KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements.

Tumours use various strategies to evade immune surveillance1,2. Immunotherapies targeting tumour immune evasion such as immune checkpoint blockade have shown considerable efficacy on multiple cancers3,4 but are ineffective for most patients due to primary or acquired resistance5-7. Recent studies showed that some epigenetic regulators suppress anti-tumour immunity2,8-12, suggesting that epigenetic therapies could boost anti-tumour immune responses and overcome resistance to current immunotherapies. Here we show that, in mouse melanoma models, depletion of KDM5B-an H3K4 demethylase that is critical for melanoma maintenance and drug resistance13-15-induces robust adaptive immune responses and enhances responses to immune checkpoint blockade. Mechanistically, KDM5B recruits the H3K9 methyltransferase SETDB1 to repress endogenous retroelements such as MMVL30 in a demethylase-independent manner. Derepression of these retroelements activates cytosolic RNA-sensing and DNA-sensing pathways and the subsequent type-I interferon response, leading to tumour rejection and induction of immune memory. Our results demonstrate that KDM5B suppresses anti-tumour immunity by epigenetic silencing of retroelements. We therefore reveal roles of KDM5B in heterochromatin regulation and immune evasion in melanoma, opening new paths for the development of KDM5B-targeting and SETDB1-targeting therapies to enhance tumour immunogenicity and overcome immunotherapy resistance.

Rats and the city: Implications of urbanization on zoonotic disease risk in Southeast Asia.

Urbanization is rapidly transforming much of Southeast Asia, altering the structure and function of the landscape, as well as the frequency and intensity of the interactions between people, animals, and the environment. In this study, we explored the impact of urbanization on zoonotic disease risk by simultaneously characterizing changes in the ecology of animal reservoirs (rodents), ectoparasite vectors (ticks), and pathogens across a gradient of urbanization in Kuching, a city in Malaysian Borneo. We sampled 863 rodents across rural, developing, and urban locations and found that rodent species diversity decreased with increasing urbanization-from 10 species in the rural location to 4 in the rural location. Notably, two species appeared to thrive in urban areas, as follows: the invasive urban exploiter Rattus rattus (n = 375) and the native urban adapter Sundamys muelleri (n = 331). R. rattus was strongly associated with built infrastructure across the gradient and carried a high diversity of pathogens, including multihost zoonoses capable of environmental transmission (e.g., Leptospira spp.). In contrast, S. muelleri was restricted to green patches where it was found at high densities and was strongly associated with the presence of ticks, including the medically important genera Amblyomma, Haemaphysalis, and Ixodes. Our analyses reveal that zoonotic disease risk is elevated and heterogeneously distributed in urban environments and highlight the potential for targeted risk reduction through pest management and public health messaging.

Targeting serine/glycine metabolism improves radiotherapy response in non-small cell lung cancer.

BACKGROUND: Lung cancer is the most lethal cancer, and 85% of cases are classified as non-small cell lung cancer (NSCLC). Metabolic rewiring is a cancer hallmark that causes treatment resistance, and lacks insights into serine/glycine pathway adaptations upon radiotherapy. METHODS: We analyzed radiotherapy responses using mass-spectrometry-based metabolomics in NSCLC patient's plasma and cell lines. Efficacy of serine/glycine conversion inhibitor sertraline with radiotherapy was investigated by proliferation, clonogenic and spheroid assays, and in vivo using a serine/glycine dependent NSCLC mouse model by assessment of tumor growth, metabolite and cytokine levels, and immune signatures. RESULTS: Serine/glycine pathway metabolites were significantly consumed in response to radiotherapy in NSCLC patients and cell models. Combining sertraline with radiotherapy impaired NSCLC proliferation, clonogenicity and stem cell self-renewal capacity. In vivo, NSCLC tumor growth was reduced solely in the sertraline plus radiotherapy combination treatment group. Tumor weights linked to systemic serine/glycine pathway metabolite levels, and were inhibited in the combination therapy group. Interestingly, combination therapy reshaped the tumor microenvironment via cytokines associated with natural killer cells, supported by eradication of immune checkpoint galectin-1 and elevated granzyme B levels. CONCLUSION: Our findings highlight that targeting serine/glycine metabolism using sertraline restricts cancer cell recovery from radiotherapy and provides tumor control through immunomodulation in NSCLC.

