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Background and aimsThe precise roles of screen media activity (SMA) and sleep problems in relation to child/adolescent psychopathology remain ambiguous. We investigated temporal relationships among sleep problems, SMA, and psychopathology and potential involvement of thalamus-prefrontal-cortex (PFC)-brainstem structural covariation.MethodsThis study utilized data from the Adolescent Brain Cognitive Development study (n = 4,641 ages 9-12) at baseline, Year1, and Year2 follow-up. Cross-Lagged Panel Models (CLPMs) investigated reciprocal predictive relationships between sleep duration/problems, SMA, and psychopathology symptoms. A potential mediating role of baseline Thalamus-PFC-brainstem covariation on SMA-externalizing relationships was examined.ResultsParticipants were divided into discovery (n = 2,359, 1,054 girls) and replication (n = 2,282, 997 girls) sets. CLPMs showed 1) bidirectional associations between sleep duration and SMA in late childhood, with higher frequency SMA predicting shorter sleep duration (β = -0.10 [95%CI: -0.16, -0.03], p = 0.004) and vice versa (β = -0.11 [95%CI: -0.18, -0.05], p < 0.001); 2) externalizing symptoms at age 10-11 predicting sleep problems (β = 0.11 [95%CI: 0.04, 0.19], p = 0.002), SMA (β = 0.07 [95%CI: 0.01, 0.13], p = 0.014), and internalizing symptoms (β = 0.09 [95%CI: 0.05, 0.13], p < 0.001) at age 11-12; and 3) externalizing behavior at age 10-11 partially mediating the relationship between baseline thalamus-PFC-brainstem covariation and SMA at age 11-12 (indirect effect = 0.032 [95%CI: 0.003, 0.067], p-value = 0.030). Findings were replicable.ConclusionWe found bi-directional SMA-sleep-duration associations in late childhood. Externalizing symptoms preceded future SMA and sleep disturbances and partially mediated relationships between structural brain covariation and SMA. The findings emphasize the need for understanding individual differences and developing and implementing integrated strategies addressing both sleep concerns and screen time to mitigate potential impacts on psychopathology.

This article considers the reauthorization of the Elementary and Secondary Education Act (ESEA) in light of current educational inequities and the impact of the pandemic. The reauthorization presents an opportunity to center equity and justice and revitalize the civil rights aspects of the law. The authors review recent studies about the myriad ways the COVID-19 pandemic affected students, teachers and school systems and situates the reauthorization within the broader political context, including federal aid to states and districts during the pandemic. The authors present overarching policy recommendations: (1) a restructuring of the law's titles to focus on students, teachers, and systems (i.e. schools and districts); (2) a focus on the principles of racial equity, an ecosystem approach to serve students' needs across policy silos (i.e., housing and health), and a focus on research evidence; (3) policy targets for students; (4) policy targets for educators, including professional renewal and retention; (5) policy targets for the education system as a whole, including a focus on fiscal equity and facilitating regional approaches to cross-sector collaborations. The article presents a coherent conceptual framework for a redesign of ESEA with an emphasis on equity, evidence use, and ecosystems that is argued would directly address the needs of students, teachers, and systems.

Youth screen media activity is a growing concern, though few studies include objective usage data. Through the longitudinal, U.S.-based Adolescent Brain Cognitive Development (ABCD) Study, youth (mage = 14; n = 1415) self-reported their typical smartphone use and passively recorded three weeks of smartphone use via the ABCD-specific Effortless Assessment Research System (EARS) application. Here we describe and validate passively-sensed smartphone keyboard and app use measures, provide code to harmonize measures across operating systems, and describe trends in adolescent smartphone use. Keyboard and app-use measures were reliable and positively correlated with one another (r = 0.33) and with self-reported use (rs = 0.21-0.35). Participants recorded a mean of 5 h of daily smartphone use, which is two more hours than they self-reported. Further, females logged more smartphone use than males. Smartphone use was recorded at all hours, peaking on average from 8 to 10 PM and lowest from 3 to 5 AM. Social media and texting apps comprised nearly half of all use. Data are openly available to approved investigators ( https://nda.nih.gov/abcd/ ). Information herein can inform use of the ABCD dataset to longitudinally study health and neurodevelopmental correlates of adolescent smartphone use.

