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Despite broad agreement that prioritizing health equity is critical to minimizing the health impacts of climate change, there is a lack of clarity about what advancing health equity means in practice. More than reducing health disparities; it also implies engaging and empowering marginalized communities. We propose a typology of health equity processes, focused on building community agency and power, and then apply it to a nonrepresentative, purposive sample of 48 community-based climate actions (CBCAs) selected from lists of projects funded by foundations and state climate programs and from other sources. All CBCAs were in the United States, community-based, active since 2015 or more recently, engaged in climate mitigation or adaptation, and stated health equity aims. Two team members reviewed project reports to assess the engagement of vulnerable and marginalized populations, agency-building, and transformation of community power relationships. Although 33 CBCAs reported efforts to build community agency, only 19 reported efforts to increase community power. City-led CBCAs showed less emphasis on agency-building and power transformation. This typology can support efforts to advance health equity by providing concrete indicators to diagnose gaps and track progress. (Am J Public Health. 2023;113(2):185–193. https://doi.org/10.2105/AJPH.2022.307143 )

Background The COVID-19 pandemic has disproportionally affected the mental health of health and social care workers (HSCWs), with many experiencing symptoms of depression, anxiety and post-traumatic stress disorder. Psychological interventions have been offered via mental health services and in-house psychology teams, but their effectiveness in this context is not well documented. Aims To evaluate a stepped-care psychological support pathway for HSCWs from Homerton Healthcare Foundation Trust in London, which offered psychological first aid, evidence-based psychological therapies and group-based well-being workshops. Method The service evaluation used a pre–post approach to assess depression, anxiety, functional impairment and post-traumatic stress disorder symptom change for those who attended sessions of psychological first aid, low- or high-intensity cognitive–behavioural therapy or a combination of these. In addition, the acceptability of the psychological first aid sessions and well-being workshops was explored via feedback data. Results Across all interventions, statistically significant reductions of depression (d = 1.33), anxiety (d = 1.37) and functional impairment (d = 0.93) were observed, and these reductions were equivalent between the interventions, as well as the demographic and occupational differences between the HSCWs (ethnicity, staff group and redeployment status). HSCWs were highly satisfied with the psychological first aid and well-being workshops. Conclusions The evaluation supports the utility of evidence-based interventions delivered as part of a stepped-care pathway for HSCWs with common mental health problems in the context of the COVID-19 pandemic. Given the novel integration of psychological first aid within the stepped-care model as a step one intervention, replication and further testing in larger-scale studies is warranted.

Somatosensory feedback from upper airway structures is essential for swallowing and airway defense but little is known about the identities and distributions of human upper airway neurons. Furthermore, whether sensory innervation modifies with aging is unknown. In this study, we quantify neuronal and chemosensory cell density in upper airway structures and correlate with age.Participants underwent biopsies from base of tongue, lateral and midline pharyngeal wall, epiglottis, and arytenoids (N = 25 13 female/12 male; 20-80 years, mean 51.4 years without clinical diagnosis of dysphagia or clinical indication for biopsy). Tissue sections were labeled with antibodies for all neurons, myelinated neurons, and chemosensory cells. Densities of lamina propria innervation, epithelial innervation, solitary chemosensory cells, and taste buds were calculated and correlated with age.Arytenoid had the highest density of innervation and chemosensory cells across all measures compared to other sites. Taste buds were frequently observed in arytenoid and epiglottis. Base of tongue, lateral pharynx, and midline posterior pharynx had minimal innervation and few chemosensory cells. Epithelial innervation was present primarily in close proximity to chemosensory cells and taste buds. Overall innervation and myelinated fibers in the arytenoid lamina propria decline with aging.Findings establish the architecture of healthy adult sensory innervation and demonstrate the varied distribution of laryngopharyngeal innervation, necessary steps toward understanding the sensory basis for swallowing and airway defense. We also document age-related decline in arytenoid innervation density. These findings suggest that sensory afferent denervation of the upper airway may be a contributing factor to presbyphagia.NA Laryngoscope, 2022.

