Interleukin-33 Signaling Controls the Development of Iron-Recycling Macrophages.

Splenic red pulp macrophages (RPMs) contribute to erythrocyte homeostasis and are required for iron recycling. Heme induces the expression of SPIC transcription factor in monocyte-derived macrophages and promotes their differentiation into RPM precursors, pre-RPMs. However, the requirements for differentiation into mature RPMs remain unknown. Here, we have demonstrated that interleukin (IL)-33 associated with erythrocytes and co-cooperated with heme to promote the generation of mature RPMs through activation of the MyD88 adaptor protein and ERK1/2 kinases downstream of the IL-33 receptor, IL1RL1. IL-33- and IL1RL1-deficient mice showed defective iron recycling and increased splenic iron deposition. Gene expression and chromatin accessibility studies revealed a role for GATA transcription factors downstream of IL-33 signaling during the development of pre-RPMs that retained full potential to differentiate into RPMs. Thus, IL-33 instructs the development of RPMs as a response to physiological erythrocyte damage with important implications to iron recycling and iron homeostasis.

HpARI Protein Secreted by a Helminth Parasite Suppresses Interleukin-33.

Infection by helminth parasites is associated with amelioration of allergic reactivity, but mechanistic insights into this association are lacking. Products secreted by the mouse parasite Heligmosomoides polygyrus suppress type 2 (allergic) immune responses through interference in the interleukin-33 (IL-33) pathway. Here, we identified H. polygyrus Alarmin Release Inhibitor (HpARI), an IL-33-suppressive 26-kDa protein, containing three predicted complement control protein (CCP) modules. In vivo, recombinant HpARI abrogated IL-33, group 2 innate lymphoid cell (ILC2) and eosinophilic responses to Alternaria allergen administration, and diminished eosinophilic responses to Nippostrongylus brasiliensis, increasing parasite burden. HpARI bound directly to both mouse and human IL-33 (in the cytokine's activated state) and also to nuclear DNA via its N-terminal CCP module pair (CCP1/2), tethering active IL-33 within necrotic cells, preventing its release, and forestalling initiation of type 2 allergic responses. Thus, HpARI employs a novel molecular strategy to suppress type 2 immunity in both infection and allergy.

Cardiac specification during gastrulation - The Yellow Brick Road leading to Tinman.

The question of how the heart develops, and the genetic networks governing this process have become intense areas of research over the past several decades. This research is propelled by classical developmental studies and potential clinical applications to understand and treat congenital conditions in which cardiac development is disrupted. Discovery of the tinman gene in Drosophila, and examination of its vertebrate homolog Nkx2.5, along with other core cardiac transcription factors has revealed how cardiac progenitor differentiation and maturation drives heart development. Careful observation of cardiac morphogenesis along with lineage tracing approaches indicated that cardiac progenitors can be divided into two broad classes of cells, namely the first and second heart fields, that contribute to the heart in two distinct waves of differentiation. Ample evidence suggests that the fate of individual cardiac progenitors is restricted to distinct cardiac structures quite early in development, well before the expression of canonical cardiac progenitor markers like Nkx2.5. Here we review the initial specification of cardiac progenitors, discuss evidence for the early patterning of cardiac progenitors during gastrulation, and consider how early gene expression programs and epigenetic patterns can direct their development. A complete understanding of when and how the developmental potential of cardiac progenitors is determined, and their potential plasticity, is of great interest developmentally and also has important implications for both the study of congenital heart disease and therapeutic approaches based on cardiac stem cell programming.

How should artificial intelligence be used in Australian health care? Recommendations from a citizens' jury.

OBJECTIVE: To support a diverse sample of Australians to make recommendations about the use of artificial intelligence (AI) technology in health care. STUDY DESIGN: Citizens' jury, deliberating the question: "Under which circumstances, if any, should artificial intelligence be used in Australian health systems to detect or diagnose disease?" SETTING, PARTICIPANTS: Thirty Australian adults recruited by Sortition Foundation using random invitation and stratified selection to reflect population proportions by gender, age, ancestry, highest level of education, and residential location (state/territory; urban, regional, rural). The jury process took 18 days (16 March - 2 April 2023): fifteen days online and three days face-to-face in Sydney, where the jurors, both in small groups and together, were informed about and discussed the question, and developed recommendations with reasons. Jurors received extensive information: a printed handbook, online documents, and recorded presentations by four expert speakers. Jurors asked questions and received answers from the experts during the online period of the process, and during the first day of the face-to-face meeting. MAIN OUTCOME MEASURES: Jury recommendations, with reasons. RESULTS: The jurors recommended an overarching, independently governed charter and framework for health care AI. The other nine recommendation categories concerned balancing benefits and harms; fairness and bias; patients' rights and choices; clinical governance and training; technical governance and standards; data governance and use; open source software; AI evaluation and assessment; and education and communication. CONCLUSIONS: The deliberative process supported a nationally representative sample of citizens to construct recommendations about how AI in health care should be developed, used, and governed. Recommendations derived using such methods could guide clinicians, policy makers, AI researchers and developers, and health service users to develop approaches that ensure trustworthy and responsible use of this technology.

