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Multivessel coronary artery disease is present in ∼50% of patients with acute coronary syndrome and, compared with single-vessel disease, entails a higher risk of new ischaemic events and a worse prognosis. Randomized controlled trials have shown the superiority of 'complete revascularization' over culprit lesion-only treatment. Trials, however, only included patients treated with percutaneous coronary intervention (PCI), and evidence regarding complete revascularization with coronary artery bypass graft (CABG) surgery after culprit lesion-only PCI ('hybrid revascularization') is lacking. The CABG after PCI is an open, non-negligible therapeutic option, for patients with non-culprit left main and/or left anterior descending coronary artery disease where evidence in chronic coronary syndrome patients points in several cases to a preference of CABG over PCI. This valuable but poorly studied 'PCI first-CABG later' option presents, however, relevant challenges, mostly in the need of interrupting post-stenting dual antiplatelet therapy (DAPT) for surgery to prevent excess bleeding. Depending on patients' clinical characteristics and coronary anatomical features, either deferring surgery after a safe interruption of DAPT or bridging DAPT interruption with intravenous short-acting antithrombotic agents appears to be a suitable option. Off-pump minimally invasive surgical revascularization, associated with less operative bleeding than open-chest surgery, may be an adjunctive strategy when revascularization cannot be safely deferred and DAPT is not interrupted. Here, the rationale, patient selection, optimal timing, and adjunctive strategies are reviewed for an ideal approach to hybrid revascularization in post-acute coronary syndrome patients to support physicians' choices in a case-by-case patient-tailored approach., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: The objective of this study is to systematically examine the efficacy of both proprietary (GPT-3.5, GPT-4) and open-source large language models (LLMs) (LLAMA 7B, 13B, 70B) in the context of matching patients to clinical trials in healthcare., Materials and Methods: The study employs a multifaceted evaluation framework, incorporating extensive automated and human-centric assessments along with a detailed error analysis for each model, and assesses LLMs' capabilities in analyzing patient eligibility against clinical trial's inclusion and exclusion criteria. To improve the adaptability of open-source LLMs, a specialized synthetic dataset was created using GPT-4, facilitating effective fine-tuning under constrained data conditions., Results: The findings indicate that open-source LLMs, when fine-tuned on this limited and synthetic dataset, achieve performance parity with their proprietary counterparts, such as GPT-3.5., Discussion: This study highlights the recent success of LLMs in the high-stakes domain of healthcare, specifically in patient-trial matching. The research demonstrates the potential of open-source models to match the performance of proprietary models when fine-tuned appropriately, addressing challenges like cost, privacy, and reproducibility concerns associated with closed-source proprietary LLMs., Conclusion: The study underscores the opportunity for open-source LLMs in patient-trial matching. To encourage further research and applications in this field, the annotated evaluation dataset and the fine-tuned LLM, Trial-LLAMA, are released for public use., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: Conflict of interest: None declared.

Introduction: Recruiting special populations to smoking cessation trials is challenging and approaches beyond in-clinic recruitment may be beneficial. This secondary analysis of data from a smoking cessation RCT for individuals with a history of cervical cancer or cervical intraepithelial neoplasia (CIN) explored differences associated with in-clinic vs. online recruitment., Aims and Methods: Participants were recruited from clinics within a university-based NCI-designated cancer center (n = 87) and online nationally via Facebook (n = 115). Baseline measures included sociodemographics, smoking history, and cancer or CIN history. Study retention and smoking abstinence were assessed 12 months post-baseline. Group differences in baseline characteristics were evaluated. Retention and abstinence were evaluated while controlling for group differences and predictors., Results: Participants recruited online (vs. in-clinic) had higher educational attainment (p = .01) and health literacy (p = .003). They were more likely to have CIN versus cancer, to be further from the time of diagnosis, and to have completed active treatment (p values < .001). While controlling for these group differences and independent predictors, retention was higher among participants recruited online (log-likelihood χ2(1) = 11.41, p < .001). There were no recruitment differences in self-reported (p = .90) or biochemically confirmed smoking abstinence (p = .18)., Conclusions: Compared to individuals recruited in-person, individuals recruited online were more educated, had higher health literacy, and presented with a different clinical profile (ie, more likely to have CIN vs. cancer and to have completed active treatment). There were few differences in participant characteristics between recruitment approaches, and no differences on any smoking-related variables. Online recruitment has the potential to improve enrollment of cancer survivors in smoking cessation trials., Implications: People with a history of CIN or cervical cancer recruited to a smoking cessation RCT online (vs. in-clinic) were more likely to have a diagnosis of CIN versus cancer and were more educated and health literate. Participants recruited online were more likely to be retained in the study and there were no differences in smoking abstinence rates at 12 months. Incorporating online recruitment increased the reach of tobacco treatment efforts to a larger and more diverse sample. This could reduce the burden of tobacco-related disease, improve CIN and cancer treatment outcomes, and reduce secondary malignancies and morbidity among this underserved group., (Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco 2024.)