Graph theory provides a convenient framework for modeling and solving structured optimization problems. Under this framework, the modeler can arrange/assemble the components of an optimization model (variables, constraints, objective functions, and data) within nodes and edges of a graph, and this representation can be used to visualize, manipulate, and solve the problem. In this work, we present a ${\tt Julia}$ framework for modeling and solving graph-structured nonlinear optimization problems. Our framework integrates the modeling package ${\tt Plasmo.jl}$ (which facilitates the construction and manipulation of graph models) and the nonlinear optimization solver ${\tt MadNLP.jl}$ (which provides capabilities for exploiting graph structures to accelerate solution). We illustrate with a simple example how model construction and manipulation can be performed in an intuitive manner using ${\tt Plasmo.jl}$ and how the model structure can be exploited by ${\tt MadNLP.jl}$. We also demonstrate the scalability of the framework by targeting a large-scale, stochastic gas network problem that contains over 1.7 million variables., 30 pages, 14 figures

Hydrogels prepared from supramolecular cross-linking motifs are appealing for use as biomaterials and drug delivery technologies. The inclusion of macromolecules (e.g., protein therapeutics) in these materials is relevant to many of their intended uses. However, the impact of dynamic network cross-linking on macromolecule diffusion must be better understood. Here, hydrogel networks with identical topology but disparate cross-link dynamics are explored. These materials are prepared from cross-linking with host-guest complexes of the cucurbit[7]uril (CB[7]) macrocycle and two guests of different affinity. Rheology confirms differences in bulk material dynamics arising from differences in cross-link thermodynamics. Fluorescence recovery after photobleaching (FRAP) provides insight into macromolecule diffusion as a function of probe molecular weight and hydrogel network dynamics. Together, both rheology and FRAP enable the estimation of the mean network mesh size, which is then related to the solute hydrodynamic diameters to further understand macromolecule diffusion. Interestingly, the thermodynamics of host-guest cross-linking are correlated with a marked deviation from classical diffusion behavior for higher molecular weight probes, yielding solute aggregation in high-affinity networks. These studies offer insights into fundamental macromolecular transport phenomena as they relate to the association dynamics of supramolecular networks. Translation of these materials from in vitro to in vivo is also assessed by bulk release of an encapsulated macromolecule. Contradictory in vitro to in vivo results with inverse relationships in release between the two hydrogels underscores the caution demanded when translating supramolecular biomaterials into application.

This study aimed to determine if dogs and cats presenting as an emergency had improved tolerance of intravenous catheterisation following the application of vapocoolant spray when compared to a saline control.A randomised controlled trial of client-owned dogs and cats presenting as an emergency and requiring intravenous catheterisation was performed. Patient signalment and mentation score were recorded. All animals were restrained and had their fur clipped over the catheterisation site. They were then randomly allocated to either have a swab saturated with vapocoolant spray (treatment) or a swab saturated with saline (control) applied to the clipped area before intravenous catheterisation. The procedure was video recorded and a single blinded observer reviewed the recordings and assigned reaction scores (0 to 3) at four time points (initial restraint, limb handling, swab application and skin puncture).Between October 2020 and January 2021, a total of 100 patients (79 dogs, 21 cats) were enrolled, with 50 in each group. No significant difference in species, age, breed, sex or mentation score was detected between the two groups. There was no significant difference in reaction scores between the groups at any time point with the exception of a significantly increased swab application reaction score in the treatment group compared to the control group.The indirect application of vapocoolant spray via a swab before catheterisation does not significantly reduce the reaction of dogs and cats to intravenous catheterisation in an emergency setting.

Diffuse intrinsic pontine glioma (DIPG) remains a fatal brainstem tumor demanding innovative therapies. As B7-H3 (CD276) is expressed on central nervous system (CNS) tumors, we designed B7-H3–specific chimeric antigen receptor (CAR) T cells, confirmed their preclinical efficacy, and opened BrainChild-03 (NCT04185038), a first-in-human phase I trial administering repeated locoregional B7-H3 CAR T cells to children with recurrent/refractory CNS tumors and DIPG. Here, we report the results of the first three evaluable patients with DIPG (including two who enrolled after progression), who received 40 infusions with no dose-limiting toxicities. One patient had sustained clinical and radiographic improvement through 12 months on study. Patients exhibited correlative evidence of local immune activation and persistent cerebrospinal fluid (CSF) B7-H3 CAR T cells. Targeted mass spectrometry of CSF biospecimens revealed modulation of B7-H3 and critical immune analytes (CD14, CD163, CSF-1, CXCL13, and VCAM-1). Our data suggest the feasibility of repeated intracranial B7-H3 CAR T-cell dosing and that intracranial delivery may induce local immune activation.Significance:This is the first report of repeatedly dosed intracranial B7-H3 CAR T cells for patients with DIPG and includes preliminary tolerability, the detection of CAR T cells in the CSF, CSF cytokine elevations supporting locoregional immune activation, and the feasibility of serial mass spectrometry from both serum and CSF.This article is highlighted in the In This Issue feature, p. 1

Supplementary Data from Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety

Statistical analysis of apoptosis assay.