Peripheral blood immune parameters, response, and adverse events after neoadjuvant chemotherapy plus durvalumab in early-stage triple-negative breast cancer.

PURPOSE: We evaluated T- and B-cell receptor (TCR and BCR) repertoire diversity and 38 serum cytokines in pre- and post-treatment peripheral blood of 66 patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy plus durvalumab and assessed associations with pathologic response and immune-related adverse events (irAEs) during treatment. METHODS: Genomic DNA was isolated from buffy coat for TCR and BCR clonotype profiling using the Immunoseq platform and diversity was quantified with Pielou's evenness index. MILLIPLEX MAP Human Cytokine/Chemokine Magnetic Bead Panel was used to measure serum cytokine levels, which were compared between groups using moderated t-statistic with Benjamini-Hochberg correction for multiple testing. RESULTS: TCR and BCR diversity was high (Pielou's index > 0.75) in all samples. Baseline receptor diversities and change in diversity pre- and post-treatment were not associated with pathologic response or irAE status, except for BCR diversity that was significantly lower post-treatment in patients who developed irAE (unadjusted p = 0.0321). Five cytokines increased after treatment in patients with pathologic complete response (pCR) but decreased in patients with RD, most prominently IL-8. IFNγ, IL-7, and GM-CSF levels were higher in pre-treatment than in post-treatment samples of patients who developed irAEs but were lower in those without irAEs. CONCLUSION: Baseline peripheral blood cytokine levels may predict irAEs in patients treated with immune checkpoint inhibitors and chemotherapy, and increased post-treatment B-cell clonal expansion might mediate irAEs.

Reproducible Reporting of the Collection and Evaluation of Annotations for Artificial Intelligence Models.

This work puts forth and demonstrates the utility of a reporting framework for collecting and evaluating annotations of medical images used for training and testing artificial intelligence (AI) models in assisting detection and diagnosis. AI has unique reporting requirements, as shown by the AI extensions to the Consolidated Standards of Reporting Trials (CONSORT) and Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklists and the proposed AI extensions to the Standards for Reporting Diagnostic Accuracy (STARD) and Transparent Reporting of a Multivariable Prediction model for Individual Prognosis or Diagnosis (TRIPOD) checklists. AI for detection and/or diagnostic image analysis requires complete, reproducible, and transparent reporting of the annotations and metadata used in training and testing data sets. In an earlier work by other researchers, an annotation workflow and quality checklist for computational pathology annotations were proposed. In this manuscript, we operationalize this workflow into an evaluable quality checklist that applies to any reader-interpreted medical images, and we demonstrate its use for an annotation effort in digital pathology. We refer to this quality framework as the Collection and Evaluation of Annotations for Reproducible Reporting of Artificial Intelligence (CLEARR-AI).

Nano-compositional imaging of the lanthanum silicide system at THz wavelengths.

Terahertz scattering-type scanning near-field optical microscopy (THz-sSNOM) provides a noninvasive way to probe the low frequency conductivity of materials and to characterize material compositions at the nanoscale. However, the potential capability of atomic compositional analysis with THz nanoscopy remains largely unexplored. Here, we perform THz near-field imaging and spectroscopy on a model rare-earth alloy of lanthanum silicide (La-Si) which is known to exhibit diverse compositional and structural phases. We identify subwavelength spatial variations in conductivity that is manifested as alloy microstructures down to much less than 1 µm in size and is remarkably distinct from the surface topography of the material. Signal contrasts from the near-field scattering responses enable mapping the local silicon/lanthanum content differences. These observations demonstrate that THz-sSNOM offers a new avenue to investigate the compositional heterogeneity of material phases and their related nanoscale electrical as well as optical properties.

