Search

Across Canada, provincial education mandates cite intellectual development, socialization, and vocational preparation as some of the central goals of public schooling (B.C., 1989; Ontario, 1990). Within Alberta's Guide to Education (2024) yet another objective is offered, which is that schooling ought to promote the leading of "meaningful, fulfilling lives." To date, little guidance has been provided on what educating for meaning might look like, nor how to achieve this laudatory goal. This paper makes the case that meaning education can be realized through the use of the Community of Philosophical Inquiry (CPI). This is the case because this model (1) makes thinking visible (2) promotes taking ownership of one's values and behaviours (3) exposes youth to the viewpoints of others, and in so doing bolsters their emotional resilience, and (4) provides an interpersonal arena for value recalibration.

Abstract Although trends toward earlier ice‐out have been documented globally, the links between ice‐out timing and lake thermal and biogeochemical structure vary spatially. In high‐latitude lakes where ice‐out occurs close to peak intensity of solar radiation, these links remain unclear. Using a long‐term dataset from 13 lakes in West Greenland, we investigated how changing ice‐out and weather conditions affect lake thermal structure and oxygen concentrations. In early ice‐out years, lakes reach higher temperatures across the water column and have deeper epilimnia. Summer hypolimnia are the warmest (~ 11°C) in years when cooler air temperatures follow early ice‐out, allowing full lake turnover. Due to the higher potential for substantive spring mixing in early ice‐out years, a warmer hypolimnion is associated with higher dissolved oxygen concentrations. By affecting variability in spring mixing, the consequences of shifts in ice phenology for lakes at high latitudes differ from expectations based on temperate regions.

Treatment of neuroblastoma is a significant clinical unmet need in paediatric oncology epitomised by high-risk disease in which relapse is common and outcomes for children with relapse or primary refractory disease are typically poor, with 4-year progression-free survival for relapse/refractory disease of 6 %. Immunotherapy targeting disialoganglioside GD2 using monoclonal antibodies (mAb) has become a component of standard of care treatment in neuroblastoma following published studies that have demonstrated clinical activity and survival benefit associated with this treatment. Hence a number of research groups have developed and clinically evaluated chimeric antigen receptor gene modified T cells (CAR-T cells) targeting GD2 in patients with relapsed and refractory neuroblastoma. Preclinical and clinical results using a range of receptor technologies and immune effectors have demonstrated the basic safety and feasibility of this approach, progressing into clinical data exhibiting promise for sustained patient benefit.

Summary: Here, we present a protocol for preclinical evaluation of locoregionally delivered CAR T cells in patient-derived xenograft models of primary, metastatic, and recurrent brain tumors. We provide instructions for isolating peripheral blood mononuclear cells (PBMCs), producing CAR T cells in conjunction with locoregional delivery, and preclinical trial design and analysis involving CAR T cells. Additionally, we describe comprehensive preclinical readouts and guidelines for critical endpoint sample collections. In line with clinical trial procedures, our protocol broadens available treatment modalities for direct clinical translation.For complete details on the use and execution of this protocol, please refer to Donovan et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract Background Real-world data on subcutaneous C1INH (C1INH[SC]) usage and patient-level impacts on hereditary angioedema (HAE)-related outcomes and quality of life (QoL) are both lacking and challenging to generate using conventional study methodologies. Using a hybrid study design involving patient interviews supplemented by retrospective medical chart data review, we conducted a real-world assessment of the impact of C1INH(SC) prophylaxis on HAE attack patterns, QoL, and on-demand medication use. Methods The study was conducted at seven US sites and included 36 adults with HAE who had been treated with C1INH(SC) long-term prophylaxis following ≥ 12 months of on-demand management only. Patients underwent 30-min interviews, facilitated and analyzed by a trained qualitative research specialist. Medical records were reviewed for 12 months before (pre-index) and after (post-index) initiation of C1INH(SC). Using interview data with descriptive terms converted to numerical values, we compared pre- versus post-index attack frequency, severity, and rescue medication usage. Results Mean (SD) annualized attack frequency per patient decreased 82.0%, from 38.8 (38.8) attacks/year pre-index to 7.0 (15.3) attacks/year (P

