Current Transthoracic Supra-Aortic Trunk Surgical Reconstruction Has Similar 30-Day Cardiovascular Outcomes Compared to Extra-Anatomic Revascularization but With Higher Morbidity Burden.

BACKGROUND: Operative risk for supra-aortic trunk (SAT) surgical revascularization for occlusive disease, particularly transthoracic reconstruction (TR), remains ill-defined. This study sought to describe and compare 30-day outcomes of TR and extra-anatomic (ER) SAT surgical reconstruction for an occlusive indication across the United States over a contemporary 15-year period. METHODS: Using the National Surgical Quality Improvement Program, TR and ER performed during 2005-2019 were identified. Procedures performed for nonocclusive indications and those concomitant with coronary or valve operations were excluded. Rates of stroke, death, myocardial infarction (MI) and these as composite outcome (S/D/M) were compared. Logistic regression with stabilized inverse probability weighting (IPW) was used to compare groups via average treatment effect (ATE) while adjusting for covariate imbalances. RESULTS: Over the 15-year period, 166 TR and 1,900 ER patients were identified. The majority of ERs were carotid-subclavian bypass (n = 1,344; 70.7%) followed by carotid-carotid bypass (n = 261; 13.7%) and subclavian/carotid transpositions (n = 123; 6.5%). TR consisted of aorto-SAT bypass (n = 120; 72.3%) and endarterectomy (n = 46; 27.7%). The median age was 64 years for TR and 65 years in ER (P = 0.039). Those undergoing TR were more often women (69.0% vs. 56.9%; P = 0.001) and less likely to have undergone previous cardiac surgery (9.2% vs. 20.8%; P = 0.006). TR were also less frequently hypertensive (68.1% vs. 75.4%; P = 0.038) and had statistically lower preoperative creatinine levels (0.86 vs 0.91; P = 0.002). Unadjusted rates of MI (0.6% vs. 1.3%; P = 0.72) and stroke (3.6% vs. 1.9%; P = 0.15) were similar between groups with mortality (3.6% vs. 1.5%; P = 0.05) and S/D/M (6.6% vs. 3.9%; P = 0.10) trending higher with TR. IPWs could be calculated for 1,754 patients (148 TR; 1,606 ER). The estimated probability of S/D/M was 3.8% in the ER group and 6.2% in TR; no difference was seen in ATE (2.4%; 95% confidence interval [CI]: -1.5 to 6.2; P = 0.23). No differences were seen in individual component ATEs (stroke: 3.0% vs. 1.7%; ATE = 1.3%; 95% CI: -3.9 to 1.3; P = 0.32; mortality: 3.8% vs. 1.4%; ATE = 2.4%; 95% CI: -5.6 to 0.7; P = 0.13). Secondary outcomes showed TR patients were more likely to have non-home discharge (18.7% vs. 6.6%; ATE = 12.1%; 95% CI: 5.0-19.2; P < 0.001) and longer lengths of stay (6.1 vs. 4.0; ATE = 2.2 days; 95% CI: 0.9-3.4; P < 0.001). Moreover, TR patients were more likely to require transfusion (22.7% vs. 5.0%; ATE = 17.7%; 95% CI: 10.2-25.2; P < 0.001) and develop sepsis (2.7% vs. 0.2%; ATE = 2.5%; 95% CI: 0.1-5.0; P = 0.04). CONCLUSIONS: Transthoracic and extra-anatomic surgical reconstruction of the SATs for occlusive disease have similar operative cardiovascular risk. However, morbidity tends to be higher with TR due to higher transfusion requirements, sepsis risk, and need for facility stay. These results suggest ER as a first-line approach in those with proper disease anatomy is reasonable with lower morbidity, while TR remains justified in appropriate patients.

Trends in the Use of Recombinant Activated Factor VII and Prothrombin Complex Concentrate in Heart Transplant Patients in Virginia.