This review has two primary objectives: (1) to offer a balanced examination of recent findings on the relationship between screen media activity (SMA) in young individuals and outcomes such as sleep patterns, mood disturbances, anxiety-related concerns, and cognitive processes; and (2) to introduce a novel multi-level system model that integrates these findings, resolves contradictions in the literature, and guides future studies in examining key covariates affecting the SMA-mental health relationship. Key findings include: (1) Several meta-analyses reveal a significant association between SMA and mental health issues, particularly anxiety and depression, including specific negative effects linked to prolonged screen time; (2) substantial evidence indicates that SMA has both immediate and long-term impacts on sleep duration and quality; (3) the relationship between SMA and cognitive functioning is complex, with mixed findings showing both positive and negative associations; and (4) the multifaceted relationship between SMA and various aspects of adolescent life is influenced by a wide range of environmental and contextual factors. SMA in youth is best understood within a complex system encompassing individual, caregiver, school, peer, and environmental factors, as framed by Bronfenbrenner's ecological systems theory, which identifies five interrelated systems (microsystem, mesosystem, exosystem, macrosystem, and chronosystem) that influence development across both proximal and distal levels of the environment. This model provides a framework for future research to examine these interactions, considering moderating factors, and to develop targeted interventions that can mitigate potential adverse effects of SMA on mental well-being.

Abstract This study investigates the desiccation process of soft-tissue in South Africa, analyzing its interaction with environmental parameters and its implications for estimating the post-mortem interval. Through the examination of four decomposing porcine bodies across two summer seasons and one winter season, the research quantifies desiccation patterns using custom-designed and constructed printed circuit boards to measure the moisture content of body tissue over time. Generalized additive models were used to determine the environmental forces driving desiccation. Tissue resistivity was tested against the environmental predictor variables to determine the amount of variation they account for, and predicted values of the region-specific tissue resistivity variables were measured for each decomposing body. Results reveal distinct desiccation trajectories between summer and winter, with summer conditions conducive to precocious natural mummification. Environmental factors, particularly temperature and solar radiation, emerge as significant drivers of desiccation. This study represents the first quantitative analysis of deep tissue desiccation internationally, but also the first quantitative assessment of desiccation and natural precocious mummification in the Western Cape, South Africa. The exploration of desiccation as a potential indicator for estimating PMI opens new avenues for research and the integration of innovative methodologies and technologies promises to revolutionize forensic taphonomy practices.

Abstract Youth screen media activity is a growing concern, though few studies include objective usage data. Through the longitudinal, U.S.-based Adolescent Brain Cognitive Development (ABCD) Study, youth (mage = 14; n = 1415) self-reported their typical smartphone use and passively recorded three weeks of smartphone use via the ABCD-specific Effortless Assessment Research System (EARS) application. Here we describe and validate passively-sensed smartphone keyboard and app use measures, provide code to harmonize measures across operating systems, and describe trends in adolescent smartphone use. Keyboard and app-use measures were reliable and positively correlated with one another (r = 0.33) and with self-reported use (rs = 0.21–0.35). Participants recorded a mean of 5 h of daily smartphone use, which is two more hours than they self-reported. Further, females logged more smartphone use than males. Smartphone use was recorded at all hours, peaking on average from 8 to 10 PM and lowest from 3 to 5 AM. Social media and texting apps comprised nearly half of all use. Data are openly available to approved investigators ( https://nda.nih.gov/abcd/ ). Information herein can inform use of the ABCD dataset to longitudinally study health and neurodevelopmental correlates of adolescent smartphone use.

This experiment (N = 1,019) examined how a state of processing fluency, induced through either an easy or difficult task (reading a simple vs. complex message or recalling few vs. many examples) impacted participants’ ability to subsequently detect misinformation. The results revealed that, as intended, easier tasks led to higher reports of processing fluency. In turn, increased processing fluency was positively associated with internal efficacy. Finally, internal efficacy was positively related to misinformation detection using a signal detection task. This work suggests that feelings of ease while processing information can promote confidence and a more discerning style of information processing. Given the proliferation of misinformation online, an understanding of how metacognitions – like processing fluency – can disrupt the tacit acceptance of information carries important democratic and normative implications.

