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Arek M Engstrom,1 Ryan A Faase,2 Grant W Marquart,3 Joe E Baio,2 Marilyn R Mackiewicz,3 Stacey L Harper1,2,4 1Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States; 2School of Chemical, Biological, and Environmental Engineering, Oregon State University, Corvallis, OR, United States; 3Department of Chemistry, Portland State University, Portland, OR, United States; 4Oregon Nanoscience and Microtechnologies Institute, Corvallis, OR, United StatesCorrespondence: Stacey L Harper Email Stacey.Harper@oregonstate.eduIntroduction: Humans are intentionally exposed to gold nanoparticles (AuNPs) where they are used in variety of biomedical applications as imaging and drug delivery agents as well as diagnostic and therapeutic agents currently in clinic and in a variety of upcoming clinical trials. Consequently, it is critical that we gain a better understanding of how physiochemical properties such as size, shape, and surface chemistry drive cellular uptake and AuNP toxicity in vivo. Understanding and being able to manipulate these physiochemical properties will allow for the production of safer and more efficacious use of AuNPs in biomedical applications.Methods and Materials: Here, AuNPs of three sizes, 5 nm, 10 nm, and 20 nm, were coated with a lipid bilayer composed of sodium oleate, hydrogenated phosphatidylcholine, and hexanethiol. To understand how the physical features of AuNPs influence uptake through cellular membranes, sum frequency generation (SFG) was utilized to assess the interactions of the AuNPs with a biomimetic lipid monolayer composed of a deuterated phospholipid 1.2-dipalmitoyl-d62-sn-glycero-3-phosphocholine (dDPPC).Results and Discussion: SFG measurements showed that 5 nm and 10 nm AuNPs are able to phase into the lipid monolayer with very little energetic cost, whereas, the 20 nm AuNPs warped the membrane conforming it to the curvature of hybrid lipid-coated AuNPs. Toxicity of the AuNPs were assessed in vivo to determine how AuNP curvature and uptake influence cell health. In contrast, in vivo toxicity tested in embryonic zebrafish showed rapid toxicity of the 5 nm AuNPs, with significant 24 hpf mortality occurring at concentrations ≥ 20 mg/L, whereas the 10 nm and 20 nm AuNPs showed no significant mortality throughout the five-day experiment.Conclusion: By combining information from membrane models using SFG spectroscopy with in vivo toxicity studies, a better mechanistic understanding of how nanoparticles (NPs) interact with membranes is developed to understand how the physiochemical features of AuNPs drive nanoparticle–membrane interactions, cellular uptake, and toxicity.Keywords: gold nanoparticle, vibrational spectroscopy, nanoparticle–biological interactions, hybrid lipid-coated nanoparticle, toxicity, size-dependent interaction, zebrafish

Joseph B Pryor,1 Bryan J Harper,1 Stacey L Harper1,21Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA; 2School of Chemical, Biological, and Environmental Engineering, Oregon State University, Corvallis, OR, USAAbstract: Dendrimers are well-defined, polymeric nanomaterials currently being investigated for biomedical applications such as medical imaging, gene therapy, and tissue targeted therapy. Initially, higher generation (size) dendrimers were of interest because of their drug carrying capacity. However, increased generation was associated with increased toxicity. The majority of studies exploring dendrimer toxicity have focused on a small range of materials using cell culture methods, with few studies investigating the toxicity across a wide range of materials in vivo. The objective of the present study was to investigate the role of surface charge and generation in dendrimer toxicity using embryonic zebrafish (Danio rerio) as a model vertebrate. Due to the generational and charge effects observed at the cellular level, higher generation cationic dendrimers were hypothesized to be more toxic than lower generation anionic or neutral dendrimers with the same core composition. Polyamidoamine (PAMAM) dendrimers elicited significant morbidity and mortality as generation was decreased. No significant adverse effects were observed from the suite of thiophosphoryl dendrimers studied. Exposure to ≥50 ppm cationic PAMAM dendrimers G3-amine, G4-amine, G5-amine, and G6-amine caused 100% mortality by 24 hours post-fertilization. Cationic PAMAM G6-amine at 250 ppm was found to be statistically more toxic than both neutral PAMAM G6-amidoethanol and anionic PAMAM G6-succinamic acid at the same concentration. The toxicity observed within the suite of varying dendrimers provides evidence that surface charge may be the best indicator of dendrimer toxicity. Dendrimer class and generation are other potential contributors to the toxicity of dendrimers. Further studies are required to better understand the relative role each plays in driving the toxicity of dendrimers. To the best of our knowledge, this is the first in vivo study to address such a broad range of dendrimers.Keywords: nanomaterials, in vivo, toxicity, generation, surface chemistry, zebrafish

