Characteristics of primary care practices by proportion of patients unvaccinated against SARS-CoV-2: a cross-sectional cohort study.

BACKGROUND: Variations in primary care practices may explain some differences in health outcomes during the COVID-19 pandemic. We sought to evaluate the characteristics of primary care practices by the proportion of patients unvaccinated against SARS-CoV-2. METHODS: We conducted a population-based, cross-sectional cohort study using linked administrative data sets in Ontario, Canada. We calculated the percentage of patients unvaccinated against SARS-CoV-2 enrolled with each comprehensive-care family physician, ranked physicians according to the proportion of patients unvaccinated, and identified physicians in the top 10% (v. the other 90%). We compared characteristics of family physicians and their patients in these 2 groups using standardized differences. RESULTS: We analyzed 9060 family physicians with 10 837 909 enrolled patients. Family physicians with the largest proportion (top 10%) of unvaccinated patients (n = 906) were more likely to be male, to have trained outside of Canada, to be older, and to work in an enhanced fee-for-service model than those in the remaining 90%. Vaccine coverage (≥ 2 doses of SARS-CoV-2 vaccine) was 74% among patients of physicians with the largest proportion of unvaccinated patients, compared with 87% in the remaining patient population. Patients in the top 10% group tended to be younger and live in areas with higher levels of ethnic diversity and immigration and lower incomes. INTERPRETATION: Primary care practices with the largest proportion of patients unvaccinated against SARS-CoV-2 served marginalized communities and were less likely to use team-based care models. These findings can guide resource planning and help tailor interventions to integrate public health priorities within primary care practices.

Public experiences and perspectives of primary care in Canada: results from a cross-sectional survey.

BACKGROUND: Through medicare, residents in Canada are entitled to medically necessary physician services without paying out of pocket, but still many people struggle to access primary care. We conducted a survey to explore people's experience with and priorities for primary care. METHODS: We conducted an online, bilingual survey of adults in Canada in fall 2022. We distributed an anonymous link through diverse channels and a closed link to 122 053 people via a national public opinion firm. We weighted completed responses to mirror Canada's population and adjusted for sociodemographic characteristics using regression models. RESULTS: We analyzed 9279 completed surveys (5.9% response rate via closed link). More than one-fifth of respondents (21.8%) reported having no primary care clinician, and among those who did, 34.5% reported getting a same or next-day appointment for urgent issues. Of respondents, 89.4% expressed comfort seeing another team member if their doctor recommended it, but only 35.9%, 9.5%, and 12.4% reported that their practice had a nurse, social worker, or pharmacist, respectively. The primary care attribute that mattered most was having a clinician who "knows me as a person and considers all the factors that affect my health." After we adjusted for respondent characteristics, people in Quebec, the Atlantic region, and British Columbia had lower odds of reporting a primary care clinician than people in Ontario (adjusted odds ratio 0.30, 0.33, and 0.39, respectively; p < 0.001). We also observed large provincial variations in timely access, interprofessional care, and walk-in clinic use. INTERPRETATION: More than 1 in 5 respondents did not have access to primary care, with large variation by province. Reforms should strive to expand access to relationship-based, longitudinal care in a team setting.

Care-seeking experiences of unattached patients in the Canadian health care system: Qualitative study.