Background and Aims: Pragmatic studies designed to test interventions in everyday clinical settings can successfully complement the evidence from registration and explanatory clinical trials. The European consensus project PRACTICE-IBD was developed to identify essential criteria and address key methodological issues needed to design valid, comparative, pragmatic studies in inflammatory bowel diseases [BDs]., Methods: Statements were issued by a panel of 11 European experts in IBD management and trial methodology, on four main topics: [I] study design; [II] eligibility, recruitment and organisation, flexibility; [III] outcomes; [IV] analysis. The consensus process followed a modified Delphi approach, involving two rounds of assessment and rating of the level of agreement [1 to 9; cut-off ≥7 for approval] with the statements by 18 additional European experts in IBD., Results: At the first voting round, 25 out of the 26 statements reached a mean score ≥7. Following the discussion that preceded the second round of voting, it was decided to eliminate two statements and to split one into two. At the second voting round, 25 final statements were approved: seven for study design; six for eligibility, recruitment and organisation, flexibility; eight for outcomes; and four for analysis., Conclusions: Pragmatic, randomised, clinical trials can address important questions in IBD clinical practice, and may provide complementary, high-level evidence, as long as they follow a methodologically rigorous approach. These 25 statements intend to offer practical guidance in the design of high-quality, pragmatic, clinical trials that can aid decision making in choosing a management strategy for IBDs., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Objective: The primary treatment of patients with advanced ovarian cancer is selected from whether primary debulking surgery or neoadjuvant chemotherapy. We investigated whether pretreatment serum microRNA profiles are useful for selecting patients with advanced high-grade serous ovarian cancer who obtain better outcomes from undergoing primary debulking surgery or neoadjuvant chemotherapy., Methods: Consecutive patients with clinical stage IIIB-IVB and serum microRNA data were selected. Patients who underwent primary debulking surgery or neoadjuvant chemotherapy were subjected to 1:1 propensity score matching before comparing their progression-free survival using Cox modelling. Progression-free probabilities for the selected microRNA profiles were calculated, and the estimated progression-free survival with the recommended primary treatment was determined and compared with the actual progression-free survival of the patients., Results: Of the 108 patients with stage IIIB-IVB disease, the data of 24 who underwent primary debulking surgery or neoadjuvant chemotherapy were compared. Eleven and three microRNAs were independent predictors of progression-free survival in patients who underwent primary debulking surgery and neoadjuvant chemotherapy, respectively. Two microRNAs correlated significantly with complete resection of the tumours in primary debulking surgery. No differences were found between the actual and estimated progression-free survival in the primary debulking surgery and neoadjuvant chemotherapy groups (P > 0.05). The recommended and actual primary treatments were identical in 27 (56.3%) of the 48 patients. The median improved survival times between recommended and actual treatment were 11.7 and 32.6 months for patients with actual primary debulking surgery and neoadjuvant chemotherapy, respectively., Conclusions: Pretreatment microRNA profiles could be used to select subgroups of patients who benefited more from primary debulking surgery or neoadjuvant chemotherapy and might contribute to selecting the optimal primary treatment modality in advanced high-grade serous ovarian cancer patients., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Somatostatin analogs, molecular-targeted agents and cytotoxic anticancer agents are available as therapeutic agents for the systemic treatment of pancreatic neuroendocrine tumors, and we have developed a first-line treatment selection MAP to enable selection of the optimal treatment strategy for pancreatic neuroendocrine tumors. The purpose of this study was to validate the usefulness of the treatment selection MAP., Methods: Patients who had received systemic therapy for a pancreatic neuroendocrine tumor between January 2017 and December 2020 were compared according to whether they had been treated as recommended by the MAP (matched patients) or not (unmatched patients) to determine whether better outcomes were achieved by the matched patients. The primary endpoint was progression-free survival of the matched group and unmatched groups in the somatostatin analog, molecular-targeted agent and cytotoxic anticancer agents areas of the MAP., Results: There were 41 (55%) MAP-matched patients in all areas among the 74 patients registered at seven hospitals. The MAP-matched rates were 100, 77 and 38% in the somatostatin analog area, molecular-targeted agent area and cytotoxic anticancer agents area, respectively. All of the unmatched patients had been selected for less intensive treatment. The median progression-free survival in the matched group and unmatched group in the molecular-targeted agent area of the MAP were 46.6 and 15.4 months, respectively, and a multivariate analysis identified MAP-matched (hazard ratio 0.18 [95% confidence interval: 0.04-0.87], P = 0.032) as the only significant independent favorable predictive factor., Conclusion: The usefulness of the MAP for treatment selection was validated in the molecular-targeted agent area of the MAP., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Evaluating transarterial radioembolization (TARE) in patients with metastatic colorectal carcinoma of the liver who have progressed on first-line chemotherapy (EPOCH) demonstrated superior outcomes using yttrium-90 glass microspheres plus chemotherapy (TARE/Chemo) vs chemotherapy (Chemo) to treat colorectal liver metastases. Additional exploratory analyses were undertaken to assess the impact of TARE/Chemo on efficacy, safety, time to subsequent therapy, time to deterioration in quality of life (QoL), and identify criteria for improved patient selection., Methods: Time to deterioration in QoL was analyzed for the primary study population. Subsequently, a post hoc analysis was undertaken to identify subgroups for which time to deterioration in QoL was improved with TARE/Chemo vs Chemo. Progression-free survival (PFS), hepatic (h)PFS, time to subsequent therapy, and safety outcomes were compared between treatments., Results: The primary population showed no significant difference in time to deterioration in QoL between treatment arms; however, significance was seen in 2 identified subgroups, namely: Subgroup A (N = 303) which excluded patients with both Eastern Cooperative Oncology Group (ECOG) 1 and baseline CEA ≥ 35 ng/mL from both treatment arms; subgroup B (N = 168) additionally excluded patients with KRAS (Kirsten rat sarcoma) mutation. In subgroup A, TARE/Chemo patients (N = 143) demonstrated superior outcomes vs Chemo (N = 160): PFS (9.4 vs. 7.6 months, hazard ratio (HR): 0.64; 1-sided P = .0020), hPFS (10.8 vs. 7.6 months, HR: 0.53; 1-sided P < .0001), time to deterioration in QoL (5.7 vs. 3.9 months, HR: 0.65; 1-sided P = .0063), and time to subsequent therapy (21.2 vs. 10.5 months, HR: 0.52; 1-sided P < .0001). Subgroup B patients showed similar but larger significant differences between treatment arms. Median PFS, hPFS, and time to deterioration in QoL were numerically greater for TARE/Chemo in both subgroups vs the primary population, with the greatest magnitude of difference in subgroup B. Both subgroups exhibited higher percentage of CEA responders and improved ORR with TARE/Chemo vs chemo alone. Safety (reported as event rate/100 patient-years) was higher with Chemo in all populations. Additional efficacy analyses in the primary population are also reported., Conclusions: Careful patient selection, including consideration of the prognostic factors ECOG, baseline CEA, and KRAS status, sets outcome expectations in patients with colorectal liver metastases suitable for TARE/Chemo as second-line treatment (Trial Registry Number: NCT01483027)., (© The Author(s) 2024. Published by Oxford University Press.)

