Adult Familial Influences on Rural Native Hawaiian and Pacific Islander Youths' E-Cigarette Use.

Background: Over the past decade, youth e-cigarette use has grown into a national epidemic, with Native Hawaiian and Pacific Islander (NHPI) youths' rates among some of the highest in the nation. Family factors significantly contribute to NHPI youths' decisions to engage in or resist substance use, yet few studies have specifically examined familial influences on NHPI youths' substance use decision-making and behaviors. Objective: The objective of this study is to examine adult familial influences on rural NHPI youths' decisions to engage in e-cigarette use. Method: Seventeen gender-specific focus groups with NHPI youths (N = 69) from eight public schools on Hawai'i Island were conducted. Results: Two family-related themes emerged from the data: 1) parental substance use permissiveness, and 2) family normalization of e-cigarette use. Conclusions: Examining adult familial contributors to NHPI youths' e-cigarette use needs to be part of a comprehensive effort to address NHPI health and substance use disparities. Prevention interventions should be explicit in addressing the family and relational context of NHPI youths' substance use.

Examining implementation determinants of a culturally grounded, school-based prevention curriculum in rural Hawai'i: A test development and validation study.

Background: This study examined the implementation determinants of a culturally grounded, school-based drug prevention curriculum in rural Hawai'i. Test development and validation procedures were used to examine the impact of implementation barriers and facilitators of the curriculum in public or charter middle/intermediate schools on Hawai'i Island. Method: A five-phase, mixed-methods approach toward test development and validation was used. These phases included item generation (Phase 1), item refinement and selection (Phase 2), item reduction (Phase 3), reliability testing (Phase 4), and validity testing (Phase 5). Educational administrators, teachers, and staff employed by the Hawai'i State Department of Education (HIDOE) participated in the study. Results: Phases 1 and 2 yielded 50 implementation barriers and 27 implementation facilitators that were evaluated by 204 HIDOE administrators, teachers, and staff. Factor analysis of the barrier items indicated a four-factor solution: (1) Innovation Barriers, (2) HIDOE State-Level Barriers, (3) Teacher-Level Barriers, and (4) Administrator-Level Barriers. Mean comparisons indicated that several barrier and facilitator items differentiated teachers from administrators in the sample. Conclusions: This study contributes to the implementation measurement literature, specifically in the areas of mental health and substance use. It also highlights the importance of addressing multiple contextual levels in the implementation of culturally focused prevention interventions. Plain Language Summary Title: Examining Implementation Barriers and Facilitators for School-Based Prevention in Hawai'i. Plain Language Summary Compared with other major ethnic groups, Native Hawaiian and Pacific Islander (NHPI) youth have substantially higher rates of substance use and higher adverse mental and physical health effects related to their use. Despite these disparities, educational and community-based practitioners have long struggled with implementing and sustaining promising substance use interventions for NHPI youth. This study contributes to our understanding of measuring implementation barriers and facilitators for substance use prevention for NHPI youth in rural school settings. It contributes to the field of health disparities and health equity promotion, by addressing calls for research to understand factors affecting successful implementation of prevention programs. This is critical toward achieving health equity for underrepresented and vulnerable populations, such as NHPI and rural youth.

Exploring Native Hawaiian and Pacific Islander Youths' E-Cigarette Resistance Strategies: Implications for Tobacco Product Use Prevention.

This study examined the e-cigarette and vaping resistance strategies used by Native Hawaiian and Pacific Islander (NHPI) youths in rural Hawai'i. Focus groups (N = 17) were conducted in eight geographically dispersed elementary, middle/intermediate, and multilevel schools in low-income communities on Hawai'i Island. Sixty-nine youths (67% NHPI, Mage = 12.5 years) participated in this study. The resistance strategies discussed across the greatest number of groups were "refuse" (saying no), "explain" (providing reasons for vaping refusal), "avoid" (avoiding people or places where e-cigarettes were used), and "leave" (walking away from a situation where e-cigarettes were being used). Participants described the challenges in using these strategies within contexts characterized by widespread peer and family vaping and strong social demands to use e-cigarettes. The findings suggest the need for multi-level interventions based on youths' resistance strategies to meaningfully reduce youth vaping use in rural and/or NHPI communities.

Measuring practice preference variation for quality improvement in neonatal respiratory care.