Kaizhi Tang,1 Xiong Liu,1 Stacey L Harper,2 Jeffery A Steevens,3 Roger Xu1 1Intelligent Automation, Inc, Rockville, MD, USA; 2Department of Environmental and Molecular Toxicology, School of Chemical, Biological, and Environmental Engineering, Oregon State University, Corvallis, OR, USA; 3US Army Engineer Research and Development Center, Vicksburg, MS, USA Abstract: As more engineered nanomaterials (eNM) are developed for a wide range of applications, it is crucial to minimize any unintended environmental impacts resulting from the application of eNM. To realize this vision, industry and policymakers must base risk management decisions on sound scientific information about the environmental fate of eNM, their availability to receptor organisms (eg, uptake), and any resultant biological effects (eg, toxicity). To address this critical need, we developed a model-driven, data mining system called NEIMiner, to study nanomaterial environmental impact (NEI). NEIMiner consists of four components: NEI modeling framework, data integration, data management and access, and model building. The NEI modeling framework defines the scope of NEI modeling and the strategy of integrating NEI models to form a layered, comprehensive predictability. The data integration layer brings together heterogeneous data sources related to NEI via automatic web services and web scraping technologies. The data management and access layer reuses and extends a popular content management system (CMS), Drupal, and consists of modules that model the complex data structure for NEI-related bibliography and characterization data. The model building layer provides an advanced analysis capability for NEI data. Together, these components provide significant value to the process of aggregating and analyzing large-scale distributed NEI data. A prototype of the NEIMiner system is available at http://neiminer.i-a-i.com/. Keywords: nanomaterial environmental impact, data integration, data management, content management system, data mining, modeling, model composition

SUMMARYThe lack of high-quality health information for accurately estimating burdens of disease in some Aboriginal populations is a challenge for developing effective and relevant public health programmes and for health research. We evaluated data from a health registry system that captured patient consultations, provided by Labrador Grenfell Health (Labrador, Canada). The goal was to evaluate the registry's utility and attributes using modified CDC guidelines for evaluating surveillance systems. Infectious gastrointestinal illness data were used as a reference syndrome to determine various aspects of data collection and quality. Key-informant interviews were conducted to provide information about system utility. The study uncovered limitations in data quality and accessibility, resulting in region-specific recommendations including conversion to an electronic system. More generally, this study emphasized how a systematic and standardized evaluation of health registry systems can help address challenges to obtaining quality health data in often remote areas where many Aboriginal communities are found. [ABSTRACT FROM AUTHOR]

OBJECTIVES: This study assessed a strategy designed to contain imported cases of syphilis and prevent reestablishment of ongoing transmission. METHODS: Reported syphilis cases during an endemic period (1990-1992) and an elimination period (1997-1998) were compared in San Diego, Calif. The elimination strategy, which focuses on rapid reporting of infectious syphilis cases by clinicians, prompt partner and sexual network management, outreach to marginalized populations, and implementation of an outbreak containment plan, was evaluated. RESULTS: Infectious syphilis incidence rates declined from 18.3 per 100,000 in 1998 to 1.0 per 100,000 in 1998. Of the 46 cases involving probable infection during 1997-1998, 19 (41%) were imported, mostly (79%) from Mexico. Outbreak containment procedures were implemented successfully for 2 small clusters. Outreach workers provided sexually transmitted disease information to a large number of individuals; however, no cases of infectious syphilis were identified, suggesting that syphilis transmission was not occurring among marginalized groups. CONCLUSIONS: This syphilis elimination and importation control strategy will require monitoring and adjustments. Controlling syphilis along the US-Mexico border is a necessary component of syphilis elimination in the United States. [ABSTRACT FROM AUTHOR]

