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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.

Abstract Serological cross-reactivity among flaviviruses makes determining the prior arbovirus exposure of animals challenging in areas where multiple flavivirus strains are circulating. We hypothesized that prior infection with ZIKV could be confirmed through the presence of subgenomic flavivirus RNA (sfRNA) of the 3′ untranslated region (UTR), which persists in tissues due to XRN-1 stalling during RNA decay. We amplified ZIKV sfRNA but not NS5 from three experimentally-infected Jamaican fruit bats, supporting the hypothesis of sfRNA tissue persistence. Applying this approach to 198 field samples from Uganda, we confirmed presence of ZIKV sfRNA, but not NS5, in four bats representing three species: Eidolon helvum (n = 2), Epomophorus labiatus (n = 1), and Rousettus aegyptiacus (n = 1). Amplified sequence was most closely related to Asian lineage ZIKV. Our results support the use of sfRNA as a means of identifying previous flavivirus infection and describe the first detection of ZIKV RNA in East African bats.

Abstract Background Long-term prophylaxis with subcutaneous C1-inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) in patients with hereditary angioedema (HAE) due to C1-INH deficiency (C1-INH-HAE) was evaluated in an open-label extension follow-up study to the international, double-blind, placebo-controlled COMPACT study. The current analysis evaluated patient-reported health-related quality of life (HRQoL) data from 126 patients in the open-label extension study randomized to treatment with C1-INH(SC) 40 IU/kg (n = 63) or 60 IU/kg (n = 63) twice weekly for 52 weeks. HRQoL was evaluated at the beginning of the open-label study and at various time points using the European Quality of Life-5 Dimensions Questionnaire (EQ-5D), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication. The disease-specific Angioedema Quality of Life Questionnaire (AE-QoL) and HAE quality of life questionnaire (HAE-QoL) instruments were administered in a subset of patients. Statistical significance was determined by change-from-baseline 95% confidence intervals (CIs) excluding zero. No adjustment for multiplicity was done. Results Mean baseline EQ-5D scores (Health State Value, 0.90; Visual Analog Scale, 81.32) were slightly higher (better) than United States population norms (0.825, 80.0, respectively) and mean HADS anxiety (5.48) and depression (2.88) scores were within “normal” range (0–7). Yet, patients using C1-INH(SC) 60 IU/kg demonstrated significant improvement from baseline to end-of-study on the EQ-5D Health State Value (mean change [95% CI], 0.07 [0.01, 0.12] and Visual Analog Scale (7.45 [3.29, 11.62]). In the C1-INH(SC) 60 IU/kg group, there were significant improvements in the HADS anxiety scale (mean change [95% CI], − 1.23 [− 2.08, − 0.38]), HADS depression scale (− 0.95 [− 1.57, − 0.34]), and WPAI-assessed presenteeism (mean change [95% CI], − 23.33% [− 34.86, − 11.81]), work productivity loss (− 26.68% [− 39.92, − 13.44]), and activity impairment (− 16.14% [− 26.36, − 5.91]). Clinically important improvements were achieved in ≥ 25% of patients for all domains except WPAI-assessed absenteeism (which was very low at baseline). Mean AE-QoL total score by visit ranged from 13.39 to 17.89 (scale 0–100; lower scores = less impairment). Mean HAE-QoL global scores at each visit (115.7–122.3) were close to the maximum (best) possible score of 135. Conclusions Long-term C1-INH(SC) replacement therapy in patients with C1-INH-HAE leads to significant and sustained improvements in multiple measures of HRQoL. Trial registration A Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema, NCT02316353. Registered December 12, 2014, https://clinicaltrials.gov/ct2/show/NCT02316353 .