Background: We described participant demographics for National Cancer Institute (NCI) clinical trials at the clinical center (NCI-CC participants) of the National Institutes of Health to identify enrollment disparities., Methods: We analyzed NCI-CC data from 2005 to 2020, calculated enrollment fractions, compared with the US cancer population represented by the Surveillance, Epidemiology, and End Results cancer incidence data (2018) and the Cancer in North America database (2018), and compared further with clinical trial disparities data from the NCI Community Oncology Research Program and National Clinical Trials Network (2005-2019), and from ClinicalTrials.gov (2003-2016)., Results: NCI-CC (38 531 participants) had higher enrollment fractions for older adults (8.5%), male (5.6%), non-Hispanic (5.1%), and Black or African American (5.3%) participants; lower women proportion across race and ethnicity; and fewer female sex-specific cancer (6.8%) than male sex-specific cancer (11.7%) participants. NCI-CC had lower median age than Surveillance, Epidemiology, and End Results (54.0 vs 65.4); more Black or African American participants (12.0% vs 11.1%); and fewer women (41.7% vs 49.5%), White (76.1% vs 80.5%), Asian or Pacific Islander (4.6% vs 6.0%), American Indian or Alaska Native (0.3% vs 0.5%), and Hispanic participants (7.1% vs 13%). NCI-CC had more Black or African American and Asian or Pacific Islander participants; fewer Hispanic participants than the NCI Community Oncology Research Program and National Clinical Trials Network; more Black or African American and Hispanic participants; fewer Asian or Pacific Islander participants than ClinicalTrials.gov data. Improvement was noted for NCI-CC (older adults, Black or African American, Asian or Pacific Islander, Hispanic participants)., Conclusion: We found lower representation of older adults, women, Asian or Pacific Islander, American Indian or Alaska Native, and Hispanic participants vs the US cancer population and higher representation of Black or African American vs US cancer population and oncology clinical trials. Multifaceted efforts are underway to reduce disparities in cancer clinical trials at the NCI-CC., (Published by Oxford University Press 2024.)

Background: Persons who speak languages other than English are underrepresented in clinical trials, likely in part because of inadequate multilevel resources. We conducted a survey of institutions affiliated with the Children's Oncology Group (COG) to characterize current research recruitment practices and resources regarding translation and interpretation services., Methods: In October 2022, a 20-item survey was distributed electronically to institutions affiliated with COG to assess consent practices and resources for recruiting participants who speak languages other than English to COG trials. Descriptive statistics were used to summarize responses; responses were compared by institution size and type as well as respondent role., Results: The survey was sent to 230 institutions, and the response rate was 60% (n = 139). In total, 60% (n = 83) of those respondents had access to short-form consent forms. Full consent form translation was required at 50% of institutions, and 12% of institutional review boards restricted use of centrally translated consent forms. Forty-six percent (n = 64) of institutions reported insufficient funding to support translation costs; 19% (n = 26) had access to no-cost translation services. Forty-four percent (n = 61) were required to use in-person interpreters for consent discussions; the most frequently cited barrier (56%) to obtaining consent was lack of available in-person interpreters. Forty-seven percent (n = 65) reported that recruiting persons who speak languages other than English to clinical trials was somewhat or very difficult., Conclusions: Institutions affiliated with COG face resource-specific challenges that impede recruitment of participants who speak languages other than English for clinical trials. These findings indicate an urgent need to identify strategies aimed at reducing recruitment barriers to ensure equitable access to clinical trials., (© The Author(s) 2024. Published by Oxford University Press.)

Objectives: Limited data are available from randomized trials comparing outcomes between transcatheter aortic valve replacement (TAVR) and surgery in patients with different risks and with follow-up of at least 4 years or longer. In this large, population-based cohort study, long-term mortality and morbidity were investigated in patients undergoing aortic valve replacement (AVR) for severe aortic stenosis using a surgically implanted bioprosthesis (surgical/biological aortic valve replacement; sB-AVR) or TAVR., Methods: Individual data from the Austrian Insurance Funds from 2010 through 2020 were analysed. The primary outcome was all-cause mortality, assessed in the overall and propensity score-matched populations. Secondary outcomes included reoperation and cardiovascular events., Results: From January 2010 through December 2020, a total of 18 882 patients underwent sB-AVR (n = 11 749; 62.2%) or TAVR (n = 7133; 37.8%); median follow-up was 5.8 (95% CI 5.7-5.9) years (maximum 12.3 years). The risk of all-cause mortality was higher with TAVR compared with sB-AVR: hazard ratio 1.552, 95% confidence interval (CI) 1.469-1.640, P < 0.001; propensity score-matched hazard ratio 1.510, 1.403-1.625, P < 0.001. Estimated median survival was 8.8 years (95% CI 8.6-9.1) with sB-AVR versus 5 years (4.9-5.2) with TAVR. Estimated 5-year survival probability was 0.664 (0.664-0.686) with sB-AVR versus 0.409 (0.378-0.444) with TAVR overall, and 0.690 (0.674-0.707) and 0.560 (0.540-0.582), respectively, with propensity score matching. Separate subgroup analyses for patients aged 65-75 years and >75 years indicated a significant survival benefit in patients selected for sB-AVR in both groups. Other predictors of mortality were age, sex, previous heart failure, diabetes and chronic kidney disease., Conclusions: In this retrospective national population-based study, selection for TAVR was significantly associated with higher all-cause mortality compared with sB-AVR in patients ≥65 years with severe, symptomatic aortic stenosis in the >2-year follow-up., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Objective: To evaluate the use of patient portal messaging to recruit individuals historically underrepresented in biomedical research (UBR) to the All of Us Research Program (AoURP) at a single recruitment site., Materials and Methods: Patient portal-based recruitment was implemented at Columbia University Irving Medical Center. Patient engagement was assessed using patient's electronic health record (EHR) at four recruitment stages: Consenting to be contacted, opening messages, responding to messages, and showing interest in participating. Demographic and socioeconomic data were also collected from patient's EHR and univariate logistic regression analyses were conducted to assess patient engagement., Results: Between October 2022 and November 2023, a total of 59 592 patients received patient portal messages inviting them to join the AoURP. Among them, 24 445 (41.0%) opened the message, 8983 (15.1%) responded, and 3765 (6.3%) showed interest in joining the program. Though we were unable to link enrollment data with EHR data, we estimate about 2% of patients contacted ultimately enrolled in the AoURP. Patients from underrepresented race and ethnicity communities had lower odds of consenting to be contacted and opening messages, but higher odds of showing interest after responding., Discussion: Patient portal messaging provided both patients and recruitment staff with a more efficient approach to outreach, but patterns of engagement varied across UBR groups., Conclusion: Patient portal-based recruitment enables researchers to contact a substantial number of participants from diverse communities. However, more effort is needed to improve engagement from underrepresented racial and ethnic groups at the early stages of the recruitment process., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: Patients with persistent atrial fibrillation (AF) experience 50% recurrence despite pulmonary vein isolation (PVI), and no consensus is established for secondary treatments. The aim of our i-STRATIFICATION study is to provide evidence for stratifying patients with AF recurrence after PVI to optimal pharmacological and ablation therapies, through in silico trials., Methods and Results: A cohort of 800 virtual patients, with variability in atrial anatomy, electrophysiology, and tissue structure (low-voltage areas, LVAs), was developed and validated against clinical data from ionic currents to electrocardiogram. Virtual patients presenting AF post-PVI underwent 12 secondary treatments. Sustained AF developed in 522 virtual patients after PVI. Second ablation procedures involving left atrial ablation alone showed 55% efficacy, only succeeding in the small right atria (<60 mL). When additional cavo-tricuspid isthmus ablation was considered, Marshall-PLAN sufficed (66% efficacy) for the small left atria (<90 mL). For the bigger left atria, a more aggressive ablation approach was required, such as anterior mitral line (75% efficacy) or posterior wall isolation plus mitral isthmus ablation (77% efficacy). Virtual patients with LVAs greatly benefited from LVA ablation in the left and right atria (100% efficacy). Conversely, in the absence