OBJECTIVES: To explore trends in intraoperative procoagulant factor concentrate use in patients undergoing heart transplantation (HTx) in Virginia. Secondarily, to evaluate their association with postoperative thrombosis. DESIGN: Patients who underwent HTx were identified using a statewide database. Trends in off-label recombinant activated factor VII (rFVIIa) use and on-label and off-label prothrombin complex concentrate (PCC) use were tested using the Mantel-Haenszel test. Multivariate logistic regression was used to test for an association between procoagulant factor concentrate administration and thrombosis. SETTING: Virginia hospitals performing HTx. PARTICIPANTS: Adults undergoing HTx between 2012 and 2022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 899 patients who required HTx, 100 (11.1%) received off-label rFVIIa, 69 (7.7%) received on-label PCC, and 80 (8.9%) received off-label PCC. There was a downward trend in the use of rFVIIa over the 10-year period (p = 0.04). There was no trend in on-label PCC use (p = 0.12); however, there was an increase in off-label PCC use (p < 0.001). Patients who received rFVIIa were transfused more and had longer cardiopulmonary bypass time (p < 0.001). Receipt of rFVIIa was associated with increased thrombotic risk (odds ratio [OR] 1.92; 95% CI 1.12-3.29; p = 0.02), whereas on-label and off-label PCC use had no association with thrombosis (OR 0.98, 95% CI 0.49-1.96, p = 0.96 for on-label use; and OR 0.61, 95% CI 0.29-1.30, p = 0.20 for off-label use). CONCLUSIONS: Use of rFVIIa in HTx decreased over the past decade, whereas off-label PCC use increased. Receipt of rFVIIa was associated with thrombosis; however, patients who received rFVIIa were more severely ill, and risk adjustment may have been incomplete.

Commentary: Small patients with big wounds.

Some would argue that kids aren't just little adults, but what about their sternums? We are reviewing a manuscript by Horriat, McCandless, and colleagues in the Journal of Cardiac Surgery describing their experience with managing sternal wound infections (SWI) after congenital heart surgery. They report encouraging results in 14 patients who required plastic surgery consultation to manage their sternal wounds. The nature of congenital cardiac abnormalities and the necessary steps to repair them leads to physiologic derangements predisposing patients to SWI. Rates of SWI vary and have been reported at 1.53% in this population. There is little guidance on how the management of the congenital cardiac surgery patient should differ from the adult patient.

Wound location is independently associated with adverse outcomes following first-time revascularization for tissue loss.

OBJECTIVE: Few studies adequately evaluate the impact of wound location on patient outcomes after lower extremity revascularization. Consequently, we evaluated the relationship between lower extremity wound location and long-term outcomes. METHODS: We reviewed all patients at our institution undergoing any first-time open surgical bypass or percutaneous transluminal angioplasty with or without stenting for tissue loss between 2005 and 2014. We categorized wounds into three distinct groups: forefoot (ie, toes and metatarsal heads), midfoot (ie, dorsal, plantar, lateral, medial surfaces excluding toes, metatarsal heads, or heel), and heel. Limbs with multiple wounds were excluded from analyses. We compared rates of perioperative complications, wound healing, reintervention, limb salvage, amputation-free survival, and survival using χ2, Kaplan-Meier, and Cox regression analyses. RESULTS: Of 2869 infrainguinal revascularizations from 2005 to 2014, 1126 underwent a first-time revascularization for tissue loss, of which 253 patients had multiple wounds, 197 had wounds proximal to the ankle, 100 had unreliable wound information, and 576 (forefoot, n = 397; midfoot, n = 61; heel, n = 118) fit our criteria and had a single foot wound with reliable information regarding wound specifics. Patients with forefoot, midfoot, and heel wounds had similar rates of coronary artery disease, hypertension, diabetes, and smoking history (all P > .05). Conversely, there were significant differences in patient age (71 vs 69 vs 70 years), prevalence of gangrene (41% vs 5% vs 21%), and dialysis dependence (18% vs 17% vs 30%) (all P < .05). There were no statistically significant differences in perioperative mortality (1.3% vs 4.9% vs 4.2%; P = .06) or postoperative complications among the three groups. Between forefoot, midfoot, and heel wounds, there were significant differences in unadjusted 6-month rates of complete wound healing (69% vs 64% vs 53%), 3-year rates of amputation-free survival (54% vs 57% vs 35%), and survival (61% vs 72% vs 41%) (all P < .05). After adjustment, compared with forefoot wounds, heel wounds were associated with higher rates of incomplete 6-month wound healing (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.1-2.]), major amputation or mortality (HR, 1.7; 95% CI, 1.1-2.7), and all-cause mortality (HR, 1.8; 95% CI, 1.1-3.0), but not major amputation alone (HR, 2.1; 95% CI, 0.9-4.5). In open surgical bypass-first patients, heel wounds were solely associated with an increased risk of all-cause mortality (HR, 1.7; 95% CI, 1.1-2.8), whereas heel wounds in percutaneous transluminal angioplasty-first patients were associated with an increased risk of incomplete wound healing (HR, 2.2; 95% CI, 1.3-3.7), major amputation or mortality (HR, 2.3; 95% CI, 1.1-5.4), and all-cause mortality (HR, 2.8; 95% CI, 1.1-7.2). CONCLUSIONS: Heel wounds confer considerably higher short- and long-term morbidity and mortality compared with midfoot or forefoot wounds in patients undergoing any first-time lower extremity revascularization.

