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Introduction Immediate access to naloxone is needed to prevent fatal opioid-related overdoses in the presence of fentanyl analogs saturating the opioid supply. Peer models engage impacted populations who are not accessing naloxone through standard venues, yet compensating peers who utilize syringe service programs with cash stipends to distribute naloxone within networks of people who use drugs is not well described. Methods As part of the HEALing Communities Study, syringe service program-based interventions were developed in Holyoke and Gloucester, MA, which paid people who use drugs (“peers”) cash to distribute naloxone. Early program outcomes were evaluated for the time each program was funded within the HCS study period. Results During 22 study-months of observation, peers in two communities distributed 1104 naloxone kits. The total cost of peer compensation for program delivery was $10,510. The rate of peer-distributed naloxone per 100 K population reached 109 kits/mo and 222 kits/mo in the two communities. Participating peers addressed gaps in harm reduction outreach and distributed naloxone and other harm reduction equipment to individuals who were not syringe service program participants, expanding organizational reach. Being compensated with unrestricted cash stipends supported dignity and acknowledged peers’ work in overdose prevention. Conclusion The underutilization of compensated peer models is often attributed to funding and organizational barriers. These programs demonstrate that providing cash stipends to peers is feasible and expanded naloxone distribution at two existing syringe service programs. Providing cash stipends for peers who engage in secondary naloxone distribution offers promise in delivering naloxone to people not accessing syringe services.

Objectives. To determine whether the Communities That HEAL (CTH) intervention is effective in increasing naloxone distribution compared with usual care. Methods. The HEALing (Helping to End Addiction Long-Term) Communities Study (HCS) is a cluster-randomized, parallel-arm, wait-list controlled implementation science trial testing the impact of the CTH intervention on increasing the use of evidence-based practices to lower opioid-related overdose deaths. Communities (n = 67) highly impacted by opioid overdose in Kentucky, Massachusetts, New York, and Ohio were allocated to CTH intervention (n = 34) or wait-list comparison (usual care; n = 33) arms. The primary outcome for this study was the number of naloxone units distributed in HCS communities during the comparison period (July 1, 2021‒June 30, 2022), examined using an intent-to-treat negative binomial regression model. Results. Naloxone distribution was 79% higher in the CTH intervention versus usual care arm (adjusted relative rate = 1.79; 95% confidence interval = 1.28, 2.51; P = .001; adjusted rates of naloxone distribution 3378 vs 1884 naloxone units per 100 000 residents), when controlling for urban‒rural status, state, baseline opioid-related overdose death rate, and baseline naloxone distribution rate. Conclusions. The CTH intervention increased naloxone distribution compared with usual care in communities highly impacted by the opioid crisis. Trial Registration. ClinicalTrials.gov identifier: NCT04111939. ( Am J Public Health. 2025;115(1):83–94. https://doi.org/10.2105/AJPH.2024.307845 )

Global reef fish diversity is studied with metrics incorporating species abundances and functional traits; these identify diversity hotspots corresponding to the diversity of functional traits amongst individuals in the community, and greater evenness in the abundance of reef fishes at higher latitudes, findings that contrast with patterns reported previously using traditional richness-based methods. Cooler biodiversity hotspots revealed Traditional measures of biodiversity record species richness across different areas — in other words, they just count the number of species. This approach takes no account of the fact that different species will have different abundances, or that the range of functional traits present in a community is not dependent solely on the number of species. This paper presents a new measure of functional diversity, incorporating species abundances and functional traits into a global census of a vertebrate group —2,473 marine reef fish species — at 1,844 sites. The results reveal previously unknown diversity hotspots in temperate regions and in the Tropical Eastern Pacific, which are outside the species-rich tropical regions traditionally associated with high biodiversity. Species richness has dominated our view of global biodiversity patterns for centuries 1 , 2 . The dominance of this paradigm is reflected in the focus by ecologists and conservation managers on richness and associated occurrence-based measures for understanding drivers of broad-scale diversity patterns and as a biological basis for management 3 , 4 . However, this is changing rapidly, as it is now recognized that not only the number of species but the species present, their phenotypes and the number of individuals of each species are critical in determining the nature and strength of the relationships between species diversity and a range of ecological functions (such as biomass production and nutrient cycling) 5 . Integrating these measures should provide a more relevant representation of global biodiversity patterns in terms of ecological functions than that provided by simple species counts. Here we provide comparisons of a traditional global biodiversity distribution measure based on richness with metrics that incorporate species abundances and functional traits. We use data from standardized quantitative surveys of 2,473 marine reef fish species at 1,844 sites, spanning 133 degrees of latitude from all ocean basins, to identify new diversity hotspots in some temperate regions and the tropical eastern Pacific Ocean. These relate to high diversity of functional traits amongst individuals in the community (calculated using Rao’s Q 6 ), and differ from previously reported patterns in functional diversity and richness for terrestrial animals, which emphasize species-rich tropical regions only 7 , 8 . There is a global trend for greater evenness in the number of individuals of each species, across the reef fish species observed at sites (‘community evenness’), at higher latitudes. This contributes to the distribution of functional diversity hotspots and contrasts with well-known latitudinal gradients in richness 2 , 4 . Our findings suggest that the contribution of species diversity to a range of ecosystem functions varies over large scales, and imply that in tropical regions, which have higher numbers of species, each species contributes proportionally less to community-level ecological processes on average than species in temperate regions. Metrics of ecological function usefully complement metrics of species diversity in conservation management, including when identifying planning priorities and when tracking changes to biodiversity values.

