New Indole-6-Carboxylic Acid Derivatives as Multi-Target Antiproliferative Agents: Synthesis, in Silico Studies, and Cytotoxicity Evaluation.

Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are commonly overexpressed in cancers making them appealing targets for cancer therapeutics. Two groups of indole-6-carboxylic acid derivatives, hydrazone derivatives targeting EGFR and oxadiazole derivatives targeting VEGFR-2, were synthesized and characterized using FT-IR, 1 H-NMR, 13 CNMR, and HR-MS techniques. Binding patterns to potential molecular targets were studied using molecular docking and compared to standard EGFR and VEGFR-2 inhibitors. The newly synthesized compounds were cytotoxic to the three cancer cell lines tested (HCT-116, HeLa, and HT-29 cell lines) as evaluated by the MTT assay. Compound 3 b (EGFR-targeting) and compound 6 e (VEGFR-2-targeting) possessed the highest antiproliferation activity, were cancer-selective, arrested cancer cells in the G2/M phase, induced the extrinsic apoptosis pathway, and had the highest EGFR/VEGFR-2 enzyme inhibitory activity, respectively. The structure-activity relationships of the new compounds showed that the presence of an aryl or heteroaryl fragment attached to a linker is required for the anti-tumor activity. In conclusion, the findings of the current study suggest that compounds 3 b and 6 e are promising cytotoxic agents that act by inhibiting EGFR and VEGFR-2 tyrosine kinases, respectively.

Novel 1,3,4-oxadiazole derivatives of naproxen targeting EGFR: Synthesis, molecular docking studies, and cytotoxic evaluation.

The close association between inflammation and cancer inspired the synthesis of a series of 1,3,4-oxadiazole derivatives (compounds H4-A-F) of 6-methoxynaphtalene. The chemical structures of the new compounds were validated utilizing Fourier-transform infrared, proton nuclear magnetic resonance, and carbon-13 nuclear magnetic resonance spectroscopic techniques and CHN analysis. Computer-aided drug design methods were used to predict the compounds biological target, ADMET properties, toxicity, and to evaluate the molecular similarities between the design compounds and erlotinib, a standard epidermal growth factor receptor (EGFR) inhibitor. The antiproliferative effects of the new compounds were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, cell cycle analysis, apoptosis detection by microscopy, quantitative reverse transcription-polymerase chain reaction, and immunoblotting, and EGFR enzyme inhibition assay. In silico analysis of the new oxadiazole derivatives indicated that these compounds target EGFR, and that compounds H4-A, H4-B, H4-C, and H4-E show similar molecular properties to erlotinib. Additionally, the results indicated that none of the synthesized compounds are carcinogenic, and that compounds H4-A, H4-C, and H4-F are nontoxic. Compound H4-A showed the best-fit score against EGFR pharmacophore model, however, the in vitro studies indicated that compound H4-C was the most cytotoxic. Compound H4-C caused cytotoxicity in HCT-116 colorectal cancer cells by inducing both apoptosis and necrosis. Furthermore, compounds H4-D, H4-C, and H4-B had potent inhibitory effect on EGFR tyrosine kinase that was comparable to erlotinib. The findings of this inquiry offer a basis for further investigation into the differences between the synthesized compounds and erlotinib. However, additional testing will be needed to assess all of these differences and to identify the most promising compound for further research.

Synthesis, docking study, and antitumor evaluation of benzamides and oxadiazole derivatives of 3-phenoxybenzoic acid as VEGFR-2 inhibitors.

Current chemotherapeutic agents have several limitations, including lack of selectivity, the development of undesirable side effects, and chemoresistance. As a result, there is an unmet need for the development of novel small molecules with minimal side effects and the ability to specifically target tumor cells. A new series of 3-phenoxybenzoic acid derivatives, including 1,3,4-oxadiazole derivatives (4a-d) and benzamides derivatives (5a-e) were synthesized; their chemical structures were confirmed by Fourier-transform infrared spectroscopy, 1H nuclear magnetic resonance (NMR), 13C NMR, and mass spectra; and various physicochemical properties were determined. The antiproliferative activities of the new derivatives were evaluated by means of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Three compounds (4b, 4c, and 4d) exhibited cytotoxicity against two of the three cell lines tested, five compounds