of LVAs, synergistic ablation and pharmacotherapy could terminate AF. In the absence of ablation, the patient's ionic current substrate modulated the response to antiarrhythmic drugs, being the inward currents critical for optimal stratification to amiodarone or vernakalant., Conclusion: In silico trials identify optimal strategies for AF treatment based on virtual patient characteristics, evidencing the power of human modelling and simulation as a clinical assisting tool., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The immediate result of percutaneous balloon mitral commissurotomy is largely determined by the anatomy of the mitral valve complex. Several scores and models have been developed to assess anatomical suitability for percutaneous balloon mitral commissurotomy. Although none has an optimal predictive power, these models look at the valvular apparatus from different perspectives bearing the potential for a complementary role., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Objectives: People with parkinsonism who are older, living in a care home, with frailty, multimorbidity or impaired capacity to consent are under-represented in research, limiting its generalisability. We aimed to evaluate more inclusive recruitment strategies., Methods: From one UK centre, we invited people with parkinsonism to participate in a cross-sectional study. Postal invitations were followed by telephone reminders and additional support to facilitate participation. Personal consultees provided information on the views regarding research participation of adults with impaired capacity. These approaches were evaluated: (i) using external data from the Parkinson's Real World Impact assesSMent (PRISM) study and Clinical Practice Research Datalink (CPRD), a sample of all cases in UK primary care, and (ii) comparing those recruited with or without intensive engagement., Results: We approached 1,032 eligible patients, of whom 542 (53%) consented and 477 (46%) returned questionnaires. The gender ratio in PRIME-UK (65% male) closely matched CPRD (61% male), unlike in the PRISM sample (46%). Mean age of PRIME participants was 75.9 (SD 8.5) years, compared to 75.3 (9.5) and 65.4 (8.9) years for CPRD and PRISM, respectively. More intensive engagement enhanced recruitment of women (13.3%; 95% CI 3.8, 22.9%; P = 0.005), care home residents (6.2%; 1.1, 11.2%; P = 0.004), patients diagnosed with atypical parkinsonism (13.7%; 5.4, 19.9%; P < 0.001), and those with a higher frailty score (mean score 0.2, 0.1, 0.2; P < 0.001)., Conclusions: These recruitment strategies resulted in a less biased and more representative sample, with greater inclusion of older people with more complex parkinsonism., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background: Recruitment for randomized controlled trials [RCTs] in inflammatory bowel diseases [IBD] has substantially dropped over time. This study aimed to assess reasons why IBD patients are not included in sponsored multicentre phase IIb-III RCTs., Methods: All IOIBD members [n = 58] were invited to participate. We divided barriers to participation as follows: [1] reasons patients with active IBD were not deemed appropriate for an RCT; [2] reasons qualified patients did not wish to participate; and [3] reasons for screen failure [SF] in patients agreeing to participate. We assess these in a 4-week prospective study including, consecutively, all patients with symptomatic disease for whom a treatment change was required. In addition, we performed a 6-month retrospective study to further evaluate reasons for SF., Results: A total of 106 patients (60 male [56.6%], 63 Crohn's disease [CD] [59.4%]), from ten centres across the world, were included in the prospective study. An RCT has not been proposed to 65 of them [mainly due to eligibility criteria]. Of the 41 patients to whom an RCT was offered, eight refused [mainly due to reluctance to receive placebo] and 28 agreed to participate. Among these 28 patients, five failed their screening and 23 were finally included in an RCT. A total of 107 patients (61 male [57%], 67 CD [62.6%]), from 13 centres worldwide, were included in our retrospective study of SFs. The main reason was insufficient disease activity., Conclusion: This first multicentre study analysing reasons for non-enrolment in IBD RCTs shows that we lose patients at each step. Eligibility criteria, the risk of placebo assignment, and insufficient disease activity were part of the main barriers., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The second generation of transcatheter pacing systems, called Micra AV, can provide atrioventricular (AV) synchronous pacing via a new pacing algorithm relying on sensing mechanical atrial contraction. Several novel programming parameters were introduced to enable AV synchronous pacing, including an A3 window and A4 window as well as a conduction mode switch and an activity mode switch. In addition to several automated features, manual programming optimization of some of the novel parameters is key to improving AV synchrony. A solid knowledge of the features and their programming is essential for electrophysiologists implanting or following patients with Micra AV devices. Differences in programming optimization might partially explain the high variability of AV synchrony published in real-world data reports. This article reviews the key programming parameters of Micra AV. Subsequently, optimal programming recommendations for defined patient profiles are presented. Those were established by consensus within an expert panel comprised of 11 European electrophysiologists from high-volume Micra AV centres. The patient profiles were (1) high degree AV block and slow sinus rhythm; (2) high degree AV block and fast sinus rhythm; and (3) intermittent AV block. The panel recommended to evaluate the mechanical atrial activity on transthoracic echocardiography prior to implant. It was also agreed that Auto A3 Threshold and Tracking Check should be turned off in all patients, AV conduction mode switch should be turned off in all patients with high degree AV block, and the lower rate should be programmed to 50 bpm with exceptions based on individual clinical assessment. Future studies will be useful to evaluate the strength of those recommendations to improve the AV synchrony., Competing Interests: Conflict of interest: C.G. receives consultant and/or speaker fees and research grants from Abbot, Biotronik, and Medtronic. A.B. has received consultant and/or speaker fees from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, Bristol-Myers Squibb, Cook Medical, Daiichi Sankyo, Medtronic, Pfizer, and Spectranetics/Philips. N.C. receives consulting fees from Medtronic. C.D.A. received research grants from Biotronik, Medtronic, Abbott, LivaNova, Boston Scientific, AtriCure, Philips, and Acutus; and received compensation for teaching purposes and proctoring from Medtronic, Abbott, Biotronik, Livanova, Boston Scientific, Atricure, Acutus Medical, and Daiichi Sankyo. J.B.J. receives consulting fees from Medtronic. T.R. receives research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, and the Sitem Insel support fund; speaker/consulting honoraria or travel support from Abbott/SJM, Bayer, Biosense Webster, Biotronik, Boston Scientific, Daiichi Sankyo, Farapulse, Medtronic, and Pfizer-BMS; support for the institution’s fellowship programme from Abbott/SJM, Biosense Webster, Biotronik, Boston Scientific, and Medtronic. All remaining authors have declared no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Older patients with multimorbidity are under-represented in experimental research., Objective: To explore the barriers and facilitators to general practitioner (GP) and older patient recruitment and retention in a cluster randomized controlled trial (RCT)., Method: This descriptive study uses qualitative and quantitative data from a cluster RCT, designed to evaluate the effectiveness of a medicines optimization intervention. The SPPiRE cluster RCT enrolled 51 general practices and 404 patients aged ≥65 years and prescribed ≥15 medicines. Quantitative data were collected from all recruited practices and 32 additional practices who were enrolled, but unable to recruit sufficient participants. Qualitative data were collected from purposive samples of intervention GPs (18/26), patients (27/208), and researcher logs and analysed thematically using inductive coding., Results: Enrolment rates for practices and patients were 37% and 25%, respectively. Barriers to GP recruitment were lack of resources and to patient recruitment were difficulty understanding trial material and concern about medicines being taken away. GPs' primary motivation was perceived importance of the research question, whereas patients' primary motivation was trust in their GP. All general practices were retained. Thirty-five patients (8.6%) were lost to follow-up for primary outcomes, mainly because they had died and 45% did not return patient-reported outcome measures (PROMs)., Conclusion: Patient retention for the primary outcome was high, as it was collected directly from patient records. Patient completion of PROM data was poor, reflecting difficulty in understanding trial material. Recruiting older patients with multimorbidity to clinical trials is possible but requires significant resource and planning., Trial Registration: ISRCTN Registry ISRCTN12752680., (© The Author(s) 2023. Published by Oxford University Press.)