In this work, we present two parallel algorithms for the large-scale discrete Fourier transform (DFT) on Tensor Processing Unit (TPU) clusters. The two parallel algorithms are associated with two DFT formulations: one formulation, denoted as KDFT, is based on the Kronecker product; the other is based on the famous Cooley-Tukey algorithm and phase adjustment, denoted as FFT. Both KDFT and FFT formulations take full advantage of TPU’s strength in matrix multiplications. The KDFT formulation allows direct use of nonuniform inputs without additional step. In the two parallel algorithms, the same strategy of data decomposition is applied to the input data. Through the data decomposition, the dense matrix multiplications in KDFT and FFT are kept local within TPU cores, which can be performed completely in parallel. The communication among TPU cores is achieved through the one-shuffle scheme in both parallel algorithms, with which sending and receiving data takes place simultaneously between two neighboring cores and along the same direction on the interconnect network. The one-shuffle scheme is designed for the interconnect topology of TPU clusters, minimizing the time required by the communication among TPU cores. Both KDFT and FFT are implemented in TensorFlow. The three-dimensional complex DFT is performed on an example of dimension $8192 \times 8192 \times 8192$ with a full TPU Pod: the run time of KDFT is 12.66 seconds and that of FFT is 8.3 seconds. Scaling analysis is provided to demonstrate the high parallel efficiency of the two DFT implementations on TPUs.

Abstract Climate and environmental condition drive biodiversity at many levels of biological organization, from populations to ecosystems. Combined with paleoecological reconstructions, palaeogenetic information on resident populations provides novel insights into evolutionary trajectories and genetic diversity driven by environmental variability. While temporal observations of changing genetic structure are often made of sexual populations, little is known about how environmental change affects the long‐term fate of asexual lineages. Here, we provide information on obligately asexual, triploid Daphnia populations from three Arctic lakes in West Greenland through the past 200–300 years to test the impact of environmental change on the temporal and spatial population genetic structure. The contrasting ecological state of the lakes, specifically regarding salinity and habitat structure may explain the observed lake‐specific clonal composition over time. Palaeolimnological reconstructions show considerable regional environmental fluctuations since 1,700 (the end of the Little Ice Age), but the population genetic structure in two lakes was almost unchanged with at most two clones per time period. Their local populations were strongly dominated by a single clone that has persisted for 250–300 years. We discuss possible explanations for the apparent population genetic stability: (a) persistent clones are general‐purpose genotypes that thrive under broad environmental conditions, (b) clonal lineages evolved subtle genotypic differences unresolved by microsatellite markers, or (c) epigenetic modifications allow for clonal adaptation to changing environmental conditions. Our results motivate research into the mechanisms of adaptation in these populations, as well as their evolutionary fate in the light of accelerating climate change in the polar regions.

BackgroundAs evidenced by the further reduction in access to testing during the COVID-19 pandemic, there is an urgent, growing need for remote cognitive assessment for individuals with cognitive impairment. The Neurotrack Cognitive Battery (NCB), our response to this need, was evaluated for its temporal reliability and stability as part of ongoing validation testing. ObjectiveThe aim of this study is to assess the temporal reliability of the NCB tests (5 total) across a 1-week period and to determine the temporal stability of these measures across 3 consecutive administrations in a single day. MethodsFor test-retest reliability, a range of 29-66 cognitively healthy participants (ages 18-68 years) completed each cognitive assessment twice, 1 week apart. In a separate study, temporal stability was assessed using data collected from 31 different cognitively healthy participants at 3 consecutive timepoints in a single day. ResultsCorrelations for the assessments were between 0.72 and 0.83, exceeding the standard acceptable threshold of 0.70 for temporal reliability. Intraclass correlations ranged from 0.60 to 0.84, indicating moderate to good temporal stability. ConclusionsThese results highlight the NCB as a brief, easy-to-administer, and reliable assessment for remote cognitive testing. Additional validation research is underway to determine the full magnitude of the clinical utility of the NCB.

Background: Bone marrow involvement is an important aspect of determining staging of disease and treatment for childhood neuroblastoma. Current standard of care relies on microscopic examination of bone marrow trephine biopsies and aspirates respectively, to define involvement. Flow cytometric analysis of disaggregated tumour cells, when using a panel of neuroblastoma specific markers, allows for potentially less subjective determination of the presence of tumour cells. Methods: A retrospective review of sequential bone marrow trephine biopsies and aspirates, performed at Great Ormond Street Hospital, London, between the years 2015 and 2018, was performed to assess whether the addition of flow cytometric analysis to these standard of care methods provided concordant or additional information. Results: There was good concurrence between all three methods for negative results 216/302 (72%). Positive results had a concordance of 52/86 (61%), comparing samples positive by flow cytometry and positive by either or both cytology and histology. Of the remaining samples, 20/86 (23%) were positive by either or both cytology and histology, but negative by flow cytometry. Whereas 14/86 (16%) of samples were positive only by flow cytometry. Conclusions: Our review highlights the ongoing importance of expert cytological and histological assessment of bone marrow results. Flow cytometry is an objective, quantitative method to assess the level of bone marrow disease in aspirates. In this study, flow cytometry identified low-level residual disease that was not detected by cytology or histology. The clinical significance of this low-level disease warrants further investigation.

