Reporting and Analysis of Sex in Vascular Surgery Research.

OBJECTIVE: To examine sex in human vascular surgery research by quantifying the inclusion and analysis of sex-based data in high-impact vascular surgery journals. METHODS: A bibliographic review of original manuscripts published in the European Journal of Vascular and Endovascular Surgery, Journal of Vascular Surgery, JVS: Venous and Lymphatic Disorders, Journal of Endovascular Therapy, and Annals of Vascular Surgery from January 1, 2018 to December 31, 2020 and January 1, 2023 to December 31, 2023 was conducted. Abstracted data included sex-based data analysis, inclusion of sex as a variable in multivariable analysis, inclusion of sex as an independent variable, and a discussion of sex-based results. RESULTS: Of the 3,762 articles that included human, animal, or cell subjects, 249 (6.6%) did not state sex. Of those 249 articles, 183 included human subjects, 55 included animal subjects and 11 utilized cell lines as the subjects. These were removed from analysis as well as the remaining 68 articles with animal subjects. Additionally, 23 researched a sex-specific pathology and were removed from analysis. Of the remaining 3,422 articles included in our study, 42.3% analyzed sex, 46.9% included sex in multivariable analysis, 4.8% included sex as an independent variable, and 26.6% of articles included a discussion of sex. There were no significant differences in all four sex variables between 2018, 2019, and 2020. Between 2018-2020 and 2023, there were significant increases in all four sex variables. Multicenter studies had significantly higher rates of independent analysis of sex over single center studies (7.4% vs 3.3%, p <0.001). There was no significant difference in independent analysis of sex between US-based and non-US-based studies. Only 191 articles (5.6%) had 90% or greater matching of men and women in their study. CONCLUSIONS: Equitable inclusion and analysis of sex is rare in vascular surgery research. Less than 5% of articles included an independent analysis of data by sex and few studies included males and females equally. Clinical research is the basis for evidence-based medicine; therefore, it is important to strive for equitable inclusion, analysis, and reporting of data to foster generalizability of clinical research to men and women.

Discordance of patient-reported outcome measures with objectively assessed walking decline in peripheral artery disease.

OBJECTIVE: Among people with peripheral artery disease (PAD), perceived change in walking difficulty over time, compared with people without PAD, is unclear. Among people reporting no change in walking difficulty over time, differences in objectively measured change in walking performance between people with and without PAD are unknown. METHODS: A total of 1289 participants were included. Eight hundred seventy-four participants with PAD (aged 71.1 ± 9.1 years) were identified from noninvasive vascular laboratories and 415 without PAD (aged 69.9 ± 7.6 years) were identified from people with normal vascular laboratory testing or general medical practices in Chicago. The Walking Impairment Questionnaire and 6-minute walk were completed at baseline and 1-year follow-up. The Walking Impairment Questionnaire assessed perceived difficulty walking due to symptoms in the calves or buttocks on a Likert scale (range, 0-4). Symptom change was determined by comparing difficulty reported at 1-year follow-up to difficulty reported at baseline. RESULTS: At 1-year follow-up, 31.9% of participants with and 20.6% of participants without PAD reported walking difficulty that was improved (P < .01), whereas 41.2% vs 55%, respectively, reported walking difficulty that was unchanged (P < .01). Among all reporting no change in walking difficulty, participants with PAD declined in 6-minute walk, whereas participants without PAD improved (-10 vs +15 meters; mean difference, -25; 95% confidence interval, -38 to -13; P < .01). CONCLUSIONS: Most people with PAD reported improvement or no change in walking difficulty from calf or buttock symptoms at one-year follow-up. Among all participants who perceived stable walking ability, those with PAD had significant greater declines in objectively measured walking performance, compared with people without PAD.

Barriers to participation in supervised exercise therapy reported by people with peripheral artery disease.

OBJECTIVE: This study identified barriers to participation in supervised exercise therapy covered by the Centers for Medicare and Medicaid Services (CMS), reported by people with lower extremity peripheral artery disease (PAD). METHODS: People with PAD participating in research studies of walking impairment due to PAD in the Chicagoland area were asked to complete a questionnaire between March 15, 2019, and July 12, 2022, assessing their experience and attitudes about supervised exercise therapy. Participants were identified using mailed postcards to people aged 50 and older in Chicagoland, from medical centers in Chicago, and using bus and train advertisements. The questionnaire was developed based on focus group feedback from people with PAD. RESULTS: Of 516 participants with PAD approached, 489 (94.8%) completed the questionnaire (mean age: 71.0 years [standard deviation: 8.7], mean ankle-brachial index: 0.71 [standard deviation: 0.25]; 204 [41.7%] women and 261 [53.4%] Black). Of the 489 participants, 416 (85.1%) reported that their physician had never prescribed or recommended supervised exercise therapy. Overall, 357 (73.2%) reported willingness to travel three times weekly to the medical center for supervised exercise participation. However, of these, 214 (59.9%) reported that they were unwilling or unable to pay the $11 per exercise session copay required for supervised exercise covered by CMS. Of 51 people with PAD who reported prior participation in supervised exercise, only 5 (9.8%) completed the 12 weeks of supervised exercise therapy covered by CMS and 29 (56.9%) completed 6 or fewer weeks. Of 131 (26.8%) unwilling to travel three times weekly to a center for supervised exercise, the most common reasons for unwillingness to participate were "too time-consuming" (55.0%), "too inconvenient" (45.8%), and "lack of interest in treadmill exercise" (28.2%). CONCLUSIONS: Approximately 2 to 4 years after CMS began covering supervised exercise for PAD, most people with PAD in this study from a large urban area had not participated in supervised exercise therapy. Of those who participated, most completed fewer than half of the sessions covered by CMS. The required CMS copayment was a common barrier to supervised exercise participation by people with PAD.