Research provides ample evidence that positive social relations and access to knowledge are supportive for educational change. However, few studies have examined how personnel turnover and restructuring in school districts influence these processes, specifically as they relate to leaders' access to research evidence and perception of organizational learning and culture. In this longitudinal exploratory mixed-methods case study, we examine the changes in social networks and organizational learning among school and district leaders during a 3-year district restructuring process. Our study uses social network analysis, bivariate analyses, and qualitative coding. We surveyed district and school leaders about their districts' capacity for organizational learning, organizational culture, and social ties around research evidence. Our results suggest a decrease in the district's capacity to diffuse ideas from research between Years 1 and 3, which may inhibit efforts for improvement. Further, the data on school and district leaders who did not leave the district indicates a decrease in the perception of organizational learning and culture in school sites, but not in the district with differences between principals and central office staff. Qualitative findings support an association between the restructuring and changes in organizational learning and social structures and provide further reasons for the changes (e.g., lack of communication, time to maintain/build relationships, and opportunities for professional development). These findings speak to the importance of leaders focusing on the social side of change during times of churn, including strengthening trust, fostering collective values and beliefs, and countering division.

BackgroundExpandable endoprostheses can be used to equalize limb length for pediatric patients requiring reconstruction following large bony oncologic resections. Outcomes of the Compress® Compliant Pre-Stress (CPS) spindle paired with an Orthopedic Salvage System expandable distal femur endoprosthesis have not been reported.MethodsWe conducted a multi-institutional retrospective study of pediatric patients with distal femoral bone sarcomas reconstructed with the above endoprostheses. Statistical analysis utilized Kaplan-Meier survival technique and competing risk analysis.ResultsThirty-six patients were included from five institutions. Spindle survivorship was 86.3% (95% confidence interval [CI], 67.7-93.5) at 10 years. Two patients had a failure of osseointegration (5.7%), both within 12 months. Twenty-two (59%) patients had 70 lengthening procedures, with mean expansions of 3.2 cm (range: 1-9) over 3.4 surgeries. The expandable mechanism failed in eight patients with a cumulative incidence of 16.1% (95% CI, 5.6-31.5) at 5 years. Twenty-nine patients sustained International Society of Limb Salvage failures requiring 63 unplanned surgeries. Periprosthetic joint infection occurred in six patients (16.7%). Limb preservation rate was 91% at 10 years.ConclusionsThere is a high rate of osseointegration of the Compress® spindle among pediatric patients when coupled with an expandable implant. However, there is a high rate of expansion mechanism failure and prosthetic joint infections requiring revision surgery.Level of evidenceLevel IV, therapeutic study.

Abstract Background Arrhythmia symptoms are frequent complaints in children and often require a pediatric cardiology evaluation. Data regarding the clinical utility of wearable technologies are limited in children. We hypothesize that an Apple Watch can capture arrhythmias in children. Methods We present an analysis of patients ≤18 years-of-age who had signs of an arrhythmia documented by an Apple Watch. We include patients evaluated at our center over a 4-year-period and highlight those receiving a formal arrhythmia diagnosis. We evaluate the role of the Apple Watch in arrhythmia diagnosis, the results of other ambulatory cardiac monitoring studies, and findings of any EP studies. Results We identify 145 electronic-medical-record identifications of Apple Watch, and find arrhythmias confirmed in 41 patients (28%) [mean age 13.8 ± 3.2 years]. The arrythmias include: 36 SVT (88%), 3 VT (7%), 1 heart block (2.5%) and wide 1 complex tachycardia (2.5%). We show that invasive EP study confirmed diagnosis in 34 of the 36 patients (94%) with SVT (2 non-inducible). We find that the Apple Watch helped prompt a workup resulting in a new arrhythmia diagnosis for 29 patients (71%). We note traditional ambulatory cardiac monitors were worn by 35 patients (85%), which did not detect arrhythmias in 10 patients (29%). In 73 patients who used an Apple Watch for recreational or self-directed heart rate monitoring, 18 (25%) sought care due to device findings without any arrhythmias identified. Conclusion We demonstrate that the Apple Watch can record arrhythmia events in children, including events not identified on traditionally used ambulatory monitors.

This article discusses what we know about the underlying social and political conditions shaping research evidence use in education and how this applies to Research-Practice Partnerships (RPPs). It discusses types of use, political dynamics and processes, brokers and intermediaries, and racial dynamics and lenses. It also recommends strategies for RPPs in light of these political and social contexts to improve the quality of use and reduce the misuse of research evidence, ending with implications for future research.

