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Objective: There is no consensus on the optimal anticoagulant regimen following lower extremity bypass. Historically, warfarin has been utilized for prosthetic or compromised vein bypasses. Direct-acting oral anticoagulants (DOACs) are increasingly replacing warfarin in this context, but their efficacy in bypass preservation has not been well-studied. Recent studies have shown that DOACs may improve outcomes following bypasses; however, it is unclear if this is dependent upon type of bypass conduit. The goal of this study was to evaluate whether a difference exists between vein and prosthetic infra-geniculate bypasses outcomes based on the anticoagulant utilized on discharge, warfarin or DOAC., Methods: The Vascular Quality Initiative infra-inguinal bypass database was queried for all patients who underwent an infra-geniculate bypass and were anticoagulation-naive at baseline but were discharged on either warfarin or DOACs. A survival analysis was performed for patients up to 1 year to determine whether the choice of discharge anticoagulation was associated with differences between those with vein vs prosthetic conduits in overall survival, primary patency, risk of amputation, or risk of major adverse limb events (MALE). A multivariable Cox proportional hazards analysis was performed to control for differences in baseline demographic factors between the groups., Results: During the study period (2003-2020), 57,887 patients underwent infra-geniculate bypass. Of these, 3230 (5.5%) were anticoagulated on discharge. There was a similar distribution of anticoagulation between vein (n = 1659; 51.4%) and prosthetic conduits (n = 1571; 48.6%). Thirty-two percent were discharged on DOACs, and 68.0% were discharged on warfarin. For prosthetic conduits, being discharged on a DOAC was associated with improved outcomes on univariate and multivariable analyses revealing lower risk of overall mortality (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.41-0.93; P = .021), loss of primary patency (HR, 0.70; 95% CI, 0.55-0.89; P = .003), risk of amputation (HR, 0.71; 95% CI, 0.54-0.93; P = .013), and risk of MALE (HR, 0.80; 95% CI, 0.64-1.00; P = .048). Patients with a vein bypass had improved univariate outcomes for survival and primary patency; however, with multivariable analysis, there were no significant differences in outcomes between DOAC and warfarin., Conclusions: Anticoagulation-naive patients who underwent an infra-geniculate prosthetic bypass had higher rates of overall survival, bypass patency, amputation-free survival, and freedom from MALE when discharged on a DOAC compared with warfarin. Those with vein bypasses had similar outcomes regardless of the choice of anticoagulation., Competing Interests: Disclosures None., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Motor vehicle crashes (MVCs) are a leading cause of traumatic death and injury. Police traffic stops (PTS) are a common approach to enforcing motor vehicle laws intended to prevent MVCs. However, it is unclear which types of PTS are most effective. This study examined the relationship of PTS subtypes among municipal police patrols on non-interstate roads and MVCs and MVC-related deaths., Methods: PTS subtype data were characterized from six North Carolina cities: Charlotte, Durham, Fayetteville, Greensboro, Raleigh, and Winston-Salem. The primary outcomes of this study were yearly non-interstate MVC and MVC-related death rates per 100 population. The data were analyzed as balanced time-series cross-sectional data. The statistical analysis accounted for time-dependent and city-dependent confounding. We used a two-way fixed effects model to analyze the relationship between PTS and MVC or MVC-related deaths. We also utilized the difference in difference (DID) analysis to analyze if the reduction of PTS following a 2012 policing administrative change in Fayetteville had an association with MVC or MVC-related deaths., Results: We found no significant overall association between non-interstate PTS and MVCs (Coeff: -0.00006; p = 0.43) or MVC-related deaths (Coeff: -0.00011; p = 0.15). Panel regression suggested no significant relationship between MVCs and MVC-related deaths and PTS related to driving while impaired (p = 0.36), safe movement violation (p = 0.43), or seatbelt violations (p = 0.17). However, speed limit violations (Coeff: -0.00025; p = 0.032) and stop-light/sign violations (Coeff: -0.00147; p = 0.017) related to PTS significantly reduced MVC-related deaths. The DID regression showed no significant impact on MVCs (p = 0.924) or MVC-related deaths (0.706) before and after the police reform period., Conclusions: The evidence regarding the absence of an overall association and any association with most PTS subtypes suggest that PTS are not effective for MVC death prevention. Policymakers may proceed with exploring modifications to policing efforts without detriments to public safety as defined by MVC and MVC-related deaths., Level of Evidence: Retrospective epidemiological study, level IV., Competing Interests: Declaration of Competing Interest Dr. Towe is a consultant for Atricure, Bristol Myers Squibb, and Zimmer Biomet. These relationships have not influenced this work in any way. The other authors have no disclaimers, sources of funding, or financial relationships that could inappropriately influence this work and its conclusions., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Cancer care guidelines based on clinical trial data in homogenous populations may not be applicable to all rectal cancer patients. The aim of this study was to evaluate whether patients enrolled in rectal cancer clinical trials (CTs) are representative of United States (U.S.) rectal cancer patients., Methods: Prospective rectal cancer CTs from 2010 to 2019 in the United States were systematically reviewed. In trials with multiple arms reporting separate demographic variables, each arm was considered a separate CT group in the analysis. Demographic variables considered in the analysis were age, sex, race/ethnicity, facility location throughout the United States, rural vs urban geography, and facility type. Participant demographics from trial and the National Cancer Database (NCDB) participants were compared using chi-squared goodness of fit and one-sample t-test where applicable., Results: Of 50 CT groups identified, 42 (82%) studies reported mean or median age. Trial participants were younger compared to NCDB patients ( P < .001 all studies). All but three trials had fewer female patients than NCDB (48.2% female, P < .001). Less than half the CT groups reported on race or ethnicity. Eighteen out of 22 trials (82%) had a smaller percentage of Black patients and 4 out of 8 (50%) trials had fewer Hispanic or Spanish origin patients than the NCDB. No CTs reported comorbidities, socioeconomic factors, or education. CT primary sites were largely at academic centers and in urban areas., Conclusion: The present study supports the need for improved demographic representation and transparency in rectal cancer clinical trials., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Studies of robotic lobectomy (Robot-L) have been performed using data from high-volume, specialty centers which may not be generalizable. The purpose of this study was to compare mortality, length of stay (LOS), and cost between Robot-L and thoracoscopic lobectomy (VATS-L) using a nationally representative database hypothesizing they would be similar., Methods: The Premier Healthcare Database was used to identify patients receiving elective lobectomy for lung cancer from 2009 to 2019. Patients were categorized as receiving Robot-L or VATS-L using ICD-9/10 codes. Survey methodology and patient level weighting were used to correct for sampling error and estimation of a nationally representative sample. A propensity match analysis was performed to reduce bias between the groups. Primary outcome of interest was in-hospital mortality. Secondary outcomes were LOS and patient charges., Results: Among 62 698 patients, 19 506 (31.1%) underwent Robot-L and 43 192 (68.9%) underwent VATS-L. Differences between the groups included age, race, comorbidities, and insurance type. A propensity matched cohort demonstrated similar in-hospital mortality for Robot-L and VATS-L (.9% vs .9%, respectively, P = .91). Patients who underwent Robot-L had a shorter LOS (4 vs 5d, respectively, P < .001) but higher patient charges (90 593.0 vs 72 733.3 USD, respectively, P < .001)., Conclusions: In a nationally representative database, Robot-L and VATS-L had similar mortality. Although Robot-L was associated with shorter hospitalization, it was also associated with excess charges of almost $20,000. As Robot-L is now the most common approach for lobectomy in the U.S., further study into the cost and benefit of robotic surgery is warranted., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Esophagectomy is a complex operation with significant morbidity and mortality. Previous studies have shown that sub-specialization is associated with improved esophagectomy outcomes. We hypothesized that disparities would exist among esophagectomy patients regarding access to thoracic surgeons based on demographic, geographic, and hospital factors. The Premier Healthcare Database was used to identify adult inpatients receiving esophagectomy for esophageal and gastric cardia cancer, Barrett's esophagus, and achalasia from 2015 to 2019 using ICD-10 codes. Patients were categorized as receiving their esophagectomy from a thoracic versus non-thoracic provider. Survey methodology was used to correct for sampling error. Backwards selection from bivariable analysis was used in a survey-weighted multivariable logistic regression to determine predictors of esophagectomy provider specialization. During the study period, 960 patients met inclusion criteria representing an estimated population size of 3894 patients. Among them, 1696 (43.5%) were performed by a thoracic surgeon and 2199 (56.5%) were performed by non-thoracic providers. On multivariable analysis, factors associated with decreased likelihood of receiving care from a thoracic provider included Black (OR 0.41, p < 0.001), Other (OR 0.21, p < 0.001), and Unknown race (OR 0.22, p = 0.04), and uninsured patients (OR 0.53, p = 0.03). Urban hospital setting was associated with an increased likelihood of care by a thoracic provider (OR 4.43, p = 0.001). In this nationally representative study, Nonwhite race, rural hospital setting, and lower socioeconomic status were factors associated with decreased likelihood of esophagectomy patients receiving care from a thoracic surgeon. Efforts to address these disparities and provide appropriate access to thoracic surgeons is warranted., (© The Author(s) 2023. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Coaching has been shown to decrease physician burnout; however, coachee outcomes have been the focus. We report the impact of coaching on women-identifying surgeons who participated as coaches in a 9-month virtual program., Methods: A coaching program was implemented in the Association of Women Surgeons (AWS) to determine the effects of coaching on well-being and burnout from 2018 to 2020. AWS members volunteered and completed training in professional development coaching. Pre- and post-study measures were assessed, and bivariate analysis performed based on burnout and professional fulfillment score., Results: Seventy-five coaches participated; 57 completed both pre- and post-study surveys. There were no significant changes in burnout or professional fulfillment including the Positive Emotion, Engagement, Relationship, Meaning, and Accomplishment scale, hardiness, self-valuation, coping, gratitude, or intolerance of uncertainty scores from baseline to post-survey. On bivariate analysis, hardiness was associated with lower burnout throughout the duration of the program. Coaches with lower burnout at the end of the program met with their coachee more frequently than coaches with higher burnout [mean (SD) 3.95(2.16) versus 2.35(2.13) p = 0.0099]., Discussion: Burnout and professional fulfillment demonstrated no change in women surgeons who participated as professional development coaches. Those with lower burnout and higher professional fulfillment at the end of the program were found to have higher hardiness, which may be worth future investigation., Conclusions: Acquisition of coaching skills did not directly improve well-being in faculty who participated in a resident coaching program. Future studies would benefit from control groups and exploration of qualitative benefits of coaching., (© 2023. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Introduction Although rectal cancer is thought to have a higher rate of metastasis to the brain compared with colon cancer, there is limited and contradictory data on the subject. This study aims to determine the prevalence of brain metastasis for colon and rectal cancers (CRC), and to explore associations and predictors of brain metastasis (BM). Methods The 2010-2016 National Cancer Database (NCDB) was queried for patients with stage IV CRC. Patients with missing data on site of metastasis and primary tumor location were excluded. Chi-square test was used for categorical data and multivariate logistic regression analysis was performed to evaluate the predictors of BM. Results Of 108,540 stage IV CRC patients, the prevalence of BM was 1.21% from the right colon, 1.29% from the left colon, and 1.59% from the rectal adenocarcinoma (p<0.001). The presence of lung, bone, and liver metastases were the strongest predictors for BM. Bone and lung metastases increased the odds for BM by 3.87 (95% CI: 3.36-4.46) and 3.38 (95% CI: 3.01-3.80), respectively while the presence of liver metastasis decreased odds for BM by 55% (OR: 0.45; 95% CI: 0.40-0.50). On multivariate analysis, primary tumor location was not predictive of BM. Discussion This study helps to characterize the prevalence and associations of BM from CRC using the NCDB. The correlation between BM and bone and lung metastases, along with negative association of liver metastasis further supports the hypothesis of systemic transmission of tumor cells. Further identification of predictors and correlations with BM may help guide surveillance among patients with advanced CRC., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Franceschi et al.)