Gender Bias in Clinical Trial Enrollment: Female Authorship Matters.

BACKGROUND: Despite initiatives to promote equal enrollment of human subjects in clinical trials, females continue to be underrepresented. The goal of this work is to determine if female enrollment in human clinical trials published in 3 high-impact journals from 2015 to 2019 is correlated with gender of first and/or senior authors. METHODS: Clinical trials published in the Journal of the American Medical Association (JAMA), The Lancet, and the New England Journal of Medicine (NEJM) from January 1, 2015, to December 31, 2019, were reviewed. Trials were excluded for ongoing enrollment, sex-specific disease research, or author name without gender assignment. One-sample χ2 pairwise comparisons and two-tailed proportion tests on the proportion of females between gender author pairings were done overall and for each subset analysis. RESULTS: In total, 1,427 articles enrolled a total of 2,104,509 females and 2,616,981 males (44.6% vs. 55.4%, P ≤ 0.0001) in clinical trials. Overall, more females were enrolled if both first and senior authors were female (51.7% vs. 48.3%, P ≤ 0.0001). Proportion of females enrolled decreased with the following first and senior author pairings: female-male (48.9%), male-female (48.6%), and male-male (40.5%, P ≤ 0.0001 compared to female-female authorship). Greater female enrollment in clinical trials with female-female compared to male-male authorship persisted in subset analyses by funding source, phase, randomization for study participants, drug and/or device trial, and geographic location. Female enrollment was higher in 3 surgical specialties: neurosurgery (all authors: 52%, P ≤ 0.01), ophthalmology (all authors: 53.6%, P ≤ 0.0001), and surgery (all authors: 54.4%, P ≤ 0.0001). The majority of surgical specialties did not publish trials with female-female authorship but when stratifying by author gender pairing, surgical oncology had the highest female enrollment with female-female authorship (98.4%, P ≤ 0.0001). CONCLUSIONS: Female authorship of clinical trial publications, specifically having both first and senior authors as female, was correlated with higher female enrollment in clinical trials when compared to male authorship and endured with multiple subset analyses.

Cardiac Surgery in Women in the Current Era: What Are the Gaps in Care?

Cardiovascular disease remains the leading cause of morbidity and mortality for women in United States and worldwide. One in 3 women dies from cardiovascular disease, and 45% of women >20 years old have some form of CVD. Historically, women have had higher morbidity and mortality after cardiac surgery. Sex influences pathogenesis, pathophysiology, presentation, postoperative complications, surgical outcomes, and survival. This review summarizes current cardiovascular surgery outcomes as they pertain to women. Specifically, this article seeks to address whether sex disparities in research, surgical referral, and outcomes still exist and to provide strategies to close these gaps. In addition, with the growing population of women of reproductive age with cardiovascular disease and cardiovascular risk factors, indications for cardiac surgery arise in pregnant women. The current review will also address the unique issues associated with this special population.

A 22-year analysis of the Society for Vascular Surgery Foundation Mentored Research Career Development Award in fostering vascular surgeon-scientists.

