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Reporting health data for large urban areas presents numerous challenges. In the case of Toronto, Ontario, amalgamation in 1998 merged six census subdivisions into one mega-city, resulting in the disappearance of standard reporting units. A population-based approach was used to define new health planning areas. Census tracts were used as building blocks and combined according to residential income homogeneity, respecting natural and man-made boundaries, forward sortation areas and the City of Toronto's community neighbourhoods whenever possible. Correlations and maps were used to establish area boundaries. The city was divided into 5 major planning areas which were further subdivided creating 15 minor areas. Both major and minor areas showed significant differences in population characteristics, health status and health service utilization. This commentary demonstrates the feasibility and describes the outcomes of one method for establishing planning and reporting areas in large urban centres. Next steps include the further generation of health data for these areas, comparisons with other Canadian urban areas, and application of these methods to recently announced Ontario Local Health Integration Networks. These areas can be used for planning and evaluating health service delivery, comparison with other Canadian urban areas and ongoing monitoring of and advocacy for equity in health. [ABSTRACT FROM AUTHOR]

Ecological theory of alternative stable communities suggests the switch between different species assemblages occurs when environmental conditions alter species composition so that it crosses a critical threshold and enters a different basin of attraction. The theory impliesthat once the threshold is crossed, rates of key ecological processes, such as predation and competition, will change. This conjecture was tested on sheltered intertidal shores of New England that are dominated by either mussel (Mytilus edulis) beds or algal (Ascophyllum nodosum) stands. Twelve sets of clearings of different sizes, which mimicked effects of ice scour, were created in algal stands, and mortality of transplanted mussels was monitored. Clearings were 1, 2, 4 and 8m in diameter. Mussel mortality due to the predatory snail Nucella lapillus declined in a step-like manner in clearings ? 4 m in diameter. Initial densities of the predator did not vary among experimental clearings or sites and were not correlated with mussel mortality. Mussel mortality was correlated with predatory snail densities during andat the end of the experiment. These results provide experimental evidence supporting conjectures about the switch between alternative states in ecological communities. [ABSTRACT FROM AUTHOR]

Objectives: To introduce quantum computing technologies as a tool for biomedical research and highlight future applications within healthcare, focusing on its capabilities, benefits, and limitations., Target Audience: Investigators seeking to explore quantum computing and create quantum-based applications for healthcare and biomedical research., Scope: Quantum computing requires specialized hardware, known as quantum processing units, that use quantum bits (qubits) instead of classical bits to perform computations. This article will cover (1) proposed applications where quantum computing offers advantages to classical computing in biomedicine; (2) an introduction to how quantum computers operate, tailored for biomedical researchers; (3) recent progress that has expanded access to quantum computing; and (4) challenges, opportunities, and proposed solutions to integrate quantum computing in biomedical applications., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

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., (© 2024 John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: The unprecedented influence of human activities on natural ecosystems in the 21st century has resulted in increasingly frequent large-scale changes in ecological communities. This has heightened interest in understanding such changes and effective means to manage them. Accurate interpretation of state changes is challenging because of difficulties translating theory to empirical study, and most theory emphasizes systems near equilibrium, which may not be relevant in rapidly changing environments., Scope: We review concepts of long-transient stages and phase shifts between stable community states, both smooth, continuous and discontinuous shifts, and the relationships among them. Three principal challenges emerge when applying these concepts. The first is how to interpret observed change in communities - distinguishing multiple stable states from long transients, or reversible shifts in the phase portrait of single attractor systems. The second is how to quantify the magnitudes of three sources of variability that cause switches between community states: (1) 'noise' in species' abundances, (2) 'wiggle' in system parameters and (3) trends in parameters that affect the topography of the basin of attraction. The third challenge is how variability of the system shapes evidence used to interpret community changes. We outline a novel approach using critical length scales to potentially address these challenges. These concepts are highlighted by a review of recent examples involving macroalgae as key players in marine benthic ecosystems., Conclusions: Real-world examples show three or more stable configurations of ecological communities may exist for a given set of parameters, and transient stages may persist for long periods necessitating their respective consideration. The characteristic length scale (CLS) is a useful metric that uniquely identifies a community 'basin of attraction', enabling phase shifts to be distinguished from long transients. Variabilities of CLSs and time series data may likewise provide proactive management measures to mitigate phase shifts and loss of ecosystem services. Continued challenges remain in distinguishing continuous from discontinuous phase shifts because their respective dynamics lack unique signatures., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Warming alters ecosystems through direct physiological effects on organisms and indirect effects via biotic interactions, but their relative impacts in the wild are unknown due to the difficulty in warming natural environments. Here we bridge this gap by embedding manipulative field experiments within a natural stream temperature gradient to test whether warming and apex fish predators have interactive effects on freshwater ecosystems. Fish exerted cascading effects on algal production and microbial decomposition via both green and brown pathways in the food web, but only under warming. Neither temperature nor the presence of fish altered food web structure alone, but connectance and mean trophic level declined as consumer species were lost when both drivers acted together. A mechanistic model indicates that this temperature-induced trophic cascade is determined primarily by altered interactions, which cautions against extrapolating the impacts of warming from reductionist approaches that do not consider the wider food web., (© 2023. The Author(s).)