Objective: No consensus has yet been reached regarding the optimal antiplatelet and anticoagulant regimen for patients after lower extremity bypass. Usually, patients who have undergone below-the-knee bypass will begin oral anticoagulation therapy. Historically, the bypass has been with prosthetic conduits and the anticoagulation therapy has been warfarin. However, the use of direct-acting oral anticoagulants (DOACs) has been increasing owing to their relative ease of dosing. The goal of the present study was to evaluate whether a difference exists in the postoperative outcomes for patients who have undergone infrageniculate bypass stratified by the use of on DOACs vs warfarin., Methods: The Vascular Quality Initiative infrainguinal bypass database was queried for all patients who had undergone infrageniculate bypass, been anticoagulation naive at baseline, and been discharged with anticoagulation therapy. A survival analysis was performed for patients for ≤2 years postoperatively to determine whether discharge with warfarin vs DOACs was associated with differences in overall mortality, loss of primary patency, risk of amputation, and risk of major adverse limb events (MALE). A multivariable Cox proportional hazards analysis was performed to control for differences in the baseline demographic factors between the two groups., Results: During the study period (2007-2020) 57,887 patients had undergone infrageniculate bypass. Of these patients, 2786 had been anticoagulation naive and discharged with either warfarin (n = 1889) or DOACs (n = 897). Discharge with a DOAC was associated with a lower risk of overall mortality (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.47-0.83; P = .001), loss of primary patency (HR, 0.74; 95% CI, 0.62-0.87; P < .001), risk of amputation (HR, 0.70; 95% CI, 0.57-0.86; P = .001), and risk of MALE (HR, 0.83; 95% CI, 0.71-0.97; P = .017)., Conclusions: Anticoagulation-naive patients who had undergone infrageniculate bypass had had higher rates of overall survival, bypass patency, amputation-free survival, and freedom from MALE when discharged with a DOAC than with warfarin., (Copyright © 2022 Society for Vascular Surgery. All rights reserved.)

