OBJECTIVE:The objective of this study was to reveal causal-level osteoarthritis (OA) disease biology by targeting regulatory interactions at GDF5. METHODS:By investigating different GDF5 regulatory regions (R2, R3-R5, R7-R9, R18-R20, GROW1), we explored their functional impacts on gene expression and joint morphology in vivo and in vitro. We additionally modeled OA variants in said enhancers in in vitro and in vivo mouse models for expression and disease effects. RESULTS:For all regulatory regions, we found evidence of activation and repression between or within said regions that impacted patterns of joint-specific expression. Examples are as follows: (1) the R4 enhancer, although considered to be activating, has dual roles repressing expression in adjacent tissues and sites, and (2) growth plate-specific expression patterns by the GROW1 regulatory region are confined by adjacent sequences to restrict its expression to the perichondrium. We next targeted different regions and variants in vivo. Testing the R2de region resulted in ~40% reduction in Gdf5 expression and joint morphology changes but no increase in OA risk; likewise, modeling the most cited OA risk variant (rs143384) in mice had no impact on expression, joint morphology, or disease. However, we identified epistatic interactions between this rs143384 risk variant and downstream disease risk variants lying within regulatory regions subject to repression, which compound to impact expression. CONCLUSION:These findings, at the best studied OA locus to date, serve as lessons on the nature of how gene regulatory interactions and local epistasis work in the etiology of OA disease risk, and that assessment of individual variants of high genome-wide association study significance need not alone be considered causal.

ters of recommendation (LORs) influence trainee selection and are vulnerable to biases. We aimed to qualitatively assess differences in LORs to integrated residency on the basis of applicant gender. Methods: LORs for applicants who interviewed at a single integrated CT residency program during one cycle were selected and pooled by applicant gender. Gendered and identifying references were redacted. Letters were analyzed by a thematic analysis approach and managed through NVivo software. Results: Thirty LORs across 8 male applicants and 43 LORs across 11 female applicants were analyzed. There was no noticeable difference between the frequency of positive attributes assigned to each gender. Research accomplishments was the most emphasized competency, with no gender-based difference identified. LORs for female applicants tended to be longer and include stronger positive adjectives. For male applicants, descriptions of external recognition were almost exclusively via mention of scholarships or research, whereas female applicants were more likely to receive word-of-mouth recognition. Letter writers often attested to male applicants' commitment to CT surgery, whereas female applicants received more commentary around effective patient care. Conclusions: Letters for men tended to focus on research accolades and career commitment, whereas letters for women were longer and more likely to emphasize patient care or faculty endorsement. Future studies may discern whether this phenomenon reflects stronger applicant-writer relationships for female applicants or a disadvantageous approach by letter writers for female applicants that relies on sub

OBJECTIVE:For patients with type A aortic dissection complicated by mesenteric malperfusion syndrome, some centers advocate a nontraditional approach based on up-front endovascular intervention and delayed open repair. However, the efficacy of this strategy cannot be understood without first understanding outcomes of the traditional open-first strategy in the same select patient population eligible for delayed repair, applying modern techniques of hybrid aortic surgery. METHODS:Patients with acute type A aortic dissection and mesenteric malperfusion syndrome were queried from a single institution. Those presenting with aortic rupture, tamponade, or cardiogenic shock (ineligible for delayed repair) were excluded. Patients were managed with immediate open aortic repair. Short-term and long-term outcomes are reported. RESULTS:A total of 1228 patients were treated for acute type A dissection in the study period, of whom 77 were included in the mesenteric malperfusion syndrome cohort. In-hospital mortality was 29% compared with 39% in an identically selected mesenteric malperfusion syndrome population undergoing delayed repair reported previously. Among patients with mesenteric malperfusion syndrome, 32% underwent additional procedures addressing distal malperfusion in a hybrid operating room during or after open repair. Concomitant proximal malperfusion (coronary, cerebral, or upper extremity) was common in the mesenteric malperfusion syndrome cohort, present in 35% of cases. Although early mortality was greater in the mesenteric malperfusion syndrome cohort compared with all acute type A dissections, 10-year survival among those discharged alive was similar (65% vs 59%, P = .18). CONCLUSIONS:The traditional open-first repair strategy performs equal to or better than the delayed repair strategy for patients with mesenteric malperfusion syndrome eligible for delayed repair.