Purpose: Validation of artificial intelligence (AI) algorithms in digital pathology with a reference standard is necessary before widespread clinical use, but few examples focus on creating a reference standard based on pathologist annotations. This work assesses the results of a pilot study that collects density estimates of stromal tumor-infiltrating lymphocytes (sTILs) in breast cancer biopsy specimens. This work will inform the creation of a validation dataset for the evaluation of AI algorithms fit for a regulatory purpose. Approach: Collaborators and crowdsourced pathologists contributed glass slides, digital images, and annotations. Here, "annotations" refer to any marks, segmentations, measurements, or labels a pathologist adds to a report, image, region of interest (ROI), or biological feature. Pathologists estimated sTILs density in 640 ROIs from hematoxylin and eosin stained slides of 64 patients via two modalities: an optical light microscope and two digital image viewing platforms. Results: The pilot study generated 7373 sTILs density estimates from 29 pathologists. Analysis of annotations found the variability of density estimates per ROI increases with the mean; the root mean square differences were 4.46, 14.25, and 26.25 as the mean density ranged from 0% to 10%, 11% to 40%, and 41% to 100%, respectively. The pilot study informs three areas of improvement for future work: technical workflows, annotation platforms, and agreement analysis methods. Upgrades to the workflows and platforms will improve operability and increase annotation speed and consistency. Conclusions: Exploratory data analysis demonstrates the need to develop new statistical approaches for agreement. The pilot study dataset and analysis methods are publicly available to allow community feedback. The development and results of the validation dataset will be publicly available to serve as an instructive tool that can be replicated by developers and researchers., (© 2022 The Authors.)

Competing Interests: Competing interest statement: The authors do not have any competing interests to declare.