This paper examines the phenomenon of joint attention and its relevance in understanding the modes of awareness of the presence of God. It explores the perspectives of Eleonore Stump and Andrew Pinsent, as well as the challenge raised by Donald Bungum, with the aim of reaching a better understanding of a distinct way of being ‘moved by God in a divine way’. According to Stump and Pinsent, joint attention can deepen our understanding of our relationship with God, emphasizing the importance of sharing attention with Him and making better sense of the way humans may be moved in a divine way. However, Bungum challenges this view by suggesting the possibility of closeness without explicit awareness. The paper concludes by emphasizing the need for a nuanced understanding of awareness and the presence of God in our spiritual lives, for our connection with God can manifest in diverse ways different from traditional accounts of explicit awareness. We suggest that a view of joint attention centered in action may be more suitable for an attempt to make sense of what ‘to be moved in a divine way’ amounts to.

This paper reports research that investigated how digital technologies were used to develop and maintain home–school connections and develop positive relationships when children transition to nursery schools and schools. School case studies, comprising four purposively selected schools with nursery provision in Northern Ireland and four primary schools in New Zealand, provided the context and evidence to enable a small-scale comparative study of how digital technologies enabled the development of relationships between homes and schools over time. In this paper, the findings were analysed using a conceptual model and framework derived from earlier studies in this field. However, given the contemporary social and technological context, it was found that the framework could be reviewed and elaborated, enabling the creation of a new conceptual framework that is offered here. Our findings reveal methods of employing digital technologies to positively support parental engagement when children transition to nurseries and schools. From the analysis of our findings using the framework developed, points to consider for future practice, policy, and research are highlighted, with an emphasis on understanding and integrating parents’ aspirations into the transition process. Opportunities that use existing and emerging methods for home–school–community connections need to be made known to teachers and schools. While the digital technologies used must be capable of maintaining appropriate regular communication, additionally, supporting ways for involving parental voice in reviews of existing practices and exploring new opportunities should be shared with teachers and schools. Future research should explore how the use of digital technologies in developing wider and deeper engagement and participation of parents and carers with nurseries and schools might lead to a longer-term and positive engagement in later years beyond nursery schools and initial transition to school.

Purpose: Prostate cancer (PCa) screening can lead to potential over-diagnosis/over-treatment of indolent cancers. There is a need to optimize practices to better risk-stratify patients. We examined initial longitudinal outcomes of mid-life men with an elevated baseline prostate-specific antigen (PSA) following initiation of a novel screening program within a system-wide network. Materials and Methods: We assessed our primary care network patients ages 40 to 49 years with a PSA measured following implementation of an electronic health record screening algorithm from 2/2/2017–2/21/2018. The multidisciplinary algorithm was developed taking factors including age, race, family history, and PSA into consideration to provide a personalized approach to urology referral to be used with shared decision-making. Outcomes of men with PSA ≥1.5 ng/mL were evaluated through 7/2021. Statistical analyses identified factors associated with PCa detection. Clinically significant PCa (csPCa) was defined as Gleason Grade Group (GGG) ≥2 or GGG1 with PSA ≥10 ng/mL. Results: The study cohort contained 564 patients, with 330 (58.5%) referred to urology for elevated PSA. Forty-nine (8.7%) underwent biopsy; of these, 20 (40.8%) returned with PCa. Eleven (2.0% of total cohort and 55% of PCa diagnoses) had csPCa. Early referral timing (odds ratio [OR], 4.58) and higher PSA (OR, 1.07) were significantly associated with PCa at biopsy on multivariable analysis (both p

Introduction The English Diabetic Eye Screening Programme (DESP) offers people living with diabetes (PLD) annual eye screening. We examined incidence and determinants of sight-threatening diabetic retinopathy (STDR) in a sociodemographically diverse multi-ethnic population.Research design and methods North East London DESP cohort data (January 2012 to December 2021) with 137 591 PLD with no retinopathy, or non-STDR at baseline in one/both eyes, were used to calculate STDR incidence rates by sociodemographic factors, diabetes type, and duration. HR from Cox models examined associations with STDR.Results There were 16 388 incident STDR cases over a median of 5.4 years (IQR 2.8–8.2; STDR rate 2.214, 95% CI 2.214 to 2.215 per 100 person-years). People with no retinopathy at baseline had a lower risk of sight-threatening diabetic retinopathy (STDR) compared with those with non-STDR in one eye (HR 3.03, 95% CI 2.91 to 3.15, p