This research, by determining teachers' organizational trust level and perception of organizational support, aims to determine how much these variables predict job satisfaction. The research has been designed within correlational screening model. The population of the research is the teachers work in public primary, secondary and high schools in Yenimahalle District of Ankara City. Sampling of the research has been done with 497 teachers determined with simple random sampling technique. "Job satisfaction scale", "organizational trust scale" and "perceived organizational support scale" has been used to collect data. Descriptive statistics, Pearson correlation coefficient, simple and multiple regression analysis has been used in the analysis of the collected data. As a result of the research, it has been established that teachers' job satisfaction is medium level. As for perceived organizational support, organizational trust and organizational sub-dimensions; these variables have been determined to be at mostly level. The relation between job satisfaction and perceived organizational support has been determined to be at positive direction and at medium level. There is a positive and medium level relation among organizational trust, trust in managers, trust in colleagues and trust in stakeholders. According to the findings of the research, perceived organizational support is a significant predictive of job satisfaction. While organizational trust, trust in managers and trust in colleagues is a significant predictive of job satisfaction; it has been established that trust in stakeholders is not a significant predictive of job satisfaction.

BackgroundSelf-reported physical activity is often inaccurate. Wearable devices utilizing multiple sensors are now widespread. The aim of this study was to determine acceptability of Fitbit Charge HR for children and their families, and to determine best practices for processing its objective data.MethodsData were collected via Fitbit Charge HR continuously over the course of 3 weeks. Questionnaires were given to each child and their parent/guardian to determine the perceived usability of the device. Patterns of data were evaluated and best practice inclusion criteria recommended.ResultsBest practices were established to extract, filter, and process data to evaluate device wear, r and establish minimum wear time to evaluate behavioral patterns. This resulted in usable data available from 137 (89%) of the sample.ConclusionsActivity trackers are highly acceptable in the target population and can provide objective data over longer periods of wear. Best practice inclusion protocols that reflect physical activity in youth are provided.

Research on microaggression has primarily focused on the experiences of adults, as researchers have yet to extensively examine the experiences of school-age children. The few studies that exist suggest that microaggressions are problematic well before young people reach college or the working world. The current study adds to the microaggression literature through an examination of the experiences of adolescents holding minoritized racial and sexual orientation identities at a Midwestern public high school. Participants in the study completed a survey that assessed their experiences with microaggressions, the degree to which they found them offensive, and their experiences with peers and school personnel. Results of the study suggest that these microaggressive exchanges are relevant for high school students and that individual differences exist in the way that adolescents notice and label microaggressive verbalizations as offensive. Future research directions are discussed, as well as implications for those working directly with students in schools.

Abstract Predictions of total water levels, the elevation of combined tides, surge, and wave runup at the shoreline, are necessary to provide guidance on potential coastal erosion and flooding. Despite the importance of early warning systems for these hazards, existing real-time meteorological and oceanographic forecast systems at regional and national scales, until now, have lacked estimates of runup necessary to predict wave-driven overwash and erosion. To address this need, we present an approach that includes wave runup in an operational, national-scale modeling system. Using this system, we quantify the contribution of waves to potential dune erosion events along 4,700 km of U.S. Atlantic and Gulf of Mexico sandy coastlines for a one-year period. Dune erosion events were predicted to occur at over 80% of coastal locations, where waves dominated shoreline total water levels, representing 73% of the signal. This shows that models that neglect the wave component underestimate the hazard. This new, national-scale operational modeling system provides communities with timely, local-scale (0.5 km resolution) coastal hazard warnings for all wave conditions, allowing for rapid decision-making related to safety and emergency management. The modeling system also enables continued research into wave-driven processes at a broad range of coastal areas.

AimTo examine individual variability between perceived physical features and hormones of pubertal maturation in 9-10-year-old children as a function of sociodemographic characteristics.MethodsCross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study-a multi-site sample of 9-10 year-olds (n = 11,875)-and included perceived physical features via the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels.ResultsPDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child's weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample.ConclusionsSociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9-10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes.

Challenging and confronting educational systems and structures, the vast majority of which come from a place of privilege, is uncomfortable but necessary. Education, from early childhood to post-secondary, should challenge and address the racial inequities that inevitably characterize such systems and structures. Yet, we do not always do this explicitly, for a number of reasons. First, this is hard work, and educators must deal with many pressing needs on a day-to-day basis, so difficult conversations about racial inequities are pushed to the sidelines. Second, many educators do not have the training or resources available to collect, access, or analyze their data with a critical lens around racial equity. Third, many educators are White, and therefore have not personally experienced what it means to navigate interactions that are based upon racial biases or systems of structural racism. Without this firsthand knowledge, they may not be aware of the impact on youth outcomes--from disengagement to academic challenges--and the critical need to address these systemic issues. Even educators of color, within a system that privileges Whiteness, can struggle with internalized oppression or the same lack of tools and training as White teachers. The authors of this article, a school district superintendent and a university professor in Rochester, New York, are an example of how educators can collaborate around diversity and racial equity. They present a framework for grounding difficult conversations on race and implicit bias in system-level data, to avoid blaming and shaming and to break through defensiveness to arrive at solutions.