OBJECTIVE: To understand how lack of attachment to a regular primary care provider influences patients' outlooks on primary care, ability to address their health care needs, and confidence in the health care system. DESIGN: Qualitative descriptive study using semistructured interviews. SETTING: Canadian provinces of Nova Scotia, Ontario, and Quebec. PARTICIPANTS: Patients aged 18 years or older who were unattached or had become attached within 1 year of being interviewed and who resided in the province in which they were interviewed. METHODS: Forty-one semistructured interviews were conducted, during which participants were asked to describe how they had become unattached, their searches to find new primary care providers, their perceptions of and experiences with the centralized waiting list in their province, their experiences seeking care while unattached, and the impact of being unattached on their health and on their perceptions of the health care system. Interviews were transcribed and analyzed using a thematic approach. MAIN FINDINGS: Two main themes were identified in interviews with unattached or recently attached patients: unmet needs of unattached patients and the impact of being unattached. Patients' perceived benefits of attachment included access to care, longitudinal relationships with health care providers, health history familiarity, and follow-up monitoring and care coordination. Being unattached was associated with negative effects on mental health, poor health outcomes, decreased confidence in the health care system, and greater pre-existing health inequities. CONCLUSION: Having a regular primary care provider is essential to having access to high-quality care and other health care services. Attachment also promotes health equity and confidence in the public health care system and has broader system-level, social, and policy implications.

Practice Facilitation to Support Family Physicians in Encouraging COVID-19 Vaccine Uptake: A Multimethod Process Evaluation.

PURPOSE: We offered a practice facilitation intervention to family physicians in Ontario, Canada, known to have large numbers of patients not yet vaccinated against coronavirus disease 2019 (COVID-19). METHODS: We conducted a multimethod process evaluation embedded within a randomized controlled trial (clinical trial #NCT05099497). We collected descriptive statistics regarding engagement and qualitative interview data from family physicians and practice facilitators, as well as data from facilitator field notes. We analyzed and triangulated the data using thematic analysis and mapped barriers to and enablers for implementation to structural, organizational, physician, and patient factors. RESULTS: Of the 300 approached, 90 family physicians (30%) accepted facilitation. Of these, 57% received technical support to identify unvaccinated patients, 29% used trained medical student volunteers to contact patients on their behalf, and 30% used automated calling to reach patients. Key factors affecting engagement with the intervention were staff shortages owing to COVID-19 (structural), clinic characteristics such as technical issues and gatekeeping by staff, which prevented facilitators from talking with physicians (organizational), burnout (physician), and specialized populations that required targeted resources (patient). The facilitator's ability to address technical issues and connect family physicians with medical students helped with engagement. CONCLUSIONS: Strategies to help underresourced family physicians serving high-needs populations for issues of public health importance, such as vaccine promotion, must acknowledge the scarcity of physicians' time and provide new resources. To successfully engage family physicians, practice facilitators should seek to build trust and relationships over time, including with front-office staff.

Family Physicians Stopping Practice During the COVID-19 Pandemic in Ontario, Canada.

We conducted 2 analyses using administrative data to understand whether more family physicians in Ontario, Canada stopped working during the COVID-19 pandemic compared with previous years. First, we found 3.1% of physicians working in 2019 (n = 385/12,247) reported no billings in the first 6 months of the pandemic; compared with other family physicians, a higher portion were aged 75 years or older (13.0% vs 3.4%, P <0.001), had fee-for-service reimbursement (37.7% vs 24.9%, P <0.001), and had a panel size under 500 patients (40.0% vs 25.8%, P <0.001). Second, a fitted regression line found the absolute increase in the percentage of family physicians stopping work was 0.03% per year from 2010 to 2019 (P = 0.042) but 1.2% between 2019 to 2020 (P <0.001). More research is needed to understand the impact of physicians stopping work on primary care attachment and access to care.

COVID-19 - an opportunity to improve access to primary care through organizational innovations? A qualitative multiple case study in Quebec and Nova Scotia (Canada).