Introduction The English National Health Service (NHS) Diabetic Eye Screening Programme (DESP) performs around 2.3 million eye screening appointments annually, generating approximately 13 million retinal images that are graded by humans for the presence or severity of diabetic retinopathy. Previous research has shown that automated retinal image analysis systems, including artificial intelligence (AI), can identify images with no disease from those with diabetic retinopathy as safely and effectively as human graders, and could significantly reduce the workload for human graders. Some algorithms can also determine the level of severity of the retinopathy with similar performance to humans. There is a need to examine perceptions and concerns surrounding AI-assisted eye-screening among people living with diabetes and NHS staff, if AI was to be introduced into the DESP, to identify factors that may influence acceptance of this technology.Methods and analysis People living with diabetes and staff from the North East London (NEL) NHS DESP were invited to participate in two respective focus groups to codesign two online surveys exploring their perceptions and concerns around the potential introduction of AI-assisted screening.Focus group participants were representative of the local population in terms of ages and ethnicity. Participants’ feedback was taken into consideration to update surveys which were circulated for further feedback. Surveys will be piloted at the NEL DESP and followed by semistructured interviews to assess accessibility, usability and to validate the surveys.Validated surveys will be distributed by other NHS DESP sites, and also via patient groups on social media, relevant charities and the British Association of Retinal Screeners. Post-survey evaluative interviews will be undertaken among those who consent to participate in further research.Ethics and dissemination Ethical approval has been obtained by the NHS Research Ethics Committee (IRAS ID: 316631). Survey results will be shared and discussed with focus groups to facilitate preparation of findings for publication and to inform codesign of outreach activities to address concerns and perceptions identified.

This study aims to review the status of the clinical use of monoclonal antibodies (mAbs) that have completed or are in ongoing clinical trials for targeted fluorescence-guided surgery (T-FGS) for the intraoperative identification of the tumor margins of extra-hematological solid tumors. For each of them, the targeted antigen, the mAb generic/commercial name and format, and clinical indications are presented, together with utility, doses, and the timing of administration. Based on the current scientific evidence in humans, the top three mAbs that could be prepared in a GMP-compliant bank ready to be delivered for surgical purposes are proposed to speed up the translation to the operating room and produce a few readily available “off-the-shelf” injectable fluorescent probes for safer and more effective solid tumor resection.

Strategic asset seeking foreign direct investment has undergone tremendous growth over the past decade. This paper first attempts to evaluate the location choice of such investments in Europe. We find that Chinese companies target strategic assets in Europe. The paper then moves to understand the efficacy of these investments in terms of the creation of strategic assets in the Chinese parent company. Our results show the intangible assets of Chinese domestic parent firms significantly increase in the wake of their investments. For greenfield investments, there is a longer time-lag in creation of intangible strategic assets than for acquisitions. However, greenfield investments result in a larger increase in intangible asset creation than acquisition investments.

Urban visual localization is the process of determining the pose (position and attitude) of the imaging sensor (or platform) with the help of existing geo-referenced data. This task is critical and challenging for many applications, such as autonomous navigation, virtual and augmented reality, and robotics, due to the dynamic and complex nature of urban environments that may obstruct Global Navigation Satellite Systems (GNSS) signals. This paper proposes a block-wise matching strategy for urban visual localization by using geo-referenced Google Street View (GSV) panoramas as the database. To determine the pose of the monocular query images collected from a moving vehicle, neighboring GSVs should be found to establish the correspondence through image-wise and block-wise matching. First, each query image is semantically segmented and a template containing all permanent objects is generated. The template is then utilized in conjunction with a template matching approach to identify the corresponding patch from each GSV image within the database. Through the conversion of the query template and corresponding GSV patch into feature vectors, their image-wise similarity is computed pairwise. To ensure reliable matching, the query images are temporally grouped into query blocks, while the GSV images are spatially organized into GSV blocks. By using the previously computed image-wise similarities, we calculate a block-wise similarity for each query block with respect to every GSV block. A query block and its corresponding GSV blocks of top-ranked similarities are then input into a photogrammetric triangulation or structure from motion process to determine the pose of every image in the query block. A total of three datasets, consisting of two public ones and one newly collected on the Purdue campus, are utilized to demonstrate the performance of the proposed method. It is shown it can achieve a meter-level positioning accuracy and is robust to changes in acquisition conditions, such as image resolution, scene complexity, and the time of day.