Our ability to pinpoint causal variants using GWAS is dependent on understanding the dynamic epigenomic and epistatic context of each associated locus. Being the best studied skeletal locus, GDF5 associates with many diseases and has a complex cis-regulatory architecture. We interrogate GDF5 regulatory interactions and model disease variants in vitro and in vivo. For all regulatory regions we see that local epigenetic activation/repression impacts patterns of joint-specific expression and disease risk. By modeling the most cited risk variant in mice we found that it had no impact on expression, joint morphology, or disease. Yet, we identified significant epistatic expression interactions between this risk variant and others lying within regulatory regions subject to repression or activation. These findings are important lessons on how regulatory interactions and local epistasis work in the etiology of disease risk, and that assessment of individual variants of high GWAS significance need not alone be considered causal.

Background:The optimal management of uncomplicated type B aortic dissection (TBAD) has become controversial in recent years, especially concerning the use and timing of thoracic endovascular aneurysm repair (TEVAR). Here, we analyze a large national cohort over 11 years to understand the current national landscape of TBAD management, trends over time, and disparities in care across the United States. Methods:Admissions for acute TBAD from 2010 to 2020 were identified in the Nationwide Readmissions Database, a large nationally representative sample of hospital admissions across 30 states. Patients were tracked through the calendar year to understand midterm treatment strategies after TBAD, specifically the use and timing of TEVAR. Results:Overall, 10,628 patients with acute TBAD were identified, of whom 7483 (70.4%) were discharged alive after upfront medical management. Among medically managed TBAD patients, 8.8% underwent interval TEVAR by 300 days. In addition to age and comorbidity burden, residence in a low-income ZIP Code (odds ratio, 0.75; 95% CI, 0.61-0.91; P = .004) and treatment at a teaching hospital (odds ratio, 1.29; 95% CI, 1.01-1.66; P = .042) were independently associated with the likelihood of interval TEVAR. Among all TBADs treated with TEVAR nationally from 2010 to 2019, a clear year-by-year trend toward greater use of TEVAR in the postacute period was observed (P = .004). Among all TEVARs for TBAD nationally, 40% were performed >14 days after dissection in 2019 compared with 17% in 2010. Conclusions:Nationally, interval TEVAR after medically managed TBAD has become much more common, although important disparities remain in its use.

Introduction: Guidelines for the medical management of aortic (AD) and coronary artery disease (CAD) recommend treatment for hypertension (HTN), hyperlipidemia (HLD), and tobacco use (TU) (Class 1). Hypothesis: Adherence to guidelines for the management of AD is low, and inferior to CAD. Methods: Adults in the Clinformatics Data Mart database diagnosed with AD or CAD and concomitant HTN, HLD, and/or TU between 2004 and 2019 were included. Those with less than six months of continuous enrollment or prior cardiovascular procedures were excluded. Adherence was calculated as the proportion of patients with a given comorbidity (or combination thereof) who received a prescription for the appropriate intervention. Any beta-blocker, ACEi, or ARB for HTN. Any statin for HLD. Bupropion, varenicline, or referral to counseling for TU. Composite adherence for patients with AD and CAD was compared using a Z-test. Temporal trends were analyzed using a Chi-square test for trend. Results: There were 354,851 patients with AD and 907,997 with CAD who met the inclusion criteria. Composite adherence was 50% for those with AD compared to 59% for CAD (p<0.01). No clinically-significant changes in composite adherence overtime occurred for either group (Figure 1A). Among those with AD, adherence was highest among those with HTN alone (73%), followed by combined HTN/HLD (58%) and HLD alone (45%). Diagnosis of TU was associated with lower adherence across all risk factor combinations. There has been a significant improvement in adherence for TU overtime (p<0.01) (Figure 1B). Conclusions: Adherence to guidelines for medical management of AD is low, and significantly lower than for CAD.