SCH Clinical and Sequencing Data

Krüppel-like factor 5 (KLF5), a member of the SP/KLF family of zinc finger transcription factors, is overexpressed in human colorectal cancer specimens, and this overabundance is associated with aggressive cancer development and progression. We demonstrated that mice haploinsufficient for Klf5 had reduced intestinal tumor burden in the background of germline mutation in Apc, a gatekeeper of intestinal tumorigenesis. Based on a high-throughput screening strategy, we developed ML264, a small-molecule compound that inhibits KLF5, and showed that it inhibits growth of colorectal cancer in vitro and in vivo. Through optimization efforts based on the structure of ML264, we have now identified a new lead compound, SR18662. We find that treatment with SR18662 significantly reduces growth and proliferation of colorectal cancer cells as compared with treatment with vehicle control, ML264, or SR15006 (a less optimized analogue from SAR efforts leading to SR18662). SR18662 showed improved efficacy in reducing the viability of multiple colorectal cancer cell lines. Flow cytometry analysis following SR18662 treatment showed an increase in cells captured in either S or G2–M phases of the cell cycle and a significant increase in the number of apoptotic cells, the latter a unique property compared with ML264 or SR15006. SR18662 treatment also reduces the expression of cyclins and components of the MAPK and WNT signaling pathways. Importantly, we observed a significant dose-dependent inhibition of xenograft growth in mice following SR18662 treatment that exceeded the effect of ML264 at equivalent doses. These findings support further development of SR18662 and its analogues for colorectal cancer therapy.

Supplementary Figure S1. Synthesis steps of SR15006 and SR18662. Supplementary Figure S2. SR18662 changes cell cycle profiles of colorectal cancer cell lines. Supplementary Figure S3. SR18662 increases apoptosis of colorectal cancer cell lines. Supplementary Figures S4 - S6. SR18662 inhibits activity of MAPK, WNT/b-catenin signaling pathways and decreases the levels of cyclins. Supplementary Figure S7. The effect of SR18662 on the mice weight during xenograft studies.

SUMMARYCells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we developed a series ofin vivomodels to induceGclcdeletion in adult animals. We find that GSH is essential to lipid abundancein vivo. GSH levels are reported to be highest in liver tissue, which is also a hub for lipid production. While the loss of GSH did not cause liver failure, it decreased lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we found that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver’s balance of redox buffering and triglyceride production.

Background Although treatment options and algorithms for rheumatoid arthritis (RA) have improved remarkably in recent decades, there continues to be no definitive cure or pharmacologic intervention with reliable long-term efficacy. For this reason, the combination of medications and healthy lifestyle modifications are essential for controlling joint disease, and extra-articular manifestations of RA, such as interstitial lung disease (ILD) and other lung pathologies, which greatly impact morbidity and mortality. Generally, exercise has been deemed beneficial in RA patients, and both patients and clinicians are motivated to incorporate effective non-pharmacologic interventions. However, there are limited evidence-based and specific exercise regimens available to support engagement in such activities for RA patients. Here, we provided the continuous opportunity for exercise to mice and implemented automated recording and quantification of wheel running behavior. This allowed us to describe the associated effects on the progression of inflammatory-erosive arthritis and ILD in the tumor necrosis factor transgenic (TNF-Tg) mouse model of RA. Methods Wild-type (WT; males, n=9; females, n=9) and TNF-Tg (males, n=12; females, n=14) mice were singly housed with free access to a running wheel starting at 2 months until 5 to 5.5 months of age. Measures of running included distance, rate, length, and number of run bouts, which were derived from continuously recorded data streams collected automatically and in real-time. In vivo lung, ankle, and knee micro-computed tomography (micro-CT), along with terminal micro-CT and histology were performed to examine the association of running behaviors and disease progression relative to sedentary controls. Results TNF-Tg males and females exhibited significantly reduced running distance, rate, length, and number of run bouts compared to WT counterparts by 5 months of age (ppρ=0.705/rate, ρ=0.693 (pρ=0.380 (p=0.06)/ρ=0.403 (pρ=−903/ρ=−0.865; female: ρ=−0.614/ρ=−0.594 (p Conclusions Implementation of automated wheel running behavior metrics allows for evaluation of longitudinal activity modifications hands-off and in real-time to relate with biomarkers of disease severity. Through such analysis, we determined that wheel running activity increases aerated lung volumes, but exacerbates inflammatory-erosive arthritis in TNF-Tg mice. To the end of a clinically relevant model, additional functional assessment of these outcomes and studies of pain behavior are warranted.