Experiences of using vedolizumab in the treatment of inflammatory bowel disease in the East Midlands UK - a retrospective observational study.

PURPOSE: Clinical trials have demonstrated efficacy of vedolizumab in ulcerative colitis (UC) and Crohn's disease (CD). Further real-world data is needed to inform clinical practice. The primary outcome was to assess corticosteroid-free and clinical remission after vedolizumab initiation. Secondary outcomes included effect on disease activity scores, biochemical markers, concomitant drug use, endoscopic remission, surgical intervention, hospital admissions and adverse events. MATERIALS AND METHODS: A multi-centre retrospective observational study was conducted with patients initiated on vedolizumab across seven UK hospitals 1/11/14-30/11/16. Clinical disease activity was assessed using the partial Mayo Scores (pMS) and Harvey Bradshaw Index (HBI). Clinical remission was defined as HBI ≤4 or pMS <2 with a combined stool frequency and rectal bleeding sub score of ≤1. Clinical response was defined as ≥2-point decrease from baseline in pMS and ≥3-point decrease from baseline in HBI. RESULTS: One hundred ninety-two patients were included in the final analysis. 45% of UC and 10% of CD patients were anti-TNF naive. Over the observation period corticosteroid-free remission rates for UC and CD were 46% and 45%, while clinical remission rates were 52% and 44%, respectively. Time to corticosteroid free remission for UC and CD was 17.6 [IQR: 8.7-29.6] and 14.1 [QR: 6.0-21.7] weeks, respectively. Time to clinical response for UC was 9.4 [IQR: 5.7-15.4] and CD was 9.5 [IQR: 6.1-18.2] weeks. There was a substantial decrease in the concomitant use of immunomodulators and a similar decrease in concomitant corticosteroid use over the study period. CONCLUSIONS: Results in this predominately anti-TNF experienced population mirror other published real-world data, demonstrating good clinical effectiveness and a comparable safety profile.

Outcomes after first-time lower extremity revascularization for chronic limb-threatening ischemia in insulin-dependent diabetic patients.

OBJECTIVE: Historically, open surgical bypass provided a durable repair among diabetic patients with chronic limb-threatening ischemia (CLTI). In the current endovascular era, however, the difference in long-term outcomes between first-time revascularization strategies among patients with insulin-dependent diabetes mellitus (IDDM) is poorly understood. METHODS: We reviewed the records of all patients with IDDM undergoing a first-time infrainguinal bypass graft (BPG) or percutaneous transluminal angioplasty with or without stenting (PTA/S) for CLTI at our institution from 2005 to 2014. We defined IDDM as use of chronic insulin administration at baseline to control blood glucose levels and recorded the most recent glycated hemoglobin value available within 3 months before the procedure and fasting blood glucose level on the day of the procedure. We compared rates of wound healing, restenosis, reintervention, major amputation, and mortality between BPG and PTA/S in our population using χ2, Kaplan-Meier, and Cox regression analyses. As a sensitivity analysis, we calculated propensity scores and employed inverse probability weighting to account for nonrandom assignment to BPG vs PTA/S. RESULTS: Of 2869 infrainguinal revascularizations from 2005 to 2014, 655 limbs (316 BPG, 339 PTA/S) in 580 patients fit our criteria and underwent a first-time revascularization for CLTI. Patients undergoing BPG, compared with PTA/S, were similar in age (69 vs 68 years; P = .55), had similar rates of tissue loss (87% vs 91%; P = .07) and dialysis dependence (26% vs 28%; P = .55), were less likely to be hypertensive (84% vs 92%; P < .001), and were more likely to be current smokers (21% vs 14%; P = .02). There were no differences between BPG and PTA/S patients in mean glycated hemoglobin levels (8.1% vs 8.0%; P = .51) or mean fasting blood glucose levels (158 vs 150 mg/dL; P = .18). Although total hospital length of stay was significantly longer among BPG patients (11 vs 8 days; P < .001), perioperative complications did not differ, including acute kidney injury (19% vs 23%; P = .24), hematoma (6.0% vs 3.8%; P = .20), acute myocardial infarction (1.3% vs 2.1%; P = .43), and mortality (3.8% vs 3.0%; P = .55). BPG-first patients had significantly lower unadjusted 6-month rates of incomplete wound healing (49% vs 57%) and 5-year rates of restenosis (53% vs 72%) and reintervention (47% vs 58%; all P < .05). After adjustment, multivariable analysis suggested PTA/S-first intervention to be significantly associated with higher risk of restenosis (hazard ratio, 1.9; 95% confidence interval, 1.3-2.7) and reintervention (1.9 [1.2-2.7]). These results remained robust after inverse probability weighting. CONCLUSIONS: Among patients with IDDM and CLTI, a bypass-first strategy is associated with similar 30-day outcomes and lower restenosis and reintervention rates. These data suggest that a bypass-first approach may best serve appropriately selected, anatomically suitable patients with IDDM and pedal ischemia that requires revascularization.