OBJECTIVE: Vascular surgeon-scientists shape the future of our specialty through rigorous scientific investigation and innovation in clinical care and by training the next generation of surgeon-scientists. The Society for Vascular Surgery Foundation (SVSF) supports the development of surgeon-scientists through the Mentored Research Career Development Award (SVSF-CDA) program, providing supplemental funds to recipients of National Institutes of Health (NIH) K08/K23 grants. We evaluated the ongoing success of this mission. METHODS: The curriculum vitae of the 41 recipients of the SVSF supplemental funding from 1999 to 2021 were collected and reviewed to evaluate the academic achievements, define the programmatic accomplishments and return on investment, and identify areas for strategic improvement. RESULTS: For nearly 22 years, the SVSF has awarded supplemental funds for 31 K08 and 10 K23 grants to SVS members from 32 institutions. Of the 41 awardees, 34 have completed their K-funding and 7 are still being supported. Eleven awardees (27%) were women, including six of the current awardees (75%). However, only slight ethnic/racial diversity was found in the program. The awardees had obtained K-funding ∼4 years after becoming faculty. Eleven awardees (27%) were supported by Howard Hughes, NIH F32, or NIH T32 grants during training. To date, the SVSF has committed $12 million to the SVSF-CDA program. Among the 34 who have completed their K-funding, 21 (62%) successfully obtained NIH R01, Veterans Affairs, or Department of Defense funding. The awardees have secured >$114 million in federal funding, representing a 9.5-fold financial return on investment for the SVSF. In addition to research endeavors, 11 awardees (27%) hold endowed professorships and 19 (46%) have secured tenure at their institution. Many of the awardees hold or have held leadership positions, including 18 division chiefs (44%), 11 program directors (27%), 5 chairs of departments of surgery (12%), and 1 dean (2%). Eleven (27%) have served as president of a regional or national society, and 24 (59%) participate in NIH study sections. Of the 34 who have completed their K-funding, 15 (44%) have continued to maintain active independent research funding. CONCLUSIONS: The SVSF-CDA program is highly effective in the development of vascular surgeon-scientists who contribute to the leadership and growth of academic vascular surgery with a 9.5-fold return on investment. The number of female awardees has increased in recent years but ethnic/racial diversity has remained poor. Although 62% successfully transitioned to federal funding, fewer than one half have remained funded over time. Retention in research and increasing diversity for the awardees are major concerns and important areas of strategic focus for the SVSF.

Increased long-term bleeding complications in females undergoing endovascular revascularization for peripheral arterial disease.

OBJECTIVE: Females with peripheral arterial disease (PAD) treated with endovascular interventions have increased limb-based procedural complications compared with males. Little is known regarding long-term bleeding risk in these patients who often require long-term antiplatelet or anticoagulation therapy. We hypothesize that females have a higher incidence of bleeding events compared with males in the year after endovascular intervention for PAD. METHODS: Adults (aged ≥65 years) who underwent endovascular revascularization for PAD between 2008 and 2015 in Medicare claims data were identified. Patients were allocated by prescribed postprocedural antithrombotic therapy, including (1) antiplatelet therapy, (2) anticoagulation therapy, (3) dual antiplatelet and anticoagulation therapy, and (4) no prescription antithrombotic therapy. Bleeding events were classified as gastrointestinal, intracranial, hematoma, airway, or other. Crude and covariate-standardized 30-, 90-, and 365-day cumulative incidence of bleeding events, overall and by sex, were estimated using Aalen-Johansen estimators accounting for death as a competing risk. Sex differences were identified using Gray's test. RESULTS: Of 31,593 eligible patients, 54% were females. Females were older (77.9 years vs 75.5 years) and tended to use antiplatelet therapy more often at 30, 90, and 365 days after the intervention. Clopidogrel was the most prescribed antiplatelet, and 32% of patients continued its use at 365 days. Anticoagulants were prescribed to 26.0% of patients at the time of the procedure, and only 8.8% continued anticoagulation at 365 days. Thirty-one percent of patients were diagnosed with a bleeding event within 1 year after the intervention. The cumulative incidence of any bleeding event during the postintervention period was higher in females compared with males with a risk difference of 3% between the sex cohorts (P < .01). Specifically, females had a higher incidence of gastrointestinal bleeding and hematoma (P < .01), but a lower incidence of airway-related bleeding at each time point as compared with males (P < .01). CONCLUSIONS: Sex disparities in bleeding complications after endovascular intervention for PAD persist in the long term. Females are more likely to be readmitted with a bleeding complication up to 1 year after the procedure. Antithrombotic therapy disproportionately increases the risk of bleeding in females. Further research is necessary to understand the mechanisms responsible for abnormal coagulopathy in females after endovascular therapy.

Cocoa to Improve Walking Performance in Older People With Peripheral Artery Disease: The COCOA-PAD Pilot Randomized Clinical Trial.

RATIONALE: Cocoa and its major flavanol component, epicatechin, have therapeutic properties that may improve limb perfusion and increase calf muscle mitochondrial activity in people with lower extremity peripheral artery disease (PAD). OBJECTIVE: In a phase II randomized clinical trial, to assess whether 6 months of cocoa improved walking performance in people with PAD, compared with placebo. METHODS AND RESULTS: Six-month double-blind, randomized clinical trial in which participants with PAD were randomized to either cocoa beverage versus placebo beverage. The cocoa beverage contained 15 g of cocoa and 75 mg of epicatechin daily. The identical appearing placebo contained neither cocoa nor epicatechin. The 2 primary outcomes were 6-month change in 6-minute walk distance measured 2.5 hours after a study beverage at 6-month follow-up and 24 hours after a study beverage at 6-month follow-up, respectively. A 1-sided P<0.10 was considered statistically significant. Of 44 PAD participants randomized (mean age, 72.3 years [±7.1]; mean ankle brachial index, 0.66 [±0.15]), 40 (91%) completed follow-up. Adjusting for smoking, race, and body mass index, cocoa improved 6-minute walk distance at 6-month follow-up by 42.6 m ([90% CI, +22.2 to +∞] P=0.005) at 2.5 hours after a final study beverage and by 18.0 m ([90% CI, -1.7 to +∞] P=0.12) at 24 hours after a study beverage, compared with placebo. In calf muscle biopsies, cocoa improved mitochondrial COX (cytochrome c oxidase) activity (P=0.013), increased capillary density (P=0.014), improved calf muscle perfusion (P=0.098), and reduced central nuclei (P=0.033), compared with placebo. CONCLUSIONS: These preliminary results suggest a therapeutic effect of cocoa on walking performance in people with PAD. Further study is needed to definitively determine whether cocoa significantly improves walking performance in people with PAD. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02876887. Visual Overview: An online visual overview is available for this article.

