Reimagining the Role of Health Departments and Their Partners in Addressing Climate Change: Revising the Building Resilience against Climate Effects (BRACE) Framework.

Public health departments have important roles to play in addressing the local health impacts of climate change, yet are often not well prepared to do so. The Climate and Health Program (CHP) at the Centers for Disease Control and Prevention (CDC) created the Building Resilience Against Climate Effects (BRACE) framework in 2012 as a five-step planning framework to support public health departments and their partners to respond to the health impacts of climate change. CHP has initiated a process to revise the framework to address learnings from a decade of experience with BRACE and advances in the science and practice of addressing climate and health. The aim of this manuscript is to describe the methodology for revising the BRACE framework and the expected outputs of this process. Development of the revised framework and associated guidance and tools will be guided by a multi-sector expert panel, and finalization will be informed by usability testing. Planned revisions to BRACE will (1) be consistent with the vision of Public Health 3.0 and position health departments as "chief health strategists" in their communities, who are responsible for facilitating the establishment and maintenance of cross-sector collaborations with community organizations, other partners, and other government agencies to address local climate impacts and prevent further harm to historically underserved communities; (2) place health equity as a central, guiding tenet; (3) incorporate greenhouse gas mitigation strategies, in addition to its previous focus on climate adaptation; and (4) feature a new set of tools to support BRACE implementation among a diverse set of users. The revised BRACE framework and the associated tools will support public health departments and their partners as they strive to prevent and reduce the negative health impacts of climate change for everyone, while focusing on improving health equity.

Determination of metarrestin (ML-246) in human plasma for a first-in-human clinical pharmacokinetic application by a simple and efficient uHPLC-MS/MS assay.

Metarrestin is a first-in-class small molecule inhibitor targeting the perinucleolar compartment, a subnuclear body associated with metastatic capacity. Promising preclinical results led to the clinical translation of the compound into a first-in-human phase I trial (NCT04222413). To characterize metarrestin's pharmacokinetic profile in humans, a uHPLC-MS/MS assay was developed and validated to determine the disposition of the drug in human plasma. Efficient sample preparation was accomplished through one-step protein precipitation paired with elution through a phospholipid filtration plate. Chromatographic separation was achieved with gradient elution through an Acuity UPLC® BEH C18 column (50 × 2.1 mm, 1.7 µm). Tandem mass spectrometry facilitated the detection of metarrestin and tolbutamide, the internal standard. The effective calibration range spanned 1-5000 ng/mL and was both accurate (range -5.9 % to 4.9 % deviation) and precise (≤9.0 %CV). Metarrestin proved stable (≤4.9 % degradation) under various assay-imposed conditions. Matrix effects, extraction efficiency, and process efficiency were assessed. Further, the assay was successfully able to determine the disposition of orally administered metarrestin in patients from the lowest dose cohort (1 mg) for 48 h post-administration. Thus, the validated analytical method detailed in this work is simple, sensitive, and clinically applicable.

A Phase II Trial of Guadecitabine in Children and Adults with SDH-Deficient GIST, Pheochromocytoma, Paraganglioma, and HLRCC-Associated Renal Cell Carcinoma.

PURPOSE: Succinate dehydrogenase (dSDH)-deficient tumors, including pheochromocytoma/paraganglioma, hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinoma (HLRCC-RCC), and gastrointestinal stromal tumors (GIST) without KIT or platelet-derived growth factor receptor alpha mutations are often resistant to cytotoxic chemotherapy, radiotherapy, and many targeted therapies. We evaluated guadecitabine, a dinucleotide containing the DNA methyltransferase inhibitor decitabine, in these patient populations. PATIENTS AND METHODS: Phase II study of guadecitabine (subcutaneously, 45 mg/m2/day for 5 consecutive days, planned 28-day cycle) to assess clinical activity (according to RECISTv.1.1) across three strata of patients with dSDH GIST, pheochromocytoma/paraganglioma, or HLRCC-RCC. A Simon optimal two-stage design (target response rate 30% rule out 5%) was used. Biologic correlates (methylation and metabolites) from peripheral blood mononuclear cells (PBMC), serum, and urine were analyzed. RESULTS: Nine patients (7 with dSDH GIST, 1 each with paraganglioma and HLRCC-RCC, 6 females and 3 males, age range 18-57 years) were enrolled. Two patients developed treatment-limiting neutropenia. No partial or complete responses were observed (range 1-17 cycles of therapy). Biologic activity assessed as global demethylation in PBMCs was observed. No clear changes in metabolite concentrations were observed. CONCLUSIONS: Guadecitabine was tolerated in patients with dSDH tumors with manageable toxicity. Although 4 of 9 patients had prolonged stable disease, there were no objective responses. Thus, guadecitabine did not meet the target of 30% response rate across dSDH tumors at this dose, although signs of biologic activity were noted.