Background: Surgical stabilization of rib fractures (SSRF) is performed on only a small subset of patients who meet guideline-recommended indications for surgery. Although previous studies show that provider specialization was associated with SSRF procedural competency, little is known about the impact of provider specialization on SSRF performance frequency. We hypothesize that provider specialization would impact performance of SSRF., Methods: The Premier Hospital Database was used to identify adult patients with rib fractures from 2015 and 2019. The outcome of interest was performance of SSRF, defined using International Classification of Diseases-10th Revision Procedure Coding System coding. Patients were categorized as receiving their procedures from a thoracic, general surgeon, or orthopedic surgeon. Patients with missing or other provider types were excluded. Multivariate modeling was performed to evaluate the effect of surgical specialization on outcomes of SSRF. Given a priori assumptions that trauma centers may have different practice patterns, a subgroup analysis was performed excluding patients with 'trauma center' admissions., Results: Among 39 733 patients admitted with rib fractures, 2865 (7.2%) received SSRF. Trauma center admission represented a minority (1034, 36%) of SSRF procedures relative to other admission types (1831, 64%, p=0.15). In a multivariable analysis, thoracic (OR 6.94, 95% CI 5.94-8.11) and orthopedic provider (OR 2.60, 95% CI 2.16-3.14) types were significantly more likely to perform SSRF. In further analyses of trauma center admissions versus non-trauma center admissions, this pattern of SSRF performance was found at non-trauma centers., Conclusion: The majority of SSRF procedures in the USA are being performed by general surgeons and at non-trauma centers. 'Subspecialty' providers in orthopedics and thoracic surgery are performing fewer total SSRF interventions, but are more likely to perform SSRF, especially at non-trauma centers. Provider specialization as a barrier to SSRF may be related to competence in the SSRF procedures and requires further study., Type: Therapeutic/care management., Level of Evidence: IV., Competing Interests: Competing interests: CWT is a consultant for Atricure, Zimmer Biomet, Sig Medical and Medtronic, but these relationships have not influenced this work in any way., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Pediatric thyroid carcinoma is on the rise. We sought to better characterize patient factors associated with this and evaluate for trends based on age groups. Additionally, we examined surgical management over time, and whether it aligns with recommendations made by the American Thyroid Association. Using the National Cancer Database (NCDB), we examined cases of thyroid cancer from 2004 to 2017, ages 1-18 years. We subdivided this cohort by age group: those <10y, 10-15y, and >15y. NCDB query yielded 5,814 cases. The annual proportion of total cases ranged from 3% to 8% for <10y, 31%-40% for 10-15y, and 52%-66% for >15y. 80-90% of cases in all age groups did indeed receive total thyroidectomy which is consistent with ATA guidelines. Our results verify an overall increase in pediatric thyroid cancer cases, occurring mostly in the 10-18 years old age range with the largest year-to-year increases in the >15y group., Competing Interests: Declaration of competing interest None of the authors have conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Lung lobectomy is the standard of care for early-stage lung cancer. Studies have suggested improved outcomes associated with lobectomy performed by specialized thoracic surgery providers. We hypothesized that disparities would exist regarding access to thoracic surgeons among patients receiving lung lobectomy for cancer., Methods: The Premier Hospital Database was used to identify adult inpatients receiving lung lobectomy from 2009 to 2019. Patients were categorized as receiving their lobectomy from a thoracic surgeon, cardiovascular surgeon, or general surgeon. Sample-weighted multivariable analysis was performed to identify factors associated with provider type., Results: When adjusted for sampling, 121,711 patients were analyzed, including 71,709 (58.9%) who received lobectomy by a thoracic surgeon, 36,630 (30.1%) by a cardiovascular surgeon, and 13,373 (11.0%) by a general surgeon. Multivariable analysis showed that thoracic surgeon provider type was less likely with Black patients, Medicaid insurance, smaller hospital size, in the western region, and in rural areas. In addition, non-thoracic surgery specialty was less likely to perform minimally-invasive (MIS) lobectomy (cardiovascular OR 0.80, p < 0.001, general surgery OR 0.85, p = 0.003)., Conclusions: In this nationally representative analysis, smaller, rural, non-teaching hospitals, and certain regions of the United States are less likely to receive lobectomy from a thoracic surgeon. Thoracic surgeon specialization is also independently associated with utilization of minimally invasive lobectomy. Combined, there are significant disparities in access to guideline-directed surgical care of patients receiving lung lobectomy.

Background: Balanced transfusion is lifesaving for hemorrhagic shock. The American Red Cross critical blood shortage in 2022 threatened the immediate availability of blood. To eliminate waste, we reviewed the utility of transfusions per unit to define expected mortality at various levels of balanced transfusion., Methods: A retrospective study of 296 patients receiving massive transfusion on presentation at a level 1 trauma center was performed from January 2018 to December 2021. Units of packed red blood cells (PRBCs), fresh frozen plasma (FFP), and platelets received in the first 4 hours were recorded. Patients were excluded if they died in the emergency department, died on arrival, received <2 U PRBCs or FFP, or received PRBC/FFP >2:1. Primary outcomes were mortality and odds of survival to discharge. Subgroups were defined as transfused if receiving 2 to 9 U PRBCs, massive transfusion for 10 to 19 U PRBCs, and ultramassive transfusion for ≥20 U PRBCs., Results: A total of 207 patients were included (median age, 32 years; median Injury Severity Score, 25; 67% with penetrating mechanism). Mortality was 29% (61 of 207 patients). Odds of survival is equal to odds of mortality at 11 U PRBCs (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.50-1.79). Beyond 16 U PRBCs, odds of mortality exceed survival (OR, 0.36; 95% CI, 0.16-0.82). Survival approaches zero >36 U PRBCs (OR, 0.09; 95% CI, 0.00-0.56). Subgroup mortality rates increased with unit transfused (16% transfused vs. 36% massive transfusion, p = 0.003; 36% massive transfusion vs. 67% ultramassive transfusion, p = 0.006)., Conclusion: Mortality increases with each unit balanced transfusion. Surgeons should view efforts heroic beyond 16 U PRBCs/4 hours and near futile beyond 36 U PRBCs/4 hours. While extreme outliers can survive, consider cessation of resuscitation beyond 36 U PRBCs. This is especially true if hemostasis has not been achieved or blood supplies are limited., Level of Evidence: Prognostic and Epidemiologic; Level IV., (Copyright © 2022 American Association for the Surgery of Trauma.)