In patients with preoperative atrial fibrillation (AF) undergoing aortic valve replacement, the addition of surgical ablation to surgical aortic valve replacement (SAVR-SA) is efficacious and a Class I guideline. We hypothesized that this subgroup may benefit from SAVR-SA compared to transcatheter aortic valve replacement (TAVR) alone. Medicare beneficiaries with persistent non-valvular AF who underwent SAVR-SA or TAVR alone between 2012 and 2018 were included. Patients with high-risk surgical comorbidities were excluded. Groups were matched using inverse probability weighting. The primary outcome was all-cause mortality. Secondary outcomes were stroke, transient ischemic attack, permanent pacemaker implantation, bleeding, rehospitalization for atrial arrhythmias, and rehospitalization for heart failure. Kaplan–Meier estimates and Cox proportional-hazards regression were used to compare outcomes. Outcomes were adjusted for variables with a standardized mean difference greater than 0.1. Of 439,492 patients who underwent aortic valve replacement, 2591 underwent SAVR-SA and 1494 underwent TAVR alone. Weighting resulted in adequately matched groups. Compared to TAVR alone, SAVR-SA was associated with a significant reduction in all-cause mortality (HR 0.65, 95% CI 0.53–0.79), permanent pacemaker implantation (HR 0.62, 95% CI 0.44–0.87), bleeding (HR 0.63, 95% CI 0.39–1.00), and rehospitalization for heart failure (HR 0.49 (0.36–0.65). There was no difference in the incidence of stroke (HR 1.07, 95% CI 0.74–1.54), transient ischemic attack (HR 1.05, 95% CI 0.75–1.47), or rehospitalization for atrial arrhythmia. Select patients with persistent non-valvular AF may benefit from SAVR-SA compared to TAVR alone.

OBJECTIVES: The purpose of this study was to evaluate the association between left ventricular (LV) dilation and outcomes following valve-sparing root reimplantation. METHODS: Patients with an indexed LV internal diameter during systole of >2.0 cm/m(2) were categorized as having LV dilation. Outcomes were postoperative aortic insufficiency (AI), reintervention and all-cause mortality. The cumulative incidence of each outcome was computed using the Kaplan-Meier estimator. Adjusted comparisons between strata were performed for each outcome using a Cox proportional-hazards model. Where possible, the competing risk of death was accounted for. Multilevel mixed-effects ordered logistic regression was performed for AI grade at follow-up. RESULTS: There were 295 patients of whom 52 had LV dilation. Operative outcomes were excellent; there were no significant differences between groups. Patients with LV dilation demonstrated significant improvement in indexed LV internal diameter during systole overtime. There was no association between LV dilation and postoperative AI grade >2 [hazard ratio 0.88, 95% confidence interval (CI) 0.21-3.67, P = 0.89] or odds of increased AI grade overtime (odds ratio = 0.76, 95% CI 0.30-1.93, P = 0.57). There were no re-interventions among those with LV dilation. Adjusted mortality was significantly higher among those with LV dilation (hazard ratio 5.56, 95% CI 1.56-19.9); however, deaths were unrelated to aortic valve dilation. CONCLUSIONS: LV dilation is not associated with poorer operative outcomes, postoperative AI or reintervention. It is associated with an increased risk of mortality, though not from valvular dysfunction. LV dilation should not deter valve-sparing root reimplantation when otherwise indicated.

BACKGROUND The University of Pennsylvania classification system (Penn class) of acute type A aortic dissection (aTAAD) is used to evaluate the impact of malperfusion on surgical outcomes. The purpose of this analysis was to determine the validity of Penn class in a larger and more contemporary cohort and to compare its performance with other classification systems.METHODS This was a retrospective study of patients who underwent aTAAD repair at our institution from 1993 to 2020. Patients were assigned to Penn class on the basis of burden of preoperative malperfusion syndrome. The association of Penn class and 30-day mortality was evaluated by multivariable regression. The discriminatory ability of Penn class for mortality was determined by a bootstrapped C statistic.RESULTS There were 1192 patients, of whom 50% were assigned to Penn class A (no ischemia), 21% (253/1192) to class B (local ischemia), 14% (171/1192) to class C (generalized ischemia), and 14% (167/1192) to class B-C (combined ischemia). The incidence of mortality rose significantly with increasing Penn class from 5% (31/601) in class A to 35% (59/167) in class B-C (P < .001). After adjustment, 30-day mortality increased significantly with class B (odds ratio [OR], 2.43; 95% CI, 1.38-4.27), class C (OR, 3.39; 95% CI, 1.90-6.03), and class B-C (OR, 13.08; 95% CI, 7.90-22.15) compared with class A. The C statistic was 0.77 (95% CI, 0.72-0.80) and was significantly higher than for models featuring alter-native classification systems (P < .05).CONCLUSIONS Penn class provides excellent discrimination for 30-day mortality after repair of aTAAD.

