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Transfer pricing practices remain a challenge for tax authorities in various countries because they can be used to reduce tax payments. This study aims to explore the impact of ownership structure on transfer pricing practices, focusing on how board experience and executive characteristics act as moderating factors. Additionally, the study considers three control variables: company size, debt to equity ratio, and ROE. The analysis encompasses all publicly listed companies on the Indonesia Stock Exchange, utilizing panel data analysis and moderated regression techniques. The dataset comprises 2,480 entries from 310 companies over an eight-year span from 2015 to 2022. The findings indicate that concentrated ownership positively influences transfer pricing, whereas managerial ownership exerts a negative influence. Meanwhile, foreign, institutional, and family ownership show no significant impact on transfer pricing activities. The experience of the board of directors only moderates the effect of ownership concentration on transfer pricing, with no other significant moderating effects observed. In contrast, executive characteristics successfully moderate the impact of foreign ownership, managerial ownership, and ownership concentration on transfer pricing but not institutional or family ownership.

La orquialgia crónica se define como un dolor escrotal unilateral o bilateral de al menos tres meses de duración. Es una de las causas más comunes de consulta urológica y continúa siendo un reto diag-nóstico y terapéutico. Las etiologías identificables de la orquialgia deben descartarse y tratarse cuando estén presentes.El tratamiento quirúrgico está reservado para los pacientes con fra-caso al tratamiento farmacológico y a intervenciones como el blo-queo del cordón espermático o la ablación con radiofrecuencia. La neurectomia de la rama genital del nervio genitofemoral, general-mente como parte de una triple neurectomia, es el tratamiento qui-rúrgico primario en el dolor escrotal. La denervación microquirúrgi-ca del cordón espermático es empleada en la orquialgia refractaria.

En este trabajo de investigación, se analizó un mineral de la zona de Yarusyacán, cuya mineralogía reveló la presencia de esfalerita tipo 2 con una granulometría de 35 a 150 micras, además de especies como cuarzo, pirita, pirrotita, silicatos de calcio y potasio, carbonatos cálcicos, galena, calcopirita e hidróxidos y óxidos de hierro. Sobre la base de la caracterización mineralógica, se realizaron pruebas a nivel de laboratorio que demostraron que la recuperación y la calidad de los concentrados de zinc pueden ser controladas a partir de la dosificación de un colector secundario, cuprocianuro, en la alimentación de la tercera limpieza. Los resultados de las pruebas demostraron que la dosificación de 35 g/t recuperó el 73.80% de Zn; en cambio, la dosificación de 50 g/t recuperó solo el 52.94%. De esta manera, quedó demostrado que tanto la ley como la recuperación de zinc aumentan cuando se dosifica cuprocianuro en mayor cantidad; sin embargo, el exceso de este reactivo tiende a disminuir estos valores.

Abstract Background Scotland currently has amongst the highest rates of drug-related deaths in Europe, leading to increased advocacy for safer drug consumption facilities (SDCFs) to be piloted in the country. In response to concerns about drug-related harms in Edinburgh, elected officials have considered introducing SDCFs in the city. This paper presents key findings from a feasibility study commissioned by City of Edinburgh Council to support these deliberations. Methods Using a multi-method needs assessment approach, we carried out a spatial and temporal analysis of drug-related data in Edinburgh including health, mortality, consumption, crime and service provision indicators; and 48 interviews including 22 people with lived/living experience (PWLE) of drug use in the city, five family members affected by drug-related harms, and 21 professional stakeholders likely to be involved in commissioning or delivering SDCFs. Data were collected using a convergent parallel design. We carried out a descriptive analysis of quantitative date and a thematic analysis of qualitative data. Quantitative data provides an overview of the local context in terms of recorded harms, service provision and consumption patterns as reported in prior surveys. Qualitative PWLE and families data captures the lived experiences of people who use drugs, and affected loved ones, within that local context, including perceived consumption trends, views on the practicality of SDCF provision, and hopes and anxieties regarding potential service provision. Professional stakeholders data provides insights into how people responsible for strategic planning and service delivery view the potential role of SDCF provision within the context described in the quantitative data. Results In Edinburgh, drug-related harms and consumption patterns are dispersed across multiple locations, with some areas of higher concentration. Reported levels of opioid use, illicit benzodiazepine use and cocaine injecting are high. Qualitative interviews revealed strong support for the provision of SDCFs, and a preference for services that include peer delivery. However, PWLE also expressed concerns regarding safety and security, and professional stakeholders remained uncertain as to the prioritisation of facilities and possible opportunity costs in the face of restricted budgets. Conclusion There is a strong case for the provision of SDCFs in Edinburgh. However, service design needs to reflect spatial distributions of consumption and harm, patterns of consumption by drug type, and expressed preferences for both informality and security among potential service users. Models of SDCF provision used elsewhere in Scotland would therefore need to be adapted to reflect such considerations. These findings may apply more broadly to potential SDCF provision in the UK and internationally, given changing patterns of use and harm.

Abstract Background This study evaluates retinal oxygen saturation and vessel density within the macula and correlates these measures in controls and subjects with type 2 diabetes (DM) with (DMR) and without (DMnR) retinopathy. Changes in retinal oxygen saturation have not been evaluated regionally in diabetic patients. Methods Data from seventy subjects (28 controls, 26 DMnR, and 16 DMR were analyzed. For those with DMR,8 were mild/moderate diabetic retinopathy (NPDR) and 8 severe NPDR/proliferative (PDR). Subjects were categorized with glycosylated hemoglobin A1c and fundus photography. Retinal oximetry measurements were performed within a 300–400 μm region at four diagonal locations 3.1 degrees from the center of the fovea in the superior nasal, superior temporal, inferior nasal, and inferior temporal locations adjacent to the foveal avascular zone (FAZ). Optical coherence tomography angiography (OCTA) was performed and corrected for refractive error. Photoshop and ImageJ were utilized to calculate the superficial capillary plexus vascular density (SCP). Oximetry and OCTA vessel density were analyzed overall and by region. Results Average retinal oxygen saturation was highest in DMR (p = 0.008). Average OCTA density was less in DMR compared to controls (p = 0.01), but not compared to DMnR subjects (p = 0.07). A significant inverse correlation was observed between averaged oxygen saturation and SCP vascular density for all subjects (p = 0.02). Duration of DM was positively associated with oxygen saturation (p = 0.01) and negatively with OCTA SCP vascular density (p = 0.009). There were no differential effects of retinal location. Conclusion To our knowledge, this study is the first to evaluate the relationship between macular oxygen saturation and SCP vascular density at different levels of retinopathy. This may be useful to track patients with DM as they move through stages of retinopathy.

Abstract Biostimulants are an emerging and innovative class of products that may mitigate the adverse effects of extreme heat, but research on their efficacy in fruit crops is limited. This study addressed this knowledge gap by evaluating the performance of three biostimulants, FRUIT ARMOR™, Optysil®, and KelpXpress™ [active ingredients glycine betaine, silicon, and kelp (Ascophyllum nodosum) extract, respectively] applied to three raspberry genotypes exposed to high temperatures (Tmax ≥ 35 °C/day) inside a glasshouse. ‘Meeker’ consistently maintained high chlorophyll fluorescence (Fv/Fm) and photosynthesis under control and biostimulant treatments. However, Fv/Fm and photosynthesis of WSU 2188 and ORUS 4715-2 increased when treated with FRUIT ARMOR™. KelpXpress™ also improved the Fv/Fm and photosynthesis of WSU 2188. ‘Meeker’ and WSU 2188 plants treated with FRUIT ARMOR™ and KelpXpress™ accumulated more anthocyanins and exhibited greater shoot and total biomass than ORUS 4715-2. Results demonstrate genotype and biostimulants vary in their ability to mitigate heat stress over time. Superior performance of ‘Meeker’ under control and biostimulant treatments manifested in improved heat tolerance. Biostimulants improved WSU 2188 and ORUS 4715-2 thermotolerance by improving PSII, photosynthetic, and antioxidative capacities. Results indicate biostimulants containing glycine betaine and kelp (Ascophyllum nodosum) extract enhance thermotolerance and may contribute to climate resiliency among commercial fruit crops exposed to heat stress.