BACKGROUND: COVID-19 catalyzed a rapid and substantial reorganization of primary care, accelerating the spread of existing strategies and fostering a proliferation of innovations. Access to primary care is an essential component of a healthcare system, particularly during a pandemic. We describe organizational innovations aiming to improve access to primary care and related contextual changes during the first 18 months of the COVID-19 pandemic in two Canadian provinces, Quebec and Nova Scotia. METHODS: We conducted a multiple case study based on 63 semi-structured interviews (n = 33 in Quebec, n = 30 in Nova Scotia) conducted between October 2020 and May 2021 and 71 documents from both jurisdictions. We recruited a diverse range of provincial and regional stakeholders (e.g., policy-makers, decision-makers, family physicians, nurses) involved in reorganizing primary care during the COVID-19 pandemic using purposeful sampling (e.g., based on role, region). Interviews were transcribed verbatim and thematic analysis was conducted in NVivo12. Emerging results were discussed by team members to identify salient themes and organized into logic models. RESULTS: We identified and analyzed six organizational innovations. Four of these - centralized public online booking systems, centralized access centers for unattached patients, interim primary care clinics for unattached patients, and a community connector to health and social services for older adults - pre-dated COVID-19 but were accelerated by the pandemic context. The remaining two innovations were created to specifically address pandemic-related needs: COVID-19 hotlines and COVID-dedicated primary healthcare clinics. Innovation spread and proliferation was influenced by several factors, such as a strengthened sense of community amongst providers, decreased patient demand at the beginning of the first wave, renewed policy and provider interest in population-wide access (versus attachment of patients only), suspended performance targets (e.g., continuity ≥80%) in Quebec, modality of care delivery, modified fee codes, and greater regional flexibility to implement tailored innovations. CONCLUSION: COVID-19 accelerated the uptake and creation of organizational innovations to potentially improve access to primary healthcare, removing, at least temporarily, certain longstanding barriers. Many stakeholders believed this reorganization would have positive impacts on access to primary care after the pandemic. Further studies should analyze the effectiveness and sustainability of innovations adapted, developed, and implemented during the COVID-19 pandemic.

Shifts in office and virtual primary care during the early COVID-19 pandemic in Ontario, Canada.

BACKGROUND: Globally, primary care changed dramatically as a result of the coronavirus disease 2019 (COVID-19) pandemic. We aimed to understand the degree to which office and virtual primary care changed, and for which patients and physicians, during the initial months of the pandemic in Ontario, Canada. METHODS: This population-based study compared comprehensive, linked primary care physician billing data from Jan. 1 to July 28, 2020, with the same period in 2019. We identified Ontario residents with at least 1 office or virtual (telephone or video) visit during the study period. We compared trends in total physician visits, office visits and virtual visits before COVID-19 with trends after pandemic-related public health measures changed the delivery of care, according to various patient and physician characteristics. We used interrupted time series analysis to compare trends in the early and later halves of the COVID-19 period. RESULTS: Compared with 2019, total primary care visits between March and July 2020 decreased by 28.0%, from 7.66 to 5.51 per 1000 people/day. The smallest declines were among patients with the highest expected health care use (8.3%), those who could not be attributed to a primary care physician (10.2%), and older adults (19.1%). In contrast, total visits in rural areas increased by 6.4%. Office visits declined by 79.1% and virtual care increased 56-fold, comprising 71.1% of primary care physician visits. The lowest uptake of virtual care was among children (57.6%), rural residents (60.6%) and physicians with panels of ≥ 2500 patients (66.0%). INTERPRETATION: Primary care in Ontario saw large shifts from office to virtual care over the first 4 months of the COVID-19 pandemic. Total visits declined least among those with higher health care needs. The determinants and consequences of these major shifts in care require further study.

Monitoring, treatment and control of blood glucose and lipids in Ontario First Nations people with diabetes.

