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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. Key words: comprehensive health care; scope of practice; primary care; family medicine; cohort effect; Canada https://doi.org/10.1370/afm.2945, INTRODUCTION Declining comprehensiveness of family physician practice has been documented across multiple jurisdictions, (1-8) with accompanying speculation that this is driven by lack of interest or inadequate training among more [...]

Niraparib was recently funded in Canada for the maintenance treatment of ovarian cancer following platinum-based chemotherapy. However, the drug's safety profile in the real world remains uncertain. We conducted a cohort study to describe the patient population using niraparib and the proportion that experienced adverse events between June 2019 and December 2022 in four Canadian provinces (Ontario, Alberta, British Columbia [BC], and Quebec). We used administrative data and electronic medical records from Ontario Health, Alberta Health Services, and BC Cancer, and registry data from Exactis Innovation. We summarized baseline characteristics using descriptive statistics and reported safety outcomes using cumulative incidence. We identified 514 patients receiving niraparib. Mean age was 67 years and most were initiated on a daily dose of 100 or 200 mg/day. Grade 3/4 anemia, neutropenia, and thrombocytopenia occurred in 11–16% of the cohort. In Ontario, the three-month cumulative incidence of grade 3/4 thrombocytopenia was 11.6% (95% CI, 8.3–15.4%), neutropenia was 7.1% (95% CI, 4.6–10.4%), and anemia was 11.3% (95% CI, 8.0–15.2%). Cumulative incidences in the remaining provinces were similar. Initial daily dose and proportions of hematological adverse events were low in the real world and may be related to cautious prescribing and close monitoring by clinicians. [ABSTRACT FROM AUTHOR]

Background Access to Primary Care Providers (PCPs) is limited for many Canadians. "Unattached patients" are persons who do not have a PCP. Older adults living with dementia may face greater challenges seeking attachment. This study investigated whether older adults living with dementia experience differential wait times for PCPs compared to those without a diagnosis of dementia. Methods This was an observational descriptive study of the centralized wait-list data from the Nova Scotia (NS) Need a Family Practice Registry (NaFPR). Time on provider wait-list by dementia diagnosis and age were compared. Number of days on the registry across these measures was estimated. Multivariable proportional hazards regression was used to compare hazards of remaining on the registry over time. Results Unattached older adults living with dementia were on the NaFPR for less time compared to those without dementia (381.4 vs. 428.8 days, respectively). After adjusting for age, self-reported gender, comorbidity, rurality, income quintiles, and overall deprivation, older adults with dementia had a 1.13-fold (95% CI: 1.04-1.24) increase in the likelihood of leaving the NaFPR. Potential contributors to this small difference could be placement in Long Term Care (LTC) and subsequent facility PCP attachment. Conclusions Analysis of the NaFPR exhibited similarly time to PCP attachment despite a diagnosis of dementia. This represented an effective equality model of health care utilized in NS. Future studies should investigate whether an equity model with priority attachment for vulnerable patients would reduce hospitalization and LTC institutionalization. [ABSTRACT FROM AUTHOR]

NaTi2(PO4)3 (NTP) and Na0.44MnO2 (NMO), and their derivatives, have emerged as the most promising materials for aqueous Na‐ion batteries. For both, NTP and NMO, avoiding the evolution of hydrogen and oxygen is found to be mandatory in order to mitigate material dissolution. Intriguingly, however, no direct determination of the hydrogen and oxygen evolution reactions (HER and OER) has yet been carried out. Using differential electrochemical mass spectrometry (DEMS) we directly identify the onset potentials for the HER and OER. Surprisingly, the potential window is found to be significantly smaller than suggested by commonly employed cyclic voltammetry measurements. CO2 evolution, upon decomposition of carbon black, is observed at an onset potential of 1.61 VRHE, which is 0.25 V more cathodic than the OER for the NMO electrode. Our results show that the state‐of‐the‐art carbon additive plays a crucial role in the stability of the positive NMO electrode in the ion battery. [ABSTRACT FROM AUTHOR]

NaTi2(PO4)3 (NTP) is known as a promising insertion‐type anode material for aqueous and non‐aqueous sodium‐ion batteries (SIBs), due to its NASICON‐type open 3D framework which makes a zero‐strain insertion mechanism possible. NTP is considered to be an environmentally friendly, low‐cost and high safety material. However, the electrochemical performance of NTP is limited due to its poor electrical conductivity. In this work a solvothermal synthesis method is used to synthesize NTP with a nanocube (NC) morphology. In a one‐step synthesis rutile titanium dioxide (TiO2) and carbon coating of NTP are achieved (NTP/C‐RT), simultaneously, which significantly improves the poor electrical conductivity of NTP. Additional rutile coating is used to further improve the electrochemical performance compared to simple carbon coating. Rate capabilities of 301 mAh/g are achieved for NTP/C‐RT compared to 248 mAh/g for NTP/C at 0.1 C. That is, to the best of our knowledge, the highest gravimetric capacity reported for SIBs using NTP as anode material up to now. The results prove that NTP, which is itself already a promising anode material for SIBs, can be further enhanced with a combined approach of NC morphology, carbon and rutile coating, leading to superior capacities, higher than anywhere else reported in literature. [ABSTRACT FROM AUTHOR]

