Is Dementia Related to a Longer Wait Time to be Assigned a New Primary Care Provider? An Analysis of the Nova Scotia Need a Family Practice Registry Derived from the PUPPY-Study.

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.

Prescription ranitidine use and population exposure in 6 Canadian provinces, 1996 to 2019: a serial cross-sectional analysis.

BACKGROUND: Ranitidine was the most prescribed histamine-2 receptor antagonist (H2RA) in Canada when recalled in 2019 because of potential carcinogenicity. We sought to compare geographic and temporal patterns in use of prescription ranitidine and 3 other HRAs and estimated population exposure to ranitidine in 6 provinces between 1996 and 2019. METHODS: This population-based serial cross-sectional study used prescription claims for H2RAs dispensed from community pharmacies in Nova Scotia, Ontario, Manitoba, Saskatchewan, Alberta and British Columbia. We estimated the period prevalence of ranitidine use per 100 population by province, age category and sex. We estimated exposure to ranitidine between 2015 and 2019 using defined daily doses (DDDs). RESULTS: Overall, 2.4 million ranitidine prescriptions were dispensed to patients aged 65 years and older, and 1.7 million were dispensed to younger adults. Among older adults, the median period prevalence of ranitidine use among females was 16% (interquartile range [IQR] 13%-27%) higher than among males. Among younger adults, the median prevalence was 50% (IQR 37%-70%) higher among females. Among older adults, between 1996 and 1999, use was highest in Nova Scotia (33%) and Ontario (30%), lower in the prairies (Manitoba [18%], Saskatchewan [26%], Alberta [17%]) and lowest in BC (11%). By 2015-2019, use of ranitidine among older adults dropped by at least 50% in all provinces except BC. We estimate that at least 142 million DDDs of prescribed ranitidine were consumed annually in 6 provinces (2015-2019). INTERPRETATION: Over the 24-year period in 6 provinces, patients aged 65 years and older were dispensed 2.4 million prescriptions of ranitidine and younger adults were dispensed 1.7 million prescriptions of ranitidine. These estimates of ranitidine exposure can be used for planning studies of cancer risk and identifying target populations for cancer surveillance.

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.

Emergency department utilization and hospital admissions for ambulatory care sensitive conditions among people seeking a primary care provider during the COVID-19 pandemic.

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.

Safety and efficacy of rimegepant orally disintegrating tablet for the acute treatment of migraine in China and South Korea: a phase 3, double-blind, randomised, placebo-controlled trial.

BACKGROUND: No acute treatments targeting calcitonin gene-related peptide (CGRP) have been approved for use in China or South Korea. We aimed to compare the efficacy and safety of rimegepant-an orally administered small molecule CGRP antagonist-with placebo in the acute treatment of migraine among adults in these countries. METHODS: This double-blind, randomised, placebo-controlled, multicentre phase 3 trial was done at 86 outpatient clinics at hospitals and academic medical centres (73 in China and 13 in South Korea). Participants were adults (≥18 years) with at least a 1-year history of migraine who had two to eight moderate or severe attacks per month and fewer than 15 headache days per month within the 3 months before the screening visit. Participants were randomly assigned (1:1) to 75 mg rimegepant or placebo to treat a single migraine attack of moderate or severe pain intensity. Randomisation was stratified by the use of preventive medication and by country. The allocation sequence was generated and implemented by study personnel using an interactive web-response system accessed online from each study centre. All participants, investigators, and the sponsor were masked to treatment assignment. The coprimary endpoints of freedom from pain and freedom from the most bothersome symptom (nausea, phonophobia, or photophobia) 2 h after dosing were assessed in the modified intention-to-treat (mITT) population (randomly assigned participants who took study medication for a migraine attack of moderate or severe pain intensity, and provided at least one efficacy datapoint after treatment) using Cochran-Mantel Haenszel tests. Safety was assessed in all participants who received rimegepant or placebo. The study is registered with ClinicalTrials.gov, number NCT04574362, and is completed. FINDINGS: 1431 participants were randomly assigned (716 [50%] to rimegepant and 715 [50%] to placebo). 668 (93%) participants in the rimegepant group and 674 (94%) participants in the placebo group received treatment. 1340 participants were included in the mITT analysis (666 [93%] in the rimegepant group and 674 [94%] in the placebo group). 2 h after dosing, rimegepant was superior to placebo for pain freedom (132 [20%] of 666 vs 72 [11%] of 674, risk difference 9·2, 95% CI 5·4-13·0; p<0·0001) and freedom from the most bothersome symptom (336 [50%] of 666 participants vs 241 [36%] of 674 participants, 14·8, 9·6-20·0; p<0·0001). The most common (≥1%) adverse events were protein in urine (8 [1%] of 668 participants in the rimepegant group vs 7 [1%] of 674 participants in the placebo group), nausea (7 [1%] of 668 vs 18 [3%] of 674), and urinary tract infection (5 [1%] of 668 vs 8 [1%] of 674). There were no rimegepant-related serious adverse events. INTERPRETATION: Among adults living in China or South Korea, a single dose of 75 mg rimegepant was effective for the acute treatment of migraine. Safety and tolerability were similar to placebo. Our findings suggest that rimegepant might be a useful new addition to the range of medications for the acute treatment of migraine in China and South Korea, but further studies are needed to support long-term efficacy and safety and to compare rimegepant with other medications for the acute treatment of migraine in this population. FUNDING: BioShin Limited. TRANSLATIONS: For the Chinese and Korean translations of the abstract see Supplementary Materials section.