Abstract The Eurasian avian-like (EA) H1N1 swine influenza virus (SIV) possesses the capacity to instigate the next influenza pandemic, owing to its heightened affinity for the human-type α-2,6 sialic acid (SA) receptor. Nevertheless, the molecular mechanisms underlying the switch in receptor binding preferences of EA H1N1 SIV remain elusive. In this study, we conduct a comprehensive genome-wide CRISPR/Cas9 knockout screen utilizing EA H1N1 SIV in porcine kidney cells. Knocking out the enzyme gamma glutamyl carboxylase (GGCX) reduces virus replication in vitro and in vivo by inhibiting the carboxylation modification of viral haemagglutinin (HA) and the adhesion of progeny viruses, ultimately impeding the replication of EA H1N1 SIV. Furthermore, GGCX is revealed to be the determinant of the D225E substitution of EA H1N1 SIV, and GGCX-medicated carboxylation modification of HA 225E contributes to the receptor binding adaption of EA H1N1 SIV to the α-2,6 SA receptor. Taken together, our CRISPR screen has elucidated a novel function of GGCX in the support of EA H1N1 SIV adaption for binding to α-2,6 SA receptor. Consequently, GGCX emerges as a prospective antiviral target against the infection and transmission of EA H1N1 SIV.

OBJECTIVES: Working outside the workplace and ordinary work hours has become common for a larger part of the working population. The objective of the current study was to examine the relationship between working after-hours and employee burnout, musculoskeletal pain, detachment and work–home conflict, delineating the independent effect of four different types of after-hours work, and the moderating role of work-time control. METHODS: The data comprised longitudinal questionnaire data from 1465 full-time employees in Norway across four waves (2021–2022). We examined the link between four types of after-hours work: (i) long daily work hours (>10 hours); (ii) late evening work (after 21:00 hours); (iii) quick returns (40 hours a week) and employee health and wellbeing (ie, work–home conflict, detachment, burnout, and musculoskeletal pain), in fixed effects models. We stratified the analyses by working-time control. RESULTS: The results support a link between late evening work, long daily and weekly work, and higher work–home conflict and lower detachment as well as between weekly work hours and higher burnout. The findings yielded limited support for work-time control as a moderating factor; the link between quick returns and burnout was only evident for employees with below-average work-time control. CONCLUSIONS: The four types of after-hours work were all independently related to at least one employee outcome, although the link with quick returns was only evident when work-time control was below average. The results are important for practitioners aiming to implement family-friendly and healthy practices.

Goal: This study aims to introduce a novel method for estimating maxillary sinus volume using smartphone technology, providing an accessible alternative to traditional imaging techniques. Methods: We recruited 40 participants to conduct a comparative analysis between Computed Tomography (CT) and face scans obtained using an Apple iPhone. Utilizing Apple's ARKit for 3D facial mesh modeling, we estimated sinus dimensions based on established craniofacial landmarks and calculated the volume through a geometric approximation of the maxillary sinus. Results: We demonstrated a high degree of agreement between CT and face scans, with Mean Absolute Percentage Errors (MAPE) of 8.006 ± 8.839% (Width), 6.725 ± 4.595% (Height), 9.952 ± 6.733% (Depth), and 10.429 ± 7.409% (Volume). These results suggest the feasibility of this non-invasive approach for clinical use. Conclusions: This method aligns with the growing focus on telemedicine, presenting significant reductions in healthcare costs and radiation exposure from CT scans. It marks a substantial advancement in otolaryngology and maxillofacial surgery, showcasing the integration of smartphone technology in medical diagnostics and opening avenues for innovative, patient-friendly, and cost-effective healthcare solutions.

This study has examined the design proposal for a support structure for a rainwater storage tank, utilizing CAD/CAE software with computational numerical analysis. These tools predict how elements will behave under specific conditions without physical construction. The necessity arises from the importance of developing the entire rainwater harvesting system to offer a sustainable water supply alternative. To this end, a storage capacity of 500 liters was determined based on locally available plastic tanks, considering the dimensions and weight the structure needs to support. 3D modeling utilized a 50 mm (2 in) square steel pipe discretized through meshing. Validation of this process achieved a skewness of 0.2401 with 414 651 elements and 601 334 nodes, defining the corresponding initial and boundary conditions. Von Mises stress measured 189.5 MPa, below the yield limit for structural steel, with structural element deformation not exceeding 0.83 mm. Design validation was accomplished through safety factor analysis, yielding a value of 1.746, closely aligning with recommended values for support structures.

Background: Rotator cuff tendon tears are a common cause of shoulder dysfunction in adults. Yet, impaired healing continues to result in higher failure rates after surgical repair resulting in patient dysfunction and prolonged recovery. This has spurred increased investigation of biologic augmentation to improve tendon healing. This study examines the outcome of peritendinous interleukin-17F (IL-17F) administration and oral low-dose lithium carbonate (Li) on rotator cuff healing following acute surgical repair in a rat model. Methods: Treatment group included an open supraspinatus peel and repair followed by a local injection of IL-17F at the bone–tendon interface and a 7-day course of oral Li. Control rats received no additional intervention before surgical closure. Evaluation of healing was then preformed using MRI imaging, biomechanical testing, and histological analysis at the bone–tendon interface. Results: Eighteen rats (9 control, 9 experimental) underwent complete testing. Combined treatment of peritendinous IL-17F and oral low-dose Li after rotator cuff repair improved rotator cuff healing in all outcomes when compared to controls. MRI imaging in the treatment group showed complete healing of all supraspinatus tendons across the anatomic footprint after repair. We also found significant increases in biomechanical stiffness compared to controls (P

Abstract Background The COVID-19 pandemic involved business closures (e.g., gyms), social distancing policies, and prolonged stressful situations that may have impacted engagement in health behaviors. Our study assessed changes in cancer-related health behaviors during the pandemic, specifically physical activity, fruit/vegetable intake, smoking/tobacco use, and alcohol consumption. Methods Eight cancer centers administered mailed/web-based/telephone surveys between June 2020 and March 2021. Surveys assessed demographics, perceptions on social distancing, and self-reported changes of behaviors (less/same/more) associated with cancer prevention or risk, e.g., physical activity, fruit/vegetable intake, tobacco/smoking use, and alcohol consumption. Descriptive analyses and logistic regression models assessed association of variables with behavior change. Results Most of the 21,911 respondents reported adhering to at least 4(of 5) social distancing measures (72%) and indicated social distancing was very/somewhat important to prevent the spread of COVID-19 (91%). 35% of respondents reported less physical activity, 11% reported less fruit/vegetable intake, 27% reported more smoking/tobacco use (among those who used tobacco/smoking products in past 30 days), and 23% reported more alcohol consumption (among those who reported at least 1 drink in past 30 days) than before the pandemic. Urban residence, younger age, female gender, and worse general health were associated with less physical activity, less fruit/vegetable intake, more smoking/tobacco use, and more alcohol intake. Higher educational attainment was associated with less physical activity and fruit/vegetable intake and more alcohol consumption. Reporting social distancing as important and adhering to more COVID-19 safety practices were associated with less physical activity and more alcohol consumption. Conclusion Our findings suggest that certain demographics and those who adhered to social distancing measures were more likely to self-report unfavorable changes in health behaviors during the pandemic. Future studies should examine if the behaviors returned to baseline following relief from pandemic restrictions, and if these behavior changes are associated with increased cancer incidence and mortality.