Mitral valve repair in a regional quality collaborative: Respect or resect?

Objective: Mitral valve repair is the gold standard for treatment of mitral regurgitation, but the optimal technique remains debated. By using a regional collaborative, we sought to determine the change in repair technique over time. Methods: We identified all patients undergoing isolated mitral valve repair from 2012 to 2022 for degenerative mitral disease. Those with endocarditis, transcatheter repair, or tricuspid intervention were excluded. Continuous variables were analyzed via Wilcoxon rank sum, and categorical variables were analyzed via chi-square testing. Results: We identified 1653 patients who underwent mitral valve repair, with 875 (59.2%) undergoing a no resection repair. Over the last decade, there was no significant trend in the proportion of repair techniques across the region (P = .96). Those undergoing no resection repairs were more likely to have undergone prior cardiac surgery (5.0% vs 2.2%, P = .002) or minimally invasive approaches (61.4% vs 24.7%, P < .001) with similar predicted risk of mortality (median 0.6% vs 0.6%, P = .75). Intraoperatively, no resection repairs were associated with longer bypass times (140 [117-167] minutes vs 122 [91-159] minutes, P < .001). Operative mortality was similar between both groups (1.1% vs 1.0%, P = .82), as were other postoperative outcomes. Anterior leaflet prolapse (odds ratio, 11.16 [6.34-19.65], P < .001) and minimally invasive approach (odds ratio, 6.40 [5.06-8.10], P < .001) were most predictive of no resection repair. Conclusions: Despite minor differences in operative times, statewide over the past decade there remains a diverse mix of both classic "resect" and newer "respect" strategies with comparable short-term outcomes and no major timewise trends. These data may suggest that both approaches are equivocal.

Extracorporeal Life Support Organization Center of Excellence recognition is associated with improved failure to rescue after cardiac arrest.

OBJECTIVE: The influence of Extracorporeal Life Support Organization (ELSO) center of excellence (CoE) recognition on failure to rescue after cardiac surgery is unknown. We hypothesized that ELSO CoE would be associated with improved failure to rescue. METHODS: Patients undergoing a Society of Thoracic Surgeons index operation in a regional collaborative (2011-2021) were included. Patients were stratified by whether or not their operation was performed at an ELSO CoE. Hierarchical logistic regression analyzed the association between ELSO CoE recognition and failure to rescue. RESULTS: A total of 43,641 patients were included across 17 centers. In total, 807 developed cardiac arrest with 444 (55%) experiencing failure to rescue after cardiac arrest. Three centers received ELSO CoE recognition, and accounted for 4238 patients (9.71%). Before adjustment, operative mortality was equivalent between ELSO CoE and non-ELSO CoE centers (2.08% vs 2.36%; P = .25), as was the rate of any complication (34.5% vs 33.8%; P = .35) and cardiac arrest (1.49% vs 1.89%; P = .07). After adjustment, patients undergoing surgery at an ELSO CoE facility were observed to have 44% decreased odds of failure to rescue after cardiac arrest, relative to patients at non-ELSO CoE facility (odds ratio, 0.56; 95% CI, 0.316-0.993; P = .047). CONCLUSIONS: ELSO CoE status is associated with improved failure to rescue following cardiac arrest for patients undergoing cardiac surgery. These findings highlight the important role that comprehensive quality programs serve in improving perioperative outcomes in cardiac surgery.