Monoclonal antibodies for treating early Alzheimer disease-a commentary on recent 'positive' trials.

Recent phase 3 randomised controlled trials of amyloid-targeting monoclonal antibodies in people with pre-clinical or early Alzheimer disease have reported positive results, raising hope of finally having disease-modifying drugs. Given their far-reaching implications for clinical practice, the methods and findings of these trials, and the disease causation theory underpinning the mechanism of drug action, need to be critically appraised. Key considerations are the representativeness of trial populations; balance of prognostic factors at baseline; psychometric properties and minimal clinically important differences of the primary efficacy outcome measures; level of study fidelity; consistency of subgroup analyses; replication of findings in similar trials; sponsor role and potential conflicts of interest; consistency of results with disease causation theory; cost and resource estimates; and alternative prevention and treatment strategies. In this commentary, we show shortcomings in each of these areas and conclude that monoclonal antibody treatment for early Alzheimer disease is lacking high-quality evidence of clinically meaningful impacts at an affordable cost.

The new paradigm in machine learning - foundation models, large language models and beyond: a primer for physicians.

Foundation machine learning models are deep learning models capable of performing many different tasks using different data modalities such as text, audio, images and video. They represent a major shift from traditional task-specific machine learning prediction models. Large language models (LLM), brought to wide public prominence in the form of ChatGPT, are text-based foundational models that have the potential to transform medicine by enabling automation of a range of tasks, including writing discharge summaries, answering patients questions and assisting in clinical decision-making. However, such models are not without risk and can potentially cause harm if their development, evaluation and use are devoid of proper scrutiny. This narrative review describes the different types of LLM, their emerging applications and potential limitations and bias and likely future translation into clinical practice.

The relationship between pain and depression and anxiety in patients with inflammatory arthritis: a systematic review protocol.

Pain is a major challenge for patients with inflammatory arthritis (IA). Depression and anxiety are common comorbidities in IA, associating with worse outcomes. How they relate to pain is uncertain, with existing systematic reviews (a) mainly considering cross-sectional studies, (b) focusing on the relationship between pain and mental health in the context of disease activity/quality of life, and (c) not specifically considering the impact of treating depression/anxiety on pain. This PROSPERO-registered (CRD42023411823) systematic review will address this knowledge-gap by synthesizing evidence to summarise the associations (and potential mediators) between pain and depression/anxiety and evaluate the impact of treating co-morbid depression/anxiety on pain in IA. Relevant databases will be searched, articles screened and their quality appraised (using Joanna Briggs Institute critical appraisal tools) by two reviewers. Eligible studies will include adults with rheumatoid arthritis or spondyloarthritis, be a clinical trial or observational study, and either (a) report the relationship between pain and depression/anxiety (observational studies/baseline trials), or (b) randomise participants to a pharmacological or psychological treatment to manage depression/anxiety with a pain outcome as an endpoint (trials). To synthesise data on the association between pain and depression/anxiety, where available adjusted coefficients from regression models will be pooled in a random-effects meta-analysis. A synthesis without meta-analysis will summarise mediators. To evaluate the impact of treating depression/anxiety on pain, endpoint mean differences between treatment arms will be combined in a random-effects meta-analysis. Through understanding how depression/anxiety contribute to pain in IA, our review has the potential to help optimise approaches to IA pain.

Nasal IL-13 production identifies patients with late-phase allergic responses.