Abstract People living with HIV are at higher risk of heart failure and associated left atrial remodeling compared to people without HIV. Mechanisms are unclear but have been linked to inflammation and premature aging. Here we obtain plasma proteomics concurrently with cardiac magnetic resonance imaging in two independent study populations to identify parallels between HIV-related and aging-related immune dysfunction that could contribute to atrial remodeling and clinical heart failure. We discover a plasma proteomic signature that may in part reflect or contribute to HIV-associated atrial remodeling, many features of which are associated with older age and time to incident heart failure among an independent community-based cohort without HIV. This proteomic profile was statistically enriched for immune checkpoint proteins, tumor necrosis factor signaling, ephrin signaling, and extracellular matrix organization, identifying possible shared pathways in HIV and aging that may contribute to risk of heart failure.

Abstract Background Remaking Recess (RR) is a school-based evidence-based peer social engagement intervention for autistic students. RR involves direct training and coaching with educators; however, educators face several barriers to implementation at both the individual- and organizational-levels. This protocol paper describes a multi-site study that will test whether an educator-level implementation strategy, coaching, with or without a school-level implementation strategy, school-based teams, will maximize educators’ use (fidelity and sustainment) of RR for autistic students and their peers who are socially-isolated, rejected, or peripheral and may need additional support during recess. Methods This study will employ a hybrid type-3 effectiveness-implementation trial. Fifty-five elementary schools will be recruited as well as 121 educators (e.g., classroom assistants, aides), 55 general and special educator teachers, and 83–138 other school personnel (e.g., administrators). Additionally, at least 118 autistic students and allistic or non-autistic classmates will be recruited as RR recipients. Participants will complete baseline assessments at the beginning of the year, and all schools will be provided RR training. Schools will be randomized to coaching with or without school-based teams. This study will measure RR fidelity (primary outcome), RR sustainment, as well as peer engagement, social network inclusion, and social skills (secondary outcomes). It is expected that coaching with school-based teams will improve both RR fidelity and social network inclusion, while coaching with and without school-based teams will result in improved peer engagement and social skills. Discussion Previous research has documented barriers to RR implementation at both the individual- (provider) and organization-level (school). Using multi-level implementation strategies such as coaching with school-based teams may address these barriers and support RR implementation in schools. Findings from this study may guide future efforts to scale up tailored implementation strategies for use in public school districts, with the ultimate goal of increasing intervention access and improving student outcomes. Trial registration Name of the Registry: clinicaltrials.gov. Trial Registration: Clinical Trials ID: NCT06559267 . Date of Registration: August 15, 2024. Prospectively registered.

Introduction: Gamification, the application of game-like elements in nongame settings, has shown promise for increasing motivation across various sectors. However, their application in healthcare volunteering, particularly in Saudi Arabia, remains limited and understudied. Healthcare volunteers play a crucial role in service delivery; however, sustaining their motivation can be challenging. Aims: This study aimed to explore the effectiveness of gamification in enhancing motivation among healthcare volunteers in Saudi Arabia. Specifically, it examined the impact of gamification on situational motivation, distinguishing between intrinsic and extrinsic motivators, and assessed volunteers’ perceptions of the effectiveness of gamification. Materials and Methods: A cross-sectional mixed-methods design was used with a sample of 24 healthcare volunteers from a single organization in the Asir region. Participants completed pre- and postintervention surveys incorporating the Situational Motivation Scale (SIMS) and open-ended questions. The 4-week gamification intervention introduced elements such as points, badges, and leaderboards, to encourage engagement. Quantitative data were analyzed using descriptive statistics and paired-sample t-tests to assess changes in motivation levels, while thematic analysis was conducted on the qualitative responses. Results and Discussion: Preintervention data indicated generally high baseline motivation, with 54.2% of participants rating their motivation as highly motivated. The postintervention results revealed a statistically significant increase in intrinsic motivation (mean SIMS score: 6.53, standard deviation: 0.76), indicating that gamification positively influenced engagement. The thematic analysis highlighted core motivators, including skill development, community services, and personal growth. While participants appreciated gamification elements such as recognition and rewards, some raised concerns regarding fairness and the potential for competition to detract from the collaborative spirit. The findings suggest that gamification can effectively enhance both intrinsic and extrinsic motivation among healthcare volunteers, particularly when designed to align with their values and motivations. The study highlights the need for thoughtful implementation, ensuring that gamification supports rather than undermines the community-focused values prevalent in volunteer settings. Conclusion: This study demonstrates the potential of gamification as a viable tool for boosting motivation in healthcare volunteers, provided it is balanced by cultural and motivational factors. Healthcare organizations that consider gamification in volunteer management should prioritize fairness, transparency, and alignment with intrinsic values to foster sustainable engagement.

Abstract Background Globally, dementia care is under strain. Rising rates across ageing populations, coupled with overstretched health and care systems, mean that people living with dementia and their carers are missing out on crucial support. Addressing dementia care is a key priority for the UK government. This has led to a period of care transformation, including the implementation of new dementia support services across integrated care systems (ICS). However, little is known about how these new services work. This evaluation identifies how a dementia care coordinator service, implemented in the largest ICS in England, works for people living with dementia, their carers and the workforce. Methods A realist evaluation using mixed methods was carried out between 2022 and 2024. This involved a repeat survey with dementia care coordinators, carried out a year apart, alongside 57 interviews with coordinators, service managers, healthcare practitioners, people living with dementia and their carers. A realist logic of analysis was applied across all data sets. Results Three broad concepts were identified including (1) workforce design and organisational culture, (2) meeting the needs of people living with dementia and their carers and (3) connecting to services and integrating care. A total of 23 context-mechanism-outcome configurations (CMOCs) across these concepts highlighted that whilst tensions exist between the service and wider system, dementia care coordinators ultimately act as bridge builders, connecting people to much-needed support. However, services like this could become a victim of their own success due to increasing caseloads and the risk of staff burnout. Conclusions The dementia care coordinator service is capable of supporting people who are pre- and post-dementia diagnosis despite the care system being under strain. This is a direct result of the bridge building work of the dementia care coordinators. Our findings support evidence-based recommendations for those wanting to implement and sustain a system-wide service and provide evidence for policy makers to consider increased funding for this service nationwide.

Abstract The TGFβ signaling pathway is known for its pleiotropic functions in a plethora of biological processes. In melanoma, TGFβ signaling promotes invasiveness and metastasis formation. However, its involvement in the response to therapy is controversial. While several studies have linked TGFβ signaling to elevated resistance to targeted therapy in melanoma, separate findings have indicated a favorable treatment response through TGFβ-mediated increase of cell death. We now found that the outcome of TGFβ signaling in the context of targeted therapy is dose dependent. Unlike low doses, high levels of TGFβ signal activation induce apoptosis upon simultaneous MAPK pathway inhibition, even in targeted therapy resistant melanoma cell lines. Using transcriptomic analyses, combined with genomic target identification of the critical TGFβ signaling effector SMAD4, we demonstrate that parallel activation of TGFβ signaling and MAPK pathway inhibition causes a complete switch of TGFβ target genes from promoting pro-invasive processes to fueling pro-apoptotic pathways. Investigations of underlying mechanisms identified a novel apoptosis-inducing gene signature. Functional validation of signature members highlighted a central role of the pro-apoptotic BCL2 family member BCL2L11 (BIM) in mediating apoptosis in this condition. Using a modified, synthetic version of the TGFB1 mRNA for intra-tumoral injections, we additionally showcase a potential therapeutic application of this treatment combination.

Abstract Background There are a myriad of ways patient partners can enact their roles on research teams. International guidelines emphasize the need for a collaborative approach to determining these roles to try to improve research impact and positive patient partner experience. The aims of this review were to: (1) describe how patient partners’ roles as co-researchers in health research are determined; and (2) identify factors that influence how these decisions are made. Methods A scoping review was conducted. Four databases were searched plus citation searching occurred. Descriptions of English language studies of any design and commentaries of studies that report on patient partners’ or researchers’ reflections on their decision-making processes for engagement were included. Two reviewers completed screening and data extraction, with a third to resolve disagreements. Results were summarized and then content analysis was undertaken to synthesize the findings. Two patient partners contributed to the protocol development, screening, data interpretation, and manuscript writing at varying times during the process. Results A total of 45 papers (25 commentaries, 19 studies and 1 both a study and commentary) were included in this review. Most papers were from the United Kingdom (n = 15) and Canada (n = 12). Most patient partners had experiences related to chronic conditions rather than acute or time-limited illnesses. The synthesis yielded two categories. The first category, the research and research team attributes shape patient partner roles, encompassed patient partner, researcher and activity related factors that influenced patient partner engagement in activities. The second category, shared and ongoing decision-making, described the decision-making process to determine patient partner engagement, timing of these decisions, and tools to support these decisions. Conclusion A dynamic, systematic and shared decision-making approach to determining patient partners’ roles in the research process has the potential to support meaningful engagement and maximize benefits. Because the research process may evolve over time and patient partners situations can change, there may be a need to renegotiate the patient partner’s role.