Abstract Clouds, especially low clouds, are crucial for regulating Earth's energy balance and mediating the response of the climate system to changes in greenhouse gas concentrations. Despite their importance for climate, they remain relatively poorly understood and are inaccurately represented in climate models. A principal reason is that the high computational expense of simulating them with large‐eddy simulations (LES) has inhibited broad and systematic numerical experimentation and the generation of large data sets for training parametrization schemes for climate models. Here we demonstrate LES of low clouds on tensor processing units (TPUs), application‐specific integrated circuits that were originally developed for machine learning applications. We show that TPUs in conjunction with tailored software implementations can be used to simulate computationally challenging stratocumulus clouds in conditions observed during the Dynamics and Chemistry of Marine Stratocumulus (DYCOMS) field study. The TPU‐based LES code successfully reproduces clouds during DYCOMS and opens up the large computational resources available on TPUs to cloud simulations. The code enables unprecedented weak and strong scaling of LES, making it possible, for example, to simulate stratocumulus with 10× speedup over real‐time evolution in domains with a 34.7 km × 53.8 km horizontal cross section. The results open up new avenues for computational experiments and for substantially enlarging the sample of LES available to train parameterizations of low clouds.

IntroductionJapan has the largest aging population with 33% of the population over the age of 60 years. The number of Japanese adults with dementia is estimated to be approximately 4.6 million, comprising nearly 15% of the older adult population. It is critical to administer cognitive assessments early in the disease state that have high reliability and low user burden to detect negative cognitive changes as early as possible; however, current preclinical AD detection methods are invasive, time-consuming, and expensive. A number of traditional and digital cognitive assessments are also available, but many of these tests are time-consuming, taxing to the user, and not widely scalable. The purpose of this study was to incorporate a digital cognitive assessment battery into a standard clinical assessment performed within a Japanese-based neuropsychology clinic to assess the diagnostic accuracy and the relationship between the digital Neurotrack Cognitive Assessment Battery (N-CAB) to traditional cognitive assessments.MethodsHealthy individuals and probable Alzheimer's patients completed the N-CAB, as well as two traditional cognitive assessments, the Mini Mental Status Exam (MMSE) and the Revised Hasegawa's Dementia Scale (HDS-R).ResultsOur results demonstrate the Image Pairs hand-response phase of the N-CAB had the highest diagnostic accuracy with 95% sensitivity and 89% specificity to probable Alzheimer's disease. This was closely followed by the Symbol Match assessment, with a 96% sensitivity and 74% specificity to probable Alzheimer's disease. Additionally, Symbol Match and Path Points used in combination resulted in a sensitivity of 94%, specificity of 90%; a model with all N-CAB assessments resulted in a sensitivity and specificity of 100%. All N-CAB assessments had moderate to strong and significant correlations with the MMSE and HDS-R.DiscussionTogether, this suggests that the N-CAB assessment battery may be an appropriate alternative for the clinical screening of cognition for earlier detection of Alzheimer's disease.

BackgroundDespite guidelines recommending the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in certain patients with type 2 diabetes (T2D), they are not being prescribed for many of these patients. Web-based continuing medical education (CME) patient simulations have been used to identify clinicians’ practice gaps and improve clinical decision-making as measured within a simulation, but the impact of this format on real-world treatment has not been researched. ObjectiveThis study aimed to evaluate the effect of a simulation-based CME intervention on real-world use of GLP-1 RAs by endocrinologists and primary care physicians. MethodsTwo evaluation phases of the CME simulation were conducted: phase I, the CME simulation phase, was a paired, pre-post study of 435 physician learners in the United States; and phase II, the real-world phase, was a retrospective, matched case-control study of 157 of the 435 physicians who had claims data available for the study period. ResultsPhase I CME results showed a 29 percentage point increase in correct decisions from pre- to postfeedback (178/435, 40.9% to 304/435, 69.9%; P