Many Indigenous People in Northern and remote areas need to travel away from home for childbirth; however, their birthing traditions and practices are intimately tied to place. This qualitative research study characterized Inuit childbirth experiences and recommendations to enhance birthing supports in the Qikiqtaaluk Region of Nunavut in Inuit Nunangat, Canada. Birthing experiences were profoundly shaped by relationships and place attachment, and recommendations related to increased Inuit involvement in maternity care systems. Place attachment is an important determinant of Inuit maternal health and may also be for other Indigenous Peoples with intrinsically place-based livelihoods, knowledge systems, and identities., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The widespread use of silver nanoparticles (AgNPs) in various applications and industries has brought to light the need for understanding the complex relationship between the physicochemical properties (shape, size, charge, and surface chemistry) of AgNPs that affect their ability to enter cells and cause toxicity. To evaluate their toxicological outcomes, this study systematically analyzed a series of homogeneous hybrid lipid-coated AgNPs spanning sizes from 5 to 100 nm with diverse shapes (spheres, triangles, and cubes). The hybrid lipid membrane comprises hydrogenated phosphatidylcholine (HPC), sodium oleate (SOA), and hexanethiol (HT), which shield the AgNP surface from surface oxidation and toxic Ag + ion release to minimize its contribution to toxicity. To reduce any significant effects by surface chemistry, the HPC, SOA, and HT membrane composition ratio was kept constant, and the AgNPs were assessed using embryonic zebrafish ( Danio rerio ). While a direct comparison cannot be drawn due to the lack of complementary sizes below 40 nm for triangular plates and cubes due to synthetic challenges, significant mortality was observed for spherical AgNPs (AgNSs) of 5, 20, 40, and 60 nm at 120 h postfertilization at concentrations ≥6 mg Ag/L. In contrast, the 10, 80, and 100 nm AgNSs, 40, 70, and 100 nm triangular plate AgNPs (AgNPLs), and 55, 75, and 100 nm cubic AgNPs (AgNCs) showed no significant mortality at 5 days postfertilization following exposure to AgNPs at concentrations up to 12 mg Ag/L. With constant surface chemistry on the AgNPs, size is the dominant factor driving toxicological responses, with smaller nanoparticles (5 to 60 nm) being the most toxic. Larger AgNSs, AgNCs, and AgNPLs from 75 to 100 nm do not show any evidence of toxicity. However, when closely examining sizes between 40 and 60 nm for AgNSs, AgNCs, and AgNPLs, there is evidence that discriminates shape as a driver of toxicity since sublethal responses generally were observed to follow a pattern, suggesting toxicity is most significant for AgNSs followed by AgNPLs and then AgNCs, which is the least toxic. Sum frequency generation vibrational spectroscopy showed that irrespective of size or shape, all hybrid lipid-coated AgNPs interact with membrane surfaces and "snorkel" between phases into the lipid monolayer with minimal energetic cost. These findings decisively demonstrate that not only smaller AgNPs but also the shape of the AgNPs influences their biological compatibility.

For many Indigenous Peoples, relationships to the land are inherent in identity and culture, and to all facets of health and wellbeing, physically, emotionally, psychologically, and spiritually. The Batwa are Indigenous Peoples of rural, southwest Uganda who have experienced tremendous social and economic upheaval, due to relatively recent forced displacement and land dispossession. This loss of physical connection to their ancestral lands has significantly impacted Batwa health, and also affected available healthcare options for Batwa. This exploratory study (1) identified and characterized factors that influence Batwa health-seeking behaviour, using acute gastrointestinal illness, a critical public health issue, as a focal point for analysis; and (2) explored possible intersections between the Batwa's connection to place-and displacement-and their health-seeking behaviour for acute gastrointestinal illness. Twenty focus group discussions, stratified by gender, were conducted in ten Batwa settlements in Kanungu District, Uganda and eleven semi-structured interviews were conducted with primary healthcare workers, community health coordinators, clinical officers, and development program coordinators. Qualitative data were thematically analyzed using a constant comparative method. Batwa identified several significant motivators to engage with Indigenous and/or biomedical forms of healthcare, including transition to life outside the forest and their reflections on health in the forest; 'intellectual access' to care and generational knowledge-sharing on the use of Indigenous medicines; and Batwa identity and way of life. These nuanced explanations for health-seeking behaviour underscore the significance of place-and displacement-to Batwa health and wellbeing, and its relationship to their health-seeking behaviour for acute gastrointestinal illness. As such, the results of this study can be used to inform healthcare practice and policy and support the development of a culturally- and contextually-appropriate healthcare system, as well as to reduce the burden of acute gastrointestinal illness among Batwa., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Brubacher et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Agricultural soils are increasingly undergoing inadvertent and purposeful exposures to engineered CeO 2 nanoparticles (NPs), which can impact crops and root-associated microbial communities. However, interactions between NP concentration and exposure duration on plant-mediated responses of root-associated bacterial communities are not well understood. Soybeans seedlings were grown in soil with uncoated NPs added at concentrations of 0, 1 or 100 mg kg -1 . Total soil exposure durations were either 190 days, starting 106 days before planting or 84 days with NP amendments coinciding with planting. We assessed plant development, bacterial diversity, differential abundance and inferred functional changes across rhizosphere, rhizoplane, and root tissue compartments. Plant non-monotonic dose responses were mirrored in bacterial communities. Most notably, effects were magnified in the rhizoplane under low-dose, short-exposures. Enriched metabolic pathways were primarily related to biosynthesis and degradation/utilization/assimilation, rather than responses to metals or oxidative stress. Our results indicate that plant-mediated bacterial responses were greater than direct NP impacts. Also, we identify needs for modeling non-monotonic legume stress responses that account for coinfection with mutualistic and parasitic bacteroids. Our findings provide new insights regarding effects of applications of soil amendments such as biosolids containing NPs or nano-enabled formulations used in cultivation of legumes and other crops., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