Training pathologists to assess stromal tumour-infiltrating lymphocytes in breast cancer synergises efforts in clinical care and scientific research.

A growing body of research supports stromal tumour-infiltrating lymphocyte (TIL) density in breast cancer to be a robust prognostic and predicive biomarker. The gold standard for stromal TIL density quantitation in breast cancer is pathologist visual assessment using haematoxylin and eosin-stained slides. Artificial intelligence/machine-learning algorithms are in development to automate the stromal TIL scoring process, and must be validated against a reference standard such as pathologist visual assessment. Visual TIL assessment may suffer from significant interobserver variability. To improve interobserver agreement, regulatory science experts at the US Food and Drug Administration partnered with academic pathologists internationally to create a freely available online continuing medical education (CME) course to train pathologists in assessing breast cancer stromal TILs using an interactive format with expert commentary. Here we describe and provide a user guide to this CME course, whose content was designed to improve pathologist accuracy in scoring breast cancer TILs. We also suggest subsequent steps to translate knowledge into clinical practice with proficiency testing.

Heteroptera research in Latin America and the Caribbean (Insecta, Hemiptera): status and perspectives in the 21st century.

Latin American and the Caribbean regions (LAC) harbor one of the most biodiverse areas of the world, the Neotropics. True bugs (Hemiptera: Heteroptera) are a diverse lineage of insects, with more than 45,000 species, particularly speciose in the Neotropical region. True bugs are fundamental in the dynamics of natural and modified ecosystems, with several species critical to agriculture and public health. We compiled Heteroptera research in LAC from 1998-2022 using bibliographic databases. Productivity, collaborative networks, and the main topics studied were analyzed. A total of 1,651 Heteroptera studies from LAC were found, with continuous growth being 2021 the most prolific. Four categories (Taxonomy of extant species, Faunistic inventories and new records, Pest species biology, and Community ecology) represent most of the published research. About 60 percent of the records evaluated correspond to five families (Pentatomidae, Reduviidae, Coreidae, Miridae, and Rhyparochromidae). We emphasize the need to keep working on Heteroptera taxonomy because it will allow further advances in other areas such as phylogenetic analyses, biogeography, ecology, and natural history, among others. The results of our analyses characterize the current state of heteropterology in the region, establishing a baseline for future studies and efforts to broaden the knowledge of the group.

Topical anaesthesia and decongestion in rhinology.

Topical anaesthesia and decongestion of the sinonasal mucosa are used commonly in rhinology practice to facilitate nasal endoscopy, as well as debridement and biopsies. Topical agents used for sinonasal anaesthesia include lignocaine, tetracaine and cocaine. Unlike lignocaine and tetracaine, cocaine also has a decongestant effect. Phenylephrine, oxymetazoline, xylometazoline or adrenaline are usually added to lignocaine and tetracaine to provide decongestion. Several studies have been performed seeking to identify the optimal nasal preparation for nasal endoscopy in the clinic setting. However, there remains no clear consensus in the literature resulting in ongoing wide variation between anaesthetic-decongestant preparations used in clinical practice. Indeed, some authors have argued that no anaesthetic is required at all for flexible nasendoscopy despite the apparent consensus that nasal instrumentation is generally uncomfortable, inferred by the persistence of ongoing research in this area. This review provides a practical summary of local anaesthetic and decongestant pharmacology as it relates to rhinologic practice and summarises the literature to date, with the goal of identifying current gaps in the literature and guiding future research efforts.

Near Room-Temperature Intrinsic Exchange Bias in an Fe Intercalated ZrSe2 Spin Glass.