Background: The misuse and abuse of opioid pain medications have become a public health crisis. Because orthopedic surgeons are the third highest prescribers of opioids, understanding their postoperative pain medication prescribing practices is key to solving the opioid crisis. To this end, we conducted a study of the variability in orthopedic foot and ankle surgery postoperative opioid prescribing practice patterns. Methods: Three hundred fifty orthopedic foot and ankle surgeons were contacted; respondents completed a survey with 4 common patient scenarios and surgical procedures followed by questions regarding typical postoperative pain medication prescriptions. The scenarios ranged from minimally painful procedures to those that would be expected to be significantly more painful. Summaries were calculated as percentages and chi-square or Fisher exact tests were used to compare survey responses between groups stratified by years in practice and type of practice. Results: Sixty-four surgeons responded to the survey (92.8% male), 31% were in practice less than 5 years, 34% 6 to 15 years and 34% more than 15 years. For each scenario, there was variation in the type of pain medication prescribed ( scenario 1 : 17% 5 mg hydrocodone, 22% 10 mg hydrocodone, 52% oxycodone, and 3% oxycodone sustained release [SR]; scenario 2 : 15% 5 mg hydrocodone, 13% 10 mg hydrocodone, 58% oxycodone, and 9% oxycodone SR; scenario 3 : 11% 5 mg hydrocodone, 13% 10 mg hydrocodone, 56% oxycodone, and 14.1% oxycodone SR; scenario 4 : 3% 5 mg hydrocodone, 5% 10 mg hydrocodone, 44% oxycodone, and 45% oxycodone SR) and the number of pills dispensed. Use of multimodal pain management was variable but most physicians use regional nerve blocks for each scenario (76%, 87%, 69%, 94%). Less experienced surgeons (less than 5 years in practice) supplement with tramadol more for scenario 1 ( P = .034) as well as use regional nerve blocks for scenario 2 ( P = .039) more than experienced surgeons (more than 15 years in practice). Conclusion: It is evident that variation exists in narcotic prescription practices for postoperative pain management by orthopedic foot and ankle surgeons. With new AAOS guidelines, it is important to try to create some standardization in opioid prescription protocols.

Abstract Background The COVID-19 pandemic has highlighted disparities in healthcare, particularly in the United States, even though disparities have existed since the organization of the modern healthcare system. Recruitment of patients from racial and ethnic minority groups is often minimal in phase 3 clinical trials, and is further exacerbated in the case of trials for rare diseases such as hereditary angioedema (HAE). This can lead to a gap in the understanding of minority patients’ experiences with these diseases and their response to potential treatment options. Methods We reviewed data from phase 3 double-blind (HELP) and open-label extension (HELP OLE) trials of lanadelumab, a monoclonal antibody developed for long-term prophylaxis against attacks of HAE. Efficacy (attack rate reduction) and safety (adverse events) results from White patients were compared descriptively to those from Hispanic/Latino patients, Black/African Americans, and other minority Americans. Results Not surprisingly, few minorities were recruited across both studies: 9.5% Black, 2.4% Asian, and 7.1% Hispanic/Latino versus 88.1% White and 91.7% non-Hispanic/non-Latino received lanadelumab in HELP, and 4.7% Black, 0.9% Asian, 0.9% other, and 6.1% Hispanic/Latino versus 93.4% White and 93.4% non-Hispanic/non-Latino were enrolled in HELP OLE. Although these studies were conducted in the United States, Canada, Europe, and Jordan, all minorities were from the United States. Despite the number of minority patients being far less than expected for the population, there was no evidence that either efficacy or adverse event profiles differed between ethnic or racial groups. Conclusions The HELP and HELP OLE studies described herein recruited far fewer minorities than would be ideal to represent these populations. However, evidence suggests that the effectiveness and tolerance of lanadelumab are similar between the groups. Nonetheless, the disparity in recruitment into research for minorities has significant room for improvement. Trial registration NCT02586805, registered 26 October 2015, https://clinicaltrials.gov/ct2/show/record/NCT02586805 . NCT02741596, registered 18 April 2016, https://clinicaltrials.gov/ct2/show/NCT02741596 .

