Oxidative stress and signaling through EGFR and PKA pathways converge on the nuclear transport factor RanBP1.

Nuclear protein trafficking requires the soluble transport factor RanBP1. The subcellular distribution of RanBP1 is dynamic, as the protein shuttles between the nucleus and cytoplasm. To date, the signaling pathways regulating RanBP1 subcellular localization are poorly understood. During interphase, RanBP1 resides mostly in the cytoplasm. We show here that oxidative stress concentrates RanBP1 in the nucleus, and our study defines the underlying mechanisms. Specifically, RanBP1's cysteine residues are not essential for its oxidant-induced relocation. Furthermore, our pharmacological approaches uncover that signaling mediated by epidermal growth factor receptor (EGFR) and protein kinase A (PKA) control RanBP1 localization during stress. In particular, pharmacological inhibitors of EGFR or PKA diminish the oxidant-dependent relocation of RanBP1. Mutant analysis identified serine 60 and tyrosine 103 as regulators of RanBP1 nuclear accumulation during oxidant exposure. Taken together, our results define RanBP1 as a target of oxidative stress and a downstream effector of EGFR and PKA signaling routes. This positions RanBP1 at the intersection of important cellular signaling circuits.

Cardiovascular Considerations in the Management of People With Suspected Long COVID.

Approximately 15% of adult Canadians with SARS-CoV-2 infection develop lingering symptoms beyond 12 weeks after acute infection, known as post-COVID condition or long COVID. Some of the commonly reported long COVID cardiovascular symptoms include fatigue, shortness of breath, chest pain, and palpitations. Suspected long-term cardiovascular complications of SARS-CoV-2 infection might present as a constellation of symptoms that can be challenging for clinicians to diagnose and treat. When assessing patients with these symptoms, clinicians need to keep in mind myalgic encephalomyelitis/chronic fatigue syndrome, postexertional malaise and postexertional symptom exacerbation, dysautonomia with cardiac manifestations such as inappropriate sinus tachycardia, and postural orthostatic tachycardia syndrome, and occasionally mast cell activation syndrome. In this review we summarize the globally evolving evidence around management of cardiac sequelae of long COVID. In addition, we include a Canadian perspective, consisting of a panel of expert opinions from people with lived experience and experienced clinicians across Canada who have been involved in management of long COVID. The objective of this review is to offer some practical guidance to cardiologists and generalist clinicians regarding diagnostic and treatment approaches for adult patients with suspected long COVID who continue to experience unexplained cardiac symptoms.

COVID-19 pandemic partnership between medical students and isolated elders improves student understanding of older adults' lived experience.

BACKGROUND: Evidence supports loneliness and social isolation as a strong risk factor for poor mental and physical health outcomes for older adults. The COVID-19 pandemic necessitated older adults isolate themselves for a prolonged duration. The Faculty of Medicine at the University of Toronto established the Student-Senior Isolation Prevention Partnership (SSIPP), a volunteer program involving telephone calls between medical students and older adults. METHODS: A mixed methods pre-post study design included collecting quantitative data from older adults using the UCLA Loneliness Scale and the Warwick-Edinburgh Mental Well-being Scale. The study included 29 medical students and 47 older adults. The medical students filled out a questionnaire on self-perceived knowledge of social isolation, perception of seniors, attitudes towards seniors, and likelihood to engage in specialties focusing on older adults. Interviews were conducted with both the older adults and the medical students to understand each groups' experiences and perspectives with taking part in the SSIPP program. RESULTS: Participation in the program resulted in significant changes for medical students in areas such as increasing their likelihood to engage in care for older adults (p < .001), improving their knowledge of social isolation for seniors (p < .001), and the value of addressing social isolation in older adults (p < .001). The interviews conducted with the medical students support these findings and provide insight into contributing factors. Loneliness and mental well-being scales did not show significant changes for older adults however, our interviews revealed they considered the program to be valuable. CONCLUSIONS: Our results showed that after the communication outreach program, medical students' perceptions were positively influenced towards older adults and they were more likely to pursue a career concentrated on older adults. The qualitative analysis revealed older adults valued the program. Timing and consistency of calls were factors identified by this group as having practical importance.