We investigated the impacts of spherical and triangular-plate-shaped lipid-coated silver nanoparticles (AgNPs) designed to prevent surface oxidation and silver ion (Ag + ) dissolution in a small-scale microcosm to examine the role of shape and surface functionalization on biological interactions. Exposures were conducted in microcosms consisting of algae, bacteria, crustaceans, and fish embryos. Each microcosm was exposed to one of five surface chemistries within each shape profile (at 0, 0.1, or 0.5 mg Ag/L) to investigate the role of shape and surface composition on organismal uptake and toxicity. The hybrid lipid-coated AgNPs did not result in any significant release of Ag + and had the most significant toxicity to D. magna , the most sensitive species, although the bacterial population growth rate was reduced in all exposures. Despite AgNPs resulting in increasing algal growth over the experiment, we found no correlation between algal growth and the survival of D. magna, suggesting that the impacts of the AgNPs on bacterial survival influenced algal growth rates. No significant impacts on zebrafish embryos were noted in any exposure. Our results demonstrate that the size, shape, and surface chemistry of AgNPs can be engineered to achieve specific goals while mitigating nanoparticle risks.

Climate change has severe and sweeping impacts on mental health. Although research is burgeoning on mental health impacts following climate and weather extremes, less is known about how common these impacts are outside of extreme events. Existing research exploring the prevalence of psychosocial responses to climate change primarily examines university students and uses non-random sampling methods. Herein, our protocol outlines an approach to data collection, processing, and analysis to estimate the population prevalence, magnitude, and distribution of mental health responses to climate change in Canada. A cross-sectional survey of youth and adults aged 13 years and older in Canada will be administered over the course of one year. The questionnaire will take approximately 10 minutes to complete orally and will be administered in English, French, and Inuktitut. The survey will consist of six sections: (1) self-reported past experiences of climate change; (2) self-reported climate-related emotions; (3) self-reported past and current impacts, anticipatory impacts, and vicarious experiences; (4) self-reported subclinical outcomes; (5) self-reported behavioural responses; and (6) demographics. A multi-stage, multi-stratified random probability sampling method will be used to obtain a sample representative of the Canadian population. We will use two different modes of recruitment: an addressed letter sent by postal mail or a telephone call (landlines and cellular). Population-weighted descriptive statistics, principal component analysis, and weighted multivariable regression will be used to analyse the data. The results of this survey will provide the first national prevalence estimates of subclinical mental health responses to climate change outcomes of people living in Canada., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Harper et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

As plastic production continues to increase globally, plastic waste accumulates and degrades into smaller plastic particles. Through chemical and biological processes, nanoscale plastic particles (nanoplastics) are formed and are expected to exist in quantities of several orders of magnitude greater than those found for microplastics. Due to their small size and low mass, nanoplastics remain challenging to detect in the environment using most standard analytical methods. The goal of this research is to adapt existing tools to address the analytical challenges posed by the identification of nanoplastics. Given the unique and well-documented properties of anthropogenic plastics, we hypothesized that nanoplastics could be differentiated by polymer type using spatiotemporal deformation data collected through irradiation with scanning electron microscopy (SEM). We selected polyvinyl chloride (PVC), polyethylene terephthalate (PET), and high-density polyethylene (HDPE) to capture a range of thermodynamic properties and molecular structures encompassed by commercially available plastics. Pristine samples of each polymer type were chosen and individually milled to generate micro and nanoscale particles for SEM analysis. To test the hypothesis that polymers could be differentiated from other constituents in complex samples, the polymers were compared against proxy materials common in environmental media, i.e., algae, kaolinite clay, and nanocellulose. Samples for SEM analysis were prepared uncoated to enable observation of polymer deformation under set electron beam parameters. For each sample type, particles approximately 1 µm in diameter were chosen, and videos of particle deformation were recorded and studied. Blinded samples were also prepared with mixtures of the aforementioned materials to test the viability of this method for identifying near-nanoscale plastic particles in environmental media. Based on the evidence collected, deformation patterns between plastic particles and particles present in common environmental media show significant differences. A computer vision algorithm was also developed and tested against manual measurements to improve the usefulness and efficiency of this method further.

Introduction: Diarrheal disease, particularly in children under 5 years old, remains a global health challenge due to its high prevalence and chronic health consequences. Public health interventions that reduce diarrheal disease risk include improving access to water, sanitation, and hygiene. Although Peru achieved the 2015 Millennium Development Goal (MDG) indicators for water access, less progress was achieved on sanitation. Furthermore, many Indigenous Peoples were overlooked in the MDG indicators, resulting in a prioritization of Indigenous Peoples in the 2030 Sustainable Development Goals (SDGs). This study aimed to estimate the prevalence of childhood diarrhea, characterize access to water and sanitation, and determine the association of childhood diarrhea with water access and sanitation indicators in 10 Shawi Indigenous communities along the Armanayacu River in the Peruvian Amazon., Methods: A cross-sectional survey (n=82) that captured data on diarrheal disease, sociodemographic variables, and water and sanitation exposures was conducted in 10 Shawi communities. Nutritional status of children under 5 was also assessed via physical examination. Descriptive and comparative statistics were conducted., Results: A small proportion (n=7; 8.54%) of participating children reported an episode of diarrhea in the previous month. Almost half (46.30%) of participating children had stunting, wasting, or both. Although not statistically significant, children living in households that used latrines were 4.29 times (95% confidence interval (CI) 1.01-18.19) more likely to report an episode of diarrhea than children living in households that practiced open defecation. Although not statistically significant, children living in households that used water treatment methods were 4.25 times (95%CI 0.54-33.71) more likely to report an episode of diarrhea than children living in households that did not., Conclusion: The prevalence of childhood diarrhea was lower for Shawi than for other Amazon areas. The higher prevalence of childhood diarrhea in households that used latrines and water treatments warrants further investigation into local risk and protective factors. These Shawi communities scored low for the WHO/UNICEF Joint Monitoring Programme indicators for water and sanitation, indicating that they should be prioritized in future water, sanitation, and hygiene initiatives. Research will be required to understand and incorporate local Indigenous values and cultural practices into water, sanitation, and hygiene initiatives to maximize intervention uptake and effectiveness.