BACKGROUND: Indigenous people worldwide are disproportionately affected by diabetes and its complications. We aimed to assess the monitoring, treatment and control of blood glucose and lipids in First Nations people in Ontario. METHODS: We conducted a longitudinal population-based study using administrative data for all people in Ontario with diabetes, stratified by First Nations status. We assessed age- and sex-specific rates of completion of recommended monitoring for low-density lipoprotein (LDL) and glycated hemoglobin (A1c) from 2001/02 to 2014/15. We used data from 2014/15 to conduct a cross-sectional analysis of rates of achievement of A1c and LDL targets and use of glucose-lowering medications. RESULTS: The study included 22 240 First Nations people and 1 319 503 other people in Ontario with diabetes. Rates of monitoring according to guidelines were 20%-50% for A1c and 30%-70% for lipids and were lowest for younger First Nations men. The mean age- and sex-adjusted A1c level was higher among First Nations people than other people (7.59 [95% confidence interval (CI) 7.57 to 7.61] v. 7.03 [95% CI 7.02 to 7.03]). An A1c level of 8.5% or higher was observed in 24.7% (95% CI 23.6 to 25.0) of First Nations people, compared to 12.8% (95% CI 12.1 to 13.5) of other people in Ontario. An LDL level of 2.0 mmol/L or less was observed in 60.3% (95% CI 59.7 to 61.6) of First Nations people, compared to 52.0% (95% CI 51.1 to 52.9) of other people in Ontario. Among those aged 65 or older, a higher proportion of First Nations people than other Ontarians were using insulin (28.1% v. 15.1%), and fewer were taking no medications (28.3% v. 40.1%). INTERPRETATION: As of 2014/15, monitoring and achievement of glycemic control in both First Nations people and other people in Ontario with diabetes remained suboptimal. Interventions to support First Nations patients to reach their treatment goals and reduce the risk of complications need further development and study.

Diabetes prevalence, incidence and mortality in First Nations and other people in Ontario, 1995-2014: a population-based study using linked administrative data.

BACKGROUND: Diabetes mellitus is an established health concern in First Nations communities and is associated with complex influences of colonization. This study, a partnership between First Nations and academic researchers, was undertaken to determine patterns of diabetes prevalence, incidence and mortality in Ontario. METHODS: Using health services and population data from Ontario for 1995 to 2014, linked with the federal Indian Register, we calculated age- and sex-adjusted annual estimates of diabetes prevalence, incidence and mortality for First Nations people (living within and outside First Nations communities) and other people in Ontario. We also examined age- and sex-specific crude diabetes prevalence. RESULTS: Between 1995 and 2014, the prevalence of diabetes increased and the incidence decreased somewhat in all populations. Both prevalence and incidence were substantially higher among First Nations people than among other people in Ontario. In particular, First Nations women had higher prevalence than other women (4.2% v. 1.6% for ages 20-34 yr and 17.6% v. 6.0% for ages 35-49 yr). The lifetime risk of diabetes was higher among First Nations people than among other people in Ontario (57.0%, 95% confidence interval [CI] 56.3%-57.6% v. 44.5%, 95% CI 44.4%-44.6%). Over time, all-cause mortality for those with diabetes declined but remained consistently higher for First Nations people than for other people in Ontario. INTERPRETATION: Diabetes is more common among First Nations people than among other people in Ontario, particularly at younger ages and in women. First Nations-led approaches to address the high prevalence of diabetes in younger First Nations women have the potential to improve metabolic health across generations.

Trends in cardiovascular care and event rates among First Nations and other people with diabetes in Ontario, Canada, 1996-2015.

BACKGROUND: Rates of cardiovascular disease among people with diabetes have declined over the last 20-30 years. To determine whether First Nations people have experienced similar declines, we compared time trends in rates of cardiac event and disease management among First Nations people with diabetes and other people with diabetes in Ontario, Canada. METHODS: We conducted a retrospective cohort study of patients aged 20 to 105 years with diabetes between 1996 and 2015, using linked health administrative databases. Outcomes compared were the annual incidence of each admission to hospital for myocardial infarction and heart failure, and death owing to ischemic heart disease. Management indicators were coronary revascularization and prescription rates for cardioprotective medications. Overall rates and annual percent changes were compared using Poisson regression. RESULTS: Incidence rates for all cardiac outcomes decreased over the study period. The greatest relative annual decline among First Nations men and women were observed in ischemic heart disease death (4.4%, 95% confidence interval [CI] 3.0 to 5.9) and heart failure (5.4%, 95% CI 4.5 to 6.4), respectively. Among other men and women, the greatest annual declines were seen in ischemic heart disease death (6.3%, 95% CI 6.1 to 6.5 and 7.3%, 95% CI 7.1 to 7.6, respectively). However, all absolute cardiac event rates were higher among First Nations people (p < 0.001). Coronary artery revascularization procedures and prescriptions for cardioprotective medications increased among First Nations people, while only prescriptions increased among other people. INTERPRETATION: Over the last 20 years, the incidence of cardiac events has declined among First Nations people with diabetes, but remains higher than other people with diabetes in Ontario. For continued reductions in incidence, future efforts need to recognize First Nations people's unique social and cultural determinants of health.