Obesity is a widespread disease which adversely impacts all organ systems and disproportionately affects African Americans and other minority groups. Physicians across medical specialties must possess current knowledge of obesity as an important, distinct disease with biological and social causes. Coverage of obesity on board certification examinations, which influence standards in medical knowledge and practice in each specialty, has not previously been examined. The member boards of the American Board of Medical Specialties offer a content outline or "blueprint" detailing material tested. We parsed the 24 available general certification exam blueprints for mentions of obesity and related keywords. We categorized blueprints into three tiers: mention of obesity (Tier 1), mention of related terminology but not obesity (Tier 2), and no mention of obesity or related terminology (Tier 3). We analyzed mentions of obesity and related terms by blueprint word count and procedural versus non-procedural specialties. Six (25.0%) of 24 board exam blueprints mentioned obesity (Tier 1), fifteen (62.5%) mentioned related terminology only (Tier 2), and three (12.5%) mentioned neither obesity nor related terminology (Tier 3). There was no significant difference in obesity-related mentions between procedural and non-procedural specialties (X-2 , p = .50). None of the blueprints included racial/ethnic disparities related to obesity. Word count was not significantly correlated with mentions of obesity in linear regression (p = .42). The absence of any mention of obesity on most content outlines and of racial/ethnic disparities on all content outlines indicates need for increased coverage of the diagnosis, prevention, and treatment of obesity across all board examinations.

General anesthesia is associated with inherent risks that can be avoided with less invasive anesthetic strategies. We hypothesized that the use of local or regional anesthesia (LRA) would be as safe and effective as general anesthesia (GA) for patients undergoing thoracic endovascular aortic repair (TEVAR). Patients who had undergone TEVAR from 2010 to 2020 in the Vascular Quality Initiative were analyzed. The exclusion criteria included receipt of branched endografts or devices extending beyond zone 5. The patients were categorized as receiving LRA or GA, and the demographics and operative details were compared using appropriate frequentists tests. Long-term survival was estimated using Kaplan-Meier analysis and compared using the log-rank test. An adjusted survival analysis was performed using a Cox proportional hazards model. A total of 7285 patients had met the inclusion criteria, of whom 276 (4%) had received LRA. During the study period, the annual proportion of TEVAR performed with LRA was between 3% and 4%, with no significant change over time (P = .99). The patients who had received LRA were older with more comorbidities compared with those receiving GA. A similar number of patients had undergone urgent repair in each group. LRA was associated with a trend in a reduced number of zones covered and devices deployed, shorter procedural durations, and less blood loss, and GA exhibited a greater frequency of zone 0 to 2 proximal landing zone and arm access (Table). No differences were found in in-hospital mortality (6% vs 6%; P = 1.00) or a composite of any complication (21% vs 23%; P = .55) between the LRA and GA groups. LRA was associated with a similar incidence of stroke (3% vs 4%; P = .32), myocardial infarction (1% vs 1%; P = 1.00), and pneumonia (1% vs 2%; P = .78) compared with GA. LRA was associated with a shorter intensive care unit length of stay (2 vs 3 days; P < .01) and hospital length of stay (4 vs 5 days; P < .01). During a median follow-up of 2 years, no difference was found in unadjusted or adjusted survival for patients receiving LRA compared with GA (hazard ratio, 1.03; 95% confidence interval, 0.78-1.36; P = .51; Fig). Despite the greater number of baseline comorbidities, patients undergoing TEVAR with LRA experienced similar operative outcomes and long-term survival compared with patients undergoing GA, with shorter intensive care unit and postoperative hospital lengths of stay. LRA should be considered more frequently for select patients undergoing TEVAR.TableBaseline and intraoperative characteristics stratified by anesthesia typeCharacteristicLRA (n = 276)GA (n = 7009)P valuePreoperative Age, years74.00 (66.00-82.00)70.00 (60.00-78.00)<.01 Male sex162 (58.7)4113 (58.7)1.00 BMI, kg/m227.11 ± 5.8128.21 ± 6.48.01 Urgent case97 (35.1)2433 (34.7).93 Transfer from another facility92 (33.3)2282 (32.6).84 CVD29 (10.5)564 (8.0).18 CAD55 (19.9)1184 (16.9).22 CHF52 (18.8)860 (12.3).00 COPD87 (31.5)1904 (27.2).13 DM44 (15.9)1190 (17.0).71 HTN248 (90.2)6212 (88.9).59 Dialysis12 (4.3)238 (3.4).49 Aortic aneurysm140 (50.7)3150 (44.9).07 Maximum aortic diameter, mm55.75 ± 17.0253.38 ± 16.75.04 Aortic dissection50 (18.1)2038 (29.1)<.01 Annual center volume First quartile42 (15.2)724 (10.3).01 Second quartile88 (31.9)1710 (24.4).01 Third quartile109 (39.5)2760 (39.4)1.00 Fourth quartile37 (13.4)1815 (25.9)<.01 Year of operation.56 20100 (0.0)6 (0.1) 20116 (2.2)165 (2.4) 201227 (9.8)528 (7.5) 201326 (9.4)798 (11.4) 201432 (11.6)916 (13.1) 201531 (11.2)747 (10.7) 201631 (11.2)648 (9.2) 201734 (12.3)788 (11.2) 201842 (15.2)898 (12.8) 201929 (10.5)902 (12.9) 202018 (6.5)613 (8.7)Intraoperative Percutaneous femoral artery access171 (98.8)3799 (97.0).13 Arm or neck access6 (2.2)438 (6.2).20 Largest sheath size, mm18.00 (16.00-19.00)20.00 (18.00-22.00).56 Proximal landing site Zone 0-24 (2.2)137 (3.1).06 Zone 227 (14.7)841 (19.2).12 Zone 2-5153 (83.2)3404 (77.7).14 Zones covered, No. ≤2155 (87.6)3722 (86.7).03 3-522 (12.4)570 (13.3).03 Devices deployed, No. 1112 (58.3)2235 (45.9).25 267 (34.9)1972 (40.5).12 313 (6.8)661 (13.6).23 Conversion to open1 (0.4)40 (0.6).03 Total procedure time, minutes84.00 (58.75-133.50)112.00 (73.00-180.00).39 Contrast volume, mL82.50 (57.00-132.00)111.00 (72.00-180.00).39 Fluoroscopic time, minutes11.80 (7.35-19.65)13.20 (8.00-24.30).20 Blood loss, mL50.00 (50.00-150.00)100.00 (50.00-200.00).16 Spinal cord ischemia3 (1.5)90 (1.8).97BMI, Body mass index; CAD, coronary artery disease; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; DM, diabetes mellitus; GA, general anesthesia; HTN, hypertension; LRA, local or regional anesthesia.Data presented as median (interquartile range), number (%), or mean ± standard deviation. Open table in a new tab