The Persistence of Sex Bias in High-Impact Clinical Research.

INTRODUCTION: Sex bias is present in clinical research resulting in disparities in the treatment of women. Our objective was to identify the prevalence of sex inclusiveness of participants in human clinical trials after the passage of National Institutes of Health (NIH) and United States Congress policies in 2015 and 2016 to increase female enrollment in clinical research. METHODS: We performed an observational analysis of data from registered clinical trials published in three high-impact biomedical journals from January 1, 2015 to December 31, 2019. RESULTS: One thousand four hundred and forty two manuscripts with 4,765,783 human subjects were included for analysis. Significantly more males (56%) than females (44%) were included in all three journals (P < 0.0001). Sex matching ≥ 80% was found in 24.6% of publications. Industry funded 43.7% of all studies enrolling significantly more males than females (60.8% versus 39.2%, P < 0.0001). NIH funded 10.2% of studies enrolling significantly more females than males (52.7% versus 47.3%, P < 0.0001). North America and Europe contributed 82.6% of the studies with each enrolling significantly more males than females (P < 0.0001). The United States was the country contributing the most studies (36.1%), enrolling significantly more males than females (55.5% versus 45.5%, P < 0.0001). Cardiovascular disease was the subject area of the most manuscripts among medical specialties (19%), enrolling significantly more males than females (64.9% versus 35.1%, P < 0.0001). Studies analyzed by clinical trial phase, type, trial, and allocation enrolled significantly more males than females (P < 0.0001). CONCLUSIONS: Sex bias remains prevalent in human clinical research trials. Improvements have been made in NIH-funded clinical trials; however, this constitutes a small percentage of overall studies.

The 2020 Pandemics: Lessons Learned in Academic Surgery and Beyond.

2020 was a significant year because of the occurrence of two simultaneous public health crises: the coronavirus pandemic and the public health crisis of racism brought into the spotlight by the murder of George Floyd. The coronavirus pandemic has affected all aspects of health care, particularly the delivery of surgical care, surgical education, and academic productivity. The concomitant public health crisis of racism and health inequality during the viral pandemic highlighted opportunities for action to address gaps in surgical care and the delivery of public health services. At the 2021 Academic Surgical Congress Hot Topics session on flexibility and leadership, we also explored how our military surgeon colleagues can provide guidance in leadership during times of crisis. The following is a summary of the issues discussed during the session and reflections on the important lessons learned in academic surgery over the past year.

Effect of Telmisartan on Walking Performance in Patients With Lower Extremity Peripheral Artery Disease: The TELEX Randomized Clinical Trial.

Importance: Patients with lower extremity peripheral artery disease (PAD) have reduced lower extremity perfusion, impaired lower extremity skeletal muscle function, and poor walking performance. Telmisartan (an angiotensin receptor blocker) has properties that reverse these abnormalities. Objective: To determine whether telmisartan improves 6-minute walk distance, compared with placebo, in patients with lower extremity PAD at 6-month follow-up. Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 2 US sites and involving 114 participants. Enrollment occurred between December 28, 2015, and November 9, 2021. Final follow-up occurred on May 6, 2022. Interventions: The trial randomized patients using a 2 × 2 factorial design to compare the effects of telmisartan plus supervised exercise vs telmisartan alone and supervised exercise alone and to compare telmisartan alone vs placebo. Participants with PAD were randomized to 1 of 4 groups: telmisartan plus exercise (n = 30), telmisartan plus attention control (n = 29), placebo plus exercise (n = 28), or placebo plus attention control (n = 27) for 6 months. The originally planned sample size was 240 participants. Due to slower than anticipated enrollment, the primary comparison was changed to the 2 combined telmisartan groups vs the 2 combined placebo groups and the target sample size was changed to 112 participants. Main Outcomes and Measures: The primary outcome was the 6-month change in 6-minute walk distance (minimum clinically important difference, 8-20 m). The secondary outcomes were maximal treadmill walking distance; Walking Impairment Questionnaire scores for distance, speed, and stair climbing; and the 36-Item Short-Form Health Survey physical functioning score. The results were adjusted for study site, baseline 6-minute walk distance, randomization to exercise vs attention control, sex, and history of heart failure at baseline. Results: Of the 114 randomized patients (mean age, 67.3 [SD, 9.9] years; 46 were women [40.4%]; and 81 were Black individuals [71.1%]), 105 (92%) completed 6-month follow-up. At 6-month follow-up, telmisartan did not significantly improve 6-minute walk distance (from a mean of 341.6 m to 343.0 m; within-group change: 1.32 m) compared with placebo (from a mean of 352.3 m to 364.8 m; within-group change: 12.5 m) and the adjusted between-group difference was -16.8 m (95% CI, -35.9 m to 2.2 m; P = .08). Compared with placebo, telmisartan did not significantly improve any of the 5 secondary outcomes. The most common serious adverse event was hospitalization for PAD (ie, lower extremity revascularization, amputation, or gangrene). Three participants (5.1%) in the telmisartan group and 2 participants (3.6%) in the placebo group were hospitalized for PAD. Conclusions and Relevance: Among patients with PAD, telmisartan did not improve 6-minute walk distance at 6-month follow-up compared with placebo. These results do not support telmisartan for improving walking performance in patients with PAD. Trial Registration: ClinicalTrials.gov Identifier: NCT02593110.