OBJECTIVES: The authors sought to measure and compare practice preference variation in neonatal respiratory care within and between neonatal intensive care units (NICUs) using the Neonatology Survey of Interdisciplinary Groups in Healthcare Tool (NSIGHT). STUDY DESIGN: Eleven NICUs completed the NSIGHT between 2019 and 2021. Net preference was measured by mean response; agreement was ranked by standard distribution of response values. Heat maps showed comparisons between NICUs and disciplines. RESULTS: NICUs and individuals agreed most often on use of pressure support with mandatory ventilation and on use of non-invasive positive pressure ventilation for apnea. High preference variation surrounded decisions for invasive ventilation versus continuous positive airway pressure for extremely low birth weight infants. Preference difference was most frequent between neonatologists and nurses. CONCLUSIONS: Patterns of practice preference variation in neonatal respiratory care are specific to clinical scenario. Measuring preference variation may inform psychology of change and strengthen quality improvement efforts.

Clear cell meningiomas-case presentation, review of radiographic identifiers, and treatment approaches.

Spinal clear cell meningiomas (CCMs) are a rare histological subtype of meningiomas that pose preoperative diagnostic challenges due to their radiographic similarities with other lesions. They are also more aggressive, exhibiting higher rates of recurrence, particularly in pediatric patients. Overcoming diagnostic challenges of these tumors can improve patient outcomes. In this report, we describe a case of a pediatric patient presenting with a lumbar CCM in whom we were able to obtain gross total resection. Our report reviews previously identified predictors of CCM recurrence, including the Ki-67 proliferation index, number of spinal segments involved, and hormonal influences related to age and sex. We describe the characteristic radiographic features that differentiate spinal CCMs from other tumors to improve pre-operative diagnosis. Furthermore, we provide our rationale for adjuvant therapy for pediatric patients to refine treatment protocols for these rare tumors.

A Case Report of Infant-Type Hemispheric Glioma with a Novel GAB1-ABL2 Kinase Fusion Treated with Dasatinib.

INTRODUCTION: Infant-type hemispheric glioma (IHG) is a rare form of cancer that affects newborns and infants. It is classified as a pediatric-type high-grade glioma and typically harbors receptor tyrosine kinase (RTK) gene fusions. Here, we present the finding of a novel gene fusion IHG treated with a targeted therapy that has yet to be implemented for any other IHG case to date. CASE PRESENTATION: We report the case of a 12-month-old boy with IHG who presented with obstructive hydrocephalus due to a large mass in the right frontal lobe. The patient initially underwent mass resection, but subsequent imaging showed rapid interval progression of the residual tumor. Comprehensive molecular analysis of the tumor tissue revealed a novel GAB1-ABL2 gene fusion, and the patient was started on dasatinib, an ABL kinase inhibitor. Shortly after initiation of dasatinib treatment, there was a significant reduction in tumor size and enhancement, followed by stabilization of disease. DISCUSSION: The patient's robust response to treatment suggests that dasatinib is an effective targeted therapy for IHG harboring a GAB1-ABL2 gene fusion. This finding may inform future investigations into the disease processes of IHG and help guide the diagnosis and treatment of IHG in the absence of previously identified gene fusions, improving clinical management of this vulnerable patient population.

Automated online deconjugation of antibody-drug conjugate for small molecule drug profiling.

Antibody-drug conjugates (ADCs) are designed by chemically linking highly potent cytotoxic small molecule drugs to monoclonal antibodies of unique specificity for targeted destruction of cancer cells. This innovative class of molecules incurs unique developmental challenges due to its structural complexity of having both small molecule and protein components. The stability of the small molecule payload on the ADC is a critical attribute as it directly relates to product efficacy and patient safety. This study describes the use of an end-to-end automated workflow for effective and robust characterization of the small molecule drug while it is conjugated to the antibody. In this approach, online deconjugation was accomplished by an autosampler user defined program and 1D size exclusion chromatography was utilized to provide separation between small molecule and protein species. The small molecule portion was then trapped and sent to the 2D for separation and quantification by reversed-phase liquid chromatography with identification of impurities and degradants by mass spectrometry. The feasibility of this system was demonstrated on an ADC with a disulfide-based linker. This fully automated approach avoids tedious sample preparation that may lead to sample loss and large assay variability. Under optimized conditions, the method was shown to have excellent specificity, sensitivity (LOD of 0.036 µg/mL and LOQ of 0.144 µg/mL), linearity (0.04-72.1 µg/mL), precision (system precision %RSD of 1.7 and method precision %RSD of 3.4), accuracy (97.4 % recovery), stability-indicating nature, and was successfully exploited to analyze the small molecule drug on a panel of stressed ADC samples. Overall, the workflow established here offers a powerful analytical tool for profiling the in-situ properties of small molecule drugs conjugated to antibodies and the obtained information could be of great significance for guiding process/formulation development and understanding pharmacokinetic/pharmacodynamic behavior of ADCs.