Some magnetic systems display a shift in the center of their magnetic hysteresis loop away from zero field, a phenomenon termed exchange bias. Despite the extensive use of the exchange bias effect, particularly in magnetic multilayers, for the design of spin-based memory/electronics devices, a comprehensive mechanistic understanding of this effect remains a longstanding problem. Recent work has shown that disorder-induced spin frustration might play a key role in exchange bias, suggesting new materials design approaches for spin-based electronic devices that harness this effect. Here, we design a spin glass with strong spin frustration induced by magnetic disorder by exploiting the distinctive structure of Fe intercalated ZrSe2, where Fe(II) centers are shown to occupy both octahedral and tetrahedral interstitial sites and to distribute between ZrSe2 layers without long-range structural order. Notably, we observe behavior consistent with a magnetically frustrated and multidegenerate ground state in these Fe0.17ZrSe2 single crystals, which persists above room temperature. Moreover, this magnetic frustration leads to a robust and tunable exchange bias up to 250 K. These results not only offer important insights into the effects of magnetic disorder and frustration in magnetic materials generally, but also highlight as design strategy the idea that a large exchange bias can arise from an inhomogeneous microscopic environment without discernible long-range magnetic order. In addition, these results show that intercalated TMDs like Fe0.17ZrSe2 hold potential for spintronic technologies that can achieve room temperature applications.

Comprehensive Case-Control Study of Protective and Risk Factors for Buruli Ulcer, Southeastern Australia.

To examine protective and risk factors for Buruli ulcer (BU), we conducted a case-control study of 245 adult BU cases and 481 postcode-matched controls across BU-endemic areas of Victoria, Australia. We calculated age- and sex-adjusted odds ratios for socio-environmental, host, and behavioral factors associated with BU by using conditional logistic regression. Odds of BU were >2-fold for persons with diabetes mellitus and persons working outdoors who had soil contact in BU-endemic areas (compared with indoor work) but were lower among persons who had bacillus Calmette-Guérin vaccinations. BU was associated with increasing numbers of possums and with ponds and bore water use at residences. Using insect repellent, covering arms and legs outdoors, and immediately washing wounds were protective; undertaking multiple protective behaviors was associated with the lowest odds of BU. Skin hygiene/protection behaviors and previous bacillus Calmette-Guérin vaccination might provide protection against BU in BU-endemic areas.

Remarkably Low KIR and HLA Diversity in Amerindians Reveals Signatures of Strong Purifying Selection Shaping the Centromeric KIR Region.

The killer-cell immunoglobulin-like receptors (KIR) recognize human leukocyte antigen (HLA) molecules to regulate the cytotoxic and inflammatory responses of natural killer cells. KIR genes are encoded by a rapidly evolving gene family on chromosome 19 and present an unusual variation of presence and absence of genes and high allelic diversity. Although many studies have associated KIR polymorphism with susceptibility to several diseases over the last decades, the high-resolution allele-level haplotypes have only recently started to be described in populations. Here, we use a highly innovative custom next-generation sequencing method that provides a state-of-art characterization of KIR and HLA diversity in 706 individuals from eight unique South American populations: five Amerindian populations from Brazil (three Guarani and two Kaingang); one Amerindian population from Paraguay (Aché); and two urban populations from Southern Brazil (European and Japanese descendants from Curitiba). For the first time, we describe complete high-resolution KIR haplotypes in South American populations, exploring copy number, linkage disequilibrium, and KIR-HLA interactions. We show that all Amerindians analyzed to date exhibit the lowest numbers of KIR-HLA interactions among all described worldwide populations, and that 83-97% of their KIR-HLA interactions rely on a few HLA-C molecules. Using multiple approaches, we found signatures of strong purifying selection on the KIR centromeric region, which codes for the strongest NK cell educator receptors, possibly driven by the limited HLA diversity in these populations. Our study expands the current knowledge of KIR genetic diversity in populations to understand KIR-HLA coevolution and its impact on human health and survival.

Transcription factor NKX2-1 drives serine and glycine synthesis addiction in cancer.