Male and female rats exhibit comparable gaping behavior but activate brain regions differently during expression of conditioned nausea.

Twenty-five to fifty percent of patients undergoing chemotherapy will develop anticipatory nausea and vomiting (ANV), in which symptoms occur in anticipation of treatment. ANV is triggered by environmental cues and shows little response to traditional antiemetic therapy, suggesting that unique neural pathways mediate this response. Understanding the underlying neural mechanisms of this disorder is critical to the development of novel therapeutic interventions. The purpose of the present study was to identify brain areas activated during ANV and characterize sex differences in both the behavior and the brain areas activated during ANV. We used a rat model of ANV by pairing a novel context with the emetic drug lithium chloride (LiCl) to produce conditioned nausea behaviors in the LiCl-paired environment. We quantitated gaping, an analog of human vomiting, after acute or repeated LiCl in a unique environment. To identify brain regions associated with gaping, we measured c-fos activation by immunochemical staining after these same treatments. We found that acute LiCl activated multiple brain regions including the supraoptic nucleus of the hypothalamus, central nucleus of the amygdala, nucleus of the solitary tract and area postrema, none of which were activated during ANV. ANV activated c-fos expression in the frontal cortex, insula and paraventricular nucleus of the hypothalamus of males but not females. These data suggest that therapies such as ondansetron which target the area postrema are not effective in ANV because it is not activated during the ANV response. Further studies aimed at characterizing the neural circuits and cell types that are activated in the conditioned nausea response will help identify novel therapeutic targets for the treatment of this condition, improving both quality of life and outcomes for patients undergoing chemotherapy.

Quantitation of the next-generation imipridone ONC206 in human plasma by a simple and sensitive UPLC-MS/MS assay for clinical pharmacokinetic application.

ONC206 is an imipridone derivative that is being developed clinically as a single agent given orally in a first-in-human trial (NCT04541082). This ongoing clinical trial requires pharmacokinetic analysis of ONC206 to fully characterize its pharmacologic profile. There is currently no published bioanalytical method for ONC206 quantitation. To understand the clinical pharmacokinetics of ONC206, a sensitive yet simple uHPLC-MS/MS method for quantitation of ONC206 in human plasma was developed. Protein-precipitation allowed rapid and sensitive bioanalytical measurement of ONC206 in human plasma. A Phenomenex Kinetex C18 (50 ×2.1 mm, 1.3 µm, 100 Å) analytical column achieved symmetrical and sharp chromatography peaks of ONC206 and the internal standard, [2H]7-ONC206, which were detected using multiple reaction monitoring. The assay calibration range was 1-500 ng/mL and was best fit by a linear regression model (r2 > 0.99732 ± 0.0010). The method proved accurate (< ± 9% deviation), precise (<11%CV), selective and specific with no interference and low inter-lot matrix variability. ONC206 demonstrated excellent short-term, long-term, and multiple freeze-thaw cycle stability in solution and human plasma. This fully validated method was used to quantitate ONC206 plasma concentrations from patients enrolled in the aforementioned clinical trial at the NCI to demonstrate its clinical applicability.

Vertical Inhibition of the RAF-MEK-ERK Cascade Induces Myogenic Differentiation, Apoptosis, and Tumor Regression in H/NRASQ61X Mutant Rhabdomyosarcoma.

Oncogenic RAS signaling is an attractive target for fusion-negative rhabdomyosarcoma (FN-RMS). Our study validates the role of the ERK MAPK effector pathway in mediating RAS dependency in a panel of H/NRASQ61X mutant RMS cells and correlates in vivo efficacy of the MEK inhibitor trametinib with pharmacodynamics of ERK activity. A screen is used to identify trametinib-sensitizing targets, and combinations are evaluated in cells and tumor xenografts. We find that the ERK MAPK pathway is central to H/NRASQ61X dependency in RMS cells; however, there is poor in vivo response to clinically relevant exposures with trametinib, which correlates with inefficient suppression of ERK activity. CRISPR screening points to vertical inhibition of the RAF-MEK-ERK cascade by cosuppression of MEK and either CRAF or ERK. CRAF is central to rebound pathway activation following MEK or ERK inhibition. Concurrent CRAF suppression and MEK or ERK inhibition, or concurrent pan-RAF and MEK/ERK inhibition (pan-RAFi + MEKi/ERKi), or concurrent MEK and ERK inhibition (MEKi + ERKi) all synergistically block ERK activity and induce myogenic differentiation and apoptosis. In vivo assessment of pan-RAFi + ERKi or MEKi + ERKi potently suppress growth of H/NRASQ61X RMS tumor xenografts, with pan-RAFi + ERKi being more effective and better tolerated. We conclude that CRAF reactivation limits the activity of single-agent MEK/ERK inhibitors in FN-RMS. Vertical targeting of the RAF-MEK-ERK cascade and particularly cotargeting of CRAF and MEK or ERK, or the combination of pan-RAF inhibitors with MEK or ERK inhibitors, have synergistic activity and potently suppress H/NRASQ61X mutant RMS tumor growth.