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.

Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial.

BACKGROUND: Intranasal formulations can provide treatment options for people with migraine in whom oral drugs are ineffective, slow-acting, or intolerable because of nausea and vomiting. Zavegepant, an intranasally administered small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, was previously assessed in a phase 2/3 trial. This phase 3 trial aimed to compare the efficacy, tolerability, safety, and timecourse of response for zavegepant nasal spray with placebo in the acute treatment of migraine. METHODS: This double-blind, randomised, placebo-controlled, multicentre phase 3 trial, conducted at 90 academic medical centres, headache clinics, and independent research facilities in the USA, recruited adults (aged ≥18 years) with a history of two to eight moderate or severe migraine attacks per month. Participants were randomly assigned (1:1) to zavegepant 10 mg nasal spray or matching placebo and self-treated a single migraine attack of moderate or severe pain intensity. Randomisation was stratified by the use or non-use of preventive medication. Study centre personnel entered eligible participants into the study using an interactive web response system that was operated and managed by an independent contract research organisation. All participants, investigators, and the funder were masked to group assignment. The coprimary endpoints, freedom from pain and freedom from the most bothersome symptom at 2 h after the treatment dose, were assessed in all randomly assigned participants who took the study medication, had a migraine attack of moderate or severe pain intensity at baseline, and provided at least one evaluable post-baseline efficacy datapoint. Safety was analysed in all randomly assigned participants who received at least one dose. The study is registered with ClinicalTrials.gov, number NCT04571060, and is closed to accrual. FINDINGS: Between Oct 27, 2020, and Aug 20, 2021, 1978 participants were recruited and assessed for eligibility. 1405 participants were eligible (703 were assigned to zavegepant and 702 to placebo), and 1269 were included in the efficacy analysis set (623 in the zavegepant group and 646 in the placebo group). 2 h after the treatment dose, more participants in the zavegepant group than in the placebo group had pain freedom (147 [24%] of 623 participants vs 96 [15%] of 646 participants, risk difference 8·8 percentage points, 95% CI 4·5-13·1; p<0·0001) and freedom from their most bothersome symptom (247 [40%] vs 201 [31%], risk difference 8·7 percentage points, 3·4-13·9; p=0·0012). The most common adverse events in either treatment group (≥2%) were dysgeusia (129 [21%] of 629 in the zavegepant group vs 31 [5%] of 653 in the placebo group), nasal discomfort (23 [4%] vs five [1%]), and nausea (20 [3%] vs seven [1%]). No signal of hepatotoxicity due to zavegepant was identified. INTERPRETATION: Zavegepant 10 mg nasal spray was efficacious in the acute treatment of migraine, with favourable tolerability and safety profiles. Additional trials are needed to establish the long-term safety and consistency of effect across attacks. FUNDING: Biohaven Pharmaceuticals.