BACKGROUND: One-third of cancers activate endogenous synthesis of serine/glycine, and can become addicted to this pathway to sustain proliferation and survival. Mechanisms driving this metabolic rewiring remain largely unknown. METHODS: NKX2-1 overexpressing and NKX2-1 knockdown/knockout T-cell leukaemia and lung cancer cell line models were established to study metabolic rewiring using ChIP-qPCR, immunoblotting, mass spectrometry, and proliferation and invasion assays. Findings and therapeutic relevance were validated in mouse models and confirmed in patient datasets. RESULTS: Exploring T-cell leukaemia, lung cancer and neuroendocrine prostate cancer patient datasets highlighted the transcription factor NKX2-1 as putative driver of serine/glycine metabolism. We demonstrate that transcription factor NKX2-1 binds and transcriptionally upregulates serine/glycine synthesis enzyme genes, enabling NKX2-1 expressing cells to proliferate and invade in serine/glycine-depleted conditions. NKX2-1 driven serine/glycine synthesis generates nucleotides and redox molecules, and is associated with an altered cellular lipidome and methylome. Accordingly, NKX2-1 tumour-bearing mice display enhanced tumour aggressiveness associated with systemic metabolic rewiring. Therapeutically, NKX2-1-expressing cancer cells are more sensitive to serine/glycine conversion inhibition by repurposed anti-depressant sertraline, and to etoposide chemotherapy. CONCLUSION: Collectively, we identify NKX2-1 as a novel transcriptional regulator of serine/glycine synthesis addiction across cancers, revealing a therapeutic vulnerability of NKX2-1-driven cancers. Transcription factor NKX2-1 fuels cancer cell proliferation and survival by hyperactivating serine/glycine synthesis, highlighting this pathway as a novel therapeutic target in NKX2-1-positive cancers.

Annual (2023) taxonomic update of RNA-directed RNA polymerase-encoding negative-sense RNA viruses (realm Riboviria: kingdom Orthornavirae: phylum Negarnaviricota).

In April 2023, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. The phylum was expanded by one new family, 14 new genera, and 140 new species. Two genera and 538 species were renamed. One species was moved, and four were abolished. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV.

Growth rate and nutrient limitation as key drivers of extracellular quorum sensing signal molecule accumulation in Pseudomonas aeruginosa.

In Pseudomonas aeruginosa, quorum sensing (QS) depends on an interconnected regulatory hierarchy involving the Las, Rhl and Pqs systems, which are collectively responsible for the co-ordinated synthesis of a diverse repertoire of N-acylhomoserine lactones (AHLs) and 2-alkyl-4-quinolones (AQs). Apparent population density-dependent phenomena such as QS may, however, be due to growth rate and/or nutrient exhaustion in batch culture. Using continuous culture, we show that growth rate and population density independently modulate the accumulation of AHLs and AQs such that the highest concentrations are observed at a slow growth rate and high population density. Carbon source (notably succinate), nutrient limitation (C, N, Fe, Mg) or growth at 25 °C generally reduces AHL and AQ levels, except for P and S limitation, which result in substantially higher concentrations of AQs, particularly AQ N-oxides, despite the lower population densities achieved. Principal component analysis indicates that ~26 % variation is due to nutrient limitation and a further 30 % is due to growth rate. The formation of N-(3-oxododecanoyl)-l-homoserine lactone (3OC12-HSL) turnover products such as the ring opened form and tetramic acid varies with the limiting nutrient limitation and anaerobiosis. Differential ratios of N-butanoyl-homoserine lactone (C4-HSL), 3OC12-HSL and the AQs as a function of growth environment are clearly apparent. Inactivation of QS by mutation of three key genes required for QS signal synthesis (lasI, rhlI and pqsA) substantially increases the concentrations of key substrates from the activated methyl cycle and aromatic amino acid biosynthesis, as well as ATP levels, highlighting the energetic drain that AHL and AQ synthesis and hence QS impose on P. aeruginosa.

Disruption of the Pseudomonas aeruginosa Tat system perturbs PQS-dependent quorum sensing and biofilm maturation through lack of the Rieske cytochrome bc1 sub-unit.