B7-H3 (CD276) has emerged as a target for cancer immunotherapy by virtue of consistent expression in many malignancies, relative absence from healthy tissues, and an emerging role as a driver of tumor immune inhibition. Recent studies have reported B7-H3 to be a suitable target for chimeric antigen receptor-modified T cell (CAR-T) therapy using CARs constructed from established anti-B7-H3 antibodies converted into single-chain Fv format (scFv). We constructed and screened binders in an scFv library to generate a new anti-B7-H3 CAR-T with favorable properties. This allowed access to numerous specificities ready formatted for CAR evaluation. Selected anti-human B7-H3 scFvs were readily cloned into CAR-T and evaluated for anti-tumor reactivity in cytotoxicity, cytokine, and proliferation assays. Two binders with divergent complementarity determining regions were found to show optimal antigen-specific cytotoxicity and cytokine secretion. One binder in second-generation CD28-CD3ζ CAR format induced sustained in vitro proliferation on repeat antigen challenge. The lead candidate CAR-T also demonstrated in vivo activity in a resistant neuroblastoma model. An empirical approach to B7-H3 CAR-T discovery through screening of novel scFv sequences in CAR-T format has led to the identification of a new construct with sustained proliferative capacity warranting further evaluation.

This is the first reported case of medication-related osteonecrosis of the jaw (MRONJ) resulting from the use of romosozumab, a new anti-resorptive medication that functions through inhibition of sclerostin. It was approved by the FDA in 2019, and mentioned in the 2022 AAOMS Position Paper on MRONJ. Although initial evidence from animal studies and clinical trials showed a low risk of MRONJ from romosozumab, recent publications on adverse event monitoring demonstrate the need for continued observation and research. Little is known regarding the risk of MRONJ from romosozumab, however, oral surgeons will inevitably be first line clinicians to manage patients on this medication. The purpose of this extremely unusual case report is to improve knowledge and heighten awareness about the association between romosozumab and MRONJ.

Violet–blue light of 405 nm in the visible spectrum at a dose of 270 J/cm2 alone has been shown to be an effective microbicidal tool for inactivating several bacteria, HIV-1, and Trypanosoma cruzi in ex vivo plasma and platelets. Unlike chemical- and ultraviolet (UV)-based pathogen inactivation methods for plasma and platelet safety, 405 nm light is shown to be less toxic to host cells at light doses that are microbicidal. In this report, we evaluated the parasiticidal activity of a 405 nm light treatment on platelets spiked with the Leishmania donovani parasite. Following the light treatment, parasite viability was observed to be near zero in both low- and high-titer-spiked platelets relative to controls. Furthermore, to test the residual infectivity after inactivation in vivo, the light-treated low-titer L. donovani-spiked platelets were evaluated in an immunodeficient Rag2−/− mouse model and monitored for 9 weeks. The parasiticidal efficacy of 405 nm light was evident from the lack of a presence of parasites in the mice spleens. Parasiticidal activity was confirmed to be mediated through 405 nm light-induced reactive oxygen species (ROS), as quantitatively measured by a 2′,7′-Dichlorodihydrofluorescein diacetate (H2DCFDA)-based assay. Overall, these results confirm the complete inactivation of L. donovani spiked in ex vivo platelets by 405 nm light treatment and exemplify the utility of the Rag2−/− mouse infection model for the preclinical validation of the parasiticidal efficacy of 405 nm light and this light-based technology as a potential PRT for ex vivo platelets.

Abstract Background Development of resistance to targeted therapies has tempered initial optimism that precision oncology would improve poor outcomes for cancer patients. Resistance mechanisms, however, can also confer new resistance-specific vulnerabilities, termed collateral sensitivities. Here we investigated anaplastic lymphoma kinase (ALK) inhibitor resistance in neuroblastoma, a childhood cancer frequently affected by activating ALK alterations. Methods Genome-wide forward genetic CRISPR-Cas9 based screens were performed to identify genes associated with ALK inhibitor resistance in neuroblastoma cell lines. Furthermore, the neuroblastoma cell line NBLW-R was rendered resistant by continuous exposure to ALK inhibitors. Genes identified to be associated with ALK inhibitor resistance were further investigated by generating suitable cell line models. In addition, tumor and liquid biopsy samples of four patients with ALK-mutated neuroblastomas before ALK inhibitor treatment and during tumor progression under treatment were genomically profiled. Results Both genome-wide CRISPR-Cas9-based screens and preclinical spontaneous ALKi resistance models identified NF1 loss and activating NRASQ61K mutations to confer resistance to chemically diverse ALKi. Moreover, human neuroblastomas recurrently developed de novo loss of NF1 and activating RAS mutations after ALKi treatment, leading to therapy resistance. Pathway-specific perturbations confirmed that NF1 loss and activating RAS mutations lead to RAS-MAPK signaling even in the presence of ALKi. Intriguingly, NF1 loss rendered neuroblastoma cells hypersensitive to MEK inhibition. Conclusions Our results provide a clinically relevant mechanistic model of ALKi resistance in neuroblastoma and highlight new clinically actionable collateral sensitivities in resistant cells.