Middle-out sequence confirmation of CRISPR/Cas9 single guide RNA (sgRNA) using DNA primers and ribonuclease T1 digestion.

Accurate sequencing of single guide RNAs (sgRNAs) for CRISPR/Cas9 genome editing is critical for patient safety, as the sgRNA guides the Cas9 nuclease to target site-specific cleavages in DNA. An approach to fully sequence sgRNA using protective DNA primers followed by ribonuclease (RNase) T1 digestion was developed to facilitate the analysis of these larger molecules by hydrophilic interaction liquid chromatography coupled with high-resolution mass spectrometry (HILIC-HRMS). Without RNase digestion, top-down mass spectrometry alone struggles to properly fragment precursor ions in large RNA oligonucleotides to provide confidence in sequence coverage. With RNase T1 digestion of these larger oligonucleotides, however, bottom-up analysis cannot confirm full sequence coverage due to the presence of short, redundant digestion products. By combining primer protection with RNase T1 digestion, digestion products are large enough to prevent redundancy and small enough to provide base resolution by tandem mass spectrometry to allow for full sgRNA sequence coverage. An investigation into the general requirements for adequate primer protection of specific regions of the RNA was conducted, followed by the development of a generic protection and digestion strategy that may be applied to different sgRNA sequences. This middle-out technique has the potential to expedite accurate sequence confirmation of chemically modified sgRNA oligonucleotides.

Development of an Amorphous Solid Dispersion Formulation for Mitigating Mechanical Instability of Crystalline Form and Improving Bioavailability for Early Phase Clinical Studies.

In this work, an amorphous solid dispersion (ASD) formulation was systematically developed to simultaneously enhance bioavailability and mitigate the mechanical instability risk of the selected crystalline form of a development drug candidate, GDC-0334. The amorphous solubility advantage calculation was applied to understand the solubility enhancement potential by an amorphous formulation for GDC-0334, which showed 2.7 times theoretical amorphous solubility advantage. This agreed reasonably well with the experimental solubility ratio between amorphous GDC-0334 and its crystalline counterpart (∼2 times) in buffers of a wide pH range. Guided by the amorphous solubility advantage, ASD screening was then carried out, focusing on supersaturation maintenance and dissolution performance. It was found that although the type of polymer carrier did not impact ASD performance, the addition of 5% (w/w) sodium dodecyl sulfate (SDS) significantly improved the GDC-0334 ASD dissolution rate. After ASD composition screening, stability studies were conducted on selected ASD powders and their hypothetical tablet formulations. Excellent stability of the selected ASD prototypes with or without tablet excipients was observed. Subsequently, ASD tablets were prepared, followed by in vitro and in vivo evaluations. Similar to the effect of facilitating the dissolution of ASD powders, the added SDS improved the disintegration and dissolution of ASD tablets. Finally, a dog pharmacokinetic study confirmed 1.8 to 2.5-fold enhancement of exposure by the developed ASD tablet over the GDC-0334 crystalline form, consistent with the amorphous solubility advantage of GDC-0334. A workflow of developing an ASD formulation for actual pharmaceutical application was proposed according to the practice of this work, which could provide potential guidance for ASD formulation development in general for other new chemical entities.

Two-dimensional reversed phase-normal phase liquid chromatography for simultaneous achiral-chiral analysis to support high-throughput experimentation.

Typical chromatographic analysis of chiral compounds requires the use of achiral methods to evaluate impurities or related substances along with separate methods to evaluate chiral purity. The use of two-dimensional liquid chromatography (2D-LC) to support simultaneous achiral-chiral analysis has become increasingly advantageous in the field of high-throughput experimentation where low reaction yields or side reactions can lead to challenging direct chiral analysis. Advancements in multi-dimensional chromatography have led to the development of robust 2D-LC instrumentation with reversed phase solvent systems (RPLC-RPLC) enabling this simultaneous analysis, eliminating the need to purify crude reaction mixtures to determine stereoselectivity. However, when chiral RPLC cannot separate a chiral impurity from the desired product, there are few viable commercial options. The coupling of NPLC to RPLC (RPLC-NPLC) continues to remain elusive due to solvent immiscibility between the two solvent systems. This solvent incompatibility leads to lack of retention, band broadening, poor resolution, poor peak shapes, and baseline issues in the second dimension. A study was conducted to understand the effect of various water-containing injections on NPLC and applied to the development of robust RPLC-NPLC methods. Following thoughtful consideration and modifications to the design of a 2D-LC system in regards to mobile phase selection, sample loop sizing, targeted mixing, and solvent compatibility, proof of concept has been demonstrated with the development of reproducible RPLC-NPLC 2D-LC methods to perform simultaneous achiral-chiral analysis. Second dimension NPLC method performance proved comparable to corresponding 1D-NPLC methods with excellent percent difference in enantiomeric excess results ≤ 1.09% and adequate limits of quantitation down to 0.0025 mg/mL for injection volumes of 2 µL, or 5 ng on-column.