Here, using methylCIBERSORT, the authors characterize the tumour-immune microenvironment of paediatric central nervous system (CNS) tumours and its association with tumour type and prognosis. These findings suggest that immuno-methylomic profiling may inform immunotherapy approaches in paediatric patients with CNS tumour.

Abstract Background Hereditary angioedema (HAE), a rare disease that is characterized by painful and recurring non‐allergic swelling episodes, is caused by the deficiency or dysfunction of C1 inhibitor (C1INH) protein. A comprehensive HAE management plan may require long‐term prophylaxis (LTP) in addition to on‐demand treatment to help “normalize” patients' lives so that they may fully engage in work, school, family, and leisure activities. Aim The main objective of this narrative review is to provide an overview of updated guideline recommendations specific to LTP of HAE and discuss clinical considerations and pharmacologic management options, with a focus on C1INH. Materials and Methods The authors reviewed relevant HAE literature for current recommendations regarding LTP and the role of C1NH. Results Acute HAE attacks are treated with on‐demand medication; however, there is a consensus that LTP should routinely be considered for risk reduction and prevention of future episodes. The 2017 World Allergy Organization/European Academy of Allergy and Clinical Immunology guidelines recommend that all patients with HAE be evaluated for LTP routinely and the 2020 HAE Association (HAEA) guidelines emphasize that the decision to use LTP should not be based on rigid criteria, but rather should be based on individual patient needs. Both guidelines recommend C1INH as first‐line/preferred therapy for LTP in a range of patient types including adults, children/adolescents, and pregnant/lactating patients. The HAEA also recommends the kallikrein inhibitor, lanadelumab, as a first‐line option for LTP. HAE pathway‐specific agents for LTP have not been associated with notable safety concerns. Discussion Plasma‐derived C1INH has been available for 40+ years in Europe and impacts multiple targets within the HAE pathway. C1INH has been used for on‐demand treatment and LTP. A subcutaneous formulation of plasma‐derived C1INH is approved for LTP and produces functional C1INH activity levels consistently above the threshold needed for protection from HAE attacks. Other pathway‐specific options for LTP include the plasma kallikrein inhibitors, lanadelumab‐flyo and berotralstat, approved for adults and pediatric patients aged ≥12 years. C1INH is approved for adults and pediatric patients aged ≥6 years. Conclusion Assessing the need for LTP is vital in the ongoing dialogue between clinicians and patients, as both disease‐related factors and patient preferences may change over time. Among available options for LTP, plasma‐derived C1INH is the broadly recommended first‐line option for LTP in patients with HAE, including pregnant/lactating women and pediatric patients (≥6 years).