Plume downwash at a large oil-gathering facility in the Prudhoe Bay, Alaska oil-field reservation was simulated in a series of numerical experiments. The model is a three-dimensional, Cartesian coordinate, finite difference code that solves the nonhydrostatic, time-averaged equations for the conservation of momentum and energy. The code uses a modified form of the standard first-order, two-equation (k-ε) engineering turbulence closure model. We have used the numerical model to simulate directly the mean features of the flow field and dispersion from a buoyant source at an industrial site. The flow features varied depending on the size, number, and orientation of the buildings. The results generally reproduce the plume downwash and dispersion observed in wind tunnel and field investigations. -from Authors

Background: Primary care attachment improves health care access and health outcomes, but many Canadians are unattached, seeking a provider via provincial wait-lists. This Nova Scotia–wide cohort study compares emergency department utilization and hospital admission associated with insufficient primary care management among patients on and off a provincial primary care wait-list, before and during the first waves of the COVID-19 pandemic. Methods: We linked wait-list and Nova Scotian administrative health data to describe people on and off wait-list, by quarter, between Jan. 1, 2017, and Dec. 24, 2020. We quantified emergency department utilization and ambulatory care sensitive condition (ACSC) hospital admission rates by wait-list status from physician claims and hospital admission data. We compared relative differences during the COVID-19 first and second waves with the previous year. Results: During the study period, 100 867 people in Nova Scotia (10.1% of the provincial population) were on the wait-list. Those on the wait-list had higher emergency department utilization and ACSC hospital admission. Emergency department utilization was higher overall for individuals aged 65 years and older, and females; lowest during the first 2 COVID-19 waves; and differed more by wait-list status for those younger than 65 years. Emergency department contacts and ACSC hospital admissions decreased during the COVID-19 pandemic relative to the previous year, and for emergency department utilization, this difference was more pronounced for those on the wait-list. Interpretation: People in Nova Scotia seeking primary care attachment via the provincial wait-list use hospital-based services more frequently than those not on the wait-list. Although both groups have had lower utilization during COVID-19, existing challenges to primary care access for those actively seeking a provider were further exacerbated during the initial waves of the pandemic. The degree to which forgone services produces downstream health burden remains in question. [ABSTRACT FROM AUTHOR]

Electrical power system operators (SOs) are free to realize grid operations according to their own strategies. However, because resulting power flows also depend on the actions of neighboring SOs, appropriate coordination is needed to improve the resulting system states from an overall perspective and from an individual SO perspective. In this paper, a new method is presented that preserves the data integrity of the SOs and their independent operation of their grids. This method is compared with a non-coordinated local control and another sequential method that has been identified as the most promising distributed optimization method in previous research. The time series simulations use transformer tap positioning as well as generation unit voltage setpoints and reactive power injections as flexibilities. The methods are tested on a multi-voltage, multi-SO, realistic benchmark grid with different objective combinations of the SOs. In conclusion, the results of the new method are much closer to the theoretical optimum represented by central optimization than those of the other two methods. Furthermore, the introduced method integrates a sophisticated procedure to provide fairness between SOs that is missing in other methods. [ABSTRACT FROM AUTHOR]

Background: Lack of patient access to family physicians in Canada is a concern. The role of recent physician graduates in this problem of supply of primary care services has not been established. We sought to establish whether career stage or graduation cohort were related to family physician practice volume and continuity of care over time. Methods: We conducted a retrospective cohort study of family physician practice from 1997/98 to 2017/18. We collected administrative health and physician claims data in British Columbia, Manitoba, Ontario and Nova Scotia. We included all physicians who registered with their respective provincial regulatory colleges as having a medical specialty of family practice or who had billed the provincial health insurance system for patient care as family physicians, or both. We used regression models to isolate the effects of 3-year categories of years in practice (at all career stages), time period and cohort on patient contacts and physician-level continuity of care. Results: Between 1997/98 and 2017/18, the median number of patient contacts per provider per year fell by between 515 and 1736 contacts in the 4 provinces examined. Median contacts peaked at 27–29 years in practice in all provinces, and median physician-level continuity of care increased until 30 or more years in practice. We found no association between graduation cohort and patient contacts or physician-level continuity of care. Interpretation: Recent cohorts of family physicians practise similarly to their predecessors in terms of practice volumes and continuity of care. Because family physicians of all career stages showed declining patient contacts, we suggest that system-wide solutions to recent challenges in the accessibility of primary care in Canada are needed. [ABSTRACT FROM AUTHOR]