Gamma delta lymphocytes (γδ T) sit at the interface between innate and adaptive immunity. They have the capacity to recognize cancer cells by interaction of their surface receptors with an array of cancer cell surface target antigens. Interactions include the binding of γδ T cell receptors, the ligands for which are diverse and do not involve classical major histocompatibility complex (MHC) molecules. Moreover, a variety of natural killer-like and fragment crystallizable gamma (Fcγ) receptors confer additional cancer reactivity. Given this innate capacity to recognize and kill cancer cells, there appears less rationale for redirecting specific to cancer cell surface antigens through chimeric antigen receptor (CAR) expression. Several groups have however reported research findings that expression of CARs in γδ T cells can confer additional specificity or functionality. Though limited in number, these studies collectively identify the potential of CAR-T engineering to augment and fine tune anti-cancer responses. Together with the lack of graft versus host disease induced by allogeneic γδ T cells, these insights should encourage researchers to explore additional γδ T-CAR refinements for the development of off-the-shelf anti-cancer cell therapies.

Introduction Diabetic retinopathy screening (DRS) attendance in young adults (YAs) is consistently below recommended levels. The aim of this study was to identify barriers and enablers of DRS attendance among YAs in the UK living with type 1 (T1D) and type 2 diabetes (T2D).Research design and methods YAs (18–34 years) were invited to complete an anonymous online survey in June 2021 assessing agreement with 30 belief statements informed by the Theoretical Domains Framework (TDF) of behavior change describing potential barriers/enablers to DRS.Results In total, 102 responses were received. Most had T1D (65.7%) and were regular attenders for DRS (76.5%). The most salient TDF domains for DRS attendance were ‘Goals’, with 93% agreeing that DRS was a high priority, and ‘Knowledge’, with 98% being aware that screening can detect eye problems early.Overall, 67.4% indicated that they would like greater appointment flexibility (Environmental context/resources) and 31.3% reported difficulties getting time off work/study to attend appointments (Environmental context/resources). This was more commonly reported by occasional non-attenders versus regular attenders (59.1% vs 23.4%, p=0.002). Most YAs were worried about diabetic retinopathy (74.3%), anxious when receiving screening results (63%) (Emotion) and would like more support after getting their results (66%) (Social influences). Responses for T1D and T2D were broadly similar, although those with T2D were more likely have developed strategies to help them to remember their appointments (63.6% vs 37.9%, p=0.019) (Behavioral regulation).Conclusions Attendance for DRS in YAs is influenced by complex interacting behavioral factors. Identifying modifiable determinants of behavior will provide a basis for designing tailored interventions to improve DRS in YAs and prevent avoidable vision loss.

Abstract Pediatric gliomas comprise a broad range of brain tumors derived from glial cells. While high-grade gliomas are often resistant to therapy and associated with a poor outcome, children with low-grade gliomas face a better prognosis. However, the treatment of low-grade gliomas is often associated with severe long-term adverse effects. This shows that there is a strong need for improved treatment approaches. Here, we highlight the potential for repurposing disulfiram to treat pediatric gliomas. Disulfiram is a drug used to support the treatment of chronic alcoholism and was found to be effective against diverse cancer types in preclinical studies. Our results show that disulfiram efficiently kills pediatric glioma cell lines as well as patient-derived glioma stem cells. We propose a novel mechanism of action to explain disulfiram’s anti-oncogenic activities by providing evidence that disulfiram induces the degradation of the oncoprotein MLL. Our results further reveal that disulfiram treatment and MLL downregulation induce similar responses at the level of histone modifications and gene expression, further strengthening that MLL is a key target of the drug and explaining its anti-oncogenic properties.