Abstract Background Symptomatic and asymptomatic enteric infections in early childhood are associated with negative effects on childhood growth and development, especially in low and middle-income countries, and food may be an important transmission route. Although basic food hygiene practices might reduce exposure to faecal pathogens and resulting infections, there have been few rigorous interventions studies to assess this, and no studies in low income urban settings where risks are plausibly very high. The aim of this study is to evaluate the impact of a novel infant food hygiene intervention on infant enteric infections and diarrhoea in peri-urban settlements of Kisumu, Kenya. Methods This is a cluster randomized control trial with 50 clusters, representing the catchment areas of Community Health Volunteers (CHVs), randomly assigned to intervention or control, and a total of 750 infants recruited on a rolling basis at 22 weeks of age and then followed for 15 weeks. The intervention targeted four key caregiver behaviours related to food hygiene: 1) hand washing with soap before infant food preparation and feeding; 2) bringing all infant food to the boil before feeding, including when reheating or reserving; 3) storing all infant food in sealed containers; and, 4) using only specific utensils for infant feeding which are kept separate and clean. Results The primary outcome of interest is the prevalence of one or more of 23 pre-specified enteric infections, determined using quantitative real-time polymerase chain reaction for enteric pathogen gene targets. In addition, infant food samples were collected at 33 weeks, and faecal indicator bacteria (Enterococcus) isolated and enumerated to assess the impact of the intervention on infant food contamination. Conclusion To our knowledge this is the first randomized controlled trial to assess the effect of an infant food hygiene intervention on enteric infections in a high burden, low income urban setting. Our trial responds to growing evidence that food may be a key pathway for early childhood enteric infection and disease and that basic food hygiene behaviours may be able to mitigate these risks. The Safe Start trial seeks to provide new evidence as to whether a locally appropriate infant food hygiene intervention delivered through the local health extension system can improve the health of young children. Trial registration The trial was registered at clinicaltrial.gov on March 16th 2018 before enrolment of any participants (https://clinicaltrials.gov/ct2/show/NCT03468114).

Abstract Arctic lakes are poised for substantial changes to their carbon (C) cycles in the near future. Autochthonous processes in lakes which consume inorganic C and create biomass that can be sequestered in sediments are accompanied by allochthonous inputs of organic matter from the surrounding watershed. Both C sources can be mineralized and degassed as CO2, but also become recalcitrant and accumulate in pelagic waters. Using stable carbon isotope (δ13C) values and elemental ratios as geochemical proxies, we investigated diverse organic matter sources to lakes located across a hydro‐climatic gradient in Southwest Greenland. Particulate organic matter (POM) and sediments were clearly of autochthonous algal origin, while dissolved organic matter (DOM) was a mix between autochthonous macrophytes and allochthonous watershed sources. Our results imply that a warmer and drier Arctic will lead to decoupled C pools: a water column dominated by increasingly autochthonous, macrophytic DOM, and sediments dominated by autochthonous algal POM.

Background: Bone marrow involvement is an important aspect of determining staging of disease and treatment for childhood neuroblastoma. Current standard of care relies on microscopic examination of bone marrow trephine biopsies and aspirates respectively, to define involvement. Flow cytometric analysis of disaggregated tumour cells, when using a panel of neuroblastoma specific markers, allows for potentially less subjective determination of the presence of tumour cells. Methods: A retrospective review of sequential bone marrow trephine biopsies and aspirates, performed at Great Ormond Street Hospital, London, between the years 2015 and 2018, was performed to assess whether the addition of flow cytometric analysis to these standard of care methods provided concordant or additional information. Results: There was good concurrence between all three methods for negative results 216/302 (72%). Positive results had a concordance of 52/86 (61%), comparing samples positive by flow cytometry and positive by either or both cytology and histology. Of the remaining samples, 20/86 (23%) were positive by either or both cytology and histology, but negative by flow cytometry. Whereas 14/86 (16%) of samples were positive only by flow cytometry. Conclusions: Our review highlights the ongoing importance of expert cytological and histological assessment of bone marrow results. Flow cytometry is an objective, quantitative method to assess the level of bone marrow disease in aspirates. In this study, flow cytometry identified low-level residual disease that was not detected by cytology or histology. The clinical significance of this low-level disease warrants further investigation.

Background: Bone marrow involvement is an important aspect of determining staging of disease and treatment for childhood neuroblastoma. Current standard of care relies on microscopic examination of bone marrow trephine biopsies and aspirates respectively, to define involvement. Flow cytometric analysis of disaggregated tumour cells, when using a panel of neuroblastoma specific markers, allows for potentially less subjective determination of the presence of tumour cells. Methods: A retrospective review of sequential bone marrow trephine biopsies and aspirates, performed at Great Ormond Street Hospital, London, between the years 2015 and 2018, was performed to assess whether the addition of flow cytometric analysis to these standard of care methods provided concordant or additional information. Results: There was good concurrence between all three methods for negative results 216/302 (72%). Positive results had a concordance of 52/86 (61%), comparing samples positive by flow cytometry and positive by either or both cytology and histology. Of the remaining samples, 20/86 (23%) were positive by either or both cytology and histology, but negative by flow cytometry. Whereas 14/86 (16%) of samples were positive only by flow cytometry. Conclusions: Our review highlights the ongoing importance of expert cytological and histological assessment of bone marrow results. Flow cytometry is an objective, quantitative method to assess the level of bone marrow disease in aspirates. In this study, flow cytometry identified low-level residual disease that was not detected by cytology or histology. The clinical significance of this low-level disease warrants further investigation.