The impact of the adoption of a patient rostering model on primary care access and continuity of care in urban family practices in Ontario, Canada.

BACKGROUND: Greater continuity and access to primary care results in improved patient health, satisfaction, and reduced healthcare costs. Although patient rostering is considered to be a cornerstone of a high performing primary care system and is believed to improve continuity and access, few studies have examined these relationships. This study examined the impact of the adoption of a patient rostering enhanced fee-for-service model (eFFS) on continuity, coordination of specialized care, and access. METHOD: A population-based longitudinal study was conducted using health administrative data from urban family practices in Ontario, Canada. Family physicians that transitioned from traditional FFS (tFFS) to eFFS between 2004 and 2013 were followed overtime. Physicians providing comprehensive primary care that had at least 4 years of pre-transition and 2 years of post-transition data were eligible. Patients were attributed to physicians on an annual basis by determining the provider that billed the largest dollar amount over a 2 year period. Outcomes of interest were the usual provider of care index (UPC), a referral index (RI) (% of total primary care referrals for a physician's roster made by the main provider), and emergency department (ED) visits for family practice sensitive conditions (FPSCs). Mixed-effects segmented linear and logistic regressions were used to examine changes in outcomes while controlling for patient and provider contextual factors. RESULTS: Prior to transitioning, UPC was decreasing at a rate of 0.27%/year (95% CI: -0.34 to - 0.21, p < 0.0001). Following the transition, UPC began decreasing by an additional 0.59%/year (95% CI: -0.69 to - 0.49, p < 0.0001) relative to the pre-transition rate. RI decreased by an additional 0.34%/year (95% CI: -0.43 to - 0.24, p < 0.0001) relative to the pre-transition period, where it had been stable. The transition had minimal impact on FPSC ED visits. CONCLUSION: Continuity and coordination of specialized care slightly decreased upon transition from tFFS to eFFS. This is likely due to physicians working in groups and sharing patients following the transition to the eFFS model. Adoption of an enrolment model with after-hours care did not decrease non-urgent ED use, which may reflect the small impact that primary care access has on these types of ED visits.

Imaging use for low back pain by Ontario primary care clinicians: protocol for a mixed methods study - the Back ON study.

BACKGROUND: At any one time, one in every five Canadians has low back pain (LBP), and LBP is one of the most common health problems in primary care. Guidelines recommend that imaging not be routinely performed in patients presenting with LBP without signs or symptoms indicating a potential pathological cause. Yet imaging rates remain high for many patients who present without such indications. Inappropriate imaging can lead to inappropriate treatments, results in worse health outcomes and causes harm from unnecessary radiation. There is a need to understand the extent of, and factors contributing to, inappropriate imaging for LBP, and to develop effective strategies that target modifiable barriers and facilitators. The primary study objectives are to determine: 1) The rate of, and factors associated with, inappropriate lumbar spine imaging (x-ray, CT scan and MRI) for people with non-specific LBP presenting to primary care clinicians in Ontario; 2) The barriers and facilitators to reduce inappropriate imaging for LBP in primary care settings. METHODS: The project will comprise an inception cohort study and a concurrent qualitative study. For the cohort study, we will recruit 175 primary care clinicians (50 each from physiotherapy and chiropractic; 75 from family medicine), and 3750 patients with a new episode of LBP who present to these clinicians. Clinicians will collect data in the clinic, and each participant will be tracked for 12 months using Ontario health administrative and self-reported data to measure diagnostic imaging use and other health outcomes. We will assess characteristics of the clinicians, patients and encounters to identify variables associated with inappropriate imaging. In the qualitative study we will conduct in-depth interviews with primary care clinicians and patients. DISCUSSION: This will be the first Canadian study to accurately document the extent of the overuse of imaging for LBP, and the first worldwide to include data from the main healthcare professions offering primary care for people with LBP. This study will provide robust information about rates of inappropriate imaging for LBP, along with factors associated with, and an understanding of, potential reasons for inappropriate imaging.