Changes over time in patient visits and continuity of care among graduating cohorts of family physicians in 4 Canadian provinces.

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.

Zavegepant nasal spray for the acute treatment of migraine: A Phase 2/3 double-blind, randomized, placebo-controlled, dose-ranging trial.

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.

The Phytotoxin Myrigalone A Triggers a Phased Detoxification Programme and Inhibits Lepidium sativum Seed Germination via Multiple Mechanisms including Interference with Auxin Homeostasis.

Molecular responses of plants to natural phytotoxins comprise more general and compound-specific mechanisms. How phytotoxic chalcones and other flavonoids inhibit seedling growth was widely studied, but how they interfere with seed germination is largely unknown. The dihydrochalcone and putative allelochemical myrigalone A (MyA) inhibits seed germination and seedling growth. Transcriptome (RNAseq) and hormone analyses of Lepidium sativum seed responses to MyA were compared to other bioactive and inactive compounds. MyA treatment of imbibed seeds triggered the phased induction of a detoxification programme, altered gibberellin, cis-(+)-12-oxophytodienoic acid and jasmonate metabolism, and affected the expression of hormone transporter genes. The MyA-mediated inhibition involved interference with the antioxidant system, oxidative signalling, aquaporins and water uptake, but not uncoupling of oxidative phosphorylation or p-hydroxyphenylpyruvate dioxygenase expression/activity. MyA specifically affected the expression of auxin-related signalling genes, and various transporter genes, including for auxin transport (PIN7, ABCG37, ABCG4, WAT1). Responses to auxin-specific inhibitors further supported the conclusion that MyA interferes with auxin homeostasis during seed germination. Comparative analysis of MyA and other phytotoxins revealed differences in the specific regulatory mechanisms and auxin transporter genes targeted to interfere with auxin homestasis. We conclude that MyA exerts its phytotoxic activity by multiple auxin-dependent and independent molecular mechanisms.

CUP study: protocol for a comparative analysis of centralised waitlist effectiveness, policies and innovations for connecting unattached patients to primary care providers.

INTRODUCTION: Access to a primary care provider is a key component of high-functioning healthcare systems. In Canada, 15% of patients do not have a regular primary care provider and are classified as 'unattached'. In an effort to link unattached patients with a provider, seven Canadian provinces implemented centralised waitlists (CWLs). The effectiveness of CWLs in attaching patients to regular primary care providers is unknown. Factors influencing CWLs effectiveness, particularly across jurisdictional contexts, have yet to be confirmed. METHODS AND ANALYSIS: A mixed methods case study will be conducted across three Canadian provinces: Ontario, Québec and Nova Scotia. Quantitatively, CWL data will be linked to administrative and provider billing data to assess the rates of patient attachment over time and delay of attachment, stratified by demographics and compared with select indicators of health service utilisation. Qualitative interviews will be conducted with policymakers, patients, and primary care providers to elicit narratives regarding the administration, use, and access of CWLs. An analysis of policy documents will be used to identify contextual factors affecting CWL effectiveness. Stakeholder dialogues will be facilitated to uncover causal pathways and identify strategies for improving patient attachment to primary care. ETHICS AND DISSEMINATION: Approval to conduct this study has been granted in Ontario (Queens University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board, file number 6028052; Western University Health Sciences Research Ethics Board, project 116591; University of Toronto Health Sciences Research Ethics Board, protocol number 40335), Québec (Centre intégré universitaire de santé et de services sociaux de l'Estrie, project number 2020-3446) and Nova Scotia (Nova Scotia Health Research Ethics Board, file number 1024979).

An Fgf-Shh positive feedback loop drives growth in developing unpaired fins.