Purpose: To compare patient preferences for eyeglasses prescribed using a low-cost, portable wavefront autorefractor versus standard subjective refraction (SR)., Design: Randomized, cross-over clinical trial., Participants: Patients aged 18 to 40 years presenting with refractive errors (REs) to a tertiary eye hospital in Southern India., Methods: Participants underwent SR followed by autorefraction (AR) using the monocular version of the QuickSee device (PlenOptika Inc). An independent optician, masked to the refraction approach, prepared eyeglasses based on each refraction approach. Participants (masked to refraction source) were randomly assigned to use SR- or AR-based eyeglasses first, followed by the other pair, for 1 week each. At the end of each week, participants had their vision checked and were interviewed about their experience with the eyeglasses., Main Outcome Measures: Patients preferring eyeglasses were chosen using AR and SR., Results: The 400 participants enrolled between March 26, 2018, and August 2, 2019, had a mean (standard deviation) age of 28.4 (6.6) years, and 68.8% were women. There was a strong correlation between spherical equivalents using SR and AR (r = 0.97, P < 0.001) with a mean difference of -0.07 diopters (D) (95% limits of agreement [LoA], -0.68 to 0.83). Of the 301 patients (75.2%) who completed both follow-up visits, 50.5% (n = 152) and 49.5% (n = 149) preferred glasses prescribed using SR and AR, respectively (95% CI, 45.7-56.3; P = 0.86). There were no differences in demographic or vision characteristics between participants with different preferences (P > 0.05 for all)., Conclusions: We observed a strong agreement between the prescriptions from SR and AR, and eyeglasses prescribed using SR and AR were equally preferred by patients. Wider use of prescribing based on AR alone in resource-limited settings is supported by these findings., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The implicit assumption that properties of natural systems deduced from the average statistics from random samples suffice for understanding them focuses the attention of ecologists on the average effects of processes and responses, and often, to view their variability as noise. Yet, both kinds of effects can drive dynamics of ecological systems and their covariation may confound interpretation. Predation by crabs and snails on competitively dominant mussels has long been recognized as an important process structuring communities on rocky shores of the Northwest Atlantic Ocean. We experimentally manipulated the average intensity of predation in plots across a gradient of mussel recruitment to separately estimate the average and variability of responses of mussel recruitment and community composition. Predation did not affect the average number of mussels recruited to plots, nor the average multivariate composition of the community. Plots from which predators were excluded showed a ~ 30% increase in spatial variability of mussel recruitment. After 1 year, the spatial variability in community composition was greater than that observed among plots that predators could access. An important, but less recognized, aspect of predation is its dampening effect on variability of community structure. As accelerating rates of environmental change disrupt species interactions, variability effects of ecological processes and corresponding responses are likely to be increasingly important determinants of community dynamics.

Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring., Competing Interests: Competing interestsJ.T. is funded by Visiopharm A/S, Denmark. A.M. is an equity holder in Elucid Bioimaging and in Inspirata Inc. He is also a scientific advisory consultant for Inspirata Inc. In addition he has served as a scientific advisory board member for Inspirata Inc, Astrazeneca, Bristol Meyers-Squibb and Merck. He also has sponsored research agreements with Philips and Inspirata Inc. His technology has been licensed to Elucid Bioimaging and Inspirata Inc. He is also involved in an NIH U24 grant with PathCore Inc, and three different R01 grants with Inspirata Inc. S.R.L. received travel and educational funding from Roche/Ventana. A.J.L. serves as a consultant for BMS, Merck, AZ/Medimmune, and Genentech. He is also provides consulting and advisory work for many other companies not relevant to this work. FPL does consulting for Astrazeneca, BMS, Roche, MSD Pfizer, Novartis, Sanofi, and Lilly. S.Ld.H., A.K., M.K., U.K., and M.B. are employees of Roche. J.M.S.B. is consultant for Insight Genetics, BioNTech AG, Biothernostics, Pfizer, RNA Diagnostics, and OncoXchange. He received funding from Thermo Fisher Scientific, Genoptix, Agendia, NanoString technologies, Stratifyer GmBH, and Biotheranostics. L.F.S.K. is a consultant for Roche and Novartis. J.K.K. and A.H.B. are employees of PathAI. D.L.R. is on the advisory board for Amgen, Astra Xeneca, Cell Signaling Technology, Cepheid, Daiichi Sankyo, GSK, Konica/Minolta, Merck, Nanostring, Perking Elmer, Roche/Ventana, and Ultivue. He has received research support from Astrazeneca, Cepheid, Navigate BioPharma, NextCure, Lilly, Ultivue, Roche/Ventana, Akoya/Perkin Elmer, and Nanostring. He also has financial conflicts of interest with BMS, Biocept, PixelGear, and Rarecyte. S.G. is a consultant for and/or receives funding from Eli Lilly, Novartis, and G1 Therapeutics. J.A.W.M.vdL. is a member of the scientific advisory boards of Philips, the Netherlands and ContextVision, Sweden, and receives research funding from Philips, the Netherlands and Sectra, Sweden. S.A. is a consultant for Merck, Genentech, and BMS, and receives funding from Merck, Genentech, BMS, Novartis, Celgene, and Amgen. T.O.N. has consulted for Nanostring, and has intellectual property rights and ownership interests from Bioclassifier LLC. S.L. receives research funding to her institution from Novartis, Bristol Meyers-Squibb, Merck, Roche-Genentech, Puma Biotechnology, Pfizer and Eli Lilly. She has acted as consultant (not compensated) to Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca and Roche-Genentech. She has acted as consultant (paid to her institution) to Aduro Biotech. J.H. is director and owner of Slide Score BV. M.M.S. is a medical advisory board member of OptraScan. R.S. has received research support from Merck, Roche, Puma; and travel/congress support from AstraZeneca, Roche and Merck; and he has served as an advisory board member of BMS and Roche and consults for BMS., (© The Author(s) 2020.)

