"I don't need any more unknowns hanging over my head": Views of patients with cancer on variants of uncertain significance and low/moderate risk results from genomic sequencing.

PURPOSE: We sought to explore patient-reported utility of all types of cancer results from genomic sequencing (GS). METHODS: Qualitative study, using semi-structured interviews with patients who underwent GS within a trial. Thematic analysis employing constant comparison was used. Two coders coded transcripts, with use of a third coder to resolve conflicts. RESULTS: 25 patients participated: female (22), >50 years (18), European (12), Ashkenazi Jewish (5), Middle Eastern (3), or other ethnicity (5), with breast cancer history (20). Patients' perceptions of the utility of cancer GS results hinged on whether they triggered clinical action. For example, when patients were enrolled into high-risk breast cancer surveillance programs for low/moderate risk breast cancer genes, they perceived the results to be very "useful" and of moderate-high utility. In contrast, patients receiving low/moderate risk or primary variants of uncertain significance results without clinical action perceived results as "concerning," leading to harms, such as hypervigilance about cancer symptoms. Overall, having supportive relatives or providers enhanced perceptions of utility. CONCLUSION: Patients' perceptions of cancer GS results hinged on whether they triggered clinical management. Consequently, patients who received results without clinical action became hypervigilant, experiencing harms. Our findings call for a need to develop practice interventions to support patients with cancer undergoing GS.

"Doctors shouldn't have to cheat the system": Clinicians' real-world experiences of the utility of genomic sequencing.

PURPOSE: Emerging genetic tests such as genomic sequencing (GS) can generate a broad range of benefits, but funding criteria only prioritize diagnosis and clinical management. There is limited evidence on all types of benefits obtained from GS in practice. We aimed to explore real-world experiences of Canadian clinicians across specialties on the full range of benefits obtained from the results from GS. METHODS: We conducted a qualitative study using semistructured interviews with Canadian clinicians. Transcripts were thematically analyzed using constant comparison. RESULTS: In total, 25 clinicians participated, including 12 geneticists, 7 genetic counselors, 4 oncologists, 1 neurologist, and 1 family physician. Although diagnoses and management were the most valued benefits of GS, clinicians also prioritized nontraditional utility, such as access to community supports. However, clinicians felt "restricted" by funding bodies, which only approved funding when GS would inform diagnoses and management. Consequently, clinicians sought ways to "cheat the system" to access GS (eg, research testing) but acknowledged workarounds were burdensome, drove inequity, and undermined patient care. CONCLUSION: Current governance structures undervalue real-world benefits of GS leading clinicians to adopt workarounds, which jeopardize patient care. These results support calls for the expansion of the definition of clinical utility and research to quantify the additional benefits.

Anticoagulant use and associated outcomes in older patients receiving home palliative care: a retrospective cohort study.

BACKGROUND: The benefits and harms of anticoagulants for people near the end of life are not well understood, nor is it known what proportion of patients discontinue these medications. We aimed to characterize anticoagulant use in older recipients of home palliative care and describe patient and provider characteristics, as well as outcomes associated with anticoagulant discontinuation in this group. METHODS: Using linked administrative health databases, we conducted a population-based cohort study of patients aged 66 years and older who initiated home palliative care in Ontario from 2010 to 2018. We calculated the prevalence of anticoagulant use. We used multilevel logistic regression models to assess patient (e.g., sociodemographic, comorbidities) and physician (e.g., demographic, training, practice) factors associated with anticoagulant discontinuation after initiation of home palliative care. We defined discontinuation as either primary (no anticoagulant claim within 1.5 times the days' supply of the previous prescription) or secondary (no subsequent anticoagulant claim at any time after the index date). In secondary analyses, we used cause-specific hazards regression to explore subsequent thrombotic and bleeding events associated with anticoagulant discontinuation, and multivariable logistic regression for location of death. RESULTS: We identified 98 089 recipients of home palliative care, of whom 15.5% were taking anticoagulants at the time of the first palliative care visit. Depending on the definition of discontinuation, 18.0% to 24.4% of patients discontinued anticoagulants after the first home palliative care visit. Compared with warfarin, use of a direct oral anticoagulant (adjusted odds ratio [OR] 0.49, 95% confidence interval [CI] 0.43-0.56) and low-molecular-weight heparin (adjusted OR 0.56, 95% CI 0.47-0.66) were associated with a lower likelihood of discontinuation. Few patient or physician characteristics - and no comorbidities or indications for therapeutic anticoagulation - were associated with discontinuation. Anticoagulant discontinuation after beginning home palliative care was associated with similar rates of thrombosis (adjusted hazard ratio [HR] 1.06, 95% CI 0.81-1.39), lower rates of bleeding (adjusted HR 0.75, 95% CI 0.62-0.90) and a higher likelihood of a home death (adjusted OR 1.22, 95% CI 1.09-1.36) compared with continuing anticoagulation. INTERPRETATION: Among recipients of home palliative care in Ontario, anticoagulant use is common, and discontinuation is not influenced by comorbidities or indication for anticoagulation. Physician preference may play an important role; patients should be made aware of their options toward the end of life and supported in shared decision-making.