Objective: Evaluate the efficacy, safety, and tolerability of zavegepant nasal spray in the acute treatment of migraine. Background: Calcitonin gene‐related peptide‐targeting agents are a novel class of therapeutics for migraine, but none are currently available as a nonoral option for acute treatment. Zavegepant, a high‐affinity, selective, and structurally unique calcitonin gene‐related peptide‐receptor antagonist in late‐stage development, is formulated as a nasal spray for the acute treatment of migraine. Methods: This randomized, dose‐ranging, placebo‐controlled, Phase 2/3 trial in adults aged ≥18 years with migraine (NCT03872453) was conducted at US study sites. Participants were randomized by an interactive web response system and treated a single attack of moderate to severe pain intensity with zavegepant nasal spray 5, 10, 20 mg, or placebo. Coprimary efficacy endpoints were pain freedom and freedom from the most bothersome symptom at 2 h postdose. Results: Of the 1673 participants aged 18 to 79 years who were randomized, 1588 were treated with study medication, and 1581 (mean age 40.8 years, 85.5% female) were analyzed for efficacy: zavegepant 5 mg (n = 387), 10 mg (n = 391), 20 mg (n = 402), and placebo (n = 401). Zavegepant 10 and 20 mg were more effective than placebo on the coprimary endpoints of pain freedom at 2 h postdose (placebo: 15.5% [98.3% confidence interval (CI), 11.1, 19.8]; 10 mg: 22.5% [98.3% CI, 17.5, 27.6; p = 0.0113]; 20 mg: 23.1% [98.3% CI, 18.1, 28.2; p = 0.0055]) and freedom from the most bothersome symptom at 2 h postdose (placebo: 33.7% [98.3% CI, 28.0, 39.3]; 10 mg: 41.9% [98.3% CI, 36.0, 47.9; p = 0.0155]; 20 mg: 42.5% [98.3% CI, 36.6, 48.4; p = 0.0094]). Findings for the 5 mg dose were not significant. The most common treatment‐emergent adverse events with zavegepant 10 and 20 mg and placebo were dysgeusia (13.5% to 16.1% vs. 3.5%), nausea (2.7% to 4.1% vs. 0.5%), and nasal discomfort (1.3% to 5.2% vs. 0.2%). Most adverse events were mild or moderate and resolved without treatment. There was no signal of hepatotoxicity. Conclusion: Zavegepant nasal spray, in single doses of 10 or 20 mg, was effective for the acute treatment of migraine, with a favorable safety profile. Additional research is needed to confirm its potential as a nonoral medication for the acute treatment of migraine. [ABSTRACT FROM AUTHOR]