With the gradual increase of microplastics in water bodies, it is essential to understand the current treatment processes for their removal. This study aims to investigate the removal of microplastics in synthetic solution by electrocoagulation (EC). The effects of electrode type, contact time (min), agitation speed (rpm) and current density (A/m²) were evaluated using a fractional factorial design. The results showed that the aluminum anode achieved a higher removal of microplastics than the iron anode, reaching 98.04% removal with the aluminum operational configuration within 15 min at 70 rpm and a current density of 20 A/m². A high correlation between the predicted and observed removal was evidenced, with values of R²= 0.99 and adjusted R²= 0.98, indicating a good agreement between the model and the experimental data, confirming the validity and feasibility of the adopted linear model. This study demonstrates that the electrocoagulation process has a great potential for the removal of microplastics.

In the world of sports today, young people have access to models of women athletes who seem to have it all, women whose actions push on gendered assumptions of love and the associated roles of women as sacrificial and subservient. And yet, young people, particularly young girls, wanting to navigate their worlds in ways that challenge conventional love, do not have the same power and privilege given their gender, age, and lack of financial autonomy. The young adult novel Furia invites young readers to evidence an adolescent character whose love of sport serves as a form of liberation from social constraints in a way that likely feels more resonant and doable, more real somehow. The protagonist’s engagement with and dedication to sport invite complications of ideological assumptions about love, particularly gendered narratives that position girls and women as bound by devotion This paper draws upon the youth lensand methods of critical context analysis to better understand how the protagonist is positioned as an athlete and a young woman and to offer interpretative thinking that explores how this title can help us (and young readers) think about love through the lens of sport.

Abstract Background The rate of suicide attempts by patients with bipolar disorder is high. In addition to patient and country specific factors, environmental factors may contribute to suicidal behavior. Sunlight has multiple diverse impacts on human physiology and behavior. Solar insolation is defined as the electromagnetic energy from the sun striking a surface area on earth. We previously found that a large change in solar insolation between the minimum and maximum monthly values was associated with an increased risk of suicide attempts in patients with bipolar I disorder. Methods The association between solar insolation and a history of suicide attempts in bipolar disorder was again investigated using an international database with 15% more data and more sites at diverse locations and countries. Results Data were available from 5641 patients with bipolar I disorder living at a wide range of latitudes in 41 countries in both hemispheres. A large change in solar insolation between the minimum and maximum monthly values was associated with a history of suicide attempts in patients with bipolar I disorder, a replication of our prior analysis. The estimated model also associated state sponsored religion in the onset country, female gender, a history of alcohol or substance abuse, and being part of a younger birth cohort with a history of suicide attempts. Conclusions A large change between the minimum and maximum monthly values of solar insolation was associated with a history of suicide attempts in bipolar I disorder, replicating our prior research. Physicians should be aware that daylight has wide ranging physiological and psychiatric impacts, and that living with large changes in solar insolation may be associated with an increased suicide risk.

Abstract Background Sleep is substantial issue for hospital inpatients and can negatively affect healing and recovery. There is a good evidence-base for interventions which can improve sleep, however currently they are not being implemented into NHS practice. To address the evidence-practice gap, we have conducted early-phase development for an inpatient sleep intervention (ASLEEP); a multi-level intervention to improve inpatient sleep in UK hospital wards. Methods We used an iterative development process incorporating Patient and Public Involvement and Engagement, ward staff surveys and stakeholder consultations (orthopaedic and acute medicine), and theoretical mapping using behaviour change theories. Development took place in four stages: identification of existing patient-level intervention components to improve sleep in hospital; identification of environmental barriers and facilitators to sleep in hospital; consultation with health professional stakeholders; and final theoretical mapping using the COM-B model and Theoretical Domains Framework, also considering who holds ‘change power’ for each change construct. Results We identified 18 variables contributing to inpatient sleep, which are malleable to change universally across hospital wards. Central domains for change were identified as the ward environment context and resources; to reduce noise from equipment (material resources), and social influence; to modulate staff and patient noise awareness and behaviours (group norms). Change power mapping identified key stakeholders as patients, ward staff, procurement/estates, and NHS management. Conclusions Improving sleep in hospital requires a whole-systems approach which targets environmental factors, staff behaviour, and patient behaviour. We have provided recommendations for a multi-level intervention, highlighting core areas for change and essential stakeholders who must be involved to progress implementation. The next stage of development will involve operationalising recommendations and piloting, including evaluating mechanisms of change. It will be important to continue working with a broad range of stakeholders to bridge the evidence-practice gap and support sustainable practice adoption.

Abstract Background The 313-variant polygenic risk score (PRS313) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Methods We explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank. The mean PRS was calculated by country in the BCAC dataset and by country of birth in the UK Biobank. We explored different approaches to reduce the observed heterogeneity in the mean PRS across the countries, and investigated the implications of the distribution variability in risk prediction. Results The mean PRS313 differed markedly across European countries, being highest in individuals from Greece and Italy and lowest in individuals from Ireland. Using the overall European PRS313 distribution to define risk categories, leads to overestimation and underestimation of risk in some individuals from these countries. Adjustment for principal components explained most of the observed heterogeneity in the mean PRS. The mean estimates derived when using an empirical Bayes approach were similar to the predicted means after principal component adjustment. Conclusions Our results demonstrate that PRS distribution differs even within European ancestry populations leading to underestimation or overestimation of risk in specific European countries, which could potentially influence clinical management of some individuals if is not appropriately accounted for. Population-specific PRS distributions may be used in breast cancer risk estimation to ensure predicted risks are correctly calibrated across risk categories.

Abstract Background Sickle cell disease (SCD) and β-thalassemia patients with elevated gamma globin (HBG1/G2) levels exhibit mild or no symptoms. To recapitulate this natural phenomenon, the most coveted gene therapy approach is to edit the regulatory sequences of HBG1/G2 to reactivate them. By editing more than one regulatory sequence in the HBG promoter, the production of fetal hemoglobin (HbF) can be significantly increased. However, achieving this goal requires precise nucleotide conversions in hematopoietic stem and progenitor cells (HSPCs) at therapeutic efficiency, which remains a challenge. Methods We employed Cas9 RNP-ssODN-mediated homology-directed repair (HDR) gene editing to mimic two naturally occurring HBG promoter point mutations; -175T > C, associated with high HbF levels, and −158 C > T, a common polymorphism in the Indian population that induces HbF under erythropoietic stress, in HSPCs. Results Asymmetric, nontarget ssODN induced high rates of complete HDR conversions, with at least 15% of HSPCs exhibiting both the −175T > C and −158 C > T mutations. Optimized conditions and treatment with the small molecule AZD-7648 increased this rate, with up to 57% of long-term engrafting human HSPCs in NBSGW mice containing at least one beneficial mutation. Functionally, in vivo erythroblasts exhibited high levels of HbF, which was sufficient to reverse the cellular phenotype of β-thalassemia. Further support through bone marrow MSC co-culture boosted complete HDR conversion rates to exceed 80%, with minimal InDels, improved cell viability, and induced fetal hemoglobin levels similar to those of Cas9 RNP-mediated indels at BCL11A enhancer and HBG promoter. Conclusions Cas9 RNP-ssODN-based nucleotide conversion at the HBG promoter offers a promising gene therapy approach to ameliorate the phenotypes of β-thalassemia and SCD. The developed approach can simplify and broaden applications that require the cointroduction of multiple nucleotide modifications in HSPCs.