Transient receptor potential vanilloid 4 channel inhibition attenuates lung ischemia-reperfusion injury in a porcine lung transplant model.

OBJECTIVE: Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel important in many physiological and pathophysiological processes, including pulmonary disease. Using a murine model, we previously demonstrated that TRPV4 mediates lung ischemia-reperfusion injury, the major cause of primary graft dysfunction after transplant. The current study tests the hypothesis that treatment with a TRPV4 inhibitor will attenuate lung ischemia-reperfusion injury in a clinically relevant porcine lung transplant model. METHODS: A porcine left-lung transplant model was used. Animals were randomized to 2 treatment groups (n = 5/group): vehicle or GSK2193874 (selective TRPV4 inhibitor). Donor lungs underwent 30 minutes of warm ischemia and 24 hours of cold preservation before left lung allotransplantation and 4 hours of reperfusion. Vehicle or GSK2193874 (1 mg/kg) was administered to the recipient as a systemic infusion after recipient lung explant. Lung function, injury, and inflammatory biomarkers were compared. RESULTS: After transplant, left lung oxygenation was significantly improved in the TRPV4 inhibitor group after 3 and 4 hours of reperfusion. Lung histology scores and edema were significantly improved, and neutrophil infiltration was significantly reduced in the TRPV4 inhibitor group. TRPV4 inhibitor-treated recipients had significantly reduced expression of interleukin-8, high mobility group box 1, P-selectin, and tight junction proteins (occludin, claudin-5, and zonula occludens-1) in bronchoalveolar lavage fluid as well as reduced angiopoietin-2 in plasma, all indicative of preservation of endothelial barrier function. CONCLUSIONS: Treatment of lung transplant recipients with TRPV4 inhibitor significantly improves lung function and attenuates ischemia-reperfusion injury. Thus, selective TRPV4 inhibition may be a promising therapeutic strategy to prevent primary graft dysfunction after transplant.

Unplanned postoperative catheterization during admission for coronary artery bypass grafting is neither cheap nor benign, but may rescue patients.

OBJECTIVE: Literature describing outcomes of myocardial ischemia after coronary artery bypass grafting is sparse. We hypothesized these patients had more complications and incurred higher costs of care. METHODS: Using adult cardiac surgery data and cardiac catheterization (CathPCI) data from the Virginia Cardiac Services Quality Initiative, we identified patients who underwent unplanned cardiac catheterization after coronary artery bypass grafting from 2018 to 2021. Adult cardiac surgery data were matched to CathPCI data examining earliest in-hospital catheterization. Patients not requiring catheterization served as the control group. RESULTS: We identified 10,597 patients who underwent isolated coronary artery bypass grafting, of whom 41 of 10,597 underwent unplanned cardiac catheterization. A total of 21 of 41 patients (51%) received percutaneous coronary intervention, most commonly for non-ST-elevation myocardial infarction (n = 7, 33%) and ST-elevation myocardial infarction (n = 6, 29%). Postoperative cardiac arrest occurred in 14 patients (40%). In patients who underwent percutaneous coronary intervention, 14 (67%) had a single lesion, 4 (19%) had 2 lesions, and 3 (14%) had 3 lesions. The left anterior descending artery (38%) was the most frequently intervened upon vessel. Patients who underwent catheterization were more likely to require balloon pump support (26% vs 11%), to have prolonged ventilation (57% vs 20%), to have renal failure (17% vs 7.1%), and to undergo reintubation (37% vs 3.8%, all P < .04). There was no statistical difference in operative mortality (4.9% vs 2.3%, P = .2) or failure to rescue (4.9% vs 1.6%, P = .14). Total costs were higher in patients who underwent unplanned catheterization ($81,293 vs $37,011, P < .001). CONCLUSIONS: Unplanned catheterization after coronary artery bypass grafting is infrequent but associated with more complications and a higher cost of care. Therefore, determination of an association with operative mortality in patients with suspected ischemia after coronary artery bypass grafting requires additional study.