Rimegepant (Nurtec ODT)—an orally administered, small‐molecule calcitonin gene–related peptide receptor antagonist indicated for the acute and preventive treatment of migraine—is a substrate for both the P‐glycoprotein and breast cancer resistance protein transporters in vitro. We evaluated the effects of concomitant administration of strong inhibitors of these transporters on the pharmacokinetics of rimegepant in healthy subjects. This single‐center, open‐label, randomized study was conducted in 2 parts, both of which were 2‐period, 2‐sequence, crossover studies. Part 1 (n = 15) evaluated the effect of a single oral dose of 200‐mg cyclosporine, a strong inhibitor of the P‐glycoprotein and breast cancer resistance protein transporters, on the pharmacokinetics of rimegepant 75 mg. Part 2 (n = 12) evaluated the effect of a single oral dose of 600‐mg quinidine, a strong selective P‐glycoprotein transporter, on the pharmacokinetics of rimegepant 75 mg. Coadministration with cyclosporine showed an increase in rimegepant area under the plasma concentration–time curve from time 0 to infinity and maximum observed concentration based on geometric mean ratios (90% confidence intervals [CIs]) of 1.6 (1.49‐1.72) and 1.41 (1.27‐1.57), respectively, versus rimegepant alone. Coadministration with quinidine showed an increase in rimegepant area under the plasma concentration–time curve from time 0 to infinity and maximum observed concentration geometric mean ratios (90% CIs) of 1.55 (1.40‐1.72) and 1.67 (1.46‐1.91), respectively, versus rimegepant alone. Strong P‐glycoprotein inhibitors (cyclosporine, quinidine) increased rimegepant exposures (>50%, <2‐fold). In parts 1 and 2, rimegepant coadministration was well tolerated and safe. The similar effect of cyclosporine and quinidine coadministration on rimegepant exposure suggests that inhibition of breast cancer resistance protein inhibition may have less influence on rimegepant exposure. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2006.03.028 Byline: Macie B. Walker (a), Craig T. Miller (a), Jared Coffin Talbot (a), David W. Stock (b), Charles B. Kimmel (a) Keywords: Sturgeon; Furin; Endothelin1; Dlx; Barx1; Sox9a; Runx2b Abstract: Endothelin1 (Edn1) signaling promotes ventral character to the facial skeleton. In zebrafish edn1 mutants, the ventral jaw structures are severely reduced and fused to their dorsal counterparts, with a loss of joints that normally form at an intermediate dorsal-ventral position. Loss of function at another locus, sturgeon, also yields joint losses, but only mild reductions in the ventral jaw structures. We show that sturgeon encodes one of two orthologs of Furin present in zebrafish, and that both furin genes may function partially redundantly to activate Edn1 signaling. Supporting this hypothesis, early expression of edn1-dependent genes is downregulated in sturgeon (furinA) mutants. Later in development, expression of most of these genes recovers to near wild-type levels in furinA mutants but not in edn1 mutants. The recovery explains the less severe furinA mutant skeletal phenotype and suggests that late gene expression is dependent on a critical level of Edn1 signaling not present in the more severe edn1 mutants. However, expression defects in the intermediate joint-forming domains in both mutants persist, explaining the joint losses observed later in both mutants. We further show that in both mutants the arches fail to correctly undergo ventral elongation before skeletogenesis begins and propose a model in which this failure is largely responsible for the loss of an Edn1-dependent compartmentation of the arch into the intermediate and ventral domains. Author Affiliation: (a) Institute of Neuroscience, 1254 University of Oregon, Eugene, OR 97403, USA (b) Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, CO 80309-0334, USA Article History: Received 14 October 2005; Revised 13 March 2006; Accepted 20 March 2006 Article Note: (footnote) [star] The zebrafish gene zgc:110654 has been renamed barx1 on April 19, 2006.

Extensive gene duplication is thought to have occurred in the vertebrate lineage after it diverged from cephalochordates and before the divergence of lobe- and ray-finned fishes, but the exact timing remains obscure. This timing was investigated by analysis of the Dlx gene family of a representative cartilaginous fish, the leopard shark, Triakis semifasciata. Dlx genes encode homeodomain transcription factors and are arranged in mammals as three convergently transcribed bigene clusters. Six Dlx genes were cloned from Triakis and shown to be orthologous to single mammalian Dlx genes. At least four of these are arranged in bigene clusters. Phylogenetic analyses of Dlx genes were used to propose an evolutionary scenario in which two genome duplications led to four Dlx bigene clusters in a common ancestor of jawed vertebrates, one of which was lost prior to the diversification of the group. Dlx genes are known to be involved in jaw development, and changes in Dlx gene number are mapped to the same branch of the vertebrate tree as the origin of jaws.

Author(s): Yoshiyuki Yamamoto [1, 3]; David W. Stock [2]; William R. Jeffery (corresponding author) [1] Hedgehog (Hh) proteins are responsible for critical signalling events during development [1] but their evolutionary [...]

We have investigated fibroblast growth factor (FGF) signaling during the development of the zebrafish pharyngeal dentition with the goal of uncovering novel roles for FGFs in tooth development as well as phylogenetic and topographic diversity in the tooth developmental pathway. We found that the tooth-related expression of several zebrafish genes is similar to that of their mouse orthologs, including both epithelial and mesenchymal markers. Additionally, significant differences in gene expression between zebrafish and mouse teeth are indicated by the apparent lack of fgf8 and pax9 expression in zebrafish tooth germs. FGF receptor inhibition with SU5402 at 32 h blocked dental epithelial morphogenesis and tooth mineralization. While the pharyngeal epithelium remained intact as judged by normal pitx2 expression, not only was the mesenchymal expression of lhx6 and lhx7 eliminated as expected from mouse studies, but the epithelial expression of dlx2a, dlx2b, fgf3, and fgf4 was as well. This latter result provides novel evidence that the dental epithelium is a target of FGF signaling. However, the failure of SU5402 to block localized expression of pitx2 suggests that the earliest steps of tooth initiation are FGF-independent. Investigations of specific FGF ligands with morpholino antisense oligonucleotides revealed only a mild tooth shape phenotype following fgf4 knockdown, while fgf8 inhibition revealed only a subtle down-regulation of dental dlx2b expression with no apparent effect on tooth morphology. Our results suggest redundant FGF signals target the dental epithelium and together are required for dental morphogenesis. Further work will be required to elucidate the nature of these signals, particularly with respect to their origins and whether they act through the mesenchyme. Keywords: Tooth; FGF; Zebrafish; Dlx; Lhx; Pitx; Morphogenesis; Epithelial-mesenchymal interactions