Objective: Chondrosarcoma is the most common primary malignant chest wall tumor and is historically associated with poor prognosis. Recommendations regarding surgical excision are on the basis of small, single-institution studies. We used a large national database to assess outcomes of surgery for chest wall chondrosarcoma (CWC) hypothesizing that surgical excision remains standard of care., Methods: The National Cancer Databases for bone and soft tissue were merged to identify patients with chondrosarcoma from 2004 to 2018. Clinical and demographic characteristics of CWC were compared with chondrosarcoma from other sites. The primary outcome was overall survival described using Kaplan-Meier estimate. Univariable and multivariable Cox analysis was used to determine risk factors for poor survival among CWC patients who underwent surgery. Multivariable analysis of predictors of margin status was performed because of worse prognosis associated with positive margins., Results: Among 11,925 patients with chondrosarcoma, 1934 (16.2%) had a CWC. Relative to other sites, CWC was associated with older age, male sex, White race, surgical resection, and care at a nonacademic institution. CWC was associated with 1-, 3-, 5-, and 10-year survival of 91.5%, 82.0%, 75.5%, and 62.7%, respectively. In univariable analysis, survival was associated with surgery (hazard ratio, 0.02; P  < .001) and adversely affected by positive margins (hazard ratio, 2.66; P  < .001). Multivariable analysis showed larger tumor size was independently associated with increased risk for positive margins (odds ratio, 1.04; 95% CI, 1.011-1.075)., Conclusions: CWC represents a different cohort of patients relative to chondrosarcoma from other sites. Surgical excision remains the optimal treatment, and positive margins are associated with poor prognosis., (© 2023 The Author(s).)

Background: Despite evidence that early-stage male breast cancer (MBC) can be treated the same as in females, we hypothesized that men undergo more extensive surgery., Methods: Patients with clinical T1-2 breast cancer were identified in the National Cancer Database 2004-2016. Trends in surgery type and overall survival were compared between sexes., Results: Of 9,782 males and 1,078,105 females, most were cN0 with AJCC stage I/II disease. Unilateral mastectomy was most common in men (67.1% vs. 24.1%, p < 0.001) and partial mastectomy in women (64.7% vs. 26.4%, p < 0.001), with no significant change over time. Over 1/3 of men received ALND in 2016. While overall survival was superior in females (HR 0.83, 95% CI 0.73-0.94, p = 0.003), partial mastectomy was associated with a 42% reduction in mortality risk for males (HR 0.58, 95% CI 0.4-0.8, p = 0.003)., Conclusions: De-escalation of surgery could be considered for MBC to improve survival and align with current standards of care., Competing Interests: Declaration of competing interest The authors of this paper have no related conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Infected Ventricular Assist Device (VAD)-associated wounds are common and associated with significant morbidity and mortality. The efficacy of hardware salvage utilizing flaps and negative pressure wound therapy (NPWT) remains understudied. We hypothesized that patients treated with flaps and/or NPWT would have higher hardware salvage rates compared with other surgical management strategies., Methods: A meta-analysis study evaluating VAD-associated wounds was performed following PRISMA guidelines. Primary predictor variables were flap-reconstruction (FR), NPWT, no FR, and infection location (mediastinum versus driveline). Primary outcomes were hardware retention (salvage) versus explantation, infection recurrence, or death. Twenty-nine studies were included. Standard statistical methods included logistic regression analysis., Results: Seventy-four subjects with nonsignificant demographic differences between cohorts were identified. Overall salvage was 59.5% in both driveline and mediastinum cohorts. Overall, NPWT significantly improved salvage compared with no NPWT [77.4% versus 46.5% respectively ( P = 0.009)], and FR significantly improved salvage compared with no FR [68.6% versus 39.1% respectively ( P = 0.022)]. Logistic regression analysis predicting odds of salvage by FR (area under curve = 0.631) was significantly three times higher (95% CI: 1.2-9.5) and predicting the odds for salvage by NPWT (area under curve = 0.656) was significantly four times higher (95% CI: 1.4-11.1) compared with other treatment., Conclusions: NPWT or flap reconstruction for treatment of threatened VAD hardware was associated with a significantly improved device salvage compared with other surgical strategies. Further study should focus on subgroup analysis of flaps utilized and synergistic treatment benefits., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: Race, access to care, and molecular features result in outcome disparities in triple-negative breast cancer (TNBC). We sought to determine the role of age in TNBC disparity by hypothesizing that younger patients receive more comprehensive treatment, resulting in survival differences., Methods: The National Cancer Database was used to identify women with unilateral TNBC treated from 2005 through 2017. Patients were stratified by age (≤40, 41-70, >70); demographics, clinical characteristics, and treatment factors were compared. Logistic regression determined factors associated with treatment received. Survival outcomes were analyzed using a stratified log-rank test., Results: Of the 168,715 patients, 16,287 (9.6%) were ≤40 years. Patients ≤40 were significantly more likely to present at higher clinical stage (P < .001) and receive neoadjuvant chemotherapy (NAC, P < .001). Bilateral mastectomy was the most common surgery for patients ≤40 (37%), whereas partial mastectomy was most often used in patients 41 to 70 years old (48%) and those >70 (49%) (P < .001). Patients ≤40 years were significantly more likely to undergo both NAC and mastectomy than those >40 (odds ratio 1.5, both P < .05) despite a greater in-breast tumor response in the youngest patients. Patients treated with mastectomy and axillary lymph node dissection had inferior survival outcomes compared to those treated with partial mastectomy and sentinel lymph node biopsy across all 3 age groups (P < .001)., Conclusion: The clinical characteristics of TNBC differ significantly at the extremes of age, likely driving treatment decisions. Although patients ≤40 present with a more advanced disease and appropriately receive NAC, they also undergo more extensive surgery that does not yield a survival benefit. Further research is needed to determine if age disparity is due to oncologic factors or patient and provider preferences., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Physician-modified endografts (PMEG) and parallel grafting (PG) are important techniques for endovascular repair of complex aortic aneurysms using off-the-shelf devices. However, there are few data regarding the relative efficacy and outcomes of these techniques in thoracoabdominal extent aneurysms. This study sought to compare the outcomes of PG and PMEG across different extents of thoracoabdominal aneurysms (TAAAs) for which they can be used., Methods: The Society for Vascular Surgery Vascular Quality Initiative thoracic endovascular aortic repair/complex endovascular aortic repair module was queried for all patients undergoing repair of an unruptured, TAAA (extents I-IV) from 2012 to 2020; aneurysm types were defined by repair extent as determined by proximal and distal seal zones. Patients were differentiated based on whether they underwent repair with a PMEG or PG. The primary outcomes for this study were overall survival and freedom from aneurysm- or procedure-related mortality at 1 year determined via Kaplan-Meier analysis, with a Cox hazard regression analysis conducted to examine the independent association of repair modality with primary outcomes., Results: There were 813 patients who met the inclusion criteria (TAAA I-III, n = 362; TAAA IV, n = 451; PG, n = 426; PMEG, n = 387). PMEG repairs were performed at centers with a nearly two- to three-fold higher annual volume of endovascular TAAA repairs. Type Ia endoleaks were reduced with PMEG repair, most significantly in TAAA IV (TAAA I-III, 2.2% PMEG vs 10% PG [P = .2]; TAAA IV, 1.2% PMEG vs 21.6% PG [P < .001]). Thoracoabdominal repairs demonstrated improved survival at 1 year with PMEG devices, significant for TAAA I to III repairs (TAAA I-III, PMEG 85% vs PG 74% [P = .01]; TAAA IV, 84% PMEG vs PG 78% [P = .08]). Freedom from aneurysm- or procedure-related mortality was also improved with PMEG repairs, remaining significant at 1 year in the case of TAAA IV (TAAA I-III:, PMEG 94% vs PG 86% [P = .06]; TAAA IV, PMEG 94% vs PG 88% [P = .02]). PMEG demonstrated decreases in several measures of postoperative morbidity, including stroke, death, major adverse cardiovascular events, and postoperative complications. In the multivariate analysis, repair modality was not associated with either primary outcome; rather, several perioperative complications conveyed the greatest hazard for both primary outcomes across repair extents., Conclusions: Survival after endovascular TAAA repair is improved with the use of PMEG compared with PG. Several key factors of this study demonstrate the shortcomings of PG in complex aneurysm repair, namely, high rates of critical endoleaks, the need for adjunctive access sites, and an increase in perioperative complications that influence longer term outcomes., (Copyright © 2022 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: With the expanding application of endovascular technology, the need to deploy into zone 0 has been encountered on occasion. In the present study, we evaluated the outcomes of great vessel debranching (GVD) as a method of extending the proximal landing zone to facilitate thoracic endovascular aortic repair (TEVAR)., Methods: We performed a single-center retrospective review of all patients who had undergone GVD followed by TEVAR between May 2013 and December 2020. The primary outcome was primary patency of all targeted vessels, with all-cause perioperative mortality as a secondary outcome. Kaplan-Meier analysis was used to account for censoring of mortality and primary patency. The extent of hybrid aortic repairs was characterized into type I (GVD plus TEVAR without ascending aorta or aortic arch reconstruction, type II (GVD plus TEVAR with ascending aorta reconstruction), and type III (GVD plus TEVAR with ascending aorta and aortic arch reconstruction with an elephant trunk (soft [surgical] or frozen [endovascular]])., Results: A total of 42 patients (23 men [54.8%]; mean age, 62.2 ± 11.2 years) had undergone GVD, with 122 vessels revascularized (42 innominate, 42 left common carotid, and 38 left subclavian arteries). The indication for TEVAR was aneurysmal degeneration from aortic dissection in 32 patients (76.2%), a thoracic aneurysm in 9 patients (21.4%), and a perforated aortic ulcer in 1 patient (2.4%). The median duration between GVD and TEVAR was 82 days. The mean follow-up period was 25.7 ± 23.5 months. Type I repair was performed in 4, type II in 16, and type III in 22 patients. The perioperative mortality, stroke, and paraplegia rates were 9.5%, 7.1%, and 2.4%, respectively. Neither the extent of repair (P = .80) nor a history of aortic repair (P = .90) was associated with early mortality. Of the 38 patients who had survived the perioperative period, 6 had died >30 days postoperatively. At 36 months, the survival estimate was 68.6% (95% confidence interval, 45.7%-83.4%). The overall primary patency of the innominate artery, left common carotid artery, and left subclavian artery was 100%, 89.5%, and 94.1%, respectively. The primary-assisted patency rate was 100% for all the vessels., Conclusions: We found GVD to be a safe and effective method of extending the proximal landing zone into zone 0 with outstanding primary patency rates. Further studies are required to confirm the safety and longer term durability for these patients., (Copyright © 2022 Society for Vascular Surgery. All rights reserved.)