The signature of early cancer dynamics on the spatial arrangement of tumour cells is poorly understood, and yet could encode information about how sub-clones grew within the expanding tumour. Novel methods of quantifying spatial tumour data at the cellular scale are required to link evolutionary dynamics to the resulting spatial architecture of the tumour. Here, we propose a framework using first passage times of random walks to quantify the complex spatial patterns of tumour cell population mixing. First, using a simple model of cell mixing we demonstrate how first passage time statistics can distinguish between different pattern structures. We then apply our method to simulated patterns of mutated and non-mutated tumour cell population mixing, generated using an agent-based model of expanding tumours, to explore how first passage times reflect mutant cell replicative advantage, time of emergence and strength of cell pushing. Finally, we explore applications to experimentally measured human colorectal cancer, and estimate parameters of early sub-clonal dynamics using our spatial computational model. We infer a wide range of sub-clonal dynamics, with mutant cell division rates varying between 1 and 4 times the rate of non-mutated cells across our sample set. Some mutated sub-clones emerged after as few as 100 non-mutant cell divisions, and others only after 50,000 divisions. The majority were consistent with boundary driven growth or short-range cell pushing. By analysing multiple sub-sampled regions in a small number of samples, we explore how the distribution of inferred dynamics could inform about the initial mutational event. Our results demonstrate the efficacy of first passage time analysis as a new methodology in spatial analysis of solid tumour tissue, and suggest that patterns of sub-clonal mixing can provide insights into early cancer dynamics.

Interest in spatial omics is on the rise, but generation of highly multiplexed images remains challenging, due to cost, expertise, methodical constraints, and access to technology. An alternative approach is to register collections of whole slide images (WSI), generating spatially aligned datasets. WSI registration is a two-part problem, the first being the alignment itself and the second the application of transformations to huge multi-gigapixel images. To address both challenges, we developed Virtual Alignment of pathoLogy Image Series (VALIS), software which enables generation of highly multiplexed images by aligning any number of brightfield and/or immunofluorescent WSI, the results of which can be saved in the ome.tiff format. Benchmarking using publicly available datasets indicates VALIS provides state-of-the-art accuracy in WSI registration and 3D reconstruction. Leveraging existing open-source software tools, VALIS is written in Python, providing a free, fast, scalable, robust, and easy-to-use pipeline for registering multi-gigapixel WSI, facilitating downstream spatial analyses. The spatial organization of a tumor affects how it grows and responds to treatment. Here, the authors present VALIS, a software to align sets of whole slide images (WSI) with state-of-the-art accuracy, enabling spatial studies of the tumor ecology.

Marine protected areas (MPAs) are an important and increasing component of marine conservation strategy, but their effectiveness is variable and debated; now a study has assembled data from a global sample of MPAs and demonstrates that effectiveness depends on five key properties: whether any fishing is allowed, enforcement levels, age, size and degree of isolation. Five steps to marine protection Marine protected areas are an important and increasing component of marine conservation strategy, but their effectiveness is variable and much debated. These authors assemble data from a global sample of fished regions and 87 marine protected areas and demonstrate that the effectiveness of a protected area depends on five key properties: how much fishing is allowed, enforcement levels, how long protection has been in place, area and degree of isolation. Conservation is assured only when all five of these boxes have been ticked. In line with global targets agreed under the Convention on Biological Diversity, the number of marine protected areas (MPAs) is increasing rapidly, yet socio-economic benefits generated by MPAs remain difficult to predict and under debate 1 , 2 . MPAs often fail to reach their full potential as a consequence of factors such as illegal harvesting, regulations that legally allow detrimental harvesting, or emigration of animals outside boundaries because of continuous habitat or inadequate size of reserve 3 , 4 , 5 . Here we show that the conservation benefits of 87 MPAs investigated worldwide increase exponentially with the accumulation of five key features: no take, well enforced, old (>10 years), large (>100 km 2 ), and isolated by deep water or sand. Using effective MPAs with four or five key features as an unfished standard, comparisons of underwater survey data from effective MPAs with predictions based on survey data from fished coasts indicate that total fish biomass has declined about two-thirds from historical baselines as a result of fishing. Effective MPAs also had twice as many large (>250 mm total length) fish species per transect, five times more large fish biomass, and fourteen times more shark biomass than fished areas. Most (59%) of the MPAs studied had only one or two key features and were not ecologically distinguishable from fished sites. Our results show that global conservation targets based on area alone will not optimize protection of marine biodiversity. More emphasis is needed on better MPA design, durable management and compliance to ensure that MPAs achieve their desired conservation value.