Introduction: Participant recruitment to clinical trials is often sub-optimal. Decentralized clinical trials have the potential to address challenges in traditional site-based clinical trial recruitment., Sources of Data: This review is based on recently published literature and the experience of running a large industry-sponsored interventional trial using both traditional and decentralized methods., Areas of Agreement: Efficient delivery of clinical trials is essential to continue to provide therapeutic improvements in a timely and cost-efficient way. Clinical trial designs are constantly evolving to achieve effective trial delivery, manage the complexity of new therapeutic algorithms and conform to cultural developments., Areas of Controversy: Digitally innovative decentralized clinical trials may be a solution to improve recruitment and retention. Although many trials incorporate digital innovations to reduce patient burden, decentralized clinical trials allow remote access to clinical research, potentially enhancing geographical diversity as well as reducing participant burden., Growing Points: Areas for development currently being discussed are developing a 'recruitment platform' that exploits the reach of digital connectivity, automated identification of eligible participants from volunteers, employing technology for remote interaction and exploring the logistic process of delivering the interventions., Areas Timely for Relevant Research: The focus of development must ensure that the overall impact will widen participation and reduce inequalities in healthcare., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Previously reported post hoc multivariable analyses exploring predictors of confirmed virologic failure (CVF) with cabotegravir + rilpivirine long-acting (CAB + RPV LA) were expanded to include data beyond week 48, additional covariates, and additional participants., Methods: Pooled data from 1651 participants were used to explore dosing regimen (every 4 or every 8 weeks), demographic, viral, and pharmacokinetic covariates as potential predictors of CVF. Prior dosing regimen experience was accounted for using 2 populations. Two models were conducted in each population-baseline factor analyses exploring factors known at baseline and multivariable analyses exploring baseline factors plus postbaseline model-predicted CAB/RPV trough concentrations (4 and 44 weeks postinjection). Retained factors were evaluated to understand their contribution to CVF (alone or in combination)., Results: Overall, 1.4% (n = 23/1651) of participants had CVF through 152 weeks. The presence of RPV resistance-associated mutations, human immunodeficiency virus-1 subtype A6/A1, and body mass index ≥30 kg/m2 were associated with an increased risk of CVF (P < .05 adjusted incidence rate ratio), with participants with ≥2 of these baseline factors having a higher risk of CVF. Lower model-predicted CAB/RPV troughs were additional factors retained for multivariable analyses., Conclusions: The presence of ≥2 baseline factors (RPV resistance-associated mutations, A6/A1 subtype, and/or body mass index ≥30 kg/m2) was associated with increased CVF risk, consistent with prior analyses. Inclusion of initial model-predicted CAB/RPV trough concentrations (≤first quartile) did not improve the prediction of CVF beyond the presence of a combination of ≥2 baseline factors, reinforcing the clinical utility of the baseline factors in the appropriate use of CAB + RPV LA., Competing Interests: Potential conflicts of interest . C. O. reports personal fees and grants from ViiV Healthcare, GSK, Gilead Sciences, MSD, and Janssen; grants from AstraZeneca; travel support from Gilead Sciences and ViiV Healthcare; and is the president of the Medical Women's Federation (UK) and a governing council member of the International AIDS Society. J. M. S. reports personal consulting fees, honoraria, travel support, participation on a Data Safety Monitoring or Advisory Board, and nonfinancial support from Gilead Sciences, Merck, ViiV Healthcare, Pfizer, Moderna, GSK, Teva, and AbbVie. C. F. P. reports consulting fees and payment or honoraria from Gilead Sciences, ViiV Healthcare, GSK, AstraZeneca, Janssen, and Merck; and participation on a Data Safety Monitoring or Advisory Board for ViiV Healthcare, Gilead Sciences, Merck, and Janssen. D. R. K. has received grants from ViiV Healthcare, Gilead Sciences, Merck, and the National Institutes of Health; reports payment for expert testimony from Gilead Sciences; consulting fees from Gilead Sciences, GSK, Janssen, AbbVie, Merck, and ViiV Healthcare; payment or honoraria from Gilead Sciences and Janssen; and participation on a Data Safety Monitoring or Advisory Board for GSK and ViiV Healthcare. P. P., Y. W., C. L. L., M. S. C., J. W. P., R. D’A., H. P. G., A. Z., W. R. S., J. v. W., and A. G. C. are employees of ViiV Healthcare and stockholders of GSK. R. D., D. D., K. H., and S. L. F. are employees and stockholders of GSK. H. C., S. V., and K. V. are employees and may be stockholders of Janssen, Pharmaceutical Companies of Johnson & Johnson. V. V. E. is an employee and may be a stockholder of Janssen, Pharmaceutical Companies of Johnson & Johnson, and has a pending patent for HIV infection treatment in children., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: The U.S. Navy offers an attractive opportunity for residency training in orthopedic surgery. The factors that Navy orthopedic residency program leadership finds important in applicant selection for training have not been reported. Additionally, data regarding the academic competitiveness of recently matched applicants have not been previously published. This study presents the results of two surveys administered to all navy orthopedic program directors and department chairmen, as well as data for United States Medical Licensing Examination (USMLE) Steps 1 and 2, medical school class percentile, leadership responsibilities, research endeavors, and letters of recommendation of both matched and unmatched applicants., Materials and Methods: Two anonymous surveys were administered to all program directors and department chairmen at Navy orthopedic residency training programs with questions designed to gauge perceived importance of various application factors when selecting for the match. The results were compiled, and mean levels of importance were reported. Deidentified data were collected on all applicants to Navy orthopedic residency programs from 2015 to 2019. Data points specific to USMLE Step 1 and 2 board scores, medical school class percentile, research, leadership, and letters of recommendation were analyzed using single and multiple logistic regression analyses, and odds ratios for each variable were calculated., Results: Navy leadership unanimously expressed that clerkship performance at the individual program director's institution was most important, followed by Steps 1 and 2 licensing examination scores. Single logistic regression analyses showed that Step 1 score and clinical, leadership, and recommendation scores were statistically significant. When controlled for Step 1 score, only academic performance and leadership scores maintained statistical significance., Conclusions: Applicants to Navy orthopedic surgery residency programs should strive to be competitive in all aspects of their application, with specific emphasis placed on outstanding performance during orthopedic clerkships, demonstration of leadership characteristics, and academic excellence. With transition to a pass/fail grading system for Step 1, there will be more emphasis on other measures of academic success, such as Step 2 scores and clinical clerkship