BACKGROUND: There is limited knowledge on how local cytokine secretion patterns after nasal allergen challenge correlate with clinical symptoms especially with regard to the "late allergic response," which occurs in approximately 40% to 50% of patients with allergy. OBJECTIVE: We sought to characterize the immunologic and clinical nasal responses to birch pollen allergen challenge with a special focus on the late allergic response. METHODS: In this randomized, double-blind, placebo-controlled trial, birch pollen-allergic participants were challenged with birch pollen extract (n = 20) or placebo (n = 10) on 3 consecutive days. On days 1 and 3, nasal secretions were collected at selected time points over a 24-hour time course for the measurement of 33 inflammatory mediators. Clinical responses were determined through subjective symptom scores and objective nasal airflow measurements. RESULTS: Provoked participants had significantly greater clinical responses and showed significant increases in tryptase and the soluble IL-33 receptor serum stimulation 2 (sST2) in nasal secretions within minutes compared with the placebo group. Eight of 20 provoked participants displayed high IL-13 levels 2 to 8 hours after allergen provocation. This group also showed significant changes in clinical parameters, with a secondary drop in nasal airflow measured by peak nasal inspiratory flow and increased symptoms of nasal obstruction, which significantly differed from IL-13 nonresponders after 6 hours. CONCLUSIONS: IL-13 response status correlates with clinical responses and type 2 cytokine responses in the late phase after allergen provocation.

Oxidised IL-33 drives COPD epithelial pathogenesis via ST2-independent RAGE/EGFR signalling complex.

BACKGROUND: Epithelial damage, repair and remodelling are critical features of chronic airway diseases including chronic obstructive pulmonary disease (COPD). Interleukin (IL)-33 released from damaged airway epithelia causes inflammation via its receptor, serum stimulation-2 (ST2). Oxidation of IL-33 to a non-ST2-binding form (IL-33ox) is thought to limit its activity. We investigated whether IL-33ox has functional activities that are independent of ST2 in the airway epithelium. METHODS: In vitro epithelial damage assays and three-dimensional, air-liquid interface (ALI) cell culture models of healthy and COPD epithelia were used to elucidate the functional role of IL-33ox. Transcriptomic changes occurring in healthy ALI cultures treated with IL-33ox and COPD ALI cultures treated with an IL-33-neutralising antibody were assessed with bulk and single-cell RNA sequencing analysis. RESULTS: We demonstrate that IL-33ox forms a complex with receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) expressed on airway epithelium. Activation of this alternative, ST2-independent pathway impaired epithelial wound closure and induced airway epithelial remodelling in vitro. IL-33ox increased the proportion of mucus-producing cells and reduced epithelial defence functions, mimicking pathogenic traits of COPD. Neutralisation of the IL-33ox pathway reversed these deleterious traits in COPD epithelia. Gene signatures defining the pathogenic effects of IL-33ox were enriched in airway epithelia from patients with severe COPD. CONCLUSIONS: Our study reveals for the first time that IL-33, RAGE and EGFR act together in an ST2-independent pathway in the airway epithelium and govern abnormal epithelial remodelling and muco-obstructive features in COPD.

Analgesic prescribing in patients with inflammatory arthritis in England: observational studies in the Clinical Practice Research Datalink.

OBJECTIVES: Despite little evidence that analgesics are effective in inflammatory arthritis (IA), studies report substantial opioid prescribing. The extent this applies to other analgesics is uncertain. We undertook a comprehensive evaluation of analgesic prescribing in patients with IA in the Clinical Practice Research Datalink Aurum to evaluate this. METHODS: From 2004 to 2020, cross-sectional analyses evaluated analgesic prescription annual prevalence in RA, PsA and axial spondyloarthritis (axSpA), stratified by age, sex, ethnicity, deprivation and geography. Joinpoint regression evaluated temporal prescribing trends. Cohort studies determined prognostic factors at diagnosis for chronic analgesic prescriptions using Cox proportional hazards models. RESULTS: Analgesic prescribing declined over time but remained common: 2004 and 2020 IA prescription prevalence was 84.2/100 person-years (PY) (95% CI 83.9, 84.5) and 64.5/100 PY (64.2, 64.8), respectively. In 2004, NSAIDs were most prescribed (56.1/100 PY; 55.8, 56.5), falling over time. Opioids were most prescribed in 2020 (39.0/100 PY; 38.7, 39.2). Gabapentinoid prescribing increased: 2004 prevalence 1.1/100 PY (1.0, 1.2); 2020 prevalence 9.9/100 PY (9.7, 10.0). Most opioid prescriptions were chronic (2020 prevalence 23.4/100 PY [23.2, 23.6]). Non-NSAID analgesic prescribing was commoner in RA, older people, females and deprived areas/northern England. Conversely, NSAID prescribing was commoner in axSpA/males, varying little by deprivation/geography. Peri-diagnosis was high-risk for starting chronic opioid/NSAID prescriptions. Prognostic factors for chronic opioid/gabapentinoid and NSAID prescriptions differed, with NSAIDs having no consistently significant association with deprivation (unlike opioids/gabapentinoids). CONCLUSION: IA analgesic prescribing of all classes is widespread. This is neither evidence-based nor in line with guidelines. Peri-diagnosis is an opportune moment to reduce chronic analgesic prescribing.