During human evolution, the knee adapted to the biomechanical demands of bipedalism by altering chondrocyte developmental programs. This adaptive process was likely not without deleterious consequences to health. Today, osteoarthritis occurs in 250 million people, with risk variants enriched in non-coding sequences near chondrocyte genes, loci that likely became optimized during knee evolution. We explore this relationship by epigenetically profiling joint chondrocytes, revealing ancient selection and recent constraint and drift on knee regulatory elements, which also overlap osteoarthritis variants that contribute to disease heritability by tending to modify constrained functional sequence. We propose a model whereby genetic violations to regulatory constraint, tolerated during knee development, lead to adult pathology. In support, we discover a causal enhancer variant (rs6060369) present in billions of people at a risk locus (GDF5-UQCC1), showing how it impacts mouse knee-shape and osteoarthritis. Overall, our methods link an evolutionarily novel aspect of human anatomy to its pathogenesis.

Purpose of review This review aims to evaluate current research findings relevant to weight stigmatization, to acknowledge the deleterious impact it has on the health of the paediatric population and to provide insight to optimize future guidelines for the treatment of individuals with overweight and obesity. Recent findings Obesity prevalence continues to rise in the USA with estimates in children from ages 2–19 years of 18.5%, an all-time high. With the increase in obesity, there has been a concomitant increase in weight stigma, which affects both youth and general population across varied levels of socioeconomic status and body sizes. Summary Weight stigma is a contributing phenomenon to the current obesity epidemic, as individuals with stigmatized experiences (weight-based teasing, bullying, victimization) have increased risks for acquiring adverse health outcomes that encompass the physical, behavioural and psychological. Weight stigma can also lead affected individuals to internalize such experiences which decrease their overall quality of life. Sources of stigma may come from peers, family, educators, media, as well as healthcare professionals, as highlighted in this review. Efforts to establish prevention and treatment strategies for weight stigma may generate further traction to help improve global obesity rates. Video abstract http://links.lww.com/COE/A15