Reports of plastics, at higher levels than previously thought, in the water that we drink and the air that we breathe, are generating considerable interest and concern. Plastics have been recorded in almost every environment in the world with estimates on the order of trillions of microplastic pieces. Yet, this may very well be an underestimate of plastic pollution as a whole. Once microplastics (<5 mm) break down in the environment, they nominally enter the nanoscale (<1,000 nm), where they cannot be seen by the naked eye or even with the use of a typical laboratory microscope. Thus far, research has focused on plastics in the macro- (>25 mm) and micro-size ranges, which are easier to detect and identify, leaving large knowledge gaps in our understanding of nanoplastic debris. Our ability to ask and answer questions relating to the transport, fate, and potential toxicity of these particles is disadvantaged by the detection and identification limits of current technology. Furthermore, laboratory exposures have been substantially constrained to the study of commercially available nanoplastics; i.e., polystyrene spheres, which do not adequately reflect the composition of environmental plastic debris. While a great deal of plastic-focused research has been published in recent years, the pattern of the work does not answer a number of key factors vital to calculating risk that takes into account the smallest plastic particles; namely, sources, fate and transport, exposure measures, toxicity and effects. These data are critical to inform regulatory decision making and to implement adaptive management strategies that mitigate risk to human health and the environment. This paper reviews the current state-of-the-science on nanoplastic research, highlighting areas where data are needed to establish robust risk assessments that take into account plastics pollution. Where nanoplastic-specific data are not available, suggested substitutions are indicated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cunningham, Sharpe, Brander, Landis and Harper.)

Lysosomal inhibition elicited by palmitoyl-protein thioesterase 1 (PPT1) inhibitors such as DC661 can produce cell death, but the mechanism for this is not completely understood. Programmed cell death pathways (autophagy, apoptosis, necroptosis, ferroptosis, and pyroptosis) were not required to achieve the cytotoxic effect of DC661. Inhibition of cathepsins, or iron or calcium chelation, did not rescue DC661-induced cytotoxicity. PPT1 inhibition induced lysosomal lipid peroxidation (LLP), which led to lysosomal membrane permeabilization and cell death that could be reversed by the antioxidant N-acetylcysteine (NAC) but not by other lipid peroxidation antioxidants. The lysosomal cysteine transporter MFSD12 was required for intralysosomal transport of NAC and rescue of LLP. PPT1 inhibition produced cell-intrinsic immunogenicity with surface expression of calreticulin that could only be reversed with NAC. DC661-treated cells primed naive T cells and enhanced T cell-mediated toxicity. Mice vaccinated with DC661-treated cells engendered adaptive immunity and tumor rejection in "immune hot" tumors but not in "immune cold" tumors. These findings demonstrate that LLP drives lysosomal cell death, a unique immunogenic form of cell death, pointing the way to rational combinations of immunotherapy and lysosomal inhibition that can be tested in clinical trials.