The origin and diversification of appendage types is a central question in vertebrate evolution. Understanding the genetic mechanisms that underlie fin and limb development can reveal relationships between different appendages. Here we demonstrate, using chemical genetics, a mutually agonistic interaction between Fgf and Shh genes in the developing dorsal fin of the channel catfish, Ictalurus punctatus. We also find that Fgf8 and Shh orthologs are expressed in the apical ectodermal ridge and zone of polarizing activity, respectively, in the median fins of representatives from other major vertebrate lineages. These findings demonstrate the importance of this feedback loop in median fins and offer developmental evidence for a median fin-first scenario for vertebrate paired appendage origins.

P-Glycoprotein and Breast Cancer Resistance Protein Transporter Inhibition by Cyclosporine and Quinidine on the Pharmacokinetics of Oral Rimegepant in Healthy Subjects.

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.

Application of microbial analyses to feeds and potential implications for poultry nutrition.

Poultry nutrition and feed manufacturing are interrelated for a variety of reasons. Diet formulation is essential for optimizing bird growth and feed conversion, but compositional differences and the presence of certain feed additives can alter the gastrointestinal microbial composition and functionality. Not only does dietary composition and digestibility influence poultry performance, but specific physical characteristics such as feed particle size and thermal treatments can impact the avian gastrointestinal tract (GIT) microbiota. Poultry feeds also have a characteristic microbial ecology consisting of pathogenic and nonpathogenic microorganisms. Some feed-borne pathogens such as Salmonella are well studied and linked with the colonization of birds consuming the feed. However, much less is known about the nonpathogenic feed microbiome and what impact that might have on the bird's GIT. This review discusses the potential interaction between poultry feed and the GIT microbiome, microbial ecology of feed, application of microbiome analyses to feed, and approaches for communicating these complex data sets to the poultry industry.

Human Milk and Plasma Pharmacokinetics of Single-Dose Rimegepant 75 mg in Healthy Lactating Women.

Objective: Investigate whether rimegepant-an oral small molecule calcitonin gene-related peptide receptor antagonist for the treatment of migraine-is excreted in human milk after a single 75 mg dose and characterize its concentration-time profile in the plasma and milk of healthy lactating women to determine the relative infant dose (RID). Methods: This open-label, single-center study enrolled healthy lactating women aged 18-40 years with a gestation of 37-42 weeks and uncomplicated delivery of a single healthy child ≥2 weeks (14 days) and ≤6 months before study drug administration. Plasma samples were collected 0, 1, 2, 4, and 8 hours postdose; human milk samples were collected at 0, 1, 2, 4, 8, 12, 16, 24, 32, and 36 hours. The milk:plasma drug concentration ratio was estimated as the ratio of the human milk:plasma areas under the curve. The RID (%) was calculated as 100 times the quotient of the body weight-normalized infant and maternal doses. Results: Subjects (N = 12) were enrolled between 25 January and 15 September 2020. The mean (standard deviation [SD]) age was 29.8 (3.6) years; mean (SD) body mass index was 26.8 (4.9) kg/m2. The mean (SD) RID of rimegepant was 0.51% (0.14). The mean (SD) body-weight normalized infant dose was 0.005 (0.001) mg/kg/day, the mean (SD) body-weight normalized maternal dose was 1.04 (0.18) mg/kg/day, and mean (SD) maternal body weight was 74.0 (13.3) kg. Conclusion: On a weight-adjusted basis, the mean RID of rimegepant was <1% of the maternal dose.

Problems in Coordinating and Accessing Primary Care for Attached and Unattached Patients Exacerbated During the COVID-19 Pandemic Year (the PUPPY Study): Protocol for a Longitudinal Mixed Methods Study.