Abstract The transition from secondary school to college or university is a well-known and well-studied risk period for weight and/or fat gain and not meeting the dietary recommendations. Higher education acts as a promising setting to implement nutrition interventions. An important condition for intervention success is that interventions are implemented as intended by the protocol and integrated in the institutional policy. Unfortunately, to date, there is only little understanding of the factors influencing adoption and implementation of nutrition interventions in higher education settings. This study aimed to provide insight into stakeholders’ perspectives on facilitators and barriers to adoption and implementation of nutrition interventions promoting healthy and sustainable diets among higher education students in Flanders. Eight online group interviews and three online individual interviews were conducted involving a total of 37 stakeholders (e.g., staff of student services and student restaurants) from ten Flemish higher education institutions with varying food policy quality scores, and one external catering company which provides catering in higher education institutions. A semi-structured interview guide based on the Consolidated Framework for Implementation Research (CFIR-framework) was used to facilitate the interviews. Afterwards, the data were analyzed using a combined inductive and deductive thematic approach led by the CFIR-framework. Most of the institutions’ food policies focused on the provision and promotion of healthy and sustainable nutrition. Therefore, the reported factors in the present study consequently relate primarily to these two strategies. Stakeholders preferred to adopt low cost and institution-tailored interventions supported by experts and evidence, considering them easier and less resourceful to implement in the specific context of the institution. They stressed the importance of considering both students’ and institution stakeholders’ needs and perspectives in the development of nutrition interventions and implementation plans. Furthermore, interventions should be focused on a combination of different ecological levels and various strategies. Future interventions should be developed participatively and should be focused on a combination of both individual and environmental levels. Higher education institutions are encouraged to use opportunities such as creating win–win situations within the institution, working together with research groups and engaging students through student associations. The findings of this research add to the literature on implementation science and inform future development and implementation of nutrition interventions in higher education settings.

Abstract Objective There is a growing number of monogenic disorders implicated in neurodevelopmental disorders (NDDs), including autism spectrum disorder and intellectual disability. Motor impairment is frequently seen in these disorders, although not clearly defined. We aimed to characterize the motor phenotype of genetic NDDs. Methods We analyzed data from Simons Searchlight, collecting information on patients with genetic NDDs. Data analyzed included Vineland Adaptive Behavior Scales Second Edition (Vineland‐II) motor standard scores, motor milestones and tone abnormalities. Results In total, 959 patients with 57 genetic disorders were included. Disorders associated with Vineland‐II motor standard score

Abstract Background Intravenous (IV) vasopressors are the mainstay of physiological support for hemodynamically unstable patients. However, the role of oral vasopressors remains unclear. The objective of our study was to evaluate the feasibility of evaluating midodrine for critically ill patients with IV vasopressor-dependent shock. Methods We conducted a single-center, concealed-allocation, parallel-group, blinded feasibility randomized controlled trial (RCT) evaluating the effect of oral midodrine versus placebo on IV vasopressor-dependent shock in the intensive care unit (ICU). The study was performed in a medical-surgical ICU at the University of Alberta Hospital from April 2021 to July 2022. We included patients aged 18 years or older admitted to the ICU with ongoing vasopressor support with decreasing vasopressor dose(s). Patients were randomly assigned 1:1 to midodrine or a placebo for the duration of their IV vasopressor therapy. The primary outcome was study feasibility and secondary outcomes included patient-centered outcomes. Feasibility was assessed through rate of recruitment, adherence to study protocol, and patient safety. Results Twenty patients were enrolled in the study and underwent randomization (n = 11 midodrine, n = 9 control). Recruitment was recorded at 1.2 participants per month, protocol adherence was 90%, and allocation remained concealed. No adverse events were reported in either group. Sepsis was the most common cause of shock in both groups. The midodrine group had a shorter length of ICU stay of 9.6 (SD 8.7) vs 10.4 (SD 14.5) days. Hospital mortality was lower for the midodrine group (n = 2, 18.2% vs n = 4, 37.5%). Vasopressor re-initiation after 24 h was more frequent in the midodrine group (n = 4, 36.4% vs n = 2, 25%). There were no readmissions to the ICU following discharge in either group. Conclusions The evaluation of midodrine for patients in the ICU is feasible and safe. This trial will inform future large-scale RCTs regarding the utility of midodrine in critically ill patients with IV vasopressor-dependent shock. Trial registration This pilot RCT was registered at clinicaltrials.gov (NCT04489589). Registered July 27, 2020. https://clinicaltrials.gov/study/NCT04489589

Abstract Background Accessible and contextually relevant healthcare research programs and networks for rural physicians are exceedingly rare, which hinders the development of social capital in an already isolating profession. This study aims to examine the impact of the Rural Health Research Capacity Building (RRCB) Program on enhancing cognitive, structural, and relational social capital through comprehensive research skills training, supported by professional teams and resources. Methods This study uses a mixed-methods approach with utilization of qualitative and quantitative data and pre-post quasi-experimental design. Data were collected prior and after completion of the program by means of surveys, focus group, and observation. Thirty-five rural physicians participated in this study from 2014 to 2021. Results The results show a significant increase in cognitive (pre-program = 0.37 vs. post-program = 0.61, p

Abstract Background Glyphosate use in the United States (US) has increased each year since the introduction of glyphosate-tolerant crops in 1996, yet little is known about its effects on the brain. We recently found that C57BL/6J mice dosed with glyphosate for 14 days showed glyphosate and its major metabolite aminomethylphosphonic acid present in brain tissue, with corresponding increases in pro-inflammatory cytokine tumor necrosis factor-⍺ (TNF-⍺) in the brain and peripheral blood plasma. Since TNF-⍺ is elevated in neurodegenerative disorders such as Alzheimer’s Disease (AD), in this study, we asked whether glyphosate exposure serves as an accelerant of AD pathogenesis. Additionally, whether glyphosate and aminomethylphosphonic acid remain in the brain after a recovery period has yet to be examined. Methods We hypothesized that glyphosate exposure would induce neuroinflammation in control mice, while exacerbating neuroinflammation in AD mice, causing elevated Amyloid-β and tau pathology and worsening spatial cognition after recovery. We dosed 4.5-month-old 3xTg-AD and non-transgenic (NonTg) control mice with either 0, 50 or 500 mg/kg of glyphosate daily for 13 weeks followed by a 6-month recovery period. Results We found that aminomethylphosphonic acid was detectable in the brains of 3xTg-AD and NonTg glyphosate-dosed mice despite the 6-month recovery. Glyphosate-dosed 3xTg-AD mice showed reduced survival, increased thigmotaxia in the Morris water maze, significant increases in the beta secretase enzyme (BACE-1) of amyloidogenic processing, amyloid-β (Aβ) 42 insoluble fractions, Aβ 42 plaque load and plaque size, and phosphorylated tau (pTau) at epitopes Threonine 181, Serine 396, and AT8 (Serine 202, Threonine 205). Notably, we found increased pro- and anti-inflammatory cytokines and chemokines persisting in both 3xTg-AD and NonTg brain tissue and in 3xTg-AD peripheral blood plasma. Conclusion Taken together, our results are the first to demonstrate that despite an extended recovery period, exposure to glyphosate elicits long-lasting pathological consequences. As glyphosate use continues to rise, more research is needed to elucidate the impact of this herbicide and its metabolites on the human brain, and their potential to contribute to dysfunctions observed in neurodegenerative diseases.