Background: Low health literacy is associated with increased resource use and poorer outcomes in medical and surgical patients with various diseases. This observational study was designed to determine (1) the prevalence of low health literacy among surgical patients with cancer at an NCI-designated Comprehensive Cancer Center (CCC), and (2) associations between health literacy and clinical outcomes., Methods: Patients receiving surgery (N=218) for gastrointestinal (60%) or genitourinary cancers (22%) or sarcomas (18%) were recruited during their postsurgical hospitalization. Patients self-reported health literacy using the Brief Health Literacy Screening Tool (BRIEF). Clinical data (length of stay [LoS], postacute care needs, and unplanned presentation for care within 30 days) were abstracted from the electronic medical records 90 days after surgery. Multivariate linear and logistic regressions were used to examine the relationship between health literacy and clinical outcomes, adjusting for potential confounding variables., Results: Of 218 participants, 31 (14%) showed low health literacy (BRIEF score ≤12). In regression analyses including 212 patients with complete data, low health literacy significantly predicted LoS (β = -1.82; 95% CI, -3.00 to -0.66; P=.002) and postacute care needs (odds ratio [OR], 0.25; 95% CI, 0.07-0.91). However, health literacy was not significantly associated with unplanned presentation for care in the 30 days after surgery (OR, 0.51; 95% CI, 0.20-1.29)., Conclusions: This study demonstrates the prevalence of low health literacy in a surgical cancer population at a high-volume NCI-designated CCC and its association with important clinical outcomes, including hospital LoS and postacute care needs. Universal screening and patient navigation may be 2 approaches to mitigate the impact of low health literacy on postsurgical outcomes.

Background Data suggests there are demographic and biological differences in colon cancer between young and typical-onset patients. However, it is unclear if these differences persist in rectal cancer patients, exclusive of colon cancer. This is a retrospective review of a large national database to evaluate age-based differences in demographics, tumor features, and treatment among patients with rectal adenocarcinoma. Methods The National Cancer Database from 2004-2014 was queried for rectal adenocarcinoma. Patients were grouped by age at diagnosis: early-onset, defined as <40 years, mid-onset 40-49, and late-onset ≥50. Propensity matching controlled for demographic variation among cohorts. Pairwise Chi-square with Bonferroni correction was used for analysis. Results Thirty thousand nine hundred seventy-eight patients were included: 1,249 (4%) early-onset, 4,156 (13%) middle-onset, and 25,573 (83%) late-onset. Significant differences existed between all three cohorts in nearly all demographic and pathologic metrics. Control for demographic variation revealed early-onset and middle-onset cohorts differed only with respect to the stage at presentation, while early-onset and late-onset cohorts differed more significantly on the basis of stage, histology, and oncologic management. Conclusion The demographic differences observed demonstrate that patients under 50 should not be considered one cohort. Propensity matching led to a decrease in tumor trait differences among cohorts, suggesting that demographics other than age drive variation in tumor biology. Young patients received more aggressive management, implying the presence of an age bias. Age-based screening is likely insufficient and may exclude the rising proportion of young patients at risk for disease, while age-based management may lead to under- or overtreatment of patients at either end of the age spectrum., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Bliggenstorfer et al.)