While evaluations play a critical role in accounting for and learning from context, it is unclear how evaluations can take account of climate change. Our objective was to explore how climate change and its interaction with other contextual factors influenced One Health food safety programs. To do so, we integrated questions about climate change into a qualitative evaluation study of an ongoing, multi-sectoral program aiming to improve pork safety in Vietnam called SafePORK. We conducted remote interviews with program researchers ( n  = 7) and program participants ( n  = 23). Based on our analysis, researchers believed climate change had potential impacts on the program but noted evidence was lacking, while program participants (slaughterhouse workers and retailers) shared how they were experiencing and adapting to the impacts of climate change. Climate change also interacted with other contextual factors to introduce additional complexities. Our study underscored the importance of assessing climate factors in evaluation and building adaptive capacity in programming., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Lysosomal autophagy inhibition (LAI) with hydroxychloroquine or DC661 can enhance cancer therapy, but tumor regrowth is common. To elucidate LAI resistance, proteomics and immunoblotting demonstrated that LAI induced lipid metabolism enzymes in multiple cancer cell lines. Lipidomics showed that LAI increased cholesterol, sphingolipids, and glycosphingolipids. These changes were associated with striking levels of GM1+ membrane microdomains (GMM) in plasma membranes and lysosomes. Inhibition of cholesterol/sphingolipid metabolism proteins enhanced LAI cytotoxicity. Targeting UDP-glucose ceramide glucosyltransferase (UGCG) synergistically augmented LAI cytotoxicity. Although UGCG inhibition decreased LAI-induced GMM and augmented cell death, UGCG overexpression led to LAI resistance. Melanoma patients with high UGCG expression had significantly shorter disease-specific survival. The FDA-approved UGCG inhibitor eliglustat combined with LAI significantly inhibited tumor growth and improved survival in syngeneic tumors and a therapy-resistant patient-derived xenograft. These findings nominate UGCG as a new cancer target, and clinical trials testing UGCG inhibition in combination with LAI are warranted., Significance: We discovered UGCG-dependent lipid remodeling drives resistance to LAI. Targeting UGCG with a drug approved for a lysosomal storage disorder enhanced LAI antitumor activity without toxicity. LAI and UGCG inhibition could be tested clinically in multiple cancers. This article is highlighted in the In This Issue feature, p. 247., (©2022 American Association for Cancer Research.)

Transportation systems in northern Canada are highly sensitive to climate change. We project how access to semi-permanent trails on land, water, and sea ice might change this century in Inuit Nunangat (the Inuit homeland in northern Canada), using CMIP6 projections coupled with trail access models developed with community members. Overall trail access is projected to diminish, with large declines in access for sea ice trails which play a central role for Inuit livelihoods and culture; limits to adaptation in southern regions of Inuit Nunangat within the next 40 years; a lengthening of the period when no trails are accessible; and an unequal distribution of impacts according to the knowledge, skills, equipment, and risk tolerance of trail users. There are opportunities for adaptation through efforts to develop skillsets and confidence in travelling in more marginal environmental conditions, which can considerably extend the envelope of days when trails are accessible and months when this is possible. Such actions could reduce impacts across emissions scenarios but their potential effectiveness declines at higher levels of global warming, and in southern regions only delays when sea ice trails become unusable., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2023.)

Customizable gold nanoparticle platforms are motivating innovations in drug discovery with massive therapeutic potential due to their biocompatibility, stability, and imaging capabilities. Further development requires the understanding of how discrete differences in shape, charge, or surface chemistry affect the drug delivery process of the nanoparticle. The nanoparticle shape can have a significant impact on nanoparticle function as this can, for example, drastically change the surface area available for modifications, such as surface ligand density. In order to investigate the effects of nanoparticle shape on the structure of cell membranes, we directly probed nanoparticle-lipid interactions with an interface sensitive technique termed sum frequency generation (SFG) vibrational spectroscopy. Both gold nanostars and gold nanospheres with positively charged ligands were allowed to interact with a model cell membrane and changes in the membrane structure were directly observed by specific SFG vibrational modes related to molecular bonds within the lipids. The SFG results demonstrate that the +Au nanostars both penetrated and impacted the ordering of the lipids that made up the membrane, while very little structural changes to the model membrane were observed by SFG for the +Au nanospheres interacting with the model membrane. This suggests that the +Au nanostars, compared to the +Au nanospheres, are more disruptive to a cell membrane. Our findings indicate the importance of shape in nanomaterial design and provide strong evidence that shape does play a role in defining nanomaterial-biological interactions.

The Batwa (Twa), an Indigenous People of southwest Uganda, were evicted from their ancestral forest lands in 1991 due to establishment of the Bwindi Impenetrable Forest. This land dispossession forced Batwa to transition from a semi-nomadic, hunting-gathering livelihood to an agricultural livelihood; eliminated access to Indigenous food, medicines, and shelter; and shifted their healthcare options. Therefore, this exploratory study investigated why Batwa choose Indigenous or biomedical treatment, or no treatment, when experiencing acute gastrointestinal illness. Ten gender-stratified focus groups were conducted in five Batwa settlements in Kanungu District, Uganda ( n  = 63 participants), alongside eleven semi-structured interviews (2014). Qualitative data were analysed thematically, using a constant comparative method. Batwa emphasised that health-seeking behaviour for acute gastrointestinal illness was diverse: some Batwa used only Indigenous or biomedical healthcare, while others preferred a combination, or no healthcare. Physical and economic access to care, and also perceived efficacy and quality of care, influenced their healthcare decisions. This study provides insight into the Kanungu District Batwa's perceptions of biomedical and Indigenous healthcare, and barriers they experience to accessing either. This study is intended to inform public health interventions to reduce their burden of acute gastrointestinal illness and ensure adequate healthcare, biomedical or Indigenous, for Batwa.