Stroke Incidence by Sex Across the Lifespan.

BACKGROUND AND PURPOSE: We evaluated the influence of age on the association between sex and the incidence of stroke or transient ischemic attack (TIA) using a population-based cohort from Ontario, Canada. METHODS: We followed a cohort of adults (≥18 years) without prior stroke from January 1, 2003 (cohort start date) to March 31, 2018, to identify incident events. We calculated hazard ratios (HRs), in women compared to men, of incident stroke or TIA, adjusted for demographics and comorbidities, overall and stratified by stroke type. We calculated piecewise adjusted HRs for each decade of age to evaluate the effect of age on sex differences in stroke incidence. RESULTS: We followed 9.2 million adults for a median of 15 years and observed 280,197 incident stroke or TIA events. Compared with men, women had an overall lower adjusted hazard of stroke or TIA (HR, 0.82 [95% CI, 0.82-0.83]), with similar findings across all stroke types except for subarachnoid hemorrhage (HR, 1.29 [95% CI, 1.24-1.33]). We found a U-shaped association between age and sex differences in the incidence of stroke or TIA: compared with men, the hazard of stroke was higher in women among those aged ≤30 years (HR, 1.26 [95% CI, 1.10-1.45]), lower among those between ages 40 and 80 years (eg, age 50-59, HR, 0.69 [95% CI, 0.68-0.70]), and similar among those aged ≥80 years (HR, 0.99 [95% CI, 0.98-1.01]). CONCLUSIONS: Overall, women have a lower hazard of stroke than men, but this association varies by age and across stroke types. Recognition of age-sex variations in stroke incidence can help guide prevention efforts to reduce stroke incidence in both men and women.

Adherence at 2 years with distribution of essential medicines at no charge: The CLEAN Meds randomized clinical trial.

BACKGROUND: Adherence to medicines is low for a variety of reasons, including the cost borne by patients. Some jurisdictions publicly fund medicines for the general population, but many jurisdictions do not, and such policies are contentious. To our knowledge, no trials studying free access to a wide range of medicines have been conducted. METHODS AND FINDINGS: We randomly assigned 786 primary care patients who reported not taking medicines due to cost between June 1, 2016 and April 28, 2017 to either free distribution of essential medicines (n = 395) or to usual medicine access (n = 391). The trial was conducted in Ontario, Canada, where hospital care and physician services are publicly funded for the general population but medicines are not. The trial population was mostly female (56%), younger than 65 years (83%), white (66%), and had a low income from wages as the primary source (56%). The primary outcome was medicine adherence after 2 years. Secondary outcomes included control of diabetes, blood pressure, and low-density lipoprotein (LDL) cholesterol in patients taking relevant treatments and healthcare costs over 2 years. Adherence to all appropriate prescribed medicines was 38.7% in the free distribution group and 28.6% in the usual access group after 2 years (absolute difference 10.1%; 95% confidence interval (CI) 3.3 to 16.9, p = 0.004). There were no statistically significant differences in control of diabetes (hemoglobin A1c 0.27; 95% CI -0.25 to 0.79, p = 0.302), systolic blood pressure (-3.9; 95% CI -9.9 to 2.2, p = 0.210), or LDL cholesterol (0.26; 95% CI -0.08 to 0.60, p = 0.130) based on available data. Total healthcare costs over 2 years were lower with free distribution (difference in median CAN$1,117; 95% CI CAN$445 to CAN$1,778, p = 0.006). In the free distribution group, 51 participants experienced a serious adverse event, while 68 participants in the usual access group experienced a serious adverse event (p = 0.091). Participants were not blinded, and some outcomes depended on participant reports. CONCLUSIONS: In this study, we observed that free distribution of essential medicines to patients with cost-related nonadherence substantially increased adherence, did not affect surrogate health outcomes, and reduced total healthcare costs over 2 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT02744963.