Abstract Boston Children’s Hospital has established a genomic sequencing and analysis research initiative to improve clinical care for pediatric rare disease patients. Through the Children’s Rare Disease Collaborative (CRDC), the hospital offers CLIA-grade exome and genome sequencing, along with other sequencing types, to patients enrolled in specialized rare disease research studies. The data, consented for broad research use, are harmonized and analyzed with CRDC-supported variant interpretation tools. Since its launch, 66 investigators representing 26 divisions and 45 phenotype-based cohorts have joined the CRDC. These studies enrolled 4653 families, with 35% of analyzed cases having a finding either confirmed or under further investigation. This accessible and harmonized genomics platform also supports additional institutional data collections, research and clinical, and now encompasses 13,800+ patients and their families. This has fostered new research projects and collaborations, increased genetic diagnoses and accelerated innovative research via integration of genomics research with clinical care.

Abstract Background Psychological distress often co-occurs with sleep disturbances; but the specific mechanisms linking the two remain unclear. A qualitative study explored perceptions and factors associated with sleep disturbances in cancer survivors between patients with varying levels of psychological distress. Methods Thirty-three Cantonese speaking mixed type cancer survivors were recruited from a community cancer care program. Participants that scored > 5 on the Pittsburgh Sleep Quality Index and had non-clinical or borderline to clinical levels of psychological distress underwent semi-structured interviews. Interviews were analyzed using grounded theory. Results Common triggers of sleep disturbances included unresolved treatment side-effects, intrusive thoughts about cancer and fear of cancer recurrence or progression, poor sleep hygiene and a lack of routine. Those with higher levels of distress exhibited more worry about recovery after cancer. Further, they engaged in thought suppression and experienced meta-worry about negative emotions and worry of poor sleep impacting recovery and cancer progression. They commonly exhibited high sleep reactivity and were observed to have limited social support. In contrast, those with low distress adopted better adaptive mechanisms, including a changed commitment to prioritizing health and positive reappraisal of their recovery progress. Self-distraction was used to cope with sleep disturbances and they had fewer expectations of good sleep quality. Conclusions Findings provided insights into the suitability of interventions for patients with sleep disturbances. Interventions targeting maladaptive emotion-focused coping may be more effective in addressing sleep disturbances in cancer survivors with higher distress. Interventions adopting a stepped-care approach may be advantageous in managing sleep disturbances by catering for varying levels of distress.

Abstract A few years into the COVID-19 pandemic, the SARS-CoV-2 Omicron strain rapidly becomes and has remained the predominant strain. To date, Omicron and its subvariants, while more transmittable, appear to cause less severe disease than prior strains. To study the cause of this reduced pathogenicity we compare SARS-CoV-2 ancestral Nsp6 with Nsp6-Omicron, which we have previously identified as one of the most pathogenic viral proteins. Here, through ubiquitous expression in Drosophila, we show that ancestral Nsp6 causes both structural and functional damage to cardiac, muscular, and tracheal (lung) tissue, whereas Nsp6-Omicron has minimal effects. Moreover, we show that ancestral Nsp6 dysregulates the glycolysis pathway and disrupts mitochondrial function, whereas Nsp6-Omicron does not. Through validation in mouse primary cardiomyocytes, we find that Nsp6-induced dysregulated glycolysis underlies the cardiac dysfunction. Together, the results indicate that the amino acid changes in Omicron might hinder its interaction with host proteins thereby minimizing its pathogenicity.

Abstract Background Urgency urinary incontinence (UUI), a risk factor for falls, affects 40% of women over the age of 70 years. Multicomponent interventions have the potential to decrease the risk of falls and urinary symptoms in women. We previously designed and conducted a pilot study of a multicomponent, theory-driven intervention in women with UUI. The Mobility and Voiding Exercises in Older Women with Urinary Incontinence (MoVEonUp) Trial will assess the efficacy of this intervention to decrease falls and urinary incontinence in community-dwelling older women. Methods In the MoVEonUp Trial, 314 women ages ≥ 70 years with UUI will be randomized to the intervention group or an attention control group. Women randomized to the intervention will participate in a home-based multicomponent program consisting of strength and balance training, bladder training with urge suppression strategies, and a home hazard assessment by an occupational therapist. Women in the control group will receive an educational booklet on falls prevention and behavioral treatment for urinary incontinence. Outcomes of falls, urinary incontinence, physical function, functional limitations, and mobility will be measured at 3, 6, 9, and 12 months. Discussion This study will determine if a home-based multicomponent program reduces the risk of falls and improves incontinence among older women with UUI. If the intervention is efficacious, it will help address the critical need to reduce falls in this population via an intervention that can be implemented in the home setting. Clinical trial registration NCT05375344

Abstract Background Ductal carcinoma in-situ (DCIS) is a pre-invasive form of invasive breast cancer (IBC). Due to improved breast cancer screening, it now accounts for ~ 25% of all breast cancers. While the treatment success rates are over 90%, this comes at the cost of considerable morbidity, considering that the majority of DCIS never become invasive and our understanding of the molecular changes occurring in DCIS that predispose to invasive disease is limited. The aim of this study is to characterize molecular changes that occur in DCIS, with the goal of improving DCIS risk stratification. Methods We identified and obtained a total of 197 breast tissue samples from 5 institutions (93 DCIS progressors, 93 DCIS non-progressors, and 11 adjacent normal breast tissues) that had at least 10-year follow-up. We isolated DNA and RNA from archival tissue blocks and characterized genome-wide mRNA expression, DNA methylation, DNA copy number variation, and RNA splicing variation. Results We obtained all four genomic data sets in 122 of the 197 samples. Our intrinsic expression subtype-stratified analyses identified multiple molecular differences both between DCIS subtypes and between DCIS and IBC. While there was heterogeneity in molecular signatures and outcomes within intrinsic subtypes, several gene sets that differed significantly between progressing and non-progressing DCIS were identified by Gene Set Enrichment Analysis. Conclusion DCIS is a molecularly highly heterogenous disease with variable outcomes, and the molecular events determining DCIS disease progression remain poorly defined. Our genome-wide multi-omic survey documents DCIS-associated alterations and reveals molecular heterogeneity within the intrinsic DCIS subtypes. Further studies investigating intrinsic subtype-stratified characteristics and molecular signatures are needed to determine if these may be exploitable for risk assessment and mitigation of DCIS progression. The highly significant associations of specific gene sets with IBC progression revealed by our Gene Set Enrichment Analysis may lend themselves to the development of a prognostic molecular score, to be validated on independent DCIS cohorts.

AbstractFalls among older adults (aged 65 years and older) are a public health concern in Canada. Fall-related injuries can cause a reduction in quality of life among older adults, and death. They also entail substantial health care costs. It is essential to monitor fallrelated injuries and deaths among older adults to better understand temporal trends and characteristics and to evaluate fall prevention strategies. We used the most up-to-date data from the Canadian Vital Statistics–Death database, Discharge Abstract Database and National Ambulatory Care Reporting System to analyze the temporal trends of fallrelated mortality, hospitalizations and emergency department (ED) visits among older adults in Canada over more than a decade. Age and sex characteristics were also examined. In 2022, 7189 older adults died due to a fall in Canada (excluding Yukon). From 2010 to 2022, deaths due to falls generally increased in both number and rates. In fiscal year 2023/24, there were 81 599 fall-related hospitalizations in Canada (excluding Quebec) and 212 570 fall-related ED visits in Ontario and Alberta. From fiscal year 2010/11 to 2023/24, even though the overall trend of the rates of fall-related hospitalizations and ED visits did not increase, the numbers generally rose year by year except in 2020/21, the early stage of the COVID-19 pandemic. As for the age and sex characteristics, the rates for deaths, hospitalizations and ED visits rose with advancing age for both men and women. With the aging population, continuous monitoring of the trends is crucial for fall prevention.