grades., (© The Association of Military Surgeons of the United States 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A crucial step in inbred plant breeding is the choice of mating design to derive high-performing inbred varieties while also maintaining a competitive breeding population to secure sufficient genetic gain in future generations. In practice, the mating design usually relies on crosses involving the best parental inbred lines to ensure high mean progeny performance. This excludes crosses involving lower performing but more complementary parents in terms of favorable alleles. We predicted the ability of crosses to produce putative outstanding progenies (high mean and high variance progeny distribution) using genomic prediction models. This study compared the benefits and drawbacks of 7 genomic cross selection criteria (CSC) in terms of genetic gain for 1 trait and genetic diversity in the next generation. Six CSC were already published, and we propose an improved CSC that can estimate the proportion of progeny above a threshold defined for the whole mating plan. We simulated mating designs optimized using different CSC. The 835 elite parents came from a real breeding program and were evaluated between 2000 and 2016. We applied constraints on parental contributions and genetic similarities between selected parents according to usual breeder practices. Our results showed that CSC based on progeny variance estimation increased the genetic value of superior progenies by up to 5% in the next generation compared to CSC based on the progeny mean estimation (i.e. parental genetic values) alone. It also increased the genetic gain (up to 4%) and/or maintained more genetic diversity at QTLs (up to 4% more genic variance when the marker effects were perfectly estimated)., Competing Interests: Conflicts of interest The authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Glioblastoma is a deadly brain tumor without any significantly successful treatments to date. Tumor antigen-targeted immunotherapy platforms including peptide and dendritic cell (DC) vaccines, have extended survival in hematologic malignancies. The relatively "cold" tumor immune microenvironment and heterogenous nature of glioblastoma have proven to be major limitations to translational application and efficacy of DC vaccines. Furthermore, many DC vaccine trials in glioblastoma are difficult to interpret due to a lack of contemporaneous controls, absence of any control comparison, or inconsistent patient populations. Here we review glioblastoma immunobiology aspects that are relevant to DC vaccines, review the clinical experience with DC vaccines targeting glioblastoma, discuss challenges in clinical trial design, and summarize conclusions and directions for future research for the development of effective DC vaccines for patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Transcatheter therapies for the treatment of structural heart diseases (SHD) have expanded dramatically over the last years, thanks to the developments and improvements of devices and imaging techniques, along with the increasing expertise of operators. Imaging, in particular echocardiography, is pivotal during patient selection, procedural monitoring, and follow-up. The imaging assessment of patients undergoing transcatheter interventions places demands on imagers that differ from those of the routine evaluation of patients with SHD, and there is a need for specific expertise for those working in the cath lab. In the context of the current rapid developments and growing use of SHD therapies, this document intends to update the previous consensus document and address new advancements in interventional imaging for access routes and treatment of patients with aortic stenosis and regurgitation, and mitral stenosis and regurgitation., Competing Interests: Conflict of interest: E.A.: speaker and proctoring fees, research and educational grant from Philips, Edwards, Abbott, GE, and Siemens. E.B.: Proctoring fees from Abbott. M.D.: speaker fees from Pfizer and have participated on advisory boards for Novartis. F.F.: speaker's fees from Philips. P.M.-H.: Shareholder of Neumann Medical Ltd. M.S.: lecturer/proctor for Abbott Vascular, Boston Scientific, Philips Healthcare, and Bioventrix inc. R.S.V.B.: Trials (un-paid): IIT IZKS University of Go¨ttingen, Abbott Vascular, Bioventrix, Boston Scientific, Edwards Lifesciences, Medtronic; Speaker/ Advisory: Abbott Lifesciences, Bioventrix, Boston Scientific, Cardiac Dimensions, Edwards Lifesciences, and Philips. J.-L.Z.: research grants from Abbott. Speaker fee Daichii Sankio, Pfizer. B.A.P.: research grants and lecture fees from GE Healthcare and Hitachi-Aloka., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Left ventricular ejection fraction (LVEF) is suboptimal as a sole marker for predicting sudden cardiac death (SCD). Machine learning (ML) provides new opportunities for personalized predictions using complex, multimodal data. This study aimed to determine if risk stratification for implantable cardioverter-defibrillator (ICD) implantation can be improved by ML models that combine clinical variables with 12-lead electrocardiograms (ECG) time-series features., Methods and Results: A multicentre study of 1010 patients (64.9 ± 10.8 years, 26.8% female) with ischaemic, dilated, or non-ischaemic cardiomyopathy, and LVEF ≤ 35% implanted with an ICD between 2007 and 2021 for primary prevention of SCD in two academic hospitals was performed. For each patient, a raw 12-lead, 10-s ECG was obtained within 90 days before ICD implantation, and clinical details were collected. Supervised ML models were trained and validated on a development cohort (n = 550) from Hospital A to predict ICD non-arrhythmic mortality at three-year follow-up (i.e. mortality without prior appropriate ICD-therapy). Model performance was evaluated on an external patient cohort from Hospital B (n = 460). At three-year follow-up, 16.0% of patients had died, with 72.8% meeting criteria for non-arrhythmic mortality. Extreme gradient boosting models identified patients with non-arrhythmic mortality with an area under the receiver operating characteristic curve (AUROC) of 0.90 [95% confidence intervals (CI) 0.80-1.00] during internal validation. In the external cohort, the AUROC was 0.79 (95% CI 0.75-0.84)., Conclusions: ML models combining ECG time-series features and clinical variables were able to predict non-arrhythmic mortality within three years after device implantation in a primary prevention population, with robust performance in an independent cohort., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

This article is an expert review of published literature with the goal of defining the ideal patient selection for Magnetic Sphincter Augmentation (MSA) in Anti-reflux Surgery (ARS). The authors performed a literature search of outcomes after MSA for different patient populations. Although MSA utilization has expanded to include patients with advanced gastroesophageal reflux disease (GERD), obese patients, and patients with a history of bariatric surgery there is still a paucity of data to support its definitive use in these cohorts. We concluded that younger patients with mild/moderate GERD as evidenced by objective studies in conjunction with normal motility on manometry have the most favorable outcomes after MSA. MSA should be avoided in patients with allergies to nickel, titanium, stainless steel, or ferrous materials. As the utilization of MSA in ARS continues to expand and as more robust data emerges the ideal patient for this device will likely expand as well., (Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus 2023.)