Educating for Equity Care Framework: Addressing social barriers of Indigenous patients with type 2 diabetes.

OBJECTIVE: To present a clinical framework for addressing critical social elements for Indigenous patients with type 2 diabetes. SOURCES OF INFORMATION: The Educating for Equity (E4E) Care Framework was developed through a rigorous analysis of qualitative research that included the perspectives of Indigenous patients (n = 32), physicians (n = 28), and Indigenous health curriculum developers (n = 5) across Canada. A national advisory group of Indigenous health experts, educators, leaders, physicians, and community members provided feedback on integrating analysis from primary research into recommendations for physicians. Systematic literature reviews were conducted and a nominal group technique process helped forge research team consensus around the framework's themes and recommendations. MAIN MESSAGE: For Indigenous patients with type 2 diabetes, social factors arising from the legacy of colonization are often barriers to improved diabetes outcomes, while culture is often not recognized as a facilitator in diabetes management. Structural competency in balance with cultural safety should be central to the clinical process when negotiating diabetes management with Indigenous patients. The E4E Care Framework presented in this article provides recommendations to navigate this terrain. CONCLUSION: A focus on social and cultural elements is fundamental to effective diabetes care among Indigenous patients. The E4E Care Framework is a resource that can help clinicians improve Indigenous patients' capacity for change in a way that acknowledges the social factors that affect the increasing diabetes rates, while using a cultural lens to facilitate improved outcomes.

National Survey of Indigenous primary healthcare capacity and delivery models in Canada: the TransFORmation of IndiGEnous PrimAry HEAlthcare delivery (FORGE AHEAD) community profile survey.

BACKGROUND: There is a significant deficiency of national health information for Indigenous peoples in Canada. This manuscript describes the Community Profile Survey (CPS), a community-based, national-level survey designed to identify and describe existing healthcare delivery, funding models, and diabetes specific infrastructure and programs in Indigenous communities. METHODS: The CPS was developed collaboratively through FORGE AHEAD and the First Nations and Inuit Health Branch of Health Canada. Regional and federal engagement and partnerships were built with Indigenous organizations to establish regionally-tailored distribution of the 8-page CPS to 440 First Nations communities. Results were collected (one survey per community) and reported in strata by region, with descriptive analyses performed on all variables. Results were shared with participating communities and regional/federal partners through tailored reports. RESULTS: A total of 84 communities completed the survey (19% response rate). The majority of communities had a health centre/office to provide service to their patients with diabetes, with limited on-reserve hospitals for ambulatory or case-sensitive conditions. Few healthcare specialists were located on-site, with patients frequently travelling off-site (> 40 km) for diabetes-related complications. The majority of healthcare professionals on-site were Health Directors, Community Health Nurses, and Home Care Nurses. Many communities had a diabetes registry but few reported a diabetes surveillance system. Regional variation in healthcare services, diabetes programs, and funding models were noted, with most communities engaging in some type of innovative strategy to improve care for patients with diabetes. CONCLUSIONS: The CPS is the first community-based, national-level survey of its kind in Canada. Although the response rate was low, the CPS was distributed and successfully administered across a broad range of First Nations communities, and future considerations would benefit from a governance structure and leadership that strengthens community engagement, and a longitudinal research approach to increase the representativeness of the data. This type of information is important for communities and regions to inform decision making (maintain successes, and identify areas for improvement), strengthen health service delivery and infrastructure, increase accessibility to healthcare personnel, and allocate funding and/or resources to build capacity and foster a proactive chronic disease prevention and management approach for Indigenous communities across Canada. TRIAL REGISTRATION: Current ClinicalTrial.gov protocol ID NCT02234973 . Registered: September 9, 2014.