Courtesy Authorship Practices Among First and Senior Authors: Evaluation of Motivations, Gender Bias, and Inequities.

OBJECTIVES: A courtesy author is an individual who has not met authorship criteria but is listed as an author. This practice is common and often seen as victimless. Because publications are used for funding and promotion decisions, it is critical to understand biases in this practice. METHODS: An anonymous survey was conducted from March to October 2020 of first and senior authors of publications from 2014 to 2015 in 8 surgical journals. Authors were surveyed about demographic data, practice setting, and courtesy author practices. RESULTS: Three hundred forty-one authors responded (16% response rate). 75% were from academic practice settings. 14% reported adding courtesy authors 5 or more times in the past year. Courtesy authors were more often male (80%, P = 0.023), older (75%), and of higher academic rank (65%) than first/senior authors. All author groups were >75% white. When a reason was reported, 46% added a courtesy author due to avoid retaliation; 64% to avoid awkwardness. 26% expected reciprocal authorship offers. 92% of respondents acknowledge understanding International Committee of Medical Journal Editors authorship criteria. Women were less common among those added from goodwill than those added from fear (P = 0.039.) When courtesy authors were of a lower rank than first/senior authors, they were nearly twice as likely to be female (P = 0.0056) or non-white (P = 0.0184.). CONCLUSION: Courtesy authors were more often male, older, and higher rank than first/senior authors. Fear of career consequences was a major motivator for including courtesy authors. Understanding the motivations and pressures leading to courtesy authorship will help to correct this practice.

Publication bias is the consequence of a lack of diversity, equity, and inclusion.

Publication bias has been shown to exist in research across medical and surgical specialties. Bias can occur at any stage of the publication process and can be related to race, ethnicity, age, religion, sex, gender, or sexual orientation. Although some improvements have been made toward addressing this issue, bias still spans the publication process from authors and peer reviewers, to editorial board members and editors, with poor inclusion of women and underrepresented minorities throughout. The result of bias remaining unchecked is the publication of research that leaves out certain groups, is not applicable to all people, and can result in harm to some populations. We have highlighted the current landscape of publication bias and strived to demonstrate the importance of addressing it. We have also provided solutions for reducing bias at multiple stages throughout the publication process. Increasing diversity, equity, and inclusion throughout all aspects of the publication process, requiring diversity, equity, and inclusion statements in reports, and providing specific education and guidelines will ensure the identification and eradication of publication bias. By following these measures, we hope that publication bias will be eliminated, which will reduce further harm to certain populations and promote better, more effective research pertinent to all people.

Clinical characteristics and response to supervised exercise therapy of people with lower extremity peripheral artery disease.

BACKGROUND: Among people with lower extremity peripheral artery disease (PAD), little is known about variation in response to supervised exercise therapy (SET). Clinical characteristics associated with greater responsiveness to SET have not been identified. METHODS: Data from participants with PAD in two randomized clinical trials comparing SET vs nonexercising control were combined. The exercise intervention consisted of three times weekly supervised treadmill exercise. The control groups received lectures on health-related topics. RESULTS: Of 309 unique participants randomized (mean age, 67.9 years [standard deviation, 9.3 years]; 132 [42.7%] women; 185 [59.9%] black), 285 (92%) completed 6-month follow-up. Compared with control, those randomized to SET improved 6-minute walk distance by 35.6 meters (95% confidence interval, 21.4-49.8; P < .001). In the 95 (62.1%) participants who attended at least 70% of SET sessions, change in 6-minute walk distance varied from -149.4 to +356.0 meters. Thirty-four (35.8%) had no 6-minute walk distance improvement. Among all participants, age, sex, race, body mass index, prior lower extremity revascularization, and other clinical characteristics did not affect the degree of improvement in 6-minute walk distance after SET relative to the control group. Participants with 6-minute walk distance less than the median of 334 meters at baseline had greater percentage improvement in 6-minute walk distance compared with those with baseline 6-minute walk distance above the median (+20.5% vs +5.3%; P for interaction = .0107). CONCLUSIONS: Among people with PAD, substantial variability exists in walking improvement after SET. Shorter 6-minute walk distance at baseline was associated with greater improvement after SET, but other clinical characteristics, including age, sex, prior lower extremity revascularization, and disease severity, did not affect responsiveness to exercise therapy.