Declining Comprehensiveness of Services Delivered by Canadian Family Physicians Is Not Driven by Early-Career Physicians.

We describe changes in the comprehensiveness of services delivered by family physicians in 4 Canadian provinces (British Columbia, Manitoba, Ontario, Nova Scotia) during the periods 1999-2000 and 2017-2018 and explore if changes differ by years in practice. We measured comprehensiveness using province-wide billing data across 7 settings (home, long-term care, emergency department, hospital, obstetrics, surgical assistance, anesthesiology) and 7 service areas (pre/postnatal care, Papanicolaou [Pap] testing, mental health, substance use, cancer care, minor surgery, palliative home visits). Comprehensiveness declined in all provinces, with greater changes in number of service settings than service areas. Decreases were no greater among new-to-practice physicians.

A Novel Domain Knowledge-Informed Machine Learning Approach for Modeling Solid Waste Management Systems.

Sustainability challenges, such as solid waste management, are usually scientifically complex and data scarce, which makes them not amenable to science-based analytical forms or data-intensive learning paradigms. Deep integration between data science and sustainability science in highly complementary manners offers new opportunities for tackling these conundrums. This study develops a novel hybrid neural network (HNN) model that imposes the holistic decision-making context of solid waste management systems (SWMS) on a traditional neural network (NN) architecture. Equipped with adaptable hybridization designs of hand-crafted model structure, constrained or predetermined parameters, and a customized loss function, the HNN model is capable of learning various technical, economic, and social aspects of SWMS from a small and heterogeneous data set. In comparison, the versatile HNN model not only outperforms traditional NN models in convergence rates, which leads to a 22% lower mean testing error of 0.20, but also offers superior interpretability. The HNN model is capable of generating insights into the enabling factors, policy interventions, and driving forces of SWMS, laying a solid foundation for data-driven decision making.

Coping with uncertainty in clinical practice: a narrative review.

Clinicians must make decisions amid the uncertainty that is ubiquitous to clinical practice. Uncertainty in clinical practice can assume many forms depending on its source, such as insufficient personal knowledge or scientific evidence, limited practical understanding or competence, challenging interpersonal relationships, and complexity and ambiguity in clinical encounters. The level and experience of uncertainty varies according to personal traits, clinical context, affective factors and sociocultural norms. Clinicians vary in their tolerance of uncertainty, and maladaptive responses may adversely affect patient care and clinician wellbeing. Various strategies can be used to minimise and manage, but not eliminate, uncertainty and to share uncertainty with patients without compromising the clinician-patient relationship or clinician credibility.

Factors influencing practice choices of early-career family physicians in Canada: a qualitative interview study.

BACKGROUND: Comprehensiveness of primary care has been declining, and much of the blame has been placed on early-career family physicians and their practice choices. To better understand early-career family physicians' practice choices in Canada, we sought to identify the factors that most influence their decisions about how to practice. METHODS: We conducted a qualitative study using framework analysis. Family physicians in their first 10 years of practice were recruited from three Canadian provinces: British Columbia, Ontario, and Nova Scotia. Interview data were coded inductively and then charted onto a matrix in which each participant's data were summarized by code. RESULTS: Of the 63 participants that were interviewed, 24 worked solely in community-based practice, 7 worked solely in focused practice, and 32 worked in both settings. We identified four practice characteristics that were influenced (scope of practice, practice type and model, location of practice, and practice schedule and work volume) and three categories of influential factors (training, professional, and personal). CONCLUSIONS: This study demonstrates the complex set of factors that influence practice choices by early-career physicians, some of which may be modifiable by policymakers (e.g., policies and regulations) while others are less so (e.g., family responsibilities). Participants described individual influences from family considerations to payment models to meeting community needs. These findings have implications for both educators and policymakers who seek to support and expand comprehensive care.

Health advocacy among medical learners: Unpacking contextual barriers and affordances.