Are quality improvement plans perceived to improve the quality of primary care in Ontario? Qualitative study.

OBJECTIVE: To explore primary care administrators' perceptions of provincially mandated quality improvement plans, and barriers to and facilitators of using quality improvement plans as tools for improving the quality of primary care. DESIGN: Qualitative descriptive study using semistructured interviews. SETTING: Ontario. PARTICIPANTS: Eleven primary care administrators (ie, executive directors, director of clinical services, office administrators) at 7 family health teams and 4 community health centres. METHODS: All interviews were audiotaped and transcribed verbatim. Data were analyzed deductively to generate a framework based on a conceptual model of structural, organizational, individual, and innovation-related factors that influence the success of improvement initiatives and, inductively, to generate additional themes. MAIN FINDINGS: Provincially mandated quality improvement plans seem to have raised awareness of and provided an overall focus on quality improvement, and have contributed to primary care organizations implementing initiatives to address quality gaps. Four factors that have contributed to the success of quality improvement plans relate to attributes of the quality improvement plans (adaptability and compatibility) and contextual factors (leadership and organizational culture). However, participants expressed that the use of quality improvement plans have not yet led to substantial improvements in the quality of primary care in Ontario, which may be owing to several challenges: poor data quality, lack of staff and physician engagement and buy-in, and lack of resources to support measurement and quality improvement. CONCLUSION: Awareness of and focused attention on the need for high-quality patient care may have increased, but participants expressed that substantial improvements in quality care have yet to be achieved in Ontario. The lack of perceived improvements is likely the result of multifaceted and complex challenges primary care organizations face when trying to improve patient care. To effect positive change, organization- and health system-level efforts are needed to improve measurement capabilities, improve staff and physician engagement, and increase capacity for quality improvement among organizations.

Association Between Immigration Status and Acute Stroke Care: A Retrospective Study.

Background and Purpose- Immigrants to high-income countries have a lower incidence of stroke compared with long-term residents; however, little is known about the care and outcomes of stroke in immigrants. Methods- We used linked clinical and administrative data to conduct a retrospective cohort study of adults seen in the emergency department or hospitalized with ischemic stroke or transient ischemic attack between July 1, 2003, and April 1, 2013, and included in the provincial stroke registry. We ascertained immigration status using immigration records and compared processes of stroke care delivery between immigrants (defined as those immigrating after 1985) and long-term residents. In the subgroup with ischemic stroke, we calculated inverse probability treatment weight (IPTW)-adjusted risk ratios for disability on discharge (modified Rankin Scale score of 3 to 5), accounting for demographic characteristics and comorbid conditions to compare outcomes between immigrants and long-term residents. Results- We included 34 987 patients with ischemic stroke or transient ischemic attack, of whom 2649 (7.6%) were immigrants. Immigrants were younger than long-term residents at the time of stroke/transient ischemic attack (median age 67 years versus 76 years; P<0.001). In the subgroup with ischemic stroke, there were no differences in stroke care delivery, except that a higher proportion of immigrants received thrombolysis than long-term residents (21.2% versus 15.5%; P<0.001). Immigrants with ischemic stroke had a higher adjusted risk of being disabled on discharge (adjusted risk ratio, 1.18; 95% CI, 1.13-1.22) compared to long-term residents. Conclusions- Stroke care is similar in Canadian immigrants and long-term residents. Future research is needed to confirm the observed association between immigration status and disability after stroke and to identify factors underlying the association.