Implementation of a non-intensive-care unit medical emergency team improves failure to rescue rates in cardiac surgery patients.

OBJECTIVE: Failure to rescue (FTR) is an emerging measure in cardiac surgery, defined as mortality after a postoperative complication. We hypothesized that establishing a medical emergency team (MET) reduced rates of FTR in adults undergoing cardiac surgery. METHODS: All patients (N = 11,218) undergoing a The Society of Thoracic Surgeons index operation at our center (1994-2018) were stratified by pre-MET or MET era based on the 2009 institutional implementation of a MET to respond to clinical decompensation in non-intensive-care patients. Patients missing The Society of Thoracic Surgeons predicted risk of mortality were excluded from all cohorts. Risk adjusted multivariable regression analyzed the association of postoperative complications, operative mortality, and FTR by era. Nearest neighbor propensity score matching utilizing patients' The Society of Thoracic Surgeons predicted risk of mortality was performed to create balanced control and exposure groups for secondary subgroup analysis. RESULTS: In the risk-adjusted multivariable analysis, surgery during the MET era was associated with decreased mortality (odds ratio [OR], 0.51; 95% CI, 0.45-0.77; P < .001), postoperative renal failure (OR, 0.57; 95% CI, 0.46-0.70; P < .001), reoperation (OR, 0.75; 95% CI, 0.59-0.95; P = .017), and deep sternal wound infection (OR, 0.16; 95% CI, 0.04-0.45; P = .002). Surgery performed during the MET era was associated with a decreased rate of FTR in the risk-adjusted analysis (OR, 0.46; 95% CI, 0.34-0.70; P < .001). CONCLUSIONS: The development of an institutional MET program was associated with a decrease in major complications and FTR. These findings support the development of MET programs to improve FTR after cardiac surgery.

Delirium is associated with failure to rescue after cardiac surgery.

Objective: Postoperative delirium after cardiac surgery is associated with long-term cognitive decline and mortality. We investigated whether increased ICU Confusion Assessment Method scores were associated with greater 30-day mortality and failure to rescue after cardiac surgery. Methods: We studied 4030 patients who underwent a Society of Thoracic Surgeons index operation at the University of Virginia Health System from 2011 to 2021. We obtained all ICU Confusion Assessment Method scores recorded during patients' admission and summarized scores for the first 7 postoperative days. Univariate and multivariable logistic regression analyzed the association between ICU Confusion Assessment Method score/delirium presence and postoperative complications, operative mortality, and failure to rescue. Results: Any episode of ICU Confusion Assessment Method screen-positive delirium and nearly all components of the score were associated with increased 30-day mortality on univariate analysis. We found that a single episode of delirium was associated with increased mortality. Feature 2 (inattention) had the strongest association with poorer outcomes, including failure to rescue in our analysis, as were patients with higher peak Richmond Agitation Sedation Scale scores. Patients with higher mean Richmond Agitation Sedation Scale scores had an association with decreased failure to rescue. Conclusions: A single episode of delirium, as measured using ICU Confusion Assessment Method scores, is associated with increased mortality. Inattention and higher peak Richmond Agitation Sedation Scale scores were associated with failure to rescue. Screening may clarify diagnosing delirium and assessing its implications on mortality and failure to rescue. Our findings suggest the importance of identifying and managing risk factors for delirium to improve patient outcomes and reduce mortality and failure to rescue rates.

Center case volume is associated with Society of Thoracic Surgeons-defined failure to rescue in cardiac surgery.

OBJECTIVE: Our understanding of the impact of a center's case volume on failure to rescue (FTR) after cardiac surgery is incomplete. We hypothesized that increasing center case volume would be associated with lower FTR. METHODS: Patients undergoing a Society of Thoracic Surgeons index operation in a regional collaborative (2011-2021) were included. After we excluded patients with missing Society of Thoracic Surgeons Predicted Risk of Mortality scores, patients were stratified by mean annual center case volume. The lowest quartile of case volume was compared with all other patients. Logistic regression analyzed the association between center case volume and FTR, adjusting for patient demographics, race, insurance, comorbidities, procedure type, and year. RESULTS: A total of 43,641 patients were included across 17 centers during the study period. Of these, 5315 (12.2%) developed an FTR complication, and 735 (13.8% of those who developed an FTR complication) experienced FTR. Median annual case volume was 226, with 25th and 75th percentile cutoffs of 136 and 284 cases, respectively. Increasing center-level case volume was associated with significantly greater center-level major complication rates but lower mortality and FTR rates (all P values < .01). Observed-to-expected FTR was significantly associated with case volume (P = .040). Increasing case volume was independently associated with decreasing FTR rate in the final multivariable model (odds ratio, 0.87 per quartile; confidence interval, 0.799-0.946, P = .001). CONCLUSIONS: Increasing center case volume is significantly associated with improved FTR rates. Assessment of low-volume centers' FTR performance represents an opportunity for quality improvement.