Quantifying species interaction strengths enhances prediction of community dynamics, but variability in the strength of species interactions in space and time complicates accurate prediction. Interaction strengths can vary in response to density, indirect effects, priority effects or a changing environment, but the mechanism(s) causing direction and magnitudes of change are often unclear. We designed an experiment to characterize how environmental factors influence the direction and the strength of priority effects between sessile species. We estimated per capita non-trophic effects of barnacles (Semibalanus balanoides) on newly settled germlings of the fucoid, Ascophyllum nodosum, in the presence and absence of consumers in experiments on rocky shores throughout the Gulf of Maine, USA. Per capita effects on germlings varied among environments and barnacle life stages, and these interaction strengths were largely unaltered by changing consumer abundance. Whereas previous evidence shows adult barnacles facilitate fucoids, here, we show that recent settlers and established juveniles initially compete with germlings. As barnacles mature, they switch to become facilitators of fucoids. Consumers caused variable mortality of germlings through time comparable to that from competition. Temporally variable effects of interactors (e.g. S. balanoides), or spatial variation in their population structure, in different regions differentially affect target populations (e.g. A. nodosum). This may affect abundance of critical stages and the resilience of target species to environmental change in different geographical regions.

The physiological mechanisms that regulate adaptive plasticity of clonal organisms are key to their success in changing environments. Here, we review the mechanisms that regulate morphological plasticity of colonial hydrozoans. There is a heritable, genetic basis to colony form, but environmentally-induced plasticity and self-reinforcing developmental physiology explain much of total phenotypic variance. Morphological development of colonial hydrozoans emerges from interactions among (1) behaviors which drive gastrovascular transport, (2) architecture of the gastrovascular system that determines hydrodynamic characteristics of vascular flow, and, (3) gene products that vary in response to physiological signals provided by gastrovascular transport. Several morphogenetic signaling mechanisms have been identified, including, reactive oxygen species and nutrient concentrations in the hydroplasm, and hydromechanical forces associated with gastrovascular transport. We present a conceptual model of the interacting forces that drive hydrozoan morphological development. Several avenues for future research are suggested by the synthesis of information from prior studies of hydrozoans. Elucidating the morphogenetic signaling pathways responsive to metabolites or hydromechanical forces and the epigenetic effect of vascular architecture on colony form may give new insight into the self-maintenance of indeterminately growing and continuously developing vascular systems., (2011 Elsevier Ltd. All rights reserved.)

Recent studies of hydrozoans suggest that metabolic factors associated with the physiology of gastrovascular fluid transport play a role in regulating morphogenetic development of colonies. In that context, the objective of this study was to develop a system to experimentally control diets of hydrozoans in culture that could be used to test effects of specific compounds. This diet delivery system consisted of a known concentration of homogenate of brine shrimp nauplii that was solidified in a 1% agar block cut to the size of, and containing the equivalent of, a single, 2-day old brine shrimp nauplius larva. We tested the utility of this system by comparing the frequencies of ingestion, and rates of gastrovascular transport and growth following feeding, between polyps of Podocoryna carnea fed either a single brine shrimp nauplius (controls) or an agar cube including brine shrimp homogenate. Polyps fed experimental diets showed similar rates of gastrovascular transport (6 and 12 h after feeding) and growth (24 h after feeding) to those of polyps fed a brine shrimp nauplius suggesting that no significant artefacts existed associated with these response variables. However, the frequency of ingestion of experimental foods by polyps was much less than that by control polyps. These results imply that this system of delivery of experimental diets has potential as a means to manipulate physiological state and assay the effects on morphogenesis of hydrozoan colonies, but must first overcome limitations of low ingestion frequency.