Effectiveness of the Genomics ADvISER decision aid for the selection of secondary findings from genomic sequencing: a randomized clinical trial.

PURPOSE: To evaluate the effectiveness of the Genomics ADvISER (www.genomicsadviser.com) decision aid (DA) for selection of secondary findings (SF), compared with genetic counseling alone. METHODS: A randomized controlled trial (RCT) was conducted to evaluate whether the Genomics ADvISER is superior to genetic counseling when hypothetically selecting SF. Participants were randomized to use the DA followed by discussion with a genetic counselor, or to genetic counseling alone. Surveys were administered at baseline and post-intervention. Primary outcome was decisional conflict. Secondary outcomes were knowledge, preparation for, and satisfaction with decision-making, anxiety, and length of counseling session. RESULTS: Participants (n = 133) were predominantly White/European (74%), female (90%), and ≥50 years old (60%). Decisional conflict (mean difference 0.05; P = 0.60), preparation for decision-making (0.17; P = 0.95), satisfaction with decision (-2.18; P = 0.06), anxiety (0.72; P = 0.56), and knowledge of sequencing limitations (0.14; P = 0.70) did not significantly differ between groups. However, intervention participants had significantly higher knowledge of SF (0.39; P < 0.001) and sequencing benefits (0.97; P = 0.01), and significantly shorter counseling time (24.40 minutes less; P < 0.001) CONCLUSIONS: The Genomics ADvISER did not decrease decisional conflict but reduced counseling time and improved knowledge. This decision aid could serve as an educational tool, reducing in-clinic time and potentially health care costs.

Subomohyoid Anterior Suprascapular Block versus Interscalene Block for Arthroscopic Shoulder Surgery: A Multicenter Randomized Trial.

BACKGROUND: Interscalene brachial plexus block, the pain relief standard for shoulder surgery, is an invasive technique associated with important complications. The subomohyoid anterior suprascapular block is a potential alternative, but evidence of its comparative analgesic effect is sparse. The authors tested the hypothesis that anterior suprascapular block is noninferior to interscalene block for improving pain control after shoulder surgery. As a secondary objective, the authors evaluated the success of superior trunk (C5-C6 dermatomes) block with suprascapular block. METHODS: In this multicenter double-blind noninferiority randomized trial, 140 patients undergoing shoulder surgery were randomized to either interscalene or anterior suprascapular block with 15 ml of ropivacaine 0.5% and epinephrine. The primary outcome was area under the curve of postoperative visual analog scale pain scores during the first 24 h postoperatively. The 90% CI for the difference (interscalene-suprascapular) was compared against a -4.4-U noninferiority margin. Secondary outcomes included presence of superior trunk blockade, pain scores at individual time points, opioid consumption, time to first analgesic request, opioid-related side-effects, and quality of recovery. RESULTS: A total of 136 patients were included in the analysis. The mean difference (90% CI) in area under the curve of pain scores for the (interscalene-suprascapular) comparison was -0.3 U (-0.8 to 0.12), exceeding the noninferiority margin of -4.4 U and demonstrating noninferiority of suprascapular block. The risk ratio (95% CI) of combined superior trunk (C5-C6 dermatomes) blockade was 0.98 (0.92 to 1.01), excluding any meaningful difference in superior trunk block success rates between the two groups. When differences in other analgesic outcomes existed, they were not clinically important. CONCLUSIONS: The suprascapular block was noninferior to interscalene block with respect to improvement of postoperative pain control, and also for blockade of the superior trunk. These findings suggest that the suprascapular block consistently blocks the superior trunk and qualify it as an effective interscalene block alternative.

PROM-ED: Development and Testing of a Patient-Reported Outcome Measure for Emergency Department Patients Who Are Discharged Home.