Objective: To assess the extent of pregnancy loss (i.e., miscarriage and/or stillbirth) and examine its association with socio-demographic characteristics among Bakiga and Indigenous Batwa women in Kanungu District, southwest Uganda., Methods: As part of a larger community-based, participatory project, a retrospective survey of maternal health histories was conducted in ten Batwa and ten Bakiga communities (n = 555 participants) collecting data on self-reported pregnancy loss (i.e., miscarriage and stillbirth) and socio-demographic characteristics. Socio-demographic associations with pregnancy loss (i.e., total miscarriages and stillbirths) were examined using multivariable Poisson and negative binomial regression., Results: Batwa women experienced pregnancy loss more commonly than Bakiga women did (149.8/1000 vs. 96.3/1000 pregnancies). In the final adjusted model for Batwa women, being in the middle (RR 1.92; CI: 1.21-3.07) and highest (RR 1.79; CI: 1.14-2.82) wealth tertiles (compared to lowest wealth tertile) and living in Community X (RR 4.33; CI 2.27-8.28) (compared to all other communities) were associated with increased pregnancy loss. For Bakiga women, the proportion of pregnancy loss was higher for those who reported drinking alcohol during pregnancy (RR: 1.54; CI: 1.04-2.13) and being food insecure (RR 1.39; CI: 1.02-1.91)., Conclusion: The proportion of, and the socio-demographic associations with, pregnancy loss differed for Bakiga and Indigenous Batwa women. These differences underscore the importance of collecting Indigenous health data to understand not only the extent of, but also the varied contextual circumstances that are associated with pregnancy loss. This nuanced and stratified information is critical for planning meaningful health programming to reduce pregnancy loss for Indigenous women., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The history of health research in Inuit communities in Canada recounts unethical and colonizing research practices. Recent decades have witnessed profound changes that have advanced ethical and community-driven research, yet much work remains. Inuit have called for research reform in Inuit Nunangat, most recently creating the National Inuit Strategy on Research (NISR) as a framework to support this work. The present study details the process undertaken to create a research program guided by the NISR to address food security, nutrition, and climate change in Inuit Nunangat. Four main elements were identified as critical to supporting the development of a meaningful and authentic community-led program of research: developing Inuit-identified research questions that are relevant and important to Inuit communities; identifying Inuit expertise to answer these questions; re-envisioning and innovating research methodologies that are meaningful to Inuit and reflect Inuit knowledge and societal values; and identifying approaches to mobilizing knowledge that can be applied to support food security and climate change adaptation. We also identify considerations for funding agencies to support the meaningful development of Inuit-led research proposals, including aligning funding with community priorities, reconsidering who the researchers are, and investing in community infrastructure. Our critical reflection on the research program development process provides insight into community-led research that can support Inuit self-determination in research, enhance local ethical conduct of research, privilege Inuit knowledge systems, and align Inuit-identified research priorities with research funding opportunities in health research. While we focus on Inuit-led research in Nunavut, Canada, these insights may be of interest more broadly to Indigenous health research.

Working in agriculture has been associated with an increased prevalence of psychological distress and mental health concerns. Farmers are also less likely than non-farmers to seek-help for their mental health. Previous research examining help-seeking among farmers has focused predominantly on male farmers, and has not included many of the Canadian agricultural commodity groups or provinces. The goal of this study was to explore perceptions of farmer help-seeking for mental health amongst farmers and people who work with farmers. The study objectives were to characterize the motivations and barriers to help-seeking behaviours. Semi-structured interviews were conducted with 75 farmers and individuals who work with farmers in Ontario, Canada, between 2017 and 2018. Interviews were conducted in person, and by telephone when needed. Topics of discussion included farming stresses and their impacts; personal well-being; agricultural crises and mental health help-seeking; use of mental health supports; motivators and barriers to help-seeking; and perceived ideals for mental health supports. Thematic analysis was conducted collaboratively by three authors using inductive and deductive coding. Our analysis resulted in five themes around help-seeking motivations and barriers: 1) Accessibility of mental health supports and services; 2) Stigma around mental health in the agricultural community; 3) Anonymity and/or lack of anonymity in seeking support; 4) Farm credibility; and 5) Recommendations for implementing mental health services for the agricultural community. This study provides insights around how farming culture and the accessibility and delivery of services may influence help-seeking for mental health, and proposes strategies to break down barriers to help-seeking in this population.