Extracellular DNA (eDNA) is a major constituent of the extracellular matrix of Pseudomonas aeruginosa biofilms and its release is regulated via pseudomonas quinolone signal (PQS) dependent quorum sensing (QS). By screening a P. aeruginosa transposon library to identify factors required for DNA release, mutants with insertions in the twin-arginine translocation (Tat) pathway were identified as exhibiting reduced eDNA release, and defective biofilm architecture with enhanced susceptibility to tobramycin. P. aeruginosa tat mutants showed substantial reductions in pyocyanin, rhamnolipid and membrane vesicle (MV) production consistent with perturbation of PQS-dependent QS as demonstrated by changes in pqsA expression and 2-alkyl-4-quinolone (AQ) production. Provision of exogenous PQS to the tat mutants did not return pqsA, rhlA or phzA1 expression or pyocyanin production to wild type levels. However, transformation of the tat mutants with the AQ-independent pqs effector pqsE restored phzA1 expression and pyocyanin production. Since mutation or inhibition of Tat prevented PQS-driven auto-induction, we sought to identify the Tat substrate(s) responsible. A pqsA::lux fusion was introduced into each of 34 validated P. aeruginosa Tat substrate deletion mutants. Analysis of each mutant for reduced bioluminescence revealed that the primary signalling defect was associated with the Rieske iron-sulfur subunit of the cytochrome bc1 complex. In common with the parent strain, a Rieske mutant exhibited defective PQS signalling, AQ production, rhlA expression and eDNA release that could be restored by genetic complementation. This defect was also phenocopied by deletion of cytB or cytC1. Thus, either lack of the Rieske sub-unit or mutation of cytochrome bc1 genes results in the perturbation of PQS-dependent autoinduction resulting in eDNA deficient biofilms, reduced antibiotic tolerance and compromised virulence factor production.

Sympatric primate seed dispersers and predators jointly contribute to plant diversity in a subtropical forest.

Mutualistic and antagonistic plant-animal interactions differentially contribute to the maintenance of species diversity in ecological communities. Although both seed dispersal and predation by fruit-eating animals are recognized as important drivers of plant population dynamics, the mechanisms underlying how seed dispersers and predators jointly affect plant diversity remain largely unexplored. Based on mediating roles of seed size and species abundance, we investigated the effects of seed dispersal and predation by two sympatric primates (Nomascus concolor and Trachypithecus crepusculus) on local plant recruitment in a subtropical forest of China. Over a 26 month period, we confirmed that these primates were functionally distinct: gibbons were legitimate seed dispersers who dispersed seeds of 44 plant species, while langurs were primarily seed predators who destroyed seeds of 48 plant species. Gibbons dispersed medium-seeded species more effectively than small- and large-seeded species, and dispersed more seeds of rare species than common and dominant species. Langurs showed a similar predation rate across different sizes of seeds, but destroyed a large number of seeds from common species. Due to gut passage effects, gibbons significantly shortened the duration of seed germination for 58% of the dispersed species; however, for 54% of species, seed germination rates were reduced significantly. Our study underlined the contrasting contributions of two primate species to local plant recruitment processes. By dispersing rare species and destroying the seeds of common species, both primates might jointly maintain plant species diversity. To maintain healthy ecosystems, the conservation of mammals that play critical functional roles needs to receive further attention.

Seebeck, Peltier, and Soret effects: On different formalisms for transport equations in thermogalvanic cells.