Cancer screening inequities in a time of primary care reform: a population-based longitudinal study in Ontario, Canada.

BACKGROUND: Primary care has been reformed in recent years in Ontario, Canada, with a move away from traditional fee-for-service to enhanced fee-for-service and capitation-based models. It is unclear how new models have affected disparities in cancer screening. We evaluated whether Ontario's enhanced fee-for-service model was associated with a change in the gaps in cancer screening for people living with low income and people who are foreign-born. METHODS: We conducted a population-based longitudinal analysis from 2002 to 2013 of Ontario family physicians who transitioned from traditional fee-for-service to enhanced fee-for-service. The binary outcomes of interest were adherence to cervical, breast and colorectal cancer screening recommendations. Outcomes were analyzed using mixed-effects logistic regression. Analyses produced annual odds ratios comparing the odds of being up-to-date for screening among patients in enhanced fee-for-service versus patients in traditional fee-for-service for each social stratum separately. We calculated the ratios of stratum-specific odds ratios to assess whether the transition from traditional to enhanced fee-for-service was associated with a change in screening gaps between immigrants and long-term residents, and between people in the lowest and highest neighbourhood income quintiles. RESULTS: Throughout the study period, cancer screening was consistently lower among immigrants and among people in the lowest income quintile. Transition to enhanced fee-for-service was generally associated with increased screening uptake for all, however for most years, ratios of ratios were significantly less than 1 for all three cancer screening types, indicating that there was a widening of the screening gap between immigrants and long-term residents and between people living in the lowest vs. highest income quintile associated with transitions. CONCLUSION: The transition to enhanced fee-for-service in Ontario was generally associated with a widening of screening inequities for foreign-born and low-income patients.

The Role of Proton Transport in Gating Current in a Voltage Gated Ion Channel, as Shown by Quantum Calculations.

Over two-thirds of a century ago, Hodgkin and Huxley proposed the existence of voltage gated ion channels (VGICs) to carry Na⁺ and K⁺ ions across the cell membrane to create the nerve impulse, in response to depolarization of the membrane. The channels have multiple physiological roles, and play a central role in a wide variety of diseases when they malfunction. The first channel structure was found by MacKinnon and coworkers in 1998. Subsequently, the structure of a number of VGICs was determined in the open (ion conducting) state. This type of channel consists of four voltage sensing domains (VSDs), each formed from four transmembrane (TM) segments, plus a pore domain through which ions move. Understanding the gating mechanism (how the channel opens and closes) requires structures. One TM segment (S4) has an arginine in every third position, with one such segment per domain. It is usually assumed that these arginines are all ionized, and in the resting state are held toward the intracellular side of the membrane by voltage across the membrane. They are assumed to move outward (extracellular direction) when released by depolarization of this voltage, producing a capacitive gating current and opening the channel. We suggest alternate interpretations of the evidence that led to these models. Measured gating current is the total charge displacement of all atoms in the VSD; we propose that the prime, but not sole, contributor is proton motion, not displacement of the charges on the arginines of S4. It is known that the VSD can conduct protons. Quantum calculations on the Kv1.2 potassium channel VSD show how; the key is the amphoteric nature of the arginine side chain, which allows it to transfer a proton. This appears to be the first time the arginine side chain has had its amphoteric character considered. We have calculated one such proton transfer in detail: this proton starts from a tyrosine that can ionize, transferring to the NE of the third arginine on S4; that arginine's NH then transfers a proton to a glutamate. The backbone remains static. A mutation predicted to affect the proton transfer has been qualitatively confirmed experimentally, from the change in the gating current-voltage curve. The total charge displacement in going from a normal closed potential of -70 mV across the membrane to 0 mV (open), is calculated to be approximately consistent with measured values, although the error limits on the calculation require caution in interpretation.