This paper analyzes how a robust and dynamic forecasting system was designed and implemented to predict material volumes for the inbound logistics network of an international automotive company. The system aims to reduce transportation logistics costs and improve demand capacity planning for freight forwarders. The forecasting horizon is set for 4 months and 12 months ahead in the future. To solve this problem, a time series modeling approach was carried out by using different time series forecasting methods like ARIMA, Neural Networks, Exponential Smoothing, Prophet, Automated Simple Moving Average, Multivariate Time Series, and Ensemble Forecast. Additionally, important data preprocessing methods and a robust model selection framework were used to train the models and select the best-performing one. This is known as Forward Chaining Nested Cross Validation with origin recalibration. The system performance was assessed using the Symmetric Mean Absolute Error (SMAPE). The final version of the forecasting system can deliver 4-month-ahead forecasts with a SMAPE lower than 10% for 86% of all material flow connections. The system’s forecast output is updated on a monthly basis and was integrated into the inbound logistics network system of the company.

Abstract Background While many studies of effective hereditary angioedema (HAE) therapy have demonstrated improved health-related quality of life (HRQoL) using validated instruments, specific reasons behind the improved scores have never been investigated using qualitative methods. A non-interventional, qualitative research study was designed to investigate the reasons for improvements in HRQoL while using effective prophylaxis, in this case subcutaneous C1INH (C1INH[SC]) replacement therapy. Methods Adult patients with HAE-C1INH type 1 or 2 who had been using C1INH(SC) for ≥ 3 consecutive months were recruited through four HAE specialty practices in the US to participate in a 60-min phone interview performed by a trained qualitative research specialist (ICON plc) using a semi-structured interview guide with open-ended questions developed with the Angioedema Quality of Life (AE-QoL) items in mind. Interview transcripts were analyzed using thematic analysis methods to identify concepts (specific symptoms/impacts) and themes (higher-level categories grouping related concepts). A cross-mapping exercise was performed between interview-identified concepts and items included in the AE-QoL. Results Fourteen patients were interviewed and included in the analysis (age range, 28–82 years [mean 47.5 years]; 64% female; 93% white). In 10 interviews, patients mentioned having no or nearly no HAE attacks, no longer feeling limited by HAE, less HAE-related anxiety/worry and depression, an improved ability to travel, fewer emergency room/hospital visits, and ease of administration of C1INH(SC), including not requiring assistance from others. Other commonly expressed concepts included: increased feelings of confidence, independence, optimism, and normalcy; less absence from work/school; better productivity; improved sleep and energy; healthier family relationships; and improved cognition. While all AE-QoL items emerged from patient interviews, a number of identified concepts were not addressed by the AE-QoL, including sensitivity to various potential attack-triggers (e.g., stress/anxiety, sports), attack frequency, not having to cancel social plans, improvements in ability to perform day-to-day tasks, and a lower burden from medical visits. Conclusions From these interviews, a large number of common themes and concepts emerged: a greater sense of freedom and normalcy, increased productivity, and improved interpersonal relationships while using convenient and effective prophylaxis. These findings provide insights into real-world experiences and the many facets of HRQoL that are important to patients with HAE-C1INH.

The γδT cell subset of peripheral lymphocytes exhibits potent cancer antigen recognition independent of classical peptide MHC complexes, making it an attractive candidate for allogeneic cancer adoptive immunotherapy. The Vδ1-T cell receptor (TCR)-expressing subset of peripheral γδT cells has remained enigmatic compared to its more prevalent Vγ9Vδ2-TCR and αβ-TCR-expressing counterparts. It took until 2021 before a first patient was dosed with an allogeneic adoptive Vδ1 cell product despite pre-clinical promise for oncology indications stretching back to the 1980s. A contributing factor to the paucity of clinical progress with Vδ1 cells is the lack of robust, consistent and GMP-compatible expansion protocols. Herein we describe a reproducible one-step, clinically translatable protocol for Vδ1-γδT cell expansion from peripheral blood mononuclear cells (PBMCs), that is further compatible with high-efficiency gene engineering for immunotherapy purposes. Briefly, αβTCR- and CD56-depleted PBMC stimulation with known-in-the-art T cell stimulators, anti-CD3 mAb (clone: OKT-3) and IL-15, leads to robust Vδ1 cell expansion of high purity and innate-like anti-tumor efficacy. These Vδ1 cells can be virally transduced to express chimeric antigen receptors (CARs) using standard techniques, and the CAR-Vδ1 exhibit antigen-specific persistence, cytotoxicity and produce IFN-γ. Practicable, GMP-compatible engineered Vδ1 cell expansion methods will be crucial to the wide-spread clinical testing of these cells for oncology indications.