Background: There is concern in the international community regarding the influence of climate change on weather variables and seasonality that, in part, determine the rates of malaria. This study examined the role of sociodemographic variables in modifying the association between temperature and malaria in Kanungu District (Southwest Uganda)., Methods: Hospital admissions data from Bwindi Community Hospital were combined with meteorological satellite data from 2011 to 2014. Descriptive statistics were used to describe the distribution of malaria admissions by age, sex, and ethnicity (i.e. Bakiga and Indigenous Batwa). To examine how sociodemographic variables modified the association between temperature and malaria admissions, this study used negative binomial regression stratified by age, sex, and ethnicity, and negative binomial regression models that examined interactions between temperature and age, sex, and ethnicity., Results: Malaria admission incidence was 1.99 times greater among Batwa than Bakiga in hot temperature quartiles compared to cooler temperature quartiles, and that 6-12 year old children had a higher magnitude of association of malaria admissions with temperature compared to the reference category of 0-5 years old (IRR = 2.07 (1.40, 3.07))., Discussion: Results indicate that socio-demographic variables may modify the association between temperature and malaria. In some cases, such as age, the weather-malaria association in sub-populations with the highest incidence of malaria in standard models differed from those most sensitive to temperature as found in these stratified models., Conclusion: The effect modification approach used herein can be used to improve understanding of how changes in weather resulting from climate change might shift social gradients in health., (© 2022. The Author(s).)

Introduction: The global burden of maternal mortality remains high and inequitably distributed between countries. Antenatal care (ANC) was identified as critical component in achieving the Millennium Development Goal of improving maternal health. This scoping review aimed to summarize trends and critically explore research about ANC attendance for East African women conducted during the Millennium Development Goals initiative, with a specific focus on barriers to ANC access., Methods: Using a scoping review methodology, aggregator databases were searched for relevant articles. Articles were screened by independent reviewers using a priori inclusion criteria. Eligible articles were retained for data charting and analysis., Results: Following screening, 211 articles were analyzed. The number of relevant articles increased over time; utilized primarily quantitative methods; and involved authors with affiliations from various African countries. Many interrelated physical, social, and cultural factors influenced women's seeking, reaching, and receiving of quality ANC. The extent of studies identified suggest that ANC is a priority research area, yet key gaps in the literature exist. Limited qualitative research, and few articles examining ANC experiences of women from vulnerable groups (e.g. adolescents, women with a disability, and Indigenous women) were identified., Discussion: These context-specific findings are important considering the Sustainable Development Goals aim to nearly triple the maternal mortality reductions by 2030. In order to achieve this goal, interventions should focus on improving the quality of ANC care and patient-provider interactions. Furthermore, additional qualitative research examining vulnerable populations of women and exploring the inclusion of men in ANC would help inform interventions intended to improve ANC attendance in East Africa., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Anthropogenic climate change and increasing antimicrobial resistance (AMR) together threaten the last 50 years of public health gains. Honey bees are a model One Health organism to investigate interactions between climate change and AMR. The objective of this scoping review was to examine the range, extent, and nature of published literature on the relationship between AMR and honey bees in the context of climate change and environmental pollutants. The review followed systematic search methods and reporting guidelines. A protocol was developed a priori in consultation with a research librarian. Resulting Boolean search strings were used to search Embase® via Ovid®, MEDLINE®, Scopus®, AGRICOLA™ and Web of Science™ databases. Two independent reviewers conducted two-stage screening on retrieved articles. To be included, the article had to examine honey bees, AMR, and either climate change or environmental pollution. Data, in accordance with Joanna Briggs Institute guidelines, were extracted from relevant articles and descriptively synthesized in tables, figures, and narrative form. A total of 22 articles met the inclusion criteria, with half of all articles being published in the last five years (n = 11/22). These articles predominantly investigated hive immunocompetence and multi-drug resistance transporter downregulation (n = 11/22), susceptibility to pests (n = 16/22), especially American foulbrood (n = 9/22), and hive product augmentation (n = 3/22). This review identified key themes and gaps in the literature, including the need for future interdisciplinary research to explore the link between AMR and environmental change evidence streams in honey bees. We identified three potential linkages between pollutive and climatic factors and risk of AMR. These interconnections reaffirm the necessity of a One Health framework to tackle global threats and investigate complex issues that extend beyond honey bee research into the public health sector. It is integral that we view these "wicked" problems through an interdisciplinary lens to explore long-term strategies for change., Competing Interests: The authors have declared that no competing interests exist.

As climate change progresses, it is crucial that researchers and policymakers understand the ways in which climate-mental health risks arise through interactions between climate hazards, human exposure and social vulnerabilities across time and location. This scoping review systematically examined the nature, range and extent of published research in North America that investigates climate-mental health interactions. Five electronic databases were searched and two independent reviewers applied pre-determined criteria to assess the eligibility of articles identified in the search. Eighty-nine articles were determined to be relevant and underwent data extraction and analysis. The published literature reported on numerous exposure pathways through which acute and chronic climate hazards interacted with social vulnerabilities to increase mental health risks, including wellbeing, trauma, anxiety, depression, suicide and substance use. This review also highlights important gaps within the North American climate-mental health evidence base, including minimal research conducted in Mexico, as well as a lack of studies investigating climate-mental health adaptation strategies and projected future mental health risks. Further research should support effective preparation for and adaptation to the current and future mental health impacts of climate change. Such strategies could reduce health risks and the long-term mental health impacts that individuals and communities experience in a changing climate.