BACKGROUND: The COVID-19 pandemic has significantly disrupted primary care in Canada, with many walk-in clinics and family practices initially closing or being perceived as inaccessible; pharmacies remaining open with restrictions on patient interactions; rapid uptake of virtual care; and reduced referrals for lab tests, diagnostics, and specialist care. OBJECTIVE: The PUPPY Study (Problems in Coordinating and Accessing Primary Care for Attached and Unattached Patients Exacerbated During the COVID-19 Pandemic Year) seeks to understand the impact of the COVID-19 pandemic across the quadruple aims of primary care, with particular focus on the effects on patients without attachment to a regular provider and those with chronic health conditions. METHODS: The PUPPY study builds on an existing research program exploring patients' access and attachment to a primary care practice, pivoted to adapt to the emerging COVID-19 context. We intend to undertake a longitudinal mixed methods study to understand critical gaps in primary care access and coordination, as well as compare prepandemic and postpandemic data across 3 Canadian provinces (Quebec, Ontario, and Nova Scotia). Multiple data sources will be used such as a policy review; qualitative interviews with primary care policymakers, providers (ie, family physicians, nurse practitioners, and pharmacists), and patients (N=120); and medication prescriptions and health care billing data. RESULTS: This study has received funding by the Canadian Institutes of Health Research COVID-19 Rapid Funding Opportunity Grant. Ethical approval to conduct this study was granted in Ontario (Queens Health Sciences & Affiliated Teaching Hospitals Research Ethics Board, file 6028052; Western University Health Sciences Research Ethics Board, project 116591; University of Toronto Health Sciences Research Ethics Board, protocol 40335) in November 2020, Québec (Centre intégré universitaire de santé et de services sociaux de l'Estrie, project 2020-3446) in December 2020, and Nova Scotia (Nova Scotia Health Research Ethics Board, file 1024979) in August 2020. CONCLUSIONS: To our knowledge, this is the first study of its kind to explore the effects of the COVID-19 pandemic on primary care systems, with particular focus on the issues of patient's attachment and access to primary care. Through a multistakeholder, cross-jurisdictional approach, the findings of the PUPPY study will inform the strengthening of primary care during and beyond the COVID-19 pandemic, as well as have implications for future policy and practice. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/29984.

Determinants of Discharge Disposition From Acute Care for Survivors of Hypoxic-Ischemic Brain Injury: Results From a Large Population-Based Cohort Data Set.

OBJECTIVE: To identify determinants of discharge disposition from acute care among survivors of hypoxic-ischemic brain injury (HIBI), stratified by sex. DESIGN: Population-based retrospective cohort study using provincial data in Ontario, Canada. The determinants were grouped into predisposing, need, and enabling factors using the Anderson Behavioral Model. SETTING: Acute care. PARTICIPANTS: Survivors of HIBI aged ≥20 years at the time of hospitalization and discharged alive from acute care between April 1, 2002, and March 31, 2017. There were 7492 patients with HIBI, of whom 28% (N=2077) survived their acute care episode. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Discharge disposition from acute care, categorized as complex continuing care (CCC), long-term care (LTC), inpatient rehabilitation (IR), home with support, home without support, and transferred to another acute care. RESULTS: The discharge dispositions for the 2077 survivors were IR 23.4% (n=487), CCC 19.5% (n=404), LTC 6.2% (n=128), home without support 31.2% (n=647), home with support 15.1% (n=314), and other 4.6%. Multinomial multivariable logistic regression analysis using home without support as the reference category revealed that female patients were significantly more likely than male patients to be discharged to LTC/CCC. Those who were older, were frail, and had longer stay in acute care or special care unit (SCU) were more likely to be discharged to LTC/CCC. The only significant determinant for IR was longer stay in acute care. Survivors with cardiac-related injury were less likely to be discharged to LTC/CCC. Income was a significant factor for male patients but not for female patients in the sex-stratified analysis. The following variables were investigated but were not significant determinants in this study: need factors (comorbidity score, prior psychiatric disorders, health care utilization) and enabling factors (income quintile, rural area of residence). CONCLUSIONS: Predisposing (age, sex) and need factors (frailty, acute care days, SCU days, type of injury) were significant determinants of discharge disposition from acute care after HIBI. In spite of a system with universal coverage, sex differences were found, with more female patients being discharged to CCC/LTC rather than IR, controlling for age and other confounders. These findings should be considered in appropriate discharge planning from acute care for survivors of HIBI.

Differences in developmental potential predict the contrasting patterns of dental diversification in characiform and cypriniform fishes.