Health care experiences of Indigenous people living with type 2 diabetes in Canada.

BACKGROUND: Indigenous social determinants of health, including the ongoing impacts of colonization, contribute to increased rates of chronic disease and a health equity gap for Indigenous people. We sought to examine the health care experiences of Indigenous people with type 2 diabetes to understand how such determinants are embodied and enacted during clinical encounters. METHODS: Sequential focus groups and interviews were conducted in 5 Indigenous communities. Focus groups occurred over 5 sessions at 4 sites; 3 participants were interviewed at a 5th site. Participants self-identified as Indigenous, were more than 18 years of age, lived with type 2 diabetes, had received care from the same physician for the previous 12 months and spoke English. We used a phenomenological thematic analysis framework to categorize diabetes experiences. RESULTS: Patient experiences clustered into 4 themes: the colonial legacy of health care; the perpetuation of inequalities; structural barriers to care; and the role of the health care relationship in mitigating harm. There was consistency across the diverse sites concerning the root causes of mistrust of health care systems. INTERPRETATION: Patients' interactions and engagement with diabetes care were influenced by personal and collective historical experiences with health care providers and contemporary exposures to culturally unsafe health care. These experiences led to nondisclosure during health care interactions. Our findings show that health care relationships are central to addressing the ongoing colonial dynamics in Indigenous health care and have a role in mitigating past harms.

Caution is required in interpretation of mutations in the voltage sensing domain of voltage gated channels as evidence for gating mechanisms.

The gating mechanism of voltage sensitive ion channels is generally considered to be the motion of the S4 transmembrane segment of the voltage sensing domains (VSD). The primary supporting evidence came from R → C mutations on the S4 transmembrane segment of the VSD, followed by reaction with a methanethiosulfonate (MTS) reagent. The cys side chain is -SH (reactive form -S-); the arginine side chain is much larger, leaving space big enough to accommodate the MTS sulfonate head group. The cavity created by the mutation has space for up to seven more water molecules than were present in wild type, which could be displaced irreversibly by the MTS reagent. Our quantum calculations show there is major reorientation of three aromatic residues that face into the cavity in response to proton displacement within the VSD. Two phenylalanines reorient sufficiently to shield/unshield the cysteine from the intracellular and extracellular ends, depending on the proton positions, and a tyrosine forms a hydrogen bond to the cysteine sulfur with its side chain -OH. These could produce the results of the experiments that have been interpreted as evidence for physical motion of the S4 segment, without physical motion of the S4 backbone. The computations strongly suggest that the interpretation of cysteine substitution reaction experiments be re-examined in the light of these considerations.

The open gate of the K(V)1.2 channel: quantum calculations show the key role of hydration.

The open gate of the Kv1.2 voltage-gated potassium channel can just hold a hydrated K(+) ion. Quantum calculations starting from the x-ray coordinates of the channel confirm this, showing little change from the x-ray coordinates for the protein. Water molecules not in the x-ray coordinates, and the ion itself, are placed by the calculation. The water molecules, including their orientation and hydrogen bonding, with and without an ion, are critical for the path of the ion, from the solution to the gate. A sequence of steps is postulated in which the potential experienced by the ion in the pore is influenced by the position of the ion. The gate structure, with and without the ion, has been optimized. The charges on the atoms and bond lengths have been calculated using natural bond orbital calculations, giving K(+) ~0.77 charges, rather than 1.0. The PVPV hinge sequence has been mutated in silico to PVVV (P407V in the 2A79 numbering). The water structure around the ion becomes discontinuous, separated into two sections, above and below the ion. PVPV conservation closely relates to maintaining the water structure. Finally, these results have implications concerning gating.