The strength by which species interact can vary throughout their ontogeny, as environments vary in space and time, and with the density of their populations. Characterizing strengths of interaction in situ for even a small number of species is logistically difficult and may apply only to those conditions under which the estimates were derived. We sought to combine data from field experiments estimating interaction strength of life stages of the barnacle, Semibalanus balanoides, on germlings of Ascophyllum nodosum, with a model that explored the consequences of variability at per capita and per population levels to the abundance of year-old algal recruits. We further simulated how this interaction affected fucoid germling abundance as the timing of their respective settlements varied relative to one another, as occurs regionally across the Gulf of Maine, USA. Juvenile S. balanoides have a weak estimated per capita effect on germlings. Germling populations are sensitive to variation in per capita effects of juvenile barnacles because of the typically large population sizes of the latter. However, high mortality of juvenile barnacles weakens the population interaction strength over time. Adult barnacles probably weakly facilitate fucoid germlings, but greater survival of adults sustains the strength of that interaction at the population level. Germling abundance is positively associated with densities of adult barnacles and negatively associated with that of juvenile barnacles. Metamorphosing cyprid larvae have the strongest per capita effect on germling abundance, but the interaction between the two stages is so short-lived that germling abundance is altered little. Variation in the timing of barnacle and A. nodosum settlement relative to one another had very little influence on the abundance of yearling germlings. Interactions between barnacles and germlings may influence the demographic structure of A. nodosum populations and the persistence of fucoid-dominated communities on sheltered rocky shores in New England.

There is growing energy behind primary mental health care reform - from political activity, research, funding and clinical practice. The evidence that early adopters have been busy reforming mental health services in primary health care is apparent in the rise of references to primary mental health care and collaborative care in national and provincial planning documents, clinical trials examining the efficacy of collaborative mental health care, funded clinical programs across the country, and the establishment of a nationally funded initiative - the Canadian Collaborative Mental Health Initiative - to research and develop tools to implement collaborative mental health care. In conclusion, there is real momentum in primary mental health care reform. Health care planners and executives will want to turn their attention to collaborative care as the benefits to individuals and their families, the health care system, and to the economy are clear.

1. In this study we investigated the ability of ascorbate to protect nitric oxide from destruction by superoxide anion. 2. Ascorbate produced concentration-dependent relaxation of rings of rat aorta, comprising two components: the first, seen at 1-300 microM, reached a maximum of 45.3+/-2.8%, and was abolished by endothelial removal or treatment with L-NAME (100 microM), demonstrating involvement of nitric oxide. The second occurred at concentrations of 1 mM and above and was associated with falls in the pH of the bathing fluid. 3. Pretreatment with ascorbate at concentrations up to 3 mM had no effect on the relaxation to acetylcholine (10 nM-10 microM) on endothelium-containing rings or adenosine (0.1 microM-3 mM) on endothelium-denuded rings. 4. An oxidant stress was applied to aortic rings, comprising inhibition of endogenous Cu/Zn superoxide dismutase by diethyldithiocarbamate (0.1 mM) followed by generation of superoxide anion by hypoxanthine (0.1 mM/xanthine oxidase (16 u ml(-1)). This reduced maximal acetylcholine-induced relaxation from 96.7+/-1.3% to 42.4+/-3.5% (P<0.001). Treatment with ascorbate (30 microM-3 mM) reversed this blockade in a concentration-dependent manner. 5. Our findings show that ascorbate has the ability to protect nitric oxide from destruction by superoxide anion. This action is seen with ascorbate at levels normally present in plasma, suggesting that this antioxidant may exert a tonic protective effect on nitric oxide within the vasculature.