Morphological diversification during adaptive radiation may depend on factors external or internal to the lineage. We provide evidence for the latter in characiform fishes (tetras and piranhas), which exhibit extensive dental diversity. Phylogenetic character mapping supported regain of lost teeth as contributing to this diversity. To test for latent potential for dentition that would facilitate its evolutionary expansion, we overexpressed a tooth initiation signal, the tumour necrosis factor pathway ligand ectodysplasin, in a model characiform, the Mexican tetra (Astyanax mexicanus). This manipulation resulted in extensive ectopic dentition, in contrast with its previously reported limited effect in the zebrafish (Danio rerio). Tooth location in the order Cypriniformes, to which the zebrafish belongs, is much more restricted than in characiforms, a pattern that may be explained by differences in the retention of ancestral developmental potential. Our results suggest that differences in evolvability between lineages may lead to contrasting patterns of diversification.

Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Rimegepant is a calcitonin gene-related peptide receptor antagonist that has shown efficacy and safety in the acute treatment of migraine. We aimed to compare the efficacy of rimegepant with placebo for preventive treatment of migraine. METHODS: We did a multicentre, phase 2/3, randomised, double-blind, placebo-controlled trial at 92 sites in the USA. Adults with at least a 1-year history of migraine were recruited. After a 4-week observation period, eligible participants were randomised using an interactive web response system to oral rimegepant 75 mg or matching placebo every other day for 12 weeks (double-blind treatment phase). The primary efficacy endpoint was change from the 4-week observation period in the mean number of migraine days per month in the last 4 weeks of the double-blind treatment phase (weeks 9-12). Participants who received at least one dose of their assigned study medication and who had 14 days or more of data in the observation period and 14 days or more of data for at least one 4-week interval during the double-blind treatment phase were analysed for efficacy. Those who received at least one dose of study medication were analysed for safety. This study is registered with ClinicalTrials.gov, NCT03732638. FINDINGS: Between Nov 14, 2018, and Aug 30, 2019, 1591 participants were recruited and assessed for eligibility, of whom 747 were randomly allocated either rimegepant (n=373) or placebo (n=374). 695 participants were included in the analysis for efficacy, of whom 348 were assigned rimegepant and 347 were allocated placebo. Rimegepant was superior to placebo on the primary endpoint of change in the mean number of migraine days per month during weeks 9-12. The change from the observation period in mean number of migraine days per month during weeks 9-12 was -4·3 days (95% CI -4·8 to -3·9) with rimegepant and -3·5 days (-4·0 to -3·0) with placebo (least squares mean difference -0·8 days, 95% CI -1·46 to -0·20; p=0·0099). 741 participants received study medication and were included in the safety analysis. 133 (36%) of 370 patients who received rimegepant reported an adverse event, compared with 133 (36%) of 371 who received placebo. Seven (2%) participants who received rimegepant and four (1%) who received placebo discontinued the study due to an adverse event; no patients died. INTERPRETATION: Taken every other day, rimegepant was effective for preventive treatment of migraine. Tolerability was similar to that of placebo, and no unexpected or serious safety issues were noted. FUNDING: Biohaven Pharmaceuticals.

Coleorhiza-enforced seed dormancy: a novel mechanism to control germination in grasses.

How the biophysical properties of overlaying tissues control growth, such as the embryonic root (radicle) during seed germination, is a fundamental question. In eudicot seeds the endosperm surrounding the radicle confers coat dormancy and controls germination responses through modulation of its cell wall mechanical properties. Far less is known for grass caryopses that differ in tissue morphology. Here we report that the coleorhiza, a sheath-like organ that surrounds the radicle in grass embryos, performs the same role in the grass weed Avena fatua (common wild oat). We combined innovative biomechanical techniques, tissue ablation, microscopy, tissue-specific gene and enzyme activity expression with the analysis of hormones and oligosaccharides. The combined experimental work demonstrates that in grass caryopses the coleorhiza indeed controls germination for which we provide direct biomechanical evidence. We show that the coleorhiza becomes reinforced during dormancy maintenance and weakened during germination. Xyloglucan endotransglycosylases/hydrolases may have a role in coleorhiza reinforcement through cell wall remodelling to confer coat dormancy. The control of germination by coleorhiza-enforced dormancy in grasses is an example of the convergent evolution of mechanical restraint by overlaying tissues.