Effects of COVID-19 pandemic on anxiety and depression in primary care: A cohort study in Ontario, Canada.

Context: Many people have experienced poorer mental health and increased distress during the COVID-19 pandemic. It is unclear to what extent this has resulted in increases in the number of patients presenting with anxiety and/or depression in primary care. Objective: To determine if there are more patients are visiting their family doctor for anxiety/depression during the COVID-19 pandemic compared to before the pandemic, and to determine whether these effects varied based on patient demographic characteristics. Study Design: A retrospective cohort study of family medicine patients from 2017-2020. Data Source: Electronic medical records (EMRs) from the University of Toronto Practice Based-Research Network (UTOPIAN) Data Safe Haven. The majority of physicians in the UTOPIAN EMR database practice in the Greater Toronto Area, a high-COVID region of Canada. Population Studied: Active family practice patients aged 10 and older with at least 1 year of EMR data. Outcome Measures: Visits for anxiety and/or depression; prescriptions for antidepressant medications. Results: Changes in visits for anxiety and depression during the COVID-19 pandemic were consistent with an increased demand for mental healthcare and an increase in the number of individuals with anxiety and depression. Increases in visits for anxiety and depression were larger for younger patients, women, and later in the pandemic. Among younger patients, prescriptions for antidepressants were substantially reduced during the first few months of the pandemic (April-May 2020) but incidences rates increased later in 2020. Increases in visit volume during the pandemic were consist with more frequent visits for anxiety/depression and more new patients presenting with anxiety or depression. Conclusion: The COVID-19 pandemic has resulted in an increased demand for mental health services from family physicians. Increases in anxiety and depression were especially pronounced among younger female patients and increased throughout the pandemic. Our findings highlight the need for continued efforts to support and addresses mental health concerns in primary care.

Bibliometric Analysis of Literature on Physical Activity and COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic induced a sudden surge in COVID-19 related publications. This bibliometric analysis aimed to analyze literature on physical activity and COVID-19 published in the PubMed database. The search terms ((physical activity [MeSH Terms] OR physical inactivity [MeSH Terms]) AND COVID-19 [MeSH Terms]) were applied to obtain publications from the inception of PubMed to February 2022. The analyses included the year of publication, type of publication, and origin of publication by country, region, and country income. The research areas were analyzed for research articles and systematic reviews. Of 1268 articles, 143 articles were excluded, and 1125 articles were analyzed. A total of 709 articles (63.02%) were published in 2021. A majority of publications were research articles (n = 678, 60.27%). The USA (n = 176, 15.64%), countries in the European Region (n = 496, 44.09%), and high-income countries (n = 861, 76.53%) were dominant publishing countries. Of 699 research articles and systematic reviews, surveillance and trends of physical activity were the main research area, followed by health outcomes, and correlates and determinants of physical activity. There is a wide gap in publication productivity in the field of physical activity and health during the pandemic among different countries' economic statuses.

Effects of COVID-19 pandemic on anxiety and depression in primary care: A retrospective cohort study.

BACKGROUND: Population-based surveys indicate that many people experienced increased psychological distress during the COVID-19 pandemic. We aimed to determine if there was a corresponding increase in patients receiving services for anxiety and depression from their family physicians. METHODS: Electronic medical records from the University of Toronto Practice Based-Research Network (UTOPIAN; N = 322,920 patients) were used to calculate incidence rates for anxiety/depression related visits and antidepressant prescriptions before the COVID-19 pandemic (January 2018-February 2020) and during the COVID-19 pandemic (March-December 2020). Data from the pre-pandemic period were used to predict expected rates during the pandemic period which was compared to the observed rate. RESULTS: The number of patients presenting with anxiety/depression symptoms in primary care varied across age groups, sex, and time since pandemic onset. Among the youngest patients (ages 10-18 years), there were fewer patients than pre-pandemic visiting for new episodes of anxiety/depression and being prescribed antidepressants in April 2020, but by the end of 2020 this trend had reversed such that incidence rates for anxiety/depression related visits were higher than pre-pandemic levels. Among older adults, incidence rates of anxiety/depression related visits increased in April 2020 with the onset of the pandemic, and remained higher than expected throughout 2020. LIMITATIONS: A convenience sample of 362 family physicians in Ontario was used. CONCLUSION: Demand for mental health services from family physicians varied by patient age and sex and changed with the onset of the COVID-19 pandemic. By the end of 2020, more patients were seeking treatment for anxiety/depression related concerns.