Background: The aim of this study is to define the cost of rib fracture hospitalization by single, multiple, and flail type using a nationally representative sample., Methods: The national inpatient sample (NIS) was used to identify patients with a primary diagnosis of rib fracture hospitalization 2007-2016. International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) codes were used to characterize patients as having single, multiple, or flail chest rib fractures. Patients with only trauma related diagnosis groups (DRG) at the time discharge were included in the final sample. The cost of hospitalization was obtained by converting reported charges into cost using the all-payer inpatient cost-to-charge ratio (CCR) for all hospitals in the NIS data. The log of cost was modeled using multivariate linear regression. The rib fracture type was the primary predictor in the model., Results: There were 373,053 rib fracture admissions during 2007-2016. The average cost per hospitalization was $10,169 (95%Confidence Interval [CI]: 9,942-10,395), which translated into a national expenditure of $3.64 billion over 10 years. The cost of rib fracture hospitalization increased from $209 million in 2007 to $469 million in 2016. Compared to single rib fracture patients, the cost of hospitalization for multiple rib fractures and flail chest was 3% (p = 0.001) and 5% (p=0.02) higher, respectively. Higher injury severity score, total number of body regions injured and longer length of stay were associated with higher rib fracture hospitalization cost., Conclusions: Rib fractures affect ~22,000-45,000 people per year in the United States. The cost of rib fractures is over $469 million per year and is increasing over time. Multiple rib fractures and flail chest rib fractures are associated with increased cost. Pathways to improve care in patients with rib fractures should consider the cost of treatment., Competing Interests: Declaration of Competing Interest VPH is supported by the Clinical and Translational Science Collaborative of Cleveland, KL2TR002547 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health. VPH spouse is consultant for Zimmer Biomet, Medtronic, Atricure, and Sig Medical. CWT is consultant for Zimmer Biomet, Medtronic, Atricure, and Sig Medical., (Copyright © 2021. Published by Elsevier Ltd.)

Objectives: Amid growing calls for police reform, it is imperative to reassess whether police actions designed to improve public safety are associated with injury prevention. This study aims to examine the relationship between the police traffic stops (PTSs) and motor vehicle crash (MVC) deaths at the state level. We hypothesize that increased PTSs would be associated with reduced MVC deaths., Methods: We retrospectively analyzed PTSs and MVC deaths at the state level from 2004 to 2016. Police traffic stops data were from 33 state patrols from the Stanford Open Policing Project. The MVC deaths data were collected from the National Highway Traffic Safety Administration. The vehicle miles traveled data were from the Federal Highway Administration Office of Highway Policy Information. All data were adjusted per 100 million vehicle miles traveled (100MVMT) and were analyzed as state-level time series cross-sectional data. The dependent variable was MVC deaths per 100MVMT, and the independent variable was number of PTSs per 100MVMT. We performed panel data analysis accounting for random and fixed state effects and changes over time., Results: Thirty-three state patrols with 235 combined years were analyzed, with a total of 161,153,248 PTSs. The PTS rate varied by state and year. Nebraska had the highest PTS rate (3,637/100MVMT in 2004), while Arizona had the lowest (0.17/100MVMT in 2009). Motor vehicle crash deaths varied by state and year, with the highest death rate occurring in South Carolina in 2005 (2.2/100MVMT) and the lowest in Rhode Island in 2015 (0.57/100MVMT). After accounting for year and state-level variability, no association was found between PTS and the MVC death rates., Conclusion: State patrol traffic stops are not associated with reduced MVC deaths. Strategies to reduce death from MVC should consider alternative strategies, such as motor vehicle modifications, community-based safety initiatives, improved access to health care, or prioritizing trauma system., Level of Evidence: Retrospective epidemiological study, level IV., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The main objective was to evaluate the preparedness of senior centers (SCs) for active shooter (AS) events and test the hypothesis that most SCs were not organized to properly handle AS incidents., Design: A cross-sectional study based on questionnaire with quantitative measures., Setting: A questionnaire-based multistate survey of SC Directors (SCDs) of public and private SCs., Participants: SCs were included upon receipt of answers from SCDs to questionnaire-based survey, resulting in 139 SCs from Ohio, Pennsylvania, Michigan, Maryland, Indiana, Illinois, New York, and West Virginia., Main Outcome Measure: SCs, SCDs, and SCs' staff preparedness and vulnerability to an AS event., Results: Over half (56 percent) of SCDs replied that their center was not prepared for an AS event. A significant (p < 0.01) association was found between the SCD's perception of being prepared and the availability of a formal AS preventive policy. The lack of panic buttons and surveillance cameras was significantly (p < 0.01) associated with the feeling of inability by SCDs to respond effectively to an AS event. Those SCDs who were confident about their AS preparedness felt significantly (p < 0.01) better prepared to respond to an AS incident. Personal interviews with content experts agreed that all SCDs should take steps to develop an official AS preparedness policy, but its implementation should be the direct responsibility of local policymakers and legislators., Conclusions: Most SDCs and SCs are unprepared for AS incidents. SCDs should review or develop specific recommendations and implement plans for a better preparedness of SCs and SCDs for AS events. Considering the inherent high vulnerability of older adults, there is an urgent need to have such AS policy in place.