Performance of Viabahn balloon-expandable stent compared with self-expandable covered stents for branched endovascular aortic repair.

OBJECTIVE: The objective of this study was to compare the performance between the Viabahn balloon-expandable stent (VBX; Viabahn [W. L. Gore & Associates, Flagstaff, Ariz]) and a covered self-expandable stent (SES; Fluency [Bard Peripheral Vascular, Tempe, Ariz]) used as bridging stents for directional branches during fenestrated or branched endovascular aneurysm repair of complex aortic aneurysms. METHODS: Patients with thoracoabdominal aortic aneurysms (type I-IV) or pararenal aortic aneurysms either at high risk for open repair or unsuitable for endovascular repair with commercially available devices were prospectively enrolled in a physician-sponsored investigational device exemption trial. Descriptive statistics of the cohort included demographics, risk factors, and anatomic and device characteristics. Individual branches were grouped as either VBX or SES and had data analyzed for primary patency, branch-related type I or type III endoleaks, branch instability, branch-related secondary intervention, and branch-related aortic rupture or death. Categorical variables were expressed as total and percentage, and continuous variables were expressed as median (interquartile range). Kaplan-Meier curves were used to estimate long-term results. Groups were compared with the log-rank test. P value <.05 was considered statistically significant. RESULTS: During the period from July 2012 through June 2019, there were 263 patients treated for complex aortic aneurysm (thoracoabdominal aortic aneurysm) with fenestrated or branched endografts. The devices used were either custom-manufactured devices or off-the-shelf p-Branch or t-Branch (Cook Medical, Bloomington, Ind) devices. The median age was 71 years (interquartile range, 66-79 years); 70% were male, and 81% were white. The most common cardiac risk factors were smoking (92%), hypertension (91%), hyperlipidemia (78%), and chronic obstructive pulmonary disease (52%). The total number of vessels incorporated into the repair was 977, with branches representing 18.4% (179 branches). Among these 179 branches, the celiac artery, superior mesenteric artery, right renal artery, and left renal artery received 54 (30%), 56 (31%), 38 (21%), and 31 (18%) branches, respectively. VBX and SES groups represented 96 (54%) and 81 (46%) of the branches implanted. The celiac artery, superior mesenteric artery, right renal artery, and left renal artery received VBX as a bridging stent in 40%, 46.7%, 33.8%, and 32.2% respectively. The overall cohort survival rate was 78.5% at 24 months. There was no branch-related rupture or mortality. Primary patency at 24 months (VBX, 98.1%; SES, 98.6%; log-rank, P = .95), freedom from endoleak (VBX, 95.6%; SES, 98.6%; log-rank, P = .66), freedom from secondary intervention (VBX, 94.7%; SES, 98.1%; log-rank, P = .33), and freedom from branch instability (VBX, 95.6%; SES, 97.2%; log-rank, P = .77) were similar between groups. CONCLUSIONS: This initial experience with VBX stents demonstrated excellent primary patency and similarly low rates of branch-related complications and endoleaks, with no branch-related aortic rupture or death. Our results demonstrate that in a high-volume, experienced aortic center, the VBX stent is a safe and effective bridging stent option during branched endovascular aortic repair. Multicenter studies with a larger cohort and longer follow-up are necessary to validate these findings.

Meaningful change in 6-minute walk in people with peripheral artery disease.