INTRODUCTION: Learners and physicians are expected to practice as health advocates in Canadian contexts, but they rarely feel competent to practice this critical role when they complete their training. This is in part because advocacy is seen as "going above and beyond" routine practice and pushing the boundaries of systems that are resistant to change. Medical learning contexts are rife with barriers to learning about and practicing advocacy, and there is now a need to understand how contexts impact advocacy. METHODS: Using constructivist grounded theory study, we generated data through individual and group interviews with medical learners to explore the barriers and facilitators to advocacy in a variety of learning/practice contexts. We used purposeful and theoretical sampling to ensure that diverse learning contexts and learners who had different views on advocacy were represented. We constructed a theoretical model to understand advocacy decision-making through cycles of initial, focused and theoretical coding, using constant comparative analysis. RESULTS: Learners' thinking about health advocacy was framed by their own unique knowledge and beliefs, as well as their institutional and organisational contexts. With these influences in mind, learners made decisions about when to advocate within a local decision-making context, guided by affordances and barriers to advocacy involved in their perceptions of the patient, their own social position, resources available and social norms. CONCLUSIONS: This framework highlights critical aspects of context that influence learners' ability to learn about and practice as health advocates. If we are to adequately prepare learners for this important work, we must address aspects of their learning and practice contexts that make this work daunting, and we offer learners the tools required to intervene in contexts that do not support their efforts.

A Toolbox for Efficient Proximity-Dependent Biotinylation in Zebrafish Embryos.

Understanding how proteins are organized in compartments is essential to elucidating their function. While proximity-dependent approaches such as BioID have enabled a massive increase in information about organelles, protein complexes, and other structures in cell culture, to date there have been only a few studies on living vertebrates. Here, we adapted proximity labeling for protein discovery in vivo in the vertebrate model organism, zebrafish. Using lamin A (LMNA) as bait and green fluorescent protein (GFP) as a negative control, we developed, optimized, and benchmarked in vivo TurboID and miniTurbo labeling in early zebrafish embryos. We developed both an mRNA injection protocol and a transgenic system in which transgene expression is controlled by a heat shock promoter. In both cases, biotin is provided directly in the egg water, and we demonstrate that 12 h of labeling are sufficient for biotinylation of prey proteins, which should permit time-resolved analysis of development. After statistical scoring, we found that the proximal partners of LMNA detected in each system were enriched for nuclear envelope and nuclear membrane proteins and included many orthologs of human proteins identified as proximity partners of lamin A in mammalian cell culture. The tools and protocols developed here will allow zebrafish researchers to complement genetic tools with powerful proteomics approaches.

Digital health competencies for the next generation of physicians.

As health care continues to change and evolve in a digital society, there is an escalating need for physicians who are skilled and enabled to deliver care using digital health technologies, while remaining able to successfully broker the triadic relationship among patients, computers and themselves. The focus needs to remain firmly on how technology can be leveraged and used to support good medical practice and quality health care, particularly around resolution of longstanding challenges in health care delivery, including equitable access in rural and remote areas, closing the gap on health outcomes and experiences for First Nations peoples and better support in aged care and those living with chronic disease and disability. We propose a set of requisite digital health competencies and recommend that the acquisition and evaluation of these competencies become embedded in physician training curricula and continuing professional development programmes.

Appropriate use of transthoracic echocardiography in the investigation of general medicine patients presenting with syncope or presyncope.

STUDY PURPOSE: Routine transthoracic echocardiography (TTE) in patients with syncope or presyncope is resource-intensive. We assessed if risk thresholds defined by a validated risk score may identify patients at low risk of cardiac abnormality in whom TTE is unnecessary. STUDY DESIGN: We conducted a retrospective study of all general medicine patients with syncope/presyncope presenting to a tertiary hospital between July 2016 and September 2020 and who underwent TTE. The Canadian Syncope Risk Score (CSRS) was used to categorise patients as low to very low risk (score -3 to 0) or moderate to high risk (score ≥1) for serious adverse events at 30 days. A cut-point of 0 was used to calculate the sensitivity, specificity, positive and negative predictive values (PPV and NPV) for CSRS and the odds ratio (OR) of a clinically significant finding on TTE in patients with CSRS ≥1 compared with all patients. RESULTS: Among 157 patients, the CSRS categorised 69 (44%) as very low to low risk in whom TTE was normal. In 88 patients deemed moderate to high risk, TTE detected a cardiac abnormality in 24 (27%). A CSRS ≥1 yielded a sensitivity of 100% (95% CI 85.7% to 100%), specificity of 51.1% (95% CI 42.3% to 59.8%), PPV of 26.5% (95% CI 26.3% to 30.1%) and NPV of 100% (95% CI 92.5% to 100%) for cardiac abnormalities and doubled the odds of an abnormality (OR = 2.05, 95% CI 1.08 to 3.87, p = 0.028). CONCLUSION: In general medicine patients with syncope/presyncope, using the CSRS to stratify risk of a cardiac abnormality on TTE can almost halve TTE use.