Background: Neoadjuvant chemoradiation is associated with improved survival of superior sulcus cancers, but little data exists regarding clinical T4 lung cancers with mediastinal invasion. We hypothesized that neoadjuvant treatment would be associated with improved survival in T4 lung cancer patients with mediastinal invasion., Methods: Clinical T4-N0/1-M0 non-small cell lung cancers from 2006-2015 were identified in the National Cancer Database. Patients with T4 extension to mediastinal structures undergoing lobectomy, bilobectomy, or pneumonectomy were included. Neoadjuvant treatment was defined as preoperative chemotherapy and/or radiation. Patients receiving surgery >120 days after radiation were excluded. Study endpoints were pathologic margin status and overall survival. To adjust for heterogeneity, a 1:1 propensity match analysis was performed., Results: A total of 1101 patients with cT4N0/1M0 cancers were analyzed; 595 (54.0%) received primary surgery and 506 (46.0%) received neoadjuvant treatment. Neoadjuvant therapy was associated with fewer positive surgical margins (46 of 506 [9.3%] vs 186 of 595 [33.1%], P < .001). Multivariate analysis showed an association of neoadjuvant therapy with a lower rate of positive margin (odds ratio 0.220, P < .001). Overall survival was longer among patients receiving neoadjuvant treatment (65.9 vs 27.5 months, P < .001). Propensity matching identified 331 matched pairs of patients. Among these, positive margins were less likely after receiving neoadjuvant treatment (10.5% vs 31.3%, P < .001). Overall survival among the matched pairs was improved in those receiving neoadjuvant treatment (57.0 vs 27.5 months, P < .001)., Conclusions: In the NCDB, T4N0/1 mediastinal invasion patients who receive neoadjuvant treatment have decreased rates of positive surgical margins and improved overall survival. The use of neoadjuvant treatment should be considered in these patients., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Despite excellent short-term outcomes of minimally invasive esophagectomy (MIE), there is minimal data on long-term outcomes compared to open esophagectomy. MIE's superior visualization may have improved lymphadenectomy and complete resection rate and therefore improved long-term outcomes. We hypothesized that MIE would have superior long-term survival. Patients undergoing an esophagectomy for cancer between 2010 and 2016 were identified in the National Cancer Database. MIE included laparoscopic/robotic approach, and conversions were categorized as open. A 1:1 propensity match was performed. Lymphadenectomy and margin status were compared between MIE and open using Stuart Maxwell marginal homogeneity and Wilcoxon matched-pair signed-rank test. Survival was compared using log-rank test. 13,083 patients were identified: 8,906 (68%) open and 4,177 (32%) MIE. Propensity matching identified 3,659 'pairs' of MIE and open esophagectomy patients. Among them, MIE was associated with higher number lymph nodes examined (16 vs. 14, P < 0.001) and similar number of positive lymph nodes (0 vs. 0, P = 0.33). MIE had higher rate of negative pathologic margin (95 vs. 93.5%, P < 0.001). MIE was also associated with shorter hospitalization (9 vs. 10 days, P < 0.001). Survival was improved among MIE patients (46.6 vs. 41.4 months for open, P = 0.003) and among pathologic node-negative patients (71.4 vs. 61.5 months, P = 0.005). These data suggest that MIE has improved short-term outcomes (improved lymphadenectomy, pathologic margins, and length of stay) and also associated improved overall survival. The etiology of superior overall survival is likely secondary to many factors related and unrelated to surgical approach., (© The Author(s) 2020. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Breast implant illness (BII) after aesthetic breast augmentation remains a poorly defined syndrome encompassing a wide spectrum of symptoms. While previously published series have observed overall symptomatic improvement after breast implant removal, there is a lack of studies evaluating changes in specific symptoms over time. The purpose of this study was to gain an understanding of symptoms associated with BII, and to evaluate how these symptoms change after removal of breast implants and total capsulectomy (explantation). We hypothesized that patients presenting with BII would experience both immediate and sustained improvement in constitutional symptoms after explantation., Methods: A retrospective study of all patients who underwent explantation by a single surgeon over 2 years was conducted. Repeated-measures analysis of variance accounting for dependency was used to compare symptoms before and after surgery. Multivariate analyses and linear regression models were used to examine the impact of patient- and implant-related factors on changes in symptoms., Results: Seven hundred fifty patients met inclusion criteria. Mean preoperative survey score (26.19 ± 11.24) was significantly different from mean postoperative survey score at less than 30 days (9.49 ± 7.56) and greater than 30 days (9.46 ± 7.82, P < 0.001). Patients with a BMI greater than 30 or those with clinically detectable contracture on examination showed greater improvement on their survey scores (P = 0.039, 0.034, respectively)., Conclusions: Although BII encompasses a large range of symptoms, subjects in this study demonstrated significant and sustained improvement in 11 common symptom domains. This improvement was demonstrable within the first 30 days postoperatively and was maintained beyond 30 days. The study demonstrated a strong association of explantation and specific symptom improvement within the patient population studied. Future investigation will further elucidate possible biologic phenomena to better characterize the pathophysiology and mechanism of BII.

The interactions with and effects of five chemically distinct, bioactive phenolic compounds on the lipid bilayers of model dipalmitoylphosphatidylcholine (DPPC) liposomes were investigated. Complementary analytical techniques, including differential scanning calorimetry (DSC) and phosphorus and proton nuclear magnetic resonance spectroscopy (NMR), were employed in order to determine the location of the compounds within the bilayer and to correlate location with their effects on bilayer characteristics and liposomal stability. As compared to the phenolic compounds localized in the glycerol region of the DPPC head group within the bilayer, which enhanced the colloidal stability of the liposomes, compounds located closer to the center of the bilayer reduced vesicle stability as a function of time. Molecules present in the upper region of liposomal DPPC acyl chains (C 1 -C 10 ) inhibited liposomal aggregation and size increase, perhaps due to tighter packing of adjoining DPPC molecules and increased surface exposure of DPPC phosphate head groups. These data may be useful for designing liposomal systems containing hydrophobic phenols and other small molecules, selecting appropriate analytical methods for determining their location within liposomal bilayers, and predicting their effects on liposome characteristics early in the liposome formulation development process.

This work was conducted in order to design, characterize, and evaluate stable liposomes containing the hydrophobic drug raloxifene HCl (RAL) and hydrophilic doxycycline HCl (DOX), two potentially synergistic agents for treating osteoporosis and other bone lesions, in conjunction with a radio frequency-induced, hydrophobic magnetic nanoparticle-dependent triggering mechanism for drug release. Both drugs were successfully incorporated into liposomes by lipid film hydration, although combination drug loading compromised liposome stability. Liposome stability was improved by reducing the drug load and by including Pluronics® (PL) in the formulations. DOX did not appear to interact with the phospholipid membranes comprising the liposomes, and its release was maximized in the presence of radio frequency (RF) heating. In contrast, differential scanning calorimetry (DSC) and phosphorus-31 nuclear magnetic resonance ((31)P-NMR) analysis revealed that RAL developed strong interactions with the phospholipid membranes, most notably with lipid phosphate head groups, resulting in significant changes in membrane thermodynamics. Likewise, RAL release from liposomes was minimal, even in the presence of RF heating. These studies may offer useful insights into the design and optimization of multidrug containing liposomes. The effects of RAL on liposome characteristics and drug release performance underscore the importance of appropriate physical-chemical analysis in order to identify and characterize drug-lipid interactions that may profoundly affect liposome properties and performance early in the formulation development process.