Changes in the top 25 reasons for primary care visits during the COVID-19 pandemic in a high-COVID region of Canada.

PURPOSE: We aimed to determine the degree to which reasons for primary care visits changed during the COVID-19 pandemic. METHODS: We used data from the University of Toronto Practice Based Research Network (UTOPIAN) to compare the most common reasons for primary care visits before and after the onset of the COVID-19 pandemic, focusing on the number of visits and the number of patients seen for each of the 25 most common diagnostic codes. The proportion of visits involving virtual care was assessed as a secondary outcome. RESULTS: UTOPIAN family physicians (N = 379) conducted 702,093 visits, involving 264,942 patients between March 14 and December 31, 2019 (pre-pandemic period), and 667,612 visits, involving 218,335 patients between March 14 and December 31, 2020 (pandemic period). Anxiety was the most common reason for visit, accounting for 9.2% of the total visit volume during the pandemic compared to 6.5% the year before. Diabetes and hypertension remained among the top 5 reasons for visit during the pandemic, but there were 23.7% and 26.2% fewer visits and 19.5% and 28.8% fewer individual patients accessing care for diabetes and hypertension, respectively. Preventive care visits were substantially reduced, with 89.0% fewer periodic health exams and 16.2% fewer well-baby visits. During the pandemic, virtual care became the dominant care format (77.5% virtual visits). Visits for anxiety and depression were the most common reasons for a virtual visit (90.6% virtual visits). CONCLUSION: The decrease in primary care visit volumes during the COVID-19 pandemic varied based on the reason for the visit, with increases in visits for anxiety and decreases for preventive care and visits for chronic diseases. Implications of increased demands for mental health services and gaps in preventive care and chronic disease management may require focused efforts in primary care.

Changes in family medicine visits across sociodemographic groups after the onset of the COVID-19 pandemic in Ontario: a retrospective cohort study.

BACKGROUND: It has been suggested that the COVID-19 pandemic has worsened socioeconomic disparities in access to primary care. Given these concerns, we investigated whether the pandemic affected visits to family physicians differently across sociodemographic groups. METHODS: We conducted a retrospective cohort study using electronic medical records from family physician practices within the University of Toronto Practice-Based Research Network. We evaluated primary care visits for a fixed cohort of patients who were active within the database as of Jan. 1, 2019, to estimate the number of patients who visited their family physician (visitor rate) and the number of distinct visits (visit volume) between Jan. 1, 2019, to June 30, 2020. We compared trends in visitor rate and visit volume during the pandemic (Mar. 14 to June 30, 2020) with the same period in the previous year (Mar. 14 to June 30, 2019) across sociodemographic factors, including age, sex, neighbourhood income, material deprivation and ethnic concentration. RESULTS: We included 365 family physicians and 372 272 patients. Compared with the previous year, visitor rates during the pandemic period dropped by 34.5%, from 357 visitors per 1000 people to 292 visitors per 1000 people. Declines in visit volume during the pandemic were less pronounced (21.8% fewer visits), as the mean number of visits per patient increased during the pandemic (from 1.64 to 1.96). The declines in visitor rate and visit volume varied based on patient age and sex, but not socioeconomic status. INTERPRETATION: Although the number of visits to family physicians dropped substantially during the first few weeks of the COVID-19 pandemic in Ontario, patients from communities with low socioeconomic status did not appear to be disproportionately affected. In this primary care setting, the pandemic appears not to have worsened socioeconomic disparities in access to care.