Breast MRI is the most sensitive imaging modality for the assessment of newly diagnosed breast cancer extent and can detect additional mammographically and clinically occult breast cancers in the ipsilateral and contralateral breasts. Nonetheless, appropriate use of breast MRI in the setting of newly diagnosed breast cancer remains debated. Though highly sensitive, MRI is less specific and may result in false positives and overestimation of disease when MRI findings are not biopsied prior to surgical excision. Furthermore, improved anatomic depiction of breast cancer on MRI has not consistently translated to improved clinical outcomes, such as lower rates of re-excision or breast cancer recurrence, though there is a paucity of well-designed studies examining these issues. In addition, current treatment paradigms have been developed in the absence of this more accurate depiction of disease span, which likely has limited the value of MRI. These issues have led to inconsistent and variable utilization of preoperative MRI across practice settings and providers. In this review, we discuss the history of breast MRI and its current use and recommendations with a focus on the preoperative setting. We review the evidence surrounding the use of preoperative MRI in the evaluation of breast malignancies and discuss the data on breast MRI in the setting of specific patient factors often used to determine breast MRI eligibility, such as age, index tumor phenotype, and breast density. Finally, we review the impact of breast MRI on surgical outcomes (re-excision and mastectomy rates) and long-term breast recurrence and survival outcomes., (© Society of Breast Imaging 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Participants enrolled in cardiovascular disease (CVD) randomized controlled trials are not often representative of the population living with the disease. Older adults, children, women, Black, Indigenous and People of Color, and people living in low- and middle-income countries are typically under-enrolled in trials relative to disease distribution. Treatment effect estimates of CVD therapies have been largely derived from trial evidence generated in White men without complex comorbidities, limiting the generalizability of evidence. This review highlights barriers and facilitators of trial enrollment, temporal trends, and the rationale for representativeness. It proposes strategies to increase representativeness in CVD trials, including trial designs that minimize the research burden on participants, inclusive recruitment practices and eligibility criteria, diversification of clinical trial leadership, and research capacity-building in under-represented regions. Implementation of such strategies could generate better and more generalizable evidence to reduce knowledge gaps and position the cardiovascular trial enterprise as a vehicle to counter existing healthcare inequalities., Competing Interests: Conflict of interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. E.L. has an American Heart Association (AHA) Strategically-Focused Research Network (SFRN) grant studying diversity in clinical trials. T.P.W. is funded by the Division of Intramural Research of the National Heart, Lung, and Blood Institute and the Intramural Research Program of the National Institute on Minority Health and Health Disparities. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institute on Minority Health and Health Disparities; the National Institutes of Health; or the U.S. Department of Health and Human Services. J.M. has received grant support from the National Heart, Lung, and Blood Institute; Alliance for Health Policy and Systems Research; Bloomberg Philanthropies; FONDECYT; British Council, British Embassy and the Newton-Paulet Fund; DFID/MRC/Wellcome Global Health Trials; Fogarty International Center; Grand Challenges Canada; International Development Research Center Canada; Inter-American Institute for Global Change Research; National Cancer Institute; National Institute of Mental Health; Swiss National Science Foundation; Wellcome; and World Diabetes Foundation. The content in this manuscript represents the views of the authors and does not represent the views of the organizations that support J.M. L.Z. is funded by the South African Medical Research Council (SAMRC) through its Division of Research Capacity Development under the Mid-Career Scientist Programme from funding received from the South African National Treasury. The content hereof is the sole responsibility of the authors and does not necessarily represent the official views of the SAMRC. L.Z. also receives support from the National Research Foundation of South Africa (NRFSA), as well as the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement, via the African Research Leader Award (MR/S005242/1)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Traditional clinical trial eligibility criteria restrict study populations, perpetuating enrollment disparities. We aimed to assess implementation of modernized eligibility criteria guidelines among pancreatic cancer (PC) clinical trials. Interventional PC trials in the United States since January 1, 2014, were identified via clinicaltrials.gov with December 31, 2017, as the transition for pre- and postguidance eras. Trials were assessed for guideline compliance and compared using Fisher exact test. In total, 198 trials were identified: 86 (43.4%) were pre- and 112 (56.6%) postguidance era. Improvements were seen in allowing patients with history of HIV (8.6% vs 43.8%; P < .0001), prior cancer (57.0% vs 72.3%; P = .034), or concurrent and/or stable cancer (2.1% vs 31.1%; P < .0001) to participate. Most (>95%) trials were compliant with laboratory reference ranges, QT interval corrected for heart rate (QTc) cutoffs, and rationalizing excluding prior therapies both pre- and postguidance eras. However, overall compliance with modernized criteria remains poor. We advocate for stakeholders to update protocols and scrutinize traditionally restrictive eligibility criteria., (© The Author(s) 2023. Published by Oxford University Press.)

