Control Study. Objective: The purpose of this retrospective study is to evaluate risk factors for developing a postoperative ileus after posterior spine surgery. Methods: Patient charts, including radiographs were evaluated retrospectively. Diagnosis of an ileus was confirmed radiographically by a CT scan in all cases. The control group was retrieved by selecting a random sample of patients undergoing posterior spine surgery who did not develop bowel dysfunction postoperatively. Results: A total of 40 patients had a postoperative ileus. The control group consisted of 80 patients. Both groups did not differ significantly in age, gender, BMI, tobacco use, comorbidities or status of previous abdominal surgery. Significant differences between the 2 groups was the length of stay (5.9 vs. 11.2; p = 0.001), surgery in the lumbar spine (47.5% vs. 87.5%; p < 0.001) and major spine surgery involving > 3 levels (35.0% vs. 57.5%; p = 0.019). Patients who suffered from an ileus were more likely to be treated in ICU (23.8% vs. 37.5%; p = 0.115), being re-admitted (0.0% vs 5.0%; p = 0.044) and having a delayed discharge (32.5% vs. 57.5%; p = 0.009). Multivariable analysis demonstrated that lumbar spine surgery compared to thoracic and/or cervical spine surgery (p = 0.00, OR 8.7 CI 2.9-25.4) and major spine surgery involving > 3 levels (p = 0.012; OR 3.0, CI 1.3-7.2) are associated with developing an ileus postoperatively. Conclusion: Surgeries of the lumbar spine as well as those involving > 3 levels are associated with developing a postoperative ileus. Further studies are needed to expand on possible risk factors and to better understand the mechanism underlying postoperative ileus in spine surgery patients.