(1) Background: In March 2020, the United Arab Emirates Ministry of Education (MoE) closed all schools and universities in response to the global COVID-19 pandemic. All lessons had to be delivered online. This mixed methods case study explores responses to this change in learning environment from 35 BA Education and Early Childhood Studies preservice teachers at a British university in Dubai. The research sought to understand the impact of the sudden move to home learning and the ways in which it affected student communities alongside student perceptions of the online learning environment. (2) Methods: Quantitative data was collected via questionnaires allowing students to consider past experiences while reflecting on their approaches to the online environment. Weekly focus groups were held online to track the student experience and understand the influence of different pedagogical approaches. (3) Results: The research found most students maintained a ‘deep’ or ‘strategic’ approach to learning. (4) Conclusions: Despite students declaring the period of emergency online learning as successful, there was a strong preference for the traditional lecture format over alternative approaches, stating subjective feelings of belongingness and connectedness to the physical campus.

Introduction The increase in intracranial pressure (ICP) is a neurological complication resulting from numerous pathologies that affect the brain and its compartments. Therefore, decompressive craniectomy (DC) is an alternative adopted to reduce ICP in emergencies, especially in cases refractory to clinical therapies, in favor of patient survival. However, DC is associated with several complications, including hydrocephalus (HC). The present study presents the results of an unusual intervention to this complication: the implantation of an external ventricular drain (EVD) in the intraoperative period of cranioplasty (CP). Methods Patients of both genders who presented with HC and externalization of the brain through the cranial vault after decompressive hemicraniectomy and underwent EVD implantation, to allow the CP procedure, in the same surgical procedure, were included. Results Five patients underwent DC due to a refractory increase in ICP, due to automobile accidents, firearm projectiles, falls from stairs, and ischemic strokes. All evolved with HC. There was no uniform time interval between DC and CP. The cerebrospinal fluid (CSF) was drained according to the need for correction of cerebral herniation in each patient, before undergoing cranioplasty. All patients progressed well, without neurological deficits in the immediate postoperative period. Conclusion There are still several uncertainties about the management of HC resulting from DC. In this context, other CP strategies simultaneous to the drainage of CSF, not necessarily related to ventriculoperitoneal shunt (VPS), should be considered and evaluated more deeply, in view of the verification of efficacy in procedures of this scope, such as the EVD addressed in this study.

Este trabalho discorre sobre a relevância da Educação Financeira para estudantes do ensino básico e tem como objetivo investigar como eles controlam suas finanças, trazendo à tona uma discussão à luz da modernidade líquida de Bauman (2001). Para realizá-lo, foi efetuada uma pesquisa com uma turma do 1º ano do ensino médio, em uma escola da rede particular, sendo 35 alunos participantes. Foram aplicadas problematizações com o intuito de identificar e analisar seus conhecimentos sobre Educação Financeira. Com base nas respostas das atividades foi possível compreender a relação dos alunos com os recursos financeiros e, para obter uma análise do entendimento dos jovens com relação à Educação Financeira, foi estabelecer algumas estratégias no sentido de orientá-los em suas limitações financeiras. Logo após análise dos dados foi possível constatar uma dificuldade dos alunos no desenvolvimento dos cálculos matemáticos. Concluiu-se que é importante que os alunos sejam educados financeiramente, pois assim, torna-se possível um planejamento em prol da qualidade de vida, em especial, a financeira. Estes resultados foram refletidos e discutidos à luz da concepção de Bauman (2001, 2008) a respeito da sociedade “líquida” e, inspirado na Teoria Das Situações Didáticas de Brousseau (1996, 2008), já que envolveram situações em sala de aula, com aluno, com professor e com o saber matemático.