When individuals self-select (or are selected) into a study based on factors that influence the outcome, conclusions may not generalize to the full population. To compensate for this, results may be adjusted, for example, by standardization on the set of common causes of participation and outcome. Although such standardization is useful in some contexts, the common causes of participation and outcome may in practice not be fully observed. Instead, the researcher may have access to one or several variables related to the common causes, that is, to proxies for the common causes. This article defines and examines different types of proxy variables and shows how these can be used to obtain generalizable study results. First of all, the researcher may exploit proxies that influence only participation or outcome but which still allow for perfect generalizability by rendering participation and outcome conditionally independent. Further, generalizability can be achieved by leveraging 2 proxies, one of which is allowed to influence participation and one of which is allowed to influence the outcome, even if participation and outcome do not become independent conditional on these. Finally, approximate generalizability may be obtained by exploiting a single proxy that does not itself influence participation or outcome., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The dosing, potential adverse effects, and clinical outcomes of the most commonly utilized pharmacologic agents for rapid sequence intubation (RSI) are reviewed for the practicing emergency medicine pharmacist (EMP)., Summary: RSI is the process of establishing a safe, functional respiratory system in patients unable to effectively breathe on their own. Various medications are chosen to sedate and even paralyze the patient to facilitate an efficient endotracheal intubation. The mechanism of action and pharmacokinetic/pharmacodynamic profiles of these agents were described in a 2011 review. Since then, the role of the EMP as well as the published evidence regarding RSI agents, including dosing, adverse effects, and clinical outcomes, has grown. It is necessary for the practicing EMP to update previous practice patterns in order to continue to provide optimal patient care., Conclusion: While the agents used in RSI have changed little, knowledge regarding optimal dosing, appropriate patient selection, and possible adverse effects continues to be gained. The EMP is a key member of the bedside care team and uniquely positioned to communicate this evolving data., (© American Society of Health-System Pharmacists 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: In patients with prior myocardial infarction (MI) on aspirin, the addition of ticagrelor reduces ischaemic risk but increases bleeding risk. The simultaneous assessment of baseline ischaemic and bleeding risk may assist clinicians in selecting patients who are most likely to have a favourable risk/benefit profile with long-term ticagrelor., Methods and Results: PEGASUS-TIMI 54 randomized 21 162 prior MI patients, 13 956 of which to the approved 60 mg dose or placebo and who had all necessary data. The primary efficacy endpoint was cardiovascular death, MI, or stroke, and the primary safety outcome was TIMI major bleeding; differences in Kaplan-Meier event rates at 3 years are presented. Post-hoc subgroups based on predictors of bleeding and ischaemic risk were merged into a selection algorithm. Patients were divided into four groups: those with a bleeding predictor (n = 2721, 19%) and then those without a bleeding predictor and either 0-1 ischaemic risk factor (IRF; n = 3004, 22%), 2 IRF (n = 4903, 35%), or ≥3 IRF (n = 3328, 24%). In patients at high bleeding risk, ticagrelor increased bleeding [absolute risk difference (ARD) +2.3%, 95% confidence interval (CI) 0.6, 3.9] and did not reduce the primary efficacy endpoint (ARD +0.08%, 95% CI -2.4 to 2.5). In patients at low bleeding risk, the ARDs in the primary efficacy endpoint with ticagrelor were -0.5% (-2.2, 1.3), -1.5% (-3.1, 0.02), and -2.6% (-5.0, -0.24, P = 0.03) in those with ≤1, 2, and 3 risk factors, respectively (P = 0.076 for trend across groups). There were significant trends for greater absolute risk reductions for cardiovascular death (P-trend 0.018), all-cause mortality (P-trend 0.027), and net outcomes (P-trend 0.037) with ticagrelor across these risk groups., Conclusion: In a post-hoc exploratory analysis of patients with prior MI, long-term ticagrelor therapy appears to be best suited for those with prior MI with multiple IRFs at low bleeding risk., Clinical Trial Registration: NCT01225562 ClinicalTrials.gov., Competing Interests: Conflict of interest: The TIMI Study Group has received significant research grant support from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, Zora Biosciences. M.P.B. reports grant support to CPC clinical research from Amgen, AstraZeneca, Bayer, Janssen, Merck, Novo Nordisk, Pfizer, Sanofi, Wraser. M.D. reports personal fees for lectures and trial steering committee participation from AstraZeneca and Novartis, personal fees for lectures from Boehringer Ingelheim, Sanofi and Bayer. Advisory Board: Amgen, Novo Nordisk, AstraZeneca, Novartis. Personal fees for serving on the Data Monitoring Committee: for the DAPA-MI trial, funded by AstraZeneca. R.F.S. reports institutional research grants/support from AstraZeneca, Cytosorbents, GlyCardial Diagnostics, and Thromboserin; and personal fees from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb/Pfizer, Chiesi, CSL Behring, Cytosorbents, GlyCardial Diagnostics, Hengrui, Idorsia, Intas Pharmaceuticals, Medscape, Novartis, PhaseBio, Sanofi Aventis, and Thromboserin. D.L.B discloses the following relationships—Advisory Board: Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; Board of Directors: Bristol Myers Squibb (stock), Boston VA Research Institute, DRS.LINQ (stock options), Society of Cardiovascular Patient Care, TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, St Jude Medical (now Abbott), Philips, Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda. P.G.S. reports research grants from Amarin, Bayer, Merck, Sanofi, and Servier, speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer Ingelheim, Bristol Myers Squibb, Idorsia, Lilly, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, and Servier. M.C. reports grants and personal fees from AstraZeneca, during the conduct of the study; personal fees from Merck, personal fees from Janssen, personal fees from Maquet, personal fees from malpractice attorneys, grants from Janssen, grants from Edwards, personal fees from Merck, personal fees from BMS/Pfizer, personal fees from Janssen, personal fees from BI, personal fees from Lilly, outside the submitted work. K.I. is the member of the TIMI Study Group which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, and Zora Biosciences. P.J. is an employee of AstraZeneca. E.B. reports grant support through Brigham and Women’s Hospital from AstraZeneca, Daiichi Sankyo, Merck, and Novartis, Consultancies with Amgen, Cardurion, MyoKardia, Novo Nordisk, and Verve. M.S.S. received research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Intarcia, Ionis, Medicines Company, MedImmune, Merck, Novartis, Pfizer, and Quark Pharmaceuticals. Consulting for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol Myers Squibb, DalCor, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics. Additionally, Dr Sabatine is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from: ARCA Biopharma, Inc., Janssen Research and Development, LLC, Siemens Healthcare Diagnostics, Inc., Softcell Medical Limited, Regeneron, Roche, and Zora Biosciences., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)