Over-use of thyroid testing in Canadian and UK primary care in frequent attenders: A cross-sectional study.

BACKGROUND: Thyroid-stimulating hormone (TSH) is a common test used to detect and monitor clinically significant hypo- and hyperthyroidism. Population-based screening of asymptomatic adults for thyroid disorders is not recommended. OBJECTIVE: The research objectives were to determine patterns of TSH testing in Canadian and English primary care practices, as well as patient and physician practice characteristics associated with testing TSH for primary care patients with no identifiable indication. METHODS: In this 2-year cross-sectional observational study, Canadian and English electronic medical record databases were used to identify patients and physician practices. Cohorts of patients aged 18 years or older, without identifiable indications for TSH testing, were generated from these databases. Analyses were performed using a random-effects logistic regression to determine patient and physician practice characteristics associated with increased testing. We determined the proportion of TSH tests performed concurrently with at least one common screening blood test (lipid profile or hemoglobin A1c). Standardised proportions of TSH test per family practice were used to examine the heterogeneity in the populations. RESULTS: At least one TSH test was performed in 35.97% (N = 489 663) of Canadian patients and 29.36% (N = 1 030 489) of English patients. Almost all TSH tests in Canada and England (95.69% and 99.23% respectively) were within the normal range (0.40-5.00 mU/L). A greater number of patient-physician encounters was the strongest predictor of TSH testing. It was determined that 51.40% of TSH tests in Canada and 76.55% in England were performed on the same day as at least one other screening blood test. There was no association between the practice size and proportion of asymptomatic patients tested. CONCLUSIONS: This comparative binational study found TSH patterns suggestive of over-testing and potentially thyroid disorder screening in both countries. There may be significant opportunities to improve the appropriateness of TSH ordering in Canada and England and therefore improve the allocation of limited system resources.

Ambient virtual scribes: Mutuo Health's AutoScribe as a case study of artificial intelligence-based technology.

Studies show that clinicians are increasingly burning out in large part from the clerical burden associated with using Electronic Medical Record (EMR) systems. At the same time, recently developed health data analytic algorithms struggle with poor quality free-text entered data in these systems. We developed AutoScribe using artificial intelligence-based natural language processing tools to automate these clerical tasks and to output high-quality EMR data. In this article, we describe the benefits and drawbacks of our technology. Furthermore, we describe how we are positioning our company's culture within the existing healthcare system and suggest steps leaders of the system should consider in order to ensure that potentially transformative artificial intelligence-based technologies like ours are optimally adopted.

AutoScribe: Extracting Clinically Pertinent Information from Patient-Clinician Dialogues.

We present AutoScribe, a system for automatically extracting pertinent medical information from dialogues between clinicians and patients. AutoScribe parses the dialogue and extracts entities such as medications and symptoms, using context to predict which entities are relevant, and automatically generates a patient note and primary diagnosis.

Educational approaches for improving physicians' use of health information technology.

The benefits of Health Information Technology (HIT) depend on the way they are being used. Education and training are often needed to move from basic to advanced, value-adding, use. In this article, we describe three educational approaches that can help in achieving this goal: "productive failure," video tutorials, and simulation. We describe the rationale behind these approaches, their strengths, and limitations and illustrate their application, respectively, to three problems associated with the use of HIT in clinical practice: improving data quality within Electronic Medical Records (EMRs) at the point of data entry, use of advanced EMR features for chronic disease management, and impact of the EMR on patient-clinician communication. We conclude that, while these approaches are promising, there is a need for innovation and diversity of educational approaches to address use of advanced HIT features, identified challenges with HIT, and usage in context-as well as for rigorous evaluation.

Computers in the clinical encounter: a scoping review and thematic analysis.