Overcoming the low oral bioavailability of many drugs due to their poor aqueous solubility is one of the major challenges in the pharmaceutical industry. The production of amorphous solid dispersions (ASDs) of these drugs using hydrophilic polymers may significantly improve their solubility. However, their storage stability and the stability of their supersaturated solutions in the gastrointestinal tract upon administration are unsolved problems. We have investigated the potential of a low viscosity grade of a cellulosic polymer, hydroxypropyl cellulose (HPC-SSL), and compared it with a commonly used vinyl polymer, polyvinylpyrrolidone vinyl acetate (PVP-VA), for stabilizing the ASDs of a poorly water soluble drug, felodipine. The ASDs were produced using hot melt mixing and stored under standard and accelerated stability conditions. The ASDs were characterized using differential scanning calorimetry, powder X-ray diffraction, and Fourier transform infrared spectroscopy. Drug dissolution and partitioning rates were evaluated using single- and biphasic dissolution studies. The ASDs displayed superior drug dissolution and partitioning as compared to the pure crystalline drug, which might be attributed to the formation of a drug-polymer molecular dispersion, amorphous conversion of the drug, and drug-polymer hydrogen bonding interactions. Late phase separation and early re-crystallization occurred at lower and higher storage temperatures, respectively, for HPC-SSL ASDs, whereas early phase separation, even at low storage temperatures, was noted for PVP-VA ASDs. Consequently, the partitioning rates for ASDs dispersed in HPC-SSL were greater than those of PVP-VA at lower and room temperature storage, whereas the performance of both of the ASDs was similar when stored at higher temperatures., (Copyright © 2014. Published by Elsevier Ltd.)

The influence of polymers on the dissolution, supersaturation, crystallization, and partitioning of poorly water soluble compounds in biphasic media was evaluated. Amorphous solid dispersions (ASDs) containing felodipine (FLD) and itraconazole (ITZ) were prepared by hot melt mixing (HMM) using various polymers. The ASDs were analyzed using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and HPLC. Amorphous drug conversion was confirmed using DSC and PXRD, and drug stability by HPLC. Single- and biphasic dissolution studies of the ASDs with concurrent dynamic light scattering (DLS) and polarized light microscopic (PLM) analysis of precipitated drugs were performed. HPLC revealed no HMM-induced drug degradation. Maximum partitioning into the organic phase was dependent upon the degree of supersaturation. Although the highest supersaturation of FLD was attained using Eudragit® EPO and AQOAT® AS-LF with better nucleation and crystal growth inhibition using the latter, higher partitioning of the drug into the organic phase was achieved using Pharmacoat® 603 and Kollidon® VA-64 by maintaining supersaturation below critical nucleation. Critical supersaturation for ITZ was surpassed using all of the polymers, and partitioning was dependent upon nucleation and crystal growth inhibition in the order of Pharmacoat® 603>Eudragit® L-100-55>AQOAT® AS-LF. HMM drug-polymer systems that prevent drug nucleation by staying below critical supersaturation are more effective for partitioning than those that achieve the highest supersaturation., (Copyright © 2013 Elsevier B.V. All rights reserved.)

HPMCAS is a widely used polymer in the pharmaceutical industry as an excipient. In this work, the physicochemical stability of HPMCAS was investigated for hot melt extrusion (HME) application. The reduction in zero rate viscosity (η0) of the polymer with the increase in temperature was determined using rheological evaluation prior to HME processing. The energy of activation for AS-MF determined by fitting Arrhenius model to the temperature dependent reduction in η0 was found to be slightly lower than that for the other grades of HPMCAS. Glassy yellowish HMEs were obtained using Haake Mini-Lab MicroCompounder operated at 160, 180, and 200°C and 100, 200, and 300 rpm for all the grades at each temperature. Various physicochemical properties of HPMCAS such as glass transition temperature, semi-crystalline nature, solid state functional group properties, moisture content, and solution viscosity were not significantly affected by the HME processing. The most significant change was the release of acetic and succinic acid with the increase in HME temperature and speed. The free acid content release due to HME was directly proportional to the speed at lower operating temperatures. AS-LF was found to be the most stable with the lowest increase in total free acid content even at higher HME temperature and speed. Although the dissolution time was not affected due to HME for AS-LF and AS-MF grades, it was notably increased for AS-HF, perhaps due to significant reduction of succinoyl content. In conclusion, the HME processing conditions for solid dispersions of HPMCAS should be based on the acceptance levels of free acid for the drug and the drug product., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Hot melt extrudates (HMEs) of indomethacin (IND) with Eudragit EPO and Kollidon VA 64 and those of itraconazole (ITZ) with HPMCAS-LF and Kollidon VA 64 were manufactured using a Leistritz twin screw extruder. The milled HMEs were stored at controlled temperature and humidity conditions. The samples were collected after specified time periods for 3 months. The stability of amorphous HMEs was assessed using moisture analysis, thermal evaluation, powder X-ray diffraction, FTIR, HPLC, and dissolution study. In general, the moisture content increased with time, temperature, and humidity levels. Amorphous ITZ was physically unstable at very high temperature and humidity levels, and its recrystallization was detected in the HMEs manufactured using Kollidon VA 64. Although physical stability of IND was better sustained by both Eudragit EPO and Kollidon VA 64, chemical degradation of the drug was identified in the stability samples of HMEs with Eudragit EPO stored at 50 °C. The dissolution rates and the supersaturation levels were significantly decreased for the stability samples in which crystallization was detected. Interestingly, the supersaturation was improved for the stability samples of IND:Eudragit EPO and ITZ:HPMCAS-LF, in which no physical or chemical instability was observed. This enhancement in supersaturation was attributed to the temperature and moisture activated electrostatic interactions between the drugs and their counterionic polymers.

The processing parameters for HME have been evaluated and the impact of solid state intermolecular drug-polymer interactions on supersaturation has been investigated. Poorly water soluble drugs Indomethacin (IND), Itraconazole (ITZ), and Griseofulvin (GSF) and hydrophilic polymers - Eudragit EPO, Eudragit L-100-55, Eudragit L-100, HPMCAS-LF, HPMCAS-MF, Pharmacoat 603, and Kollidon VA-64 were selected for this study. Solubility parameters calculations (SPCs), differential scanning calorimetry (DSC), and rheological analysis of drug-polymer physical mixtures (PMs) was performed. The solid dispersions were manufactured using HME and characterized by powder X-ray diffraction (PXRD), polarized light microscopy (PLM), Fourier transform infra-red (FTIR) Spectroscopy, and dissolution study. Results obtained by DSC correlated well with SPC, showing single glass transition temperatures for all the PMs except ITZ in Eudragit EPO that depicted the highest difference in solubility parameters. The zero rate viscosity (η₀) was dependent on the melting point and consequently the state of the drug in the polymer at the softening temperature. The η₀ of PMs was useful to estimate the processing conditions for HME and to produce transparent glassy HMEs from most of the PMs. The amorphous conversion due to HME was confirmed by PXRD and PLM. The solid state drug-polymer interactions occurred during HME could be confirmed by FTIR analysis. Highest supersaturation could be achieved for IND, ITZ, and GSF using Eudragit EPO, HPMCAS-LF, and Eudragit L-100-55, respectively where relatively higher stretching of the carbonyl peaks was observed by FTIR. Thus, the highest dissolution rate and supersaturation of poorly water soluble drugs could be attributed to drug-polymer interactions occurred during HME., (Copyright © 2012 Elsevier B.V. All rights reserved.)