OBJECTIVE: The 6-minute walk test is a common outcome measure in clinical trials of people with lower extremity peripheral artery disease (PAD). However, what constitutes a meaningful change in the 6-minute walk distance has not been well defined for people with PAD. The present study related the change in the 6-minute walk distance to the degree of participant-reported improvement or decline in the 6-minute walk distance to define a meaningful change in the 6-minute walk distance for those with PAD. METHODS: Participants with PAD from three observational longitudinal studies completed the walking impairment questionnaire (WIQ) distance score and 6-minute walk at baseline and 1 year later. The WIQ distance score measures participants' perceived difficulty walking seven different distances without stopping (ranging from walking around the home to walking 5 blocks) on a 0 to 4 Likert scale, with 0 representing an inability to walk the distance and 4 representing no difficulty. The mean changes in the 6-minute walk distance corresponding to the participants' report of no change, 1-unit change, or 2-unit change, respectively, in the Likert scale score between the baseline and 1-year follow-up measures were calculated for each WIQ distance. RESULTS: A total of 777 participants with PAD (mean age, 71.2 ± 8.8 years; mean baseline 6-minute walk distance, 350.1 ± 118.1 meters) completed 5439 questions about their difficulty walking each WIQ distance at baseline and follow-up. Participants with PAD who reported no change in their difficulty in walking each WIQ distance between baseline and follow-up had a decline of 7.2 meters (95% confidence interval [CI], -11.6 to -2.8 meters) in the 6-minute walk test. Relative to those reporting no change in difficulty walking, the participants reporting 1- and 2-point improvements in walking ability showed 6-minute walk distance improvements of 7.8 meters (95% CI, -0.3 to 15.9 meters) and 20.1 meters (95% CI, 1.1-39.2 meters), respectively. Relative to those reporting no change in walking difficulty, those reporting 1- and 2-point declines in perceived walking difficulty showed declines of -11.2 meters (95% CI, -19.0 to -3.4 meters) and -23.8 meters (95% CI, -37.4 to -10.3 meters) in the 6-minute walk distance. CONCLUSIONS: Among people with PAD, ∼8- and ∼20-meter improvements in the 6-minute walk distance represent small and large improvements in walking ability, respectively. People with PAD who reported no change in their ability to walk distances over 1 year simultaneously declined by a mean of 7 meters in the 6-minute walk test. These findings will be useful for interpreting the results from randomized trials of interventions to improve the walking performance of people with PAD.

Emerging antenatal therapies for congenital diaphragmatic hernia-induced pulmonary hypertension in preclinical models.

Congenital diaphragmatic hernia (CDH)-related deaths are the largest contributor to in-hospital neonatal deaths in children with congenital malformations. Morbidity and mortality in CDH are directly related to the development of pulmonary hypertension (PH). Current treatment consists of supportive measures. To date, no pharmacotherapy has been shown to effectively reverse the hallmark finding of pulmonary vascular remodeling that is associated with pulmonary hypertension in CDH (CDH-PH). As such, there is a great need for novel therapies to effectively manage CDH-PH. Our review aims to evaluate emerging therapies, and specifically focuses on those that are still under investigation and not approved for clinical use by the Food and Drug Administration. Therapies were categorized into antenatal pharmacotherapies or antenatal regenerative therapies and assessed on their method of administration, safety profile, the effect on pulmonary vascular pathophysiology, and overall efficacy. In general, emerging antenatal pharmaceutical and regenerative treatments primarily aim to alleviate pulmonary vascular remodeling by restoring normal function and levels of key regulatory factors involved in pulmonary vascular development and/or in promoting angiogenesis. Overall, while these emerging therapies show great promise for the management of CDH-PH, most require further assessment of safety and efficacy in preclinical models before translation into the clinical setting. IMPACT: Emerging antenatal therapies for congenital diaphragmatic hernia-induced pulmonary hypertension (CDH-PH) show promise to effectively mitigate vascular remodeling in preclinical models. Further investigation is needed in preclinical and human studies to evaluate safety and efficacy prior to translation into the clinical arena. This review offers a comprehensive and up-to-date summary of emerging therapies currently under investigation in experimental animal models. There is no cure for CDH-PH. This review explores emerging therapeutic options for the treatment of CDH-PH and evaluates their impact on key molecular pathways and clinical markers of disease to determine efficacy in the preclinical stage.

Sustained physical activity in peripheral artery disease: Associations with disease severity, functional performance, health-related quality of life, and subsequent serious adverse events in the LITE randomized clinical trial.

This study investigated cross-sectional associations of peripheral artery disease (PAD) severity (defined by the ankle-brachial index (ABI)) and amounts of daily sustained physical activity (PA) (defined as > 100 activity counts per minute lasting 5 consecutive minutes or more). This study also investigated associations of amounts of daily sustained PA with 6-minute walk (6MW) distance and the Short Form-36 physical functioning domain (SF-36 PF) score in cross-sectional analyses and with serious adverse events (SAEs) in longitudinal analyses of people with PAD. PA was measured continuously for 10 days using a tri-axial accelerometer at baseline in 277 participants with PAD randomized to the LITE clinical trial. In regression analyses, each 0.15 lower ABI value was associated with a 5.67% decrease in the number of daily bouts of sustained PA (95% CI: 3.85-6.54; p < 0.001). Every additional bout of sustained PA per day was associated with a 4.56-meter greater 6MW distance (95% CI: 2.67-6.46; p < 0.0001), and a 0.81-point improvement in SF-36 PF score (95% CI: 0.34-1.28; p < 0.001). Participants with values of daily bouts of sustained PA below the median had higher rates of SAEs during follow-up, compared to participants above the median (41% vs 24%; p = 0.002). In conclusion, among participants with PAD, lower ABI values were associated with fewer bouts of daily sustained PA. A greater number of bouts of daily sustained PA were associated with better 6MW performance and SF-36 PF score, and, in longitudinal analyses, lower rates of SAEs. Clinicaltrials.gov ID: NCT02538900.