OBJECTIVE: Patient-clinician communication has been associated with increased patient satisfaction, trust in the clinician, adherence to prescribed therapy, and various health outcomes. The impact of health information technology (HIT) on the clinical encounter in general and patient-clinician communication in particular is a growing concern. The purpose of this study was to review the current literature on HIT use during the clinical encounter to update best practices and inform the continuous development of HIT policies and educational interventions. METHODS: We conducted a literature search of four databases. After removing duplicates, reviewing titles and abstracts, performing a full-text review, and snowballing from references and citations, 51 articles were included in the analysis. We employed a qualitative thematic analysis to compare and contrast the findings across studies. RESULTS: Our analysis revealed that the use of HIT affects consultations in complex ways, impacting eye contact and gaze, information sharing, building relationships, and pauses in the conversation. Whether these impacts are positive or negative largely depends on the combination of consultation room layout, patient and clinician styles of interaction with HIT as well as each other, and the strategies and techniques employed by clinicians to integrate HIT into consultations. DISCUSSION: The in-depth insights into the impact of HIT on the clinical encounter, especially the strategies and techniques employed by clinicians to adapt to using HIT in consultations, can inform policies, educational interventions, and research. CONCLUSION: In contrast to the common negative views of HIT, it affects the clinical encounter in multiple ways. By applying identified strategies and best practices, HIT can support patient-clinician interactions rather than interfering with them.

Traffic control at the nuclear pore.

The proper communication between organelles is essential for many aspects of eukaryotic life. The coordination of nuclear and cytoplasmic activities in particular is of pivotal importance and depends on transport in and out of the nucleus. The material which translocates through nuclear pores is diverse; it includes numerous proteins, RNAs and large ribonucleoprotein complexes like ribosomal subunits. To ensure the correct nucleocytoplasmic distribution of these components, appropriate mechanisms have to be in place which control traffic across the nuclear envelope. A growing number of studies support the notion that transport through nuclear pore complexes is intimately linked to cell physiology. As such, it has become evident that changes in the cellular environment, either by externally applied stress, aging or disease, alter nuclear traffic. Due to the progress made in the past few years, we are now beginning to understand these processes at the molecular level. Thus, the concept emerges that stress or disease conditions correlate with signaling events which aim at the nuclear transport apparatus. Here, we summarize results from recent publications that provide evidence for the hypothesis that changes in cell physiology modulate nuclear traffic by targeting multiple transport factors. We propose that this traffic control is at least in part mediated by specific signaling events.

Oxidative stress inhibits nuclear protein export by multiple mechanisms that target FG nucleoporins and Crm1.

Nuclear transport of macromolecules is regulated by the physiological state of the cell and thus sensitive to stress. To define the molecular mechanisms that control nuclear export upon stress, cells were exposed to nonlethal concentrations of the oxidant diethyl maleate (DEM). These stress conditions inhibited chromosome region maintenance-1 (Crm1)-dependent nuclear export and increased the association between Crm1 and Ran. In addition, we identified several repeat-containing nucleoporins implicated in nuclear export as targets of oxidative stress. As such, DEM treatment reduced Nup358 levels at the nuclear envelope and redistributed Nup98. Furthermore, oxidative stress led to an increase in the apparent molecular masses of Nup98, Nup214, and Nup62. Incubation with phosphatase or beta-N-acetyl-hexosaminidase showed that oxidative stress caused the phosphorylation of Nup98, Nup62, and Nup214 as well as O-linked N-acetylglucosamine modification of Nup62 and Nup214. These oxidant-induced changes in nucleoporin modification correlated first with the increased binding of Nup62 to the exporter Crm1 and second with the reduced interaction of Nup62 with other FxFG-containing nucleoporins. Together, oxidative stress up-regulated the binding of Crm1 to Ran and affected multiple repeat-containing nucleoporins by changing their localization, phosphorylation, O-glycosylation, or interaction with other transport components. We propose that the combination of these events contributes to the stress-dependent regulation of Crm1-mediated protein export.