STUDY OBJECTIVE: Common outcomes of care valued by emergency department (ED) patients who are not hospitalized have been characterized, but no measurement instrument has been developed to date. We developed and validated a patient-reported outcome measure for use with adult ED patients who are discharged home (PROM-ED). METHODS: In previous research, 4 main outcomes of importance to ED patients were defined: symptom relief, understanding, reassurance, and having a plan. We developed a bank of potential questions (phase 1) that were first tested for suitability through cognitive debriefing with patients (phase 2). Revised questions were then tested quantitatively with a large panel of participants who had recently received ED care (phase 3). Informed by these results, a panel of experts used a modified Delphi process to make decisions on item reduction. The resulting instrument (PROM-ED 1.0) was then evaluated for its measurement properties (structural validity, hypothesis testing, and reliability). RESULTS: Sixty-seven questions divided among 4 scales (1 for each outcome domain) were assembled. In accordance with cognitive debriefing with 8 patients (phase 2), 15 questions were modified and 13 removed. Testing of these questions with 444 participants (phase 3) identified problematic floor or ceiling effects (n=10), excessive correlations between items (n=11), and low item-total correlations (n=7). The expert panel (22 participants, phase 4) made decisions using this information on the exclusion of items, resulting in 22 questions across 4 scales that together constitute the PROM-ED 1.0. Testing provided good evidence of validity and test-retest reliability (n=200). CONCLUSION: The PROM-ED enables the measurement of patient-centered outcomes of importance to patients receiving care in the ED who are not hospitalized. These data could have important applications in research and care improvement.

Top ten priorities for anesthesia and perioperative research: a report from the Canadian Anesthesia Research Priority Setting Partnership.

PURPOSE: The purpose of the Canadian Anesthesia Research Priority Setting Partnership (CAR PSP) was to identify a top ten list of shared priorities for research in anesthesia and perioperative care in Canada. METHODS: We used the methods of the James Lind Alliance to involve patients, caregivers, healthcare professionals, and researchers in determining the research priorities in Canada. In a first survey, participants submitted questions that they want research to answer about anesthesia and perioperative care. We summarized those responses into a longlist of questions. We reviewed the literature to see if any of those questions were already answered. In a second survey, participants chose up to ten questions from the longlist that they thought were most important to be answered with research. From that list, the highest ranking questions were discussed and assigned a final rank at an in-person workshop. RESULTS: A total of 254 participants submitted 574 research suggestions that were then summarized into 49 questions. Those questions were checked against the literature to be sure they were not already adequately addressed, and in a second survey of those 49 questions, participants chose up to 10 that they thought were most important. A total of 233 participants submitted their priorities, which were then used to choose 24 questions for discussion at the final workshop. At the final workshop, 22 participants agreed on a top ten list of priorities. CONCLUSION: The CAR PSP top ten priorities reflect a wide variety of priorities captured by a broad spectrum of Canadians who receive and provide anesthesia care. The priorities are a tool to initiate and guide patient-oriented research in anesthesia and perioperative care.

RéSUMé: OBJECTIF: L'objectif du Partenariat canadien pour l'établissement des priorités de la recherche en anesthésie (CAR-PSP) était d'établir une liste des dix principales priorités pour la recherche sur les soins anesthésiques et périopératoires au Canada. MéTHODES: Nous avons utilisé la méthodologie de la James Lind Alliance pour impliquer des patients, des aidants, des professionnels de la santé et des chercheurs afin de déterminer quelles étaient les priorités en matière de recherche au Canada. Dans une première enquête, les participants ont envoyé des questions sur les soins anesthésiques et périopératoires auxquelles ils voulaient que la recherche réponde. Nous avons résumé ces envois par une liste exhaustive de questions. Nous avons passé en revue les publications pour voir s'il existait déjà des réponses à ces questions. Dans une deuxième étude, les participants ont choisi dans la liste jusqu'à dix questions qui leur semblaient les plus importantes et pour lesquelles la recherche devrait fournir des réponses. À partir de cette liste, les questions les mieux classées ont été discutées et un classement définitif leur a été attribué au cours d'un atelier où tous les participants étaient présents en personne. RéSULTATS: Au total, 254 participants ont envoyé 574 suggestions de recherche qui ont été résumées en 49 questions. La littérature a été examinée pour s'assurer que ces questions n'avaient pas déjà reçu des réponses adéquates, et dans une seconde étude, les participants ont choisi jusqu'à 10 questions qu'ils jugeaient les plus importantes parmi ces 49 questions. Au total, 233 participants ont communiqué leurs priorités qui ont alors servi à choisir 24 questions ouvertes pour la discussion dans un atelier final. Dans cet atelier, 22 participants se sont mis d'accord sur une liste des dix principales priorités. CONCLUSION: Les dix principales priorités du CAR-PSP sont le reflet d'un grand éventail de priorités venant de Canadiens de tous horizons qui reçoivent ou fournissent des soins d'anesthésie. Ces priorités sont un outil permettant d'entamer et de guider une recherche axée sur le patient dans le domaine des soins anesthésiques et périopératoires.