RésuméLes chutes chez les aînés (65 ans et plus) constituent un problème de santé publique au Canada. Les blessures liées aux chutes sont susceptibles d’entraîner une réduction de la qualité de vie chez les aînés ou de causer la mort. Elles entraînent également des coûts importants en matière de soins de santé. Il est essentiel de réaliser un suivi des blessures et des décès liés aux chutes chez les aînés afin de mieux en comprendre les tendances temporelles et les caractéristiques et d’évaluer les stratégies de prévention des chutes. Nous avons utilisé les plus récentes données de la Base canadienne de données de l’état civil – Décès, de la Base de données sur les congés des patients et du Système national d’information sur les soins ambulatoires pour analyser les tendances des décès, des hospitalisations et des visites à l’urgence liées aux chutes chez les aînés au Canada sur plus de dix ans. Nous avons également effectué une analyse en fonction de l’âge et du sexe. En 2022, dans l’ensemble du Canada (à l’exception du Yukon), 7 189 aînés sont décédés en raison d’une chute. Entre 2010 et 2022, de manière générale, le nombre et le taux de décès attribuables aux chutes ont augmenté. Au cours de l’exercice 2023-2024, il y a eu 81 599 hospitalisations liées aux chutes dans l’ensemble du Canada (à l’exception du Québec) et 212 570 visites à l’urgence liées aux chutes en Ontario et en Alberta. Entre 2010-2011 et 2023-2024, si la tendance générale des taux d’hospitalisation et de visite à l’urgence liées aux chutes n’a pas augmenté, leur nombre a généralement augmenté d’une année sur l’autre, sauf en 2020-2021, soit au début de la pandémie de COVID-19. En ce qui a trait à l’âge et au sexe, les taux de décès, d’hospitalisation et de visite à l’urgence ont augmenté avec l’âge à la fois chez les hommes et chez les femmes. Compte tenu du vieillissement de la population, la surveillance continue des tendances est essentielle pour la prévention des chutes.

Purpose: Stroke is one of the leading causes of disability with life-long implications requiring assessment and treatment of several functional domains. This review identifies the results from research into music-based interventions (MBIs), including music therapy (MT), for executive functions (EFs) and emotional well-being (EWB) in adults with stroke and highlights opportunities for clinical practice and future research. Methods: APA PsycInfo (EBSCOhost), and CINAHL (EBSCOhost) were searched, in addition to grey literature. Results: A total of 49 studies were included and encompassed experimental, analytic, and descriptive observational studies, and case reports, involving a total of 1663 participants. In total, 32 studies included MT interventions, and 17 were MBIs. EFs were an outcome in 20.41%, and EWB in 61.22% of studies, for which active interventions were the most utilized. Overall, 73.47% of the studies reported positive results. Conclusions: This scoping review indicates that music interventions can be beneficial for the improvement of different aspects of EFs and EWB at different stages of stroke recovery. Further research may benefit clinical practice by including standardized protocols, outcome and self-reported measures, and brain imaging data to determine the effects of interventions and support evidence-based decisions for treatment policies for stroke survivors.

Gifted education is of utmost importance in the development and growth of intellectually advanced students; however, it often encounters various obstacles that hinder its effectiveness. This research delves into the perspectives of teachers regarding the overcoming of these barriers to providing effective gifted education. Employing qualitative research methods, a combination of interviews and surveys is conducted to gather valuable insights from a diverse group of teachers. The findings shed light on several challenges faced by teachers, including limited resources, inadequate training, and insufficient support from stakeholders. To address these challenges, teachers put forth potential solutions that could lead to the improvement of gifted education. These solutions encompass enhanced professional development opportunities for teachers, increased funding to allocate resources effectively, and the promotion of collaboration among all stakeholders involved. By effectively addressing these barriers, a more inclusive and nurturing environment can be fostered for gifted students. The study underlines the importance of integrating modules on gifted education into teacher education programs. By incorporating these modules, future educators can be equipped with the knowledge and skills necessary to effectively support and educate gifted students. Consequently, the implementation of the GATE policy to promote good practice plays a key role in gifted education. Ultimately, this research contributes to a deeper understanding of the challenges faced in gifted education and provides valuable insights that can inform policies and practices aimed at supporting the education of gifted students.

Abstract This paper studies the performance of target detection and classification algorithms applied to synthetic aperture radar (SAR) data. We describe a process to merge measured environmental SAR scene images with target image chips to produce a large dataset for training deep learning algorithms. Three algorithms, RetinaNet, EfficientDet, and YOLOv5, were trained using a powerful cloud server. Performance at inference time, in terms of speed and accuracy, was tested on both the cloud server and a low size weight and power (SWAP) single board computer. YOLOv5 was found to be the most accurate and fastest algorithm on the cloud server but the slowest on the low‐SWAP device. RetinaNet and EfficientDet produced operationally useful throughput on the low‐SWAP device for surveillance applications, with RetinaNet having the higher accuracy. Further qualitative analysis of algorithm performance on additional data with different characteristics highlighted the importance of gathering relevant training data and carrying out suitable pre‐processing steps.

Abstract The provision of social care for people in prison in England has historically been lacking. Seeking to address this, the 2014 Care Act clarified that local authorities are responsible for identifying, assessing and meeting prisoners’ social care needs. Against this background, in 2020 we undertook a survey to explore the emerging services for this group. Eighty-six (57%) local authorities responded. A mixed methods approach was taken. Numerical data were analysed through descriptive statistics with comparisons made to the previous survey. An inductive approach to thematic analysis was used to analyse the free text responses. The findings revealed some improvements since the 2015/16 surveys, including the wider introduction of self-referral systems, the success of peer supporters in identifying people in need of social care and greater multi-disciplinary working. However, other issues remained stubbornly persistent, including a dearth of systematic processes to identify those needing social care on release from prison, a lack of timely information sharing and disputes over the sending and receiving authorities’ responsibilities. There were also particular concerns about the shortage of appropriate accommodation for people leaving prison. Perhaps the most striking finding, however, was how little most authorities knew about this population. Building on discussions in previous papers, we explore three ways in which arrangements could be strengthened for this group: the collection of better data, the wider use of release on temporary licence and the greater employment of technology in planning people’s release.

Abstract Medical educators face wicked (complex) problems. Few faculty development (FD) programs exist specifically designed for rural physicians. Memorial University created the 6for6 program, a longitudinal FD program in foundational research skills for rural physicians. This work explores the use of the Adaptive Action Method in tackling wicked problems in rural faculty development.

Abstract Exon skipping technologies enable exclusion of targeted exons from mature mRNA transcripts, which have broad applications in medicine and biotechnology. Existing techniques including antisense oligonucleotides, targetable nucleases, and base editors, while effective for specific applications, remain hindered by transient effects, genotoxicity, and inconsistent exon skipping. To overcome these limitations, here we develop SPLICER, a toolbox of next-generation base editors containing near-PAMless Cas9 nickase variants fused to adenosine or cytosine deaminases for the simultaneous editing of splice acceptor (SA) and splice donor (SD) sequences. Synchronized SA and SD editing improves exon skipping, reduces aberrant splicing, and enables skipping of exons refractory to single splice site editing. To demonstrate the therapeutic potential of SPLICER, we target APP exon 17, which encodes amino acids that are cleaved to form Aβ plaques in Alzheimer’s disease. SPLICER reduces the formation of Aβ42 peptides in vitro and enables efficient exon skipping in a mouse model of Alzheimer’s disease. Overall, SPLICER is a widely applicable and efficient exon skipping toolbox.

Abstract Blood transcriptional biomarkers of acute viral infections typically reflect type 1 interferon (IFN) signalling, but it is not known whether there are biological differences in their regulation that can be leveraged for distinct translational applications. We use high frequency sampling in the SARS-CoV-2 human challenge model to show induction of IFN-stimulated gene (ISG) expression with different temporal and cellular profiles. MX1 gene expression correlates with a rapid and transient wave of ISG expression across all cell types, which may precede PCR detection of replicative infection. Another ISG, IFI27, shows a delayed but sustained response restricted to myeloid cells, attributable to gene and cell-specific epigenetic regulation. These findings are reproducible in experimental and naturally acquired infections with influenza, respiratory syncytial virus and rhinovirus. Blood MX1 expression is superior to IFI27 expression for diagnosis of early infection, as a correlate of viral load and for discrimination of virus culture positivity. Therefore, MX1 expression offers potential to stratify patients for antiviral therapy or infection control interventions. Blood IFI27 expression is superior to MX1 expression for diagnostic accuracy across the time course of symptomatic infection and thereby, offers higher diagnostic yield for respiratory virus infections that incur a delay between transmission and testing.