A nine-month-old boy with regression of milestones and severe constipation: an unusual case of a large spinal NTRK1 fusion pilocytic astrocytoma.

INTRODUCTION: Pilocytic astrocytoma, a World Health Organization grade 1 tumor, is the most common brain tumor in children between 5 and 14 years of age and the second most common in children younger than 5 and older than 14. Although classical to the cerebellum and hypothalamic regions, it can also arise in the spinal cord. Larotrectinib, a selective inhibitor of tropomyosin receptor kinase, has been effective in pediatric tumors with NTRK fusion mutations in children as young as 1-month-old. CASE: We share the case of a 9-month-old boy who presented with a 4-month history of regression of his milestones and severe constipation who was found to have a large spinal pilocytic astrocytoma with multiple intracranial periventricular lesions.

High-Level Data Fusion Enables the Chemoinformatically Guided Discovery of Chiral Disulfonimide Catalysts for Atropselective Iodination of 2-Amino-6-arylpyridines.

The atropselective iodination of 2-amino-6-arylpyridines catalyzed by chiral disulfonimides (DSIs) is described. Key to the development of this transformation was the use of a chemoinformatically guided workflow for the curation of a structurally diverse training set of DSI catalysts. Utilization of this catalyst training set in the atropselective iodination across a variety 2-aminopyridine substrates allowed for the recommendation of statistically higher-performing DSIs for this reaction. Data Fusion techniques were implemented to successfully predict the performance of catalysts when classical linear regression analysis failed to provide suitable models. This effort identified a privileged class of 3,3'-alkynyl-DSI catalysts which were effective in catalyzing the iodination of a variety of 2-amino-6-arylpyridines with high stereoselectivity and generality. Subsequent preparative-scale demonstrations highlighted the utility of this reaction by providing iodinated pyridines >90:10 er and in good chemical yield.

Protocol for a multi-site randomized controlled trial of a stepped-care intervention for emergency department patients with panic-related anxiety.

BACKGROUND: Approximately 40% of Emergency Department (ED) patients with chest pain meet diagnostic criteria for panic-related anxiety, but only 1-2% are correctly diagnosed and appropriately managed in the ED. A stepped-care model, which focuses on providing evidence-based interventions in a resource-efficient manner, is the state-of-the art for treating panic disorder patients in medical settings such as primary care. Stepped-care has yet to be tested in the ED setting, which is the first point of contact with the healthcare system for most patients with panic symptoms. METHODS: This multi-site randomized controlled trial (RCT) aims to evaluate the clinical, patient-centred, and economic effectiveness of a stepped-care intervention in a sample of 212 patients with panic-related anxiety presenting to the ED of Singapore's largest public healthcare group. Participants will be randomly assigned to either: 1) an enhanced care arm consisting of a stepped-care intervention for panic-related anxiety; or 2) a control arm consisting of screening for panic attacks and panic disorder. Screening will be followed by baseline assessments and blocked randomization in a 1:1 ratio. Masked follow-up assessments will be conducted at 1, 3, 6, and 12 months. Clinical outcomes will be panic symptom severity and rates of panic disorder. Patient-centred outcomes will be health-related quality of life, daily functioning, psychiatric comorbidity, and health services utilization. Economic effectiveness outcomes will be the incremental cost-effectiveness ratio of the stepped-care intervention relative to screening alone. DISCUSSION: This trial will examine the impact of early intervention for patients with panic-related anxiety in the ED setting. The results will be used to propose a clinically-meaningful and cost-effective model of care for ED patients with panic-related anxiety. TRIAL REGISTRATION: ClinicalTrials.gov NCT03632356. Retrospectively registered 15 August 2018.

Ho'ouna Pono implementation: applying concept mapping to a culturally grounded substance use prevention curriculum in rural Hawai'i schools.