Behavior and Fos activation reveal that male and female rats differentially assess affective valence during CTA learning and expression.

Females are more affected by psychiatric illnesses including eating disorders, depression, and post-traumatic stress disorder than males. However, the neural mechanisms mediating these sex differences are poorly understood. Animal models can be useful in exploring such neural mechanisms. Conditioned taste aversion (CTA) is a behavioral task that assesses how animals process the competition between associated reinforcing and aversive stimuli in subsequent task performance, a process critical to healthy behavior in many domains. The purpose of the present study was to identify sex differences in this behavior and associated neural responses. We hypothesized that females would value the rewarding stimulus (Boost®) relative to the aversive stimulus (LiCl) more than males in performing CTA. We evaluated behavior (Boost® intake, LiCl-induced behaviors, ultrasonic vocalizations (USVs), CTA performance) and Fos activation in relevant brain regions after the acute stimuli [acute Boost® (AB), acute LiCl (AL)] and the context-only task control (COT), Boost® only task (BOT) and Boost®-LiCl task (BLT). Acutely, females drank more Boost® than males but showed similar aversive behaviors after LiCl. Females and males performed CTA similarly. Both sexes produced 55 kHz USVs anticipating BOT and inhibited these calls in the BLT. However, more females emitted both 22 kHz and 55 kHz USVs in the BLT than males: the latter correlated with less CTA. Estrous cycle stage also influenced 55 kHz USVs. Fos responses were similar in males and females after AB or AL. Females engaged the gustatory cortex and ventral tegmental area (VTA) more than males during the BOT and males engaged the amygdala more than females in both the BOT and BLT. Network analysis of correlated Fos responses across brain regions identified two unique networks characterizing the BOT and BLT, in both of which the VTA played a central role. In situ hybridization with RNAscope identified a population of D1-receptor expressing cells in the CeA that responded to Boost® and D2 receptor-expressing cells that responded to LiCl. The present study suggests that males and females differentially process the affective valence of a stimulus to produce the same goal-directed behavior.

Ibrutinib's off-target mechanism: cause for dose optimization.

Ibrutinib (Imbruvica®, 2013) is a Bruton's tyrosine kinase (BTK) inhibitor approved for multiple B-cell malignancies and cGVHD. Its treatment is associated with increased risk of cardiac adverse events. Atrial fibrillation is a common cause of therapy discontinuation and interruptions, which have been correlated with shorter progression-free survival in chronic lymphocyte leukemia (CLL) patients. Recently, Xiao et al. identified that ibrutinib-mediated atrial fibrillation is likely due to off-target CSK inhibition. Given promising in vitro and in vivo evidence of maintained biological activity in CLL at lower-than-labeled ibrutinib doses, this elucidated mechanism substantiates the case to investigate alternative dosing schedules. The potential to minimize ibrutinib's off-target effects while conserving response warrants further discussion and investigation of optimal ibrutinib dosing.

Development and validation of a simple, selective, and sensitive LC-MS/MS assay for the quantification of remdesivir in human plasma.

Remdesivir, formerly GS-5734, has recently become the first antiviral drug approved by the U.S. Food and Drug Administration (FDA) to treat COVID-19, the disease caused by SARS-CoV-2. Therapeutic dosing and pharmacokinetic studies require a simple, sensitive, and selective validated assay to quantify drug concentrations in clinical samples. Therefore, we developed a rapid and sensitive LC-MS/MS assay for the quantification of remdesivir in human plasma with its deuterium-labeled analog, remdesivir-2H5, as the internal standard. Chromatographic separation was achieved on a Phenomenex® Synergi™ HPLC Fusion-RP (100 × 2 mm, 4 µm) column by gradient elution. Excellent accuracy and precision (<5.2% within-run variations and. <9.8% between-run variations) were obtained over the range of 0.5-5000 ng/mL. The assay met the FDA Bioanalytical Guidelines for selectivity and specificity, and low inter-matrix lot variability (<2.7%) was observed for extraction efficiency (77%) and matrix effect (123%) studies. Further, stability tests showed that the analyte does not degrade under working conditions, nor during freezing and thawing processes.

Walking School Bus Programs: Implementation Factors, Implementation Outcomes, and Student Outcomes, 2017-2018.