BACKGROUND:Fused deposition modeling 3D printing is used in medicine for diverse purposes such as creating patient-specific anatomical models and surgical instruments. For use in the sterile surgical field, it is necessary to understand the mechanical behavior of these prints across 3D printing materials and after autoclaving. It has been previously understood that steam sterilization weakens polylactic acid, however, annealing heat treatment of polylactic acid increases its crystallinity and mechanical strength. We aim to identify an optimal and commercially available 3D printing process that minimizes distortion after annealing and autoclaving and to quantify mechanical strength after these interventions. METHODS:Thirty millimeters cubes with four different infill geometries were 3D printed and subjected to hot water-bath annealing then immediate autoclaving. Seven commercially available 3D printing materials were tested to understand their mechanical behavior after intervention. The dimensions in the X, Y, and Z axes were measured before and after annealing, and again after subsequent autoclaving. Standard and strength-optimized Army-Navy retractor designs were printed using the 3D printing material and infill geometry that deformed the least. These retractors were subjected to annealing and autoclaving interventions and tested for differences in mechanical strength. RESULTS:For both the annealing and subsequent autoclaving intervention, the material and infill geometry that deformed the least, respectively, was Essentium PLA Gray and "grid". Standard retractors without intervention failed at 95 N +/- 2.4 N. Annealed retractors failed at 127.3 N +/- 10 N. Autoclave only retractors failed at 15.7 N +/- 1.4 N. Annealed then autoclaved retractors failed at 19.8 N +/- 3.1 N. Strength-optimized retractors, after the annealing then autoclaving intervention, failed at 164.8 N +/- 12.5 N. CONCLUSION:For 30 mm cubes, the 3D printing material and infill geometry that deformed the least, respectively, was Essentium PLA and "grid". Hot water-bath annealing results in increased 3D printed model strength, however autoclaving 3D prints markedly diminishes strength. Strength-optimized 3D printed PLA Army-Navy retractors overcome the strength limitation due to autoclaving.

AimTo examine individual variability between perceived physical features and hormones of pubertal maturation in 9-10-year-old children as a function of sociodemographic characteristics.MethodsCross-sectional metrics of puberty were utilized from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study-a multi-site sample of 9-10 year-olds (n = 11,875)-and included perceived physical features via the pubertal development scale (PDS) and child salivary hormone levels (dehydroepiandrosterone and testosterone in all, and estradiol in females). Multi-level models examined the relationships among sociodemographic measures, physical features, and hormone levels. A group factor analysis (GFA) was implemented to extract latent variables of pubertal maturation that integrated both measures of perceived physical features and hormone levels.ResultsPDS summary scores indicated more males (70%) than females (31%) were prepubertal. Perceived physical features and hormone levels were significantly associated with child's weight status and income, such that more mature scores were observed among children that were overweight/obese or from households with low-income. Results from the GFA identified two latent factors that described individual differences in pubertal maturation among both females and males, with factor 1 driven by higher hormone levels, and factor 2 driven by perceived physical maturation. The correspondence between latent factor 1 scores (hormones) and latent factor 2 scores (perceived physical maturation) revealed synchronous and asynchronous relationships between hormones and concomitant physical features in this large young adolescent sample.ConclusionsSociodemographic measures were associated with both objective hormone and self-report physical measures of pubertal maturation in a large, diverse sample of 9-10 year-olds. The latent variables of pubertal maturation described a complex interplay between perceived physical changes and hormone levels that hallmark sexual maturation, which future studies can examine in relation to trajectories of brain maturation, risk/resilience to substance use, and other mental health outcomes.