BACKGROUND: Despite their potential to ameliorate health disparities and address youth substance use, prevention programs have been poorly disseminated and implemented across Hawai'i, which begs the question: Why are effective prevention programs not being used in communities most in need of them? Implementing and sustaining culturally grounded prevention programs is critical to address equitable healthcare and minimize health disparities in communities. The field of implementation science provides frameworks, theories, and methods to examine factors associated with community adoption of these programs. METHOD: Our project applies concept mapping methods to a culturally grounded youth drug prevention program with state level educational leadership in rural Hawai'i schools. The goal is to integrate barrier and facilitator salience collected through teacher and school staff surveys and specific implementation strategies to regionally tailored implementation plans on Hawai'i island. This protocol paper describes the concept mapping steps and how they will be applied in public and public-charter schools. DISCUSSION: Improving prevention program implementation in rural schools can result in sustained support for populations that need it most. The project will integrate implementation science and culturally grounded methods in rural Hawai'i, where most youth are of Native Hawaiian and Pacific Islander descent. This project addresses health disparities among Native Hawaiian and Pacific Islander youth and provides actionable plans for rural Hawai'i communities to implement effective prevention programming.

Proposing a Practical, Simplified Framework for Implementing Integrated Diabetes Data and Technology Solutions.

Diabetes is a uniquely quantifiable disease, and as technology and data have proliferated over the past two decades, so have the tools to manage diabetes. Patients and providers have at their disposal devices, applications, and data platforms that generate immense amounts of data, provide critical insights into a patient's disease, and allow for personalization of treatment plans. However, the proliferation of options also comes with new burdens for providers: selecting the right tool, getting buy-in from leadership, defining the business case, implementation, and maintenance of the new technology. The complexity of these steps can be overwhelming and sometimes lead to inaction, depriving providers and patients of the advantages of technology-assisted diabetes care. Conceptually, the adoption of digital health solutions can be thought of as occurring in five interconnected phases: Needs Assessment, Solution Identification, Integration, Implementation, and Evaluation. There are a number of existing frameworks to help guide much of this process, but relatively little attention has been focused on integration. Integration is a critical phase for a number of contractual, compliance, financial, and technical processes. Missing a step or doing them out of order can lead to significant delays and potentially wasted resources. To address this gap, we have developed a practical, simplified framework for integrating diabetes data and technology solutions that can guide clinicians and clinical leaders on the critical steps in adopting and implementing a new technology.

Discovery of a dual pathway aggregation mechanism for a therapeutic constrained peptide.

Constrained peptides (CPs) have emerged as attractive candidates for drug discovery and development. To fully unlock the therapeutic potential of CPs, it is crucial to understand their physical stability and minimize the formation of aggregates that could induce immune responses. Although amyloid like aggregates have been researched extensively, few studies have focused on aggregates from other peptide scaffolds (e.g., CPs). In this work, a streamlined approach to effectively profile the nature and formation pathway of CP aggregates was demonstrated. Aggregates of various sizes were detected and shown to be amorphous. Though no major changes were found in peptide structure upon aggregation, these aggregates appeared to have mixed natures, consisting of primarily non-covalent aggregates with a low level of covalent species. This co-existence phenomenon was also supported by two kinetic pathways observed in time- and temperature-dependent aggregation studies. Furthermore, a stability study with 8 additional peptide variants exhibited good correlation between aggregation propensity and peptide hydrophobicity. Therefore, a dual aggregation pathway was proposed, with the non-covalent aggregates driven by hydrophobic interactions, whereas the covalent ones formed through disulfide scrambling. Overall, the workflow presented here provides a powerful strategy for comprehensive characterization of peptide aggregates and understanding their mechanisms of formation.

Infant-Family Mental Health in the NICU: A Mixed-Methods Study Exploring Referral Pathways and Family Engagement.

Parents and infants in the neonatal intensive care unit (NICU) are exposed to considerable stress, and infant-family mental health (IFMH) services foster emotional well-being in the context of the parent-infant relationship. This mixed-methods study examined the role of an IFMH program introduced in a level 4 NICU. The study included (1) retrospective medical record review of NICU patients who were referred to the IFMH program and (2) qualitative interviews with NICU nurse managers, neonatologists, and medical social workers to explore their understanding of the IFMH program, explore the referral pathways and factors that supported family engagement, and identify specific recommendations for program improvement. Of the 311 infant-parent dyads referred to the IFMH program, 62% had at least one session and Spanish-speaking families were more likely to engage. Of those families receiving services, about one-third had brief intervention, one-third had 4 to 10 sessions, and one-third had long-term services, including in-home after-discharge services. Qualitative interviews with health providers identified unique qualities of the IFMH program and why families were and were not referred to the program. Recommendations centered on adding a full-time IFMH mental health provider to the NICU and increasing communication and integration between the IFMH program and the medical team.