Regional differences in susceptibility to spinosyn insecticides registered for Colorado potato beetle management in Canada.

The Colorado potato beetle (CPB) is the most economically important pest of Canadian potato, and if left uncontrolled, it can completely consume the crop. In the past decade, the control of CPB has relied heavily on systemic insecticides, principally the neonicotinoids thiamethoxam and clothianidin. Resistance to neonicotinoids in CPB has been well documented in the past 2 decades and mechanisms underlying the resistance better understood. In contrast, resistance to other insecticide classes, including spinosyns (spinosad and spinetoram) and anthranillic diamides (chlorantraniliprole and cyantraniliprole), have not been studied to the same degree in CPB. Spinosyns are the only insecticide certified for organic potato growers in Canada and are frequently applied as a mid-season foliar spray by conventional growers when seed treatments with neoniconitoid or diamide experience control breaks. Improved knowledge on resistance to spinosyns in CPB would allow for the development of regional management strategies. A survey of insecticide susceptibility in CPB populations from 6 potato growing regions between 2018 and 2022 observed: 1) spatial and temporal resistance trends; 2) cross-resistance; and 3) evidence of regional differences in susceptibility to spinosyns. The proportion of populations within each province considered resistant to spinosyns was, in descending order: Québec (16%) > Ontario (14%) > Manitoba (13%) > New Brunswick (9%) > Prince Edward Island (2%) > Alberta (0%). There was a significant change in CPB mortality at the diagnostic concentration (DC = LC90) for spinosad and spinetoram in the 6 provinces but only for year 5 relative to the previous 4 years. Moderate cross-resistance was determined between spinosad and spinetoram with the DC mortality for all populations based on a positive and significant correlation (adjusted R2 = 0.3758; P = 1.263e-13). There was also a positive relationship observed between the number of spinosyn applications (years applied at the sampling location) and declining susceptibility to spinosad (R2 = 0.0927; P < 0.002). Cross-resistance was observed between spinosyns and insecticides in the other two classes, the more significant correlation was between spinosad and tetraniliprole (R2 = 0.3025; P < 0.0002). In Québec, the greater spinosad use in organic potato farms led to resistance in those CPB populations, but spinosyn resistance at conventional farms was not related to greater application of neonicotinoids and diamides. Spinosyns remain relatively effective, nevertheless growers should be concerned over the increasing cases of reduced susceptibility in conventional potato farms and resistance where organic production occurs. Resistance management should continue to encourage rotation with products from the other classes in season and between years in order to extend spinosyn use for CPB control.

Changes in comprehensiveness of services delivered by Canadian family physicians: Analysis of population-based linked data in 4 provinces.

OBJECTIVE: To describe changes in the comprehensiveness of services delivered by family physicians across service settings and service areas in 4 Canadian provinces, to identify which settings and areas have changed the most, and to compare the magnitude of changes by physician characteristics. DESIGN: Descriptive analysis of province-wide, population-based billing data linked to population and physician registries. SETTING: British Columbia, Manitoba, Ontario, and Nova Scotia. PARTICIPANTS: Family physicians registered to practise in the 1999-2000 and 2017-2018 fiscal years. MAIN OUTCOME MEASURES: Comprehensiveness was measured across 7 service settings (home care, long-term care, emergency departments, hospitals, obstetric care, surgical assistance, anesthesiology) and in 7 service areas consistent with office-based practice (prenatal and postnatal care, Papanicolaou testing, mental health, substance use, cancer care, minor surgery, palliative home visits). The proportion of physicians with activity in each setting and area are reported and the average number of service settings and areas by physician characteristics is described (years in practice, sex, urban or rural practice setting, and location of medical degree training). RESULTS: Declines in comprehensiveness were observed across all provinces studied. Declines were greater for comprehensiveness of settings than for areas consistent with office-based practice. Changes were observed across all physician characteristics. On average across provinces, declines in the number of service settings and service areas were highest among physicians in practice 20 years or longer, male physicians, and physicians practising in urban areas. CONCLUSION: Declining comprehensiveness was observed across all physician characteristics, pointing to changes in the practice and policy contexts in which all family physicians work.