This article is a historical case study of an attempt to build a citywide coalition in Rochester, NY. The coalition wanted to improve urban education by implementing community based wrap-around supports in a similar form as the well-respected Harlem Children's Zone. Our study found that groups had difficulty creating buy-in for this reform effort because of fragmented coalitions, changeover in leadership, and ambitious, yet evolving goals. Political theories relating to coalition building and civic capacity suggest fragmented coalitions can hamper initiatives when bridging between communities of color and power elites fails to take place, but our study suggests additional limitations when varying communities of color are not aligned in their efforts. Our historical case study suggests that strategic development of trust and coalition building is necessary to build civic capacity relating to urban education improvement--particularly between communities of color and power elites, as well as across communities of color.

In this article, Kara Finnigan and Alan Daly argue that studying churn among central office leaders and school principals can improve retention of high-quality leaders who can better support teachers. Constant churn often means that initiatives barely have the opportunity to get off the ground before a new central office administrator or principal comes on board and rolls out a different approach. In essence, constant churn at the leadership level has a significant social cost that affects teachers on multiple levels. To study administrator churn, the authors use social network theory, a core aspect of which is social capital. The ability to access relationships with others and the quality of those relationships often determine opportunities for success. Networks can be seen as the patterned structure of relationships that exist within a particular organization or group. To make this come to life in an educational setting, the authors use a technique called social network analysis to answer two questions: (1) To what extent do leaders in low-performing school districts have the relationships necessary for large-scale learning and improvement?; and (2) How does network churn affect the underlying social networks of educators? The authors surveyed individuals in formal leadership positions in a midsize urban school district in the northeastern United States, including the superintendent, chiefs and directors from the central office, and principals at each school. Results from the survey, which was administered annually during the four-year study, found substantial leadership churn at 51%. The study revealed that those leaders who were really important in terms of sharing expertise and knowledge were overwhelmingly those who left. Work-related relationships increased while emotional relationships diminished among district leaders. This article provides details of the study as well as its significance for teachers.

BYL719 is a PI3K inhibitor that has demonstrated efficacy in the treatment of head and neck squamous cell carcinoma. BYL719 exerts its therapeutic effect by suppressing AKT and other proliferative signaling mechanisms. Despite PI3K inhibition and AKT suppression, residual activity of protein S6, a core marker of proliferative activation, has been observed. HER3, either via dimerization or activation by its ligand neurgeulin (NRG), is known to activate PI3K. Thus, we hypothesized that co-targeting HER3 and PI3K would lead to greater suppression of the PI3K-AKT signaling pathway and greater tumor suppression than with BYL719 alone. We investigated biochemical expression and activation of the HER3-PI3K-AKT-S6 pathway in HNSCC cell lines and patient-derived xenografts (PDXs). Antitumor effects of HER3 and PI3K inhibitors alone and in combination were evaluated in cell culture and murine models. Treatment of HNSCC cell lines with BYL719 significantly reduced AKT activation and suppressed tumor growth. However, S6 was persistently activated despite suppression of AKT. Combination treatment with KTN3379, a monoclonal antibody targeted against HER3, and BYL719 led to enhanced suppression of in vitro and in vivo cancer growth and durable suppression of AKT and S6. Therefore, inhibition of HER3 with KTN3379 enhanced the effects of PI3K inhibition in pre-clinical HNSCC models. These data support co-targeting HER3 and PI3K for the treatment of HSNCC.

Abstract Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among all infants worldwide and remains a significant cause of morbidity and mortality. To address this unmet medical need, MK‐1654, a half‐life extended RSV neutralizing monoclonal antibody, is in clinical development for the prevention of RSV disease in infants. This was a phase I, randomized, placebo‐controlled, single‐site, double‐blind trial of MK‐1654 in 44 healthy Japanese adults. The safety, tolerability, pharmacokinetics, antidrug antibodies (ADAs), and serum neutralizing antibody (SNA) titers against RSV were evaluated for 1 year after a single intramuscular (i.m.) or intravenous (i.v.) dose of MK‐1654 or placebo in five groups (100 mg i.m., 300 mg i.m., 300 mg i.v., 1000 mg i.v., or placebo). MK‐1654 was generally well‐tolerated in Japanese adults. There were no serious drug‐related adverse events (AEs) reported in any MK‐1654 recipient and no discontinuations due to any AEs in the study. The half‐life of MK‐1654 ranged from 76 to 91 days across dosing groups. Estimated bioavailability was 86% for 100 mg i.m. and 77% for 300 mg i.m. One participant out of 33 (3.0%) developed detectable ADA with no apparent associated AEs. The RSV SNA titers increased in a dose‐dependent manner among participants who received MK‐1654. These data support the development of MK‐1654 for use in Japanese infants.