Engaging Patients and Caregivers in Research for Pediatric Inflammatory Bowel Disease: Top 10 Research Priorities.

INTRODUCTION: Including individuals with lived experience in pediatric inflammatory bowel disease (IBD) is essential to establishing a research agenda that is mutually impactful to both those treating and those experiencing the disease. METHODS: Using the James Lind Alliance approach to research priority setting, a 10-member steering committee composed of current and former pediatric patients with IBD, caregivers, and clinicians was formed. A national survey, disseminated across Canada, elicited uncertainties which were divided into unanswered and answered research questions. Subsequently a research prioritization survey was disseminated where respondents ranked their top 20 research uncertainties. A final prioritization meeting was held to agree upon the top 10 uncertainties. RESULTS: From 1209 research questions submitted by 363 participants, the list was reduced to 105 indicative questions that were within scope and deemed unanswered in the literature. Via the national research prioritization survey, this list was further reduced. The top 10 uncertainties identified at the final research consensus meeting, with 21 participants from all stakeholder groups, included "What are the causes of IBD?," "Can IBD be prevented?," "What role does diet have in the management of pediatric IBD?." Other questions concerned flare ups, biomarkers, optimal patient education, long-term effects of medication and early-diagnosis, role of psychological support, and optimal approach to diagnosis. CONCLUSION: This research adds a unique perspective by deriving a list of pediatric IBD research uncertainties important by patients and caregivers and clinicians.

Emerging Trends in Clinical Research: With Implications for Population Health and Health Policy.

Policy Points: Significant advances in clinical medicine that have broader societal relevance may be less accessible to population health researchers and policymakers because of increased specialization within fields. We describe important recent clinical advances and discuss their broader societal impact. These advances include more expansive strategies for disease prevention, the rise of precision medicine, applications of human microbiome research, and new and highly successful treatments for hepatitis C infection. These recent developments in clinical research raise important issues surrounding health care costs and equitable resource allocation that necessitate an ongoing dialogue among the fields of clinical medicine, population health, and health policy. CONTEXT: Developments in clinical medicine have important implications for population health, and there is a need for interdisciplinary engagement among clinical medicine, the social sciences, and public health research. The aim of this article is to help bridge the divide between these fields by exploring major recent advances in clinical medicine that have important implications for population health. METHODS: We reviewed the most cited articles published from 2010 to 2015 in 5 high-impact clinical journals and selected 5 randomized controlled trials and 2 related clinical practice guidelines that are broadly relevant to population health and policy. FINDINGS: We discuss the following themes: (1) expanding indications for drug therapy and the inherent medicalization of the population as highlighted by studies and clinical guidelines supporting lower blood pressure targets or widespread statin use; (2) the tension in nutritional research between quantifying the impact of isolated nutrients and studying specific foods and dietary patterns, for example, the role of the Mediterranean diet in the primary prevention of cardiovascular disease; (3) the issue of high medication costs and the challenge of providing equitable access raised by the development of new and effective treatments for hepatitis C infection; (4) emerging clinical applications of research on the human microbiome as illustrated by fecal transplant to treat Clostridium difficile infections; and (5) the promise and limitations of precision medicine as demonstrated by the rise of novel targeted therapies in oncology. CONCLUSIONS: These developments in clinical science hold promise for improving individual and population health and raise important questions about resource allocation, the role of prevention, and health disparities.