PURPOSE AND OBJECTIVES: Walking school bus programs increase children's physical activity through active travel to school; however, research to inform large-scale implementation of such programs is limited. We investigated contextual factors, implementation outcomes, and student outcomes in existing walking school bus programs in the United States and internationally. INTERVENTION APPROACH: Walking school bus programs involve a group of children walking to school together with an adult leader. On the trip to school, these adults provide social support, address potential traffic and interpersonal safety, and serve as role models to the children while children increase their physical activity levels. EVALUATION METHODS: We conducted surveys with existing walking school bus programs identified through internet searches, referrals, and relevant email listservs. Leaders from 184 programs that operated at least 1 trip per week completed the survey. We used regression analyses to compare differences in contextual factors by area income and location, associations between contextual factors and implementation outcomes, and associations between implementation outcomes and student outcomes. RESULTS: Walking school bus programs in low-income communities had more route leaders and engaged in more active travel to school-related activities of being sustained than those in higher income. Programs that had no external funding, multiple route leaders, and coordination by a school or district staff member (as opposed to a parent) had greater student participation than other programs. Providing more trips than other programs per week was associated with reduced tardiness, reduced bullying, and improved neighborhood walkability. The greatest barriers to implementation were recruiting and maintaining students and identifying and maintaining route leaders. IMPLICATIONS FOR PUBLIC HEALTH: Walking school bus programs can be implemented successfully in many contexts using various models. The involvement of several people in leadership roles is critical for sustainability. Evidence-based implementation strategies that overcome barriers can improve reach, implementation, and sustainability of walking school bus programs and can increase children's physical activity.

Overcoming legal liability concerns for school-based physical activity promotion.

Schools have been identified as a priority environment for physical activity promotion as a component of efforts to help prevent childhood obesity. A variety of school-based environmental and programmatic strategies have been proven effective in promoting physical activity both on-site and in the surrounding community. However, many schools are deterred by fears of increased risk of legal liability for personal injuries. We examine 3 school-based strategies for promoting physical activity--Safe Routes to School programs, joint use agreements, and playground enhancement--from a tort liability perspective, and describe how schools can substantially minimize any associated liability risk through injury prevention and other strategies. We also recommend approaches to help schools overcome their liability concerns and adopt these critically needed healthy school policies.

Calorie and protein intake in acute rehabilitation inpatients with traumatic spinal cord injury versus other diagnoses.

BACKGROUND: Obesity and its consequences affect patients with spinal cord injury (SCI). There is a paucity of data with regard to the dietary intake patterns of patients with SCI in the acute inpatient rehabilitation setting. Our hypothesis is that acute rehabilitation inpatients with SCI consume significantly more calories and protein than other inpatient rehabilitation diagnoses. OBJECTIVE: To compare calorie and protein intake in patients with new SCI versus other diagnoses (new traumatic brain injury [TBI], new stroke, and Parkinson's disease [PD]) in the acute inpatient rehabilitation setting. METHODS: The intake of 78 acute rehabilitation inpatients was recorded by registered dieticians utilizing once-weekly calorie and protein intake calculations. RESULTS: Mean ± SD calorie intake (kcal) for the SCI, TBI, stroke, and PD groups was 1,967.9 ± 611.6, 1,546.8 ± 352.3, 1,459.7 ± 443.2, and 1,459.4 ± 434.6, respectively. ANOVA revealed a significant overall group difference, F(3, 74) = 4.74, P = .004. Mean ± SD protein intake (g) for the SCI, TBI, stroke, and PD groups was 71.5 ± 25.0, 61.1 ± 12.8, 57.6 ± 16.6, and 55.1 ± 19.1, respectively. ANOVA did not reveal an overall group difference, F(3, 74) = 2.50, P = .066. CONCLUSIONS: Given the diet-related comorbidities and energy balance abnormalities associated with SCI, combined with the intake levels demonstrated in this study, education with regard to appropriate calorie intake in patients with SCI should be given in the acute inpatient rehabilitation setting.

Reorganization in coping behavior at 1 1/2 years: dynamic systems and normative change.

By the age of 1 year toddlers demonstrate distinct coping habits for dealing with frustration. However, these habits may be open to change and reorganization at subsequent developmental junctures. We investigated change in coping habits at 18-20 months, a normative age for major advances in social cognition, focusing on the dynamic systems principles of fluctuation and novelty at transitions. Specifically, we asked whether month-to-month fluctuation, novel behavioral habits and real-time variability increased at the age of a normative transition, despite individual differences in the content of behavior. Infants were given frustrating toys while their mothers sat nearby without helping, on monthly visits at 14-25 months (before, during and after the hypothesized transition). State space grids representing patterns of behavioral durations were constructed for each episode and compared over age. As predicted, month-to-month fluctuation in grid patterns increased temporarily between 17 and 20 months, partly independently of a concurrent peak in distress, and new behavioral habits replaced old ones at the same age. Coping habits changed differently for high-and low-distressed toddlers. However, changes in real-time variability did not generally meet our expectations.