Effect of Low-Intensity vs High-Intensity Home-Based Walking Exercise on Walk Distance in Patients With Peripheral Artery Disease: The LITE Randomized Clinical Trial.

Importance: Supervised high-intensity walking exercise that induces ischemic leg symptoms is the first-line therapy for people with lower-extremity peripheral artery disease (PAD), but adherence is poor. Objective: To determine whether low-intensity home-based walking exercise at a comfortable pace significantly improves walking ability in people with PAD vs high-intensity home-based walking exercise that induces ischemic leg symptoms and vs a nonexercise control. Design, Setting, and Participants: Multicenter randomized clinical trial conducted at 4 US centers and including 305 participants. Enrollment occurred between September 25, 2015, and December 11, 2019; final follow-up was October 7, 2020. Interventions: Participants with PAD were randomized to low-intensity walking exercise (n = 116), high-intensity walking exercise (n = 124), or nonexercise control (n = 65) for 12 months. Both exercise groups were asked to walk for exercise in an unsupervised setting 5 times per week for up to 50 minutes per session wearing an accelerometer to document exercise intensity and time. The low-intensity group walked at a pace without ischemic leg symptoms. The high-intensity group walked at a pace eliciting moderate to severe ischemic leg symptoms. Accelerometer data were viewable to a coach who telephoned participants weekly for 12 months and helped them adhere to their prescribed exercise. The nonexercise control group received weekly educational telephone calls for 12 months. Main Outcomes and Measures: The primary outcome was mean change in 6-minute walk distance at 12 months (minimum clinically important difference, 8-20 m). Results: Among 305 randomized patients (mean age, 69.3 [SD, 9.5] years, 146 [47.9%] women, 181 [59.3%] Black patients), 250 (82%) completed 12-month follow-up. The 6-minute walk distance changed from 332.1 m at baseline to 327.5 m at 12-month follow-up in the low-intensity exercise group (within-group mean change, -6.4 m [95% CI, -21.5 to 8.8 m]; P = .34) and from 338.1 m to 371.2 m in the high-intensity exercise group (within-group mean change, 34.5 m [95% CI, 20.1 to 48.9 m]; P < .001) and the mean change for the between-group comparison was -40.9 m (97.5% CI, -61.7 to -20.0 m; P < .001). The 6-minute walk distance changed from 328.1 m at baseline to 317.5 m at 12-month follow-up in the nonexercise control group (within-group mean change, -15.1 m [95% CI, -35.8 to 5.7 m]; P = .10), which was not significantly different from the change in the low-intensity exercise group (between-group mean change, 8.7 m [97.5% CI, -17.0 to 34.4 m]; P = .44). Of 184 serious adverse events, the event rate per participant was 0.64 in the low-intensity group, 0.65 in the high-intensity group, and 0.46 in the nonexercise control group. One serious adverse event in each exercise group was related to study participation. Conclusions and Relevance: Among patients with PAD, low-intensity home-based exercise was significantly less effective than high-intensity home-based exercise and was not significantly different from the nonexercise control for improving 6-minute walk distance. These results do not support the use of low-intensity home-based walking exercise for improving objectively measured walking performance in patients with PAD. Trial Registration: ClinicalTrials.gov Identifier: NCT02538900.

A comparative study of a preclinical survival model of smoke inhalation injury in mice and rats.

Smoke inhalation injury increases morbidity and mortality. Clinically relevant animal models are necessary for the continued investigation of the pathophysiology of inhalation injury and the development of therapeutics. The goal of our research was threefold: 1) to develop a reproducible survival model of smoke inhalation injury in rats that closely resembled our previous mouse model, 2) to validate the rat smoke inhalation injury model using a variety of laboratory techniques, and 3) to compare and contrast our rat model with both the well-established mouse model and previously published rat models to highlight our improvements on smoke delivery and lung injury. Mice and rats were anesthetized, intubated, and placed in custom-built smoke chambers to passively inhale woodchip-generated smoke. Bronchoalveolar lavage fluid (BALF) and lung tissue were collected for confirmatory tests. Lung sections were hematoxylin and eosin stained, lung edema was assessed with wet-to-dry (W/D) ratio, and inflammatory cell infiltration and cytokine elevation were evaluated using flow cytometry, immunohistochemistry, and ELISA. We confirmed that our mouse and rat models of smoke inhalation injury mimic the injury seen after human burn inhalation injury with evidence of pulmonary edema, neutrophil infiltration, and inflammatory cytokine elevation. Interestingly, rats mounted a more severe immunological response compared with mice. In summary, we successfully validated a reliable and clinically translatable survival model of lung injury and immune response in rats and mice and characterized the extent of this injury. These animal models allow for the continued study of smoke inhalation pathophysiology to ultimately develop a better therapeutic.