Thermogalvanic cells convert waste heat directly to electric work. There is an abundance of waste heat in the world and thermogalvanic cells may be underused. We discuss theoretical tools that can help us understand and therefore improve on cell performance. One theory is able to describe all aspects of the energy conversion: nonequilibrium thermodynamics. We recommend to use the theory with operationally defined, independent variables, as others have done before. These describe well-defined experiments. Three invariance criteria serve as a basis for any description: of local electroneutrality, entropy production invariance, and emf's independence of the frame of reference. Alternative formalisms, using different sets of variables, start with ionic or neutral components. We show that the heat flux is not the same in the two formalisms and derive a new relationship between the heat fluxes. The heat flux enters the definition of the Peltier coefficient and is essential for the understanding of the Peltier heat at the electrode interfaces and of the Seebeck coefficient of the cell. The Soret effect can occur independently of any Seebeck effect, but the Seebeck effect will be affected by the presence of a Soret effect. Common misunderstandings are pointed out. Peltier coefficients are needed for the interpretation and design of experiments.

Using geographic rescue time contours, point-of-care strategies, and spatial care paths to prepare island communities for global warming, rising oceans, and weather disasters.

OBJECTIVES: To perform geographic contour analysis of sea and land ambulance rescue times in an archipelago subject to super typhoons; to design point-of-care testing strategies for medical emergencies and weather disasters made more intense by global warming and rising oceans; and to assess needs for prehospital testing on spatial care paths that accelerate decision making, increase efficiency, improve outcomes, and enhance standards of care in island nations. METHODS: We performed needs assessments, inspected healthcare facilities, and collected ambulance rescue times from professionals in the Bantayan Archipelago, Philippines. We mapped sea/land ambulance rescue routes and time contours. To reveal gaps, we statistically compared the fastest and slowest patient rescue times from islands/islets and barangays to the District Hospital on Bantayan Island. We developed spatial care paths (the fastest routes to care) for acute myocardial infarction, community care, and infectious diseases. We generated a compendium of prehospital diagnostic testing and integrated outcomes evidence, diagnostic needs, and public health goals to recommend point-of-care strategies that build geographic health resilience. RESULTS: We observed limited access to COVID-19 assays, absence of blood gas/pH testing for critical care support, and spatial gaps in land and airborne rescues that worsened during inclement weather and sea swells. Mean paired differences (slowest-fastest) in ambulance rescue times to the District Hospital for both islands and barangays were significant (P < 0.0001). Spatial care path analysis showed where point-of-care cardiac troponin testing should be implemented for expedited care of acute myocardial infarction. Geospatial strengths comprised distributed primary care that can be facilitated by point-of-care testing, logical interisland transfers for which decision making and triage could be accelerated with onboard diagnostics, and healthcare networks amenable to medical advances in prehospital testing that accelerate treatment. CONCLUSIONS: Point-of-care testing should be positioned upstream close to homes and island populations that have prolonged rescue time contours. Geospatially optimized point-of-need diagnostics and distributed prehospital testing have high potential to improve outcomes. These improvements will potentially decrease disparities in mortality among archipelago versus urban dwellers, help improve island public health, and enhance resilience for increasingly adverse and frequent climate change weather disasters that impact vulnerable coastal areas. [350 words].

Understanding medical mistrust and HPV vaccine hesitancy among multiethnic parents in Los Angeles.

Determinants of parental HPV vaccine hesitancy, including medical mistrust and exposure to negative vaccine information, are understudied in racial/ethnic minority communities where vaccine uptake is low. We conducted a cross-sectional survey (March 2021) among parents of adolescents, ages 9-17 years, from an academic enrichment program serving low-income, first-generation, underrepresented minority families in Los Angeles to understand determinants of parental HPV vaccine hesitancy. Parents completed self-administered surveys, including a 9-item HPV vaccine hesitancy scale, in either English, Spanish, or Chinese. Logistic regression was used to identify individual and interpersonal factors associated with parental hesitancy and adolescent HPV vaccination. One-fifth of parents (n = 357) reported high HPV vaccine hesitancy and > 50% reported concerns about safety or side effects. High medical mistrust was associated with high parental HPV vaccine hesitancy (adjusted-OR 1.69, 95% CI: 1.13, 2.37). Community-tailored and multilevel strategies to increase vaccine confidence are needed to improve HPV and other adolescent vaccinations.