Electrical impedance tomography (EIT) is a bedside imaging technique in which voltage data arising from current applied on electrodes is used to compute images of admittivity in real time. Due to the severe ill-posedness of the inverse problem, good spatial resolution poses a challenge in EIT. Conversely, the temporal resolution is high, facilitating dynamic bedside imaging. In this work, we propose a real-time linearized reconstruction algorithm that makes use of an anatomical atlas to provide prior spatial information at two stages of the reconstruction with the goal of improving the spatial resolution. The algorithm updates a non-constant initial estimate of an anatomically relevant distribution of conductivity and susceptivity obtained from the mean of the atlas, and using the Schur complement method as a post-processing technique. Two atlases are constructed from a database of CT scans of 89 infants; one for the reconstruction of ventilation and one for the reconstruction of pulsatile perfusion. The algorithm is applied to data collected on 16 premature infants with lung disease of prematurity and 5 healthy control infants to reconstruct conductivity and susceptivity images of both ventilation and pulsatile perfusion in real time using the ACT 5 EIT system. EIT parameters describing homogeneity of ventilation distribution throughout the lung and the distribution anterior/posterior and in the left versus right lung were computed for each infant. The left/right ventilation distribution was found to distinguish between the healthy and the preterm infants with statistical significance (p-value< 0.05). The reconstructions demonstrate qualitatively improved resolution when compared to the NOSER algorithm currently used on the ACT 5 system for real-time bedside imaging, and the ability to image changes due to ventilation and pulsatile perfusion, as well as regional inhomogeneity. Since CT scans were not available for these infants, there is no gold standard for validation. In conclusion, we present a novel real-time algorithm with the goal of improving spatial resolution for bedside imaging with EIT for conductivity and susceptivity imaging of ventilation and pulsatile perfusion, with the potential to aid in the evaluation of lung function in infants at the bedside.

Cancer treatment frequently fails due to the evolution of drug-resistant cell phenotypes driven by genetic or non-genetic changes. The origin, timing, and rate of spread of these adaptations are critical for understanding drug resistance mechanisms but remain challenging to observe directly. We present a mathematical framework to infer drug resistance dynamics from genetic lineage tracing and population size data without direct measurement of resistance phenotypes. Simulation experiments demonstrate that the framework accurately recovers ground-truth evolutionary dynamics. Experimental evolution to 5-Fu chemotherapy in colorectal cancer cell lines SW620 and HCT116 validates the framework. In SW620 cells, a stable pre-existing resistant subpopulation was inferred, whereas in HCT116 cells, resistance emerged through phenotypic switching into a slow-growing resistant state with stochastic progression to full resistance. Functional assays, including scRNA-seq and scDNA-seq, validate these distinct evolutionary routes. This framework facilitates rapid characterisation of resistance mechanisms across diverse experimental settings. Understanding the dynamics of how drug resistance originates in cancer remains crucial, but it is not possible to observe them directly. Here, the authors construct a mathematical framework to infer drug resistance dynamics in cancer using lineage tracing and population size data, which is confirmed with experimental evidence and single-cell sequencing.

Compared to intramuscular vaccines, nasally administered vaccines have the advantage of inducing local mucosal immune responses that may block infection and interrupt transmission of respiratory pathogens. Live attenuated influenza vaccine (LAIV) is effective in preventing influenza in children, but a correlate of protection for LAIV remains unclear. Studying young adult volunteers, we observe that LAIV induces distinct, compartmentalized, antibody responses in the mucosa and blood. Seeking immunologic correlates of these distinct antibody responses we find associations with mucosal IL-33 release in the first 8 hours post-inoculation and divergent CD8 + and circulating T follicular helper (cTfh) T cell responses 7 days post-inoculation. Mucosal antibodies are induced separately from blood antibodies, are associated with distinct immune responses early post-inoculation, and may provide a correlate of protection for mucosal vaccination. This study was registered as NCT04110366 and reports primary (mucosal antibody) and secondary (blood antibody, and nasal viral load and cytokine) endpoint data. Nasally delivered live attenuated influenza vaccines (LAIV) have been shown to be effective in vaccine trials yet immune responses are mostly measured in blood. Here the authors report a clinical trial in young adults and measure immune responses in the mucosa and blood to identify compartmentalised responses.

Emerging evidence suggests that cancer cell metabolism can be regulated by cancer-associated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells. Cancer associated fibroblasts (CAFs) have been suggested to regulate cancer cell metabolism, but the mechanisms are not completely elucidated. Here, the authors show that low FAK expression in stromal cells correlates with poor prognosis in breast and pancreatic cancer patients and that FAK-silencing in CAFs promotes tumourigenesis by the paracrine regulation of cancer cell metabolism.