The history of the discovery of vitamin D and its daughter steroid hormone.

It is largely through historical accident in the interval of 1920-1940 that vitamin D(3) became classified as a vitamin rather than as a steroid hormone. The formal definition of a vitamin is that it is a trace dietary constituent required to produce the normal function of a physiological process or processes. The emphasis here is on trace and the fact that the vitamin must be supplied regularly in the diet; this implies that the body is unable to metabolically synthesize the vitamin in question. However, the ultraviolet exposure of 7-dehydrocholesterol present in the skin results in the photochemical production of vitamin D(3). Thus, vitamin D(3) becomes a true vitamin only when the animal or human does not have regular access to sunlight or ultraviolet light. Under normal physiological circumstances, all mammals, including humans, can generate, via ultraviolet exposure of 7-dehydrocholesterol present in the skin, adequate quantities of vitamin D(3) to meet their nutritionally defined requirements. There is a vibrant historical record beginning in 1650 and culminating in 1963 concerned with the determination of the chemical structures of vitamin D(3) and vitamin D(2). A surprising aspect concerning vitamin D(3) is that it is itself biologically inert. There are no known essential biological actions or contributions that rely specifically on the molecule vitamin D(3). While chemists had certainly appreciated the strong structural similarity between the vitamins D and other steroids, this correlation was never widely acknowledged in the biological, clinical, or nutritional sciences until 1965-1970. The biological role of vitamin D(3) is to serve as a substrate for the liver 25-hydroxylase which produces 25-hydroxyvitamin D(3) [25(OH)D(3)]. 25(OH)D(3) in turn serves as the substrate for the kidney proximal tubule 25(OH)D(3)-1α-hydroxylase enzyme which produces the steroid hormone 1α,25(OH)(2)-vitamin D(3) [1α,25(OH)(2)D(3)].

On the mechanism underlying (23S)-25-dehydro-1alpha(OH)-vitamin D3-26,23-lactone antagonism of hVDRwt gene activation and its switch to a superagonist.

(23S)-25-Dehydro-1alpha(OH)-vitamin D(3)-26,23-lactone (MK) is an antagonist of the 1alpha,25(OH)(2)-vitamin D(3) (1,25D)/human nuclear vitamin D receptor (hVDR) transcription initiation complex, where the activation helix (i.e. helix-12) is closed. To study the mode of antagonism of MK an hVDR mutant library was designed to alter the free molecular volume in the region of the hVDR ligand binding pocket occupied by the ligand side-chain atoms (i.e. proximal to helix-12). The 1,25D-hVDR structure-function studies demonstrate that 1) van der Waals contacts between helix-12 residues Leu-414 and Val-418 and 1,25D enhance the stability of the closed helix-12 conformer and 2) removal of the side-chain H-bonds to His-305(F) and/or His-397(F) have no effect on 1,25D transactivation, even though they reduce the binding affinity of 1,25D. The MK structure-function results demonstrate that the His-305, Leu-404, Leu-414, and Val-418 mutations, which increase the free volume of the hVDR ligand binding pocket, significantly enhance MK antagonist potency. Surprisingly, the H305F and H305F/H397F mutations turn MK into a VDR superagonist (EC(50) approximately 0.05 nm) but do not concomitantly alter MK binding affinity. Molecular modeling studies demonstrate that MK antagonism stems from its side chain energetically preferring a pose in the VDR ligand binding pocket where its terminal C26-methylene atom is far removed from helix-12. MK superagonism results from an energetically favored increase in interaction between Leu-404/Val-418 and C26, resulting in an increase in the stability and population of the closed, helix-12 conformer. Finally, the results/model generated, coupled with application of a VDR ensemble allosterics model, provide an understanding for the species specificity of MK.