Abstract Background Socio-economic status is associated with self-harm at the individual and area level. In Canada, there is limited evidence on the relationship between area-level markers of socio-economic status and self-harm. The objective of this study was to assess the impact of small area-level material and social deprivation on rates of hospitalization due to self-harm. Methods Administrative data on hospitalizations from two databases in Canada (Discharge Abstract Database and Ontario Mental Health Reporting System) for the period April 1, 2015 to March 31, 2022, were analyzed. Rates of self-harm hospitalization and percentage of repeated admissions were estimated across quintiles of material and social deprivation. Rate ratios were computed to evaluate disparities. The rates were stratified by sex and age group; the percentage of repeated admissions were stratified by sex. Results In total, the study included 109,398 hospitalizations due to self-harm. Populations in more deprived areas had higher rates of self-harm hospitalizations than those in less deprived areas. The rate ratios for people who lived in the most deprived areas over the least deprived areas were 1.48 (95% CI: 1.38–1.58) and 1.71 (95% CI: 1.60–1.82) for material and social deprivation, separately. The largest disparity was among people aged 25–44 years for material and 45–64 years for social deprivation. Percentages of repeated self-harm hospitalizations were significantly higher in more deprived areas compared to less deprived areas for social deprivation, and among males but not females for material deprivation. Conclusions Both material and social deprivation were associated with self-harm hospitalization and repeated admissions; the disparity varied by subgroup and the deprivation components. This study demonstrated a need to consider interventions at the neighbourhood level and address both community and population-level conditions of social and material need.

Abstract Background Cancer navigation programs aim to support, educate, and empower patients and families, addressing barriers to diagnostics, treatment, and care. Navigators engage with people to ensure timely access to services and resources. While promising for older people with cancer, these programs are scarce in Europe, and research on their effectiveness and implementation is limited. We describe the protocol of the EU NAVIGATE randomized controlled trial, aimed to evaluate (1) effectiveness and cost-effectiveness of NavCare-EU, an intervention that aims to support older people with cancer throughout their illness trajectory, spanning the continuum of supportive, palliative, and end-of-life care, and (2) the intervention’s implementation processes and feasibility of its integration into different health care systems in Europe, contextual barriers and facilitators for effective and sustainable implementation, and mechanisms involved in reaching the outcomes. Methods We will conduct a multisite pragmatic fast-track randomized controlled trial with embedded convergent mixed-method process evaluation in Belgium, Ireland, Italy, Netherlands, Poland, and Portugal. The study targets people with cancer and declining health, 70 years or older, and their close family caregivers. The trial compares the NavCare-EU intervention plus standard care with standard care alone. We will perform a baseline measurement prior to randomization and follow-up measurements at 12 weeks, 24 weeks, and 48 weeks in intervention and control group, and an additional measurement at 72 weeks in the control group. Primary outcomes, measured at 24 weeks are (1) the older person’s global health status/quality of life, a 2-item subscale from EORTC-QLQ-C30 (revised) measuring health-related quality of life, (2) level of social support measured with Medical Outcomes Study Social Support Survey (MOS-SSS scale). The study will include at least 246 older persons with completed global health status/quality of life at 24 weeks. Discussion The EU NAVIGATE trial will cross-nationally test the effectiveness and cost-effectiveness of a navigation intervention for older people with cancer and their family caregivers, and its implementation in different health care systems in Europe. As continuity and access to health, social, and community care is a priority for patients and caregivers, the trial is timely and critically needed. Trial registration Clinicaltrials.gov: identifier NCT06110312 (2023/10/31).

Highlights The inaugural Clinical and Scientific Conference on Adenylosuccinate Synthetase 1 (ADSS1) myopathy was held on June 3, 2024, at the National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS) in Rockville, Maryland, USA. ADSS1 myopathy is an ultra-rare, inherited neuromuscular disease. Features of geographical patient clusters in South Korea, Japan, India and the United States of America were characterised and discussed. Pre-clinical animal and cell-based models were discussed, providing unique insight into disease pathogenesis. The biochemical pathogenesis was discussed, and potential therapeutic targets identified. Potential clinical and pre-clinical biomarkers were discussed. An ADSS1 myopathy consortium was established and a roadmap for therapeutic development created.

Abstract Triple-negative inflammatory breast cancer (TN-IBC) is the most aggressive type of breast cancer, yet its defining genomic, molecular, and immunological features remain largely unknown. In this study, we performed the largest and most comprehensive genomic and transcriptomic analyses of prospectively collected TN-IBC patient samples from a phase II clinical trial (ClinicalTrials.gov, NCT02876107, registered on August 22, 2016) and compared them to similarly analyzed stage III TN-non-IBC patient samples (ClinicalTrials.gov, NCT02276443, registered on October 21, 2014). We found that TN-IBC tumors have distinctive genomic, molecular, and immunological characteristics, including a lower tumor mutation load than TN-non-IBC, and an association of immunosuppressive tumor-infiltrating immune components with an unfavorable response to neoadjuvant chemotherapy. To our knowledge, this is the only study in which TN-IBC and TN-non-IBC samples were collected prospectively. Our analysis improves the understanding of the molecular landscape of the most aggressive subtype of breast cancer. Further studies are needed to discover novel prognostic biomarkers and druggable targets for TN-IBC.

Abstract Primary care clinicians play a key role in asthma and asthma exacerbation management worldwide because most patients with asthma are treated in primary care settings. The high burden of asthma exacerbations persists and important practice gaps remain, despite continual advances in asthma care. Lack of primary care-specific guidance, uncontrolled asthma, incomplete assessment of exacerbation and asthma control history, and reliance on systemic corticosteroids or short-acting beta2-agonist-only therapy are challenges clinicians face today with asthma care. Evidence supports the use of inhaled corticosteroids (ICS) + fast-acting bronchodilator treatments when used as needed in response to symptoms to improve asthma control and reduce rates of exacerbations, and the symptoms that occur leading up to an asthma exacerbation provide a window of opportunity to intervene with ICS. Incorporating patient perspectives and preferences when designing asthma regimens will help patients be more engaged in their therapy and may contribute to improved adherence and outcomes. This expert consensus contains 10 Best Practice Advice Points from a panel of primary care clinicians and a patient representative, formed in collaboration with the International Primary Care Respiratory Group (IPCRG), a clinically led charitable organization that works locally and globally in primary care to improve respiratory health. The panel met virtually and developed a series of best practice statements, which were drafted and subsequently voted on to obtain consensus. Primary care clinicians globally are encouraged to review and adapt these best practice advice points on preventing and managing asthma exacerbations to their local practice patterns to enhance asthma care within their practice.

Abstract Historic inequalities among different income groups remain a contentious issue affecting neighbourhood sustainability, particularly in South Africa. Prior studies frequently focused on the separate influence of income and other variables of neighbourhood satisfaction, failing to thoroughly explore how these variables intersect and interact with one another. The key objective of this study is to examine the interplay of income and other drivers of neighbourhood satisfaction in the Gauteng Province of South Africa to determine the net importance of household income on one’s neighbourhood satisfaction. The study analyses a sample of 8996 adult respondents interviewed in the Quality of Life 6 Survey (2020/21) conducted in the highly urbanised Gauteng province of South Africa. Bivariate and multivariable statistical techniques are employed to estimate the magnitude of the association between household income and neighbourhood satisfaction. The results show a strong association between household income and individuals’ neighbourhood satisfaction. However, neighbourhood satisfaction based on income alone does not offset the adverse roles of other non-monetary factors as individual and contextual factors. It is imperative to comprehensively understand the interactions between income and other drivers of neighbourhood satisfaction to address various disparities and inequities among income groups and create customised interventions to enhance good housing outcomes and neighbourhood satisfaction in Gauteng.