Structural basis of the histidine-mediated vitamin D receptor agonistic and antagonistic mechanisms of (23S)-25-dehydro-1alpha-hydroxyvitamin D3-26,23-lactone.

TEI-9647 antagonizes vitamin D receptor (VDR) mediated genomic actions of 1alpha,25(OH)2D3 in human cells but is agonistic in rodent cells. The presence of Cys403, Cys410 or of both residues in the C-terminal region of human VDR (hVDR) results in antagonistic action of this compound. In the complexes of TEI-9647 with wild-type hVDR (hVDRwt) and H397F hVDR, TEI-9647 functions as an antagonist and forms a covalent adduct with hVDR according to MALDI-TOF MS. The crystal structures of complexes of TEI-9647 with rat VDR (rVDR), H305F hVDR and H305F/H397F hVDR showed that the agonistic activity of TEI-9647 is caused by a hydrogen-bond interaction with His397 or Phe397 located in helix 11. Both biological activity assays and the crystal structure of H305F hVDR complexed with TEI-9647 showed that the interaction between His305 and TEI-9647 is crucial for antagonist activity. This study indicates the following stepwise mechanism for TEI-9647 antagonism. Firstly, TEI-9647 forms hydrogen bonds to His305, which promote conformational changes in hVDR and draw Cys403 or Cys410 towards the ligand. This is followed by the formation of a 1,4-Michael addition adduct between the thiol (-SH) group of Cys403 or Cys410 and the exo-methylene group of TEI-9647.

Prolactin blocks nuclear translocation of VDR by regulating its interaction with BRCA1 in osteosarcoma cells.

Based on their content of prolactin receptors, osteosarcoma cells were predicted to be responsive to prolactin (PRL), but whether PRL would be beneficial or contribute to pathogenesis was unclear. 1,25(OH)(2) vitamin D(3) [1alpha,25(OH)(2)D(3)] has antiproliferative effects on osteosarcoma cells, and a complex interregulatory situation exists between PRL and 1alpha,25(OH)(2)D(3). Using osteosarcoma cells, Western blot, real time RT-PCR, and promoter-luciferase assays, we have examined the interaction between PRL and 1alpha,25(OH)(2)D(3) and demonstrated that physiological concentrations of PRL block increased osteocalcin and vitamin D receptor (VDR) expression in response to 1alpha,25(OH)(2)D(3.) This blockade was shown to be the result of lack of nuclear accumulation of the VDR in response to 1alpha,25(OH)(2)D(3). Although inhibition of proteasomic degradation with MG132 had no effect on the VDR itself in a 30-min time frame, it relieved the blockade by PRL. Analysis of ubiquitinated proteins brought down by immunoprecipitation with anti-VDR showed PRL regulation of a 250-kDa protein-VDR complex. P250 was identified as the breast cancer tumor suppressor gene product, BRCA1, by Western blot of the VDR immunoprecipitate and confirmed by immunoprecipitation with anti-BRCA1 and blotting for the VDR in the absence and presence of PRL. Knockdown of BRCA1 inhibited nuclear translocation of the VDR and the ability of 1alpha,25(OH)(2)D(3) to induce the VDR. This, to our knowledge, is the first demonstration of a role for BRCA1 in nuclear accumulation of a steroid hormone and the first demonstration that PRL has the potential to affect the cell cycle through effects on BRCA1.

Multiple congenital plaquelike glomuvenous malformations with type 2 segmental involvement.

Multiple congenital glomuvenous malformations (GVMs) are rare. Almost all reported cases describe the multiple congenital plaquelike GVM variant. We report a case of multiple congenital plaquelike GVMs suggestive of type 2 segmental involvement following Blaschko lines.

Melkersson-Rosenthal Syndrome with migraine-like headaches treated with minocycline: a case report and review of the literature.

Cheilitis granulomatosa (CG), which presents clinically as persistent lip swelling, is characterized histologically by noncaseating granulomatous inflammation of unknown origin. CG may also be part of the classic triad of the Melkersson-Rosenthal Syndrome (MRS) and alone is considered by some to be an oligosymptomatic form of MRS. We report a case of CG associated with migraine-like headaches in a 44-year-old woman. The clinical presentation, histologic findings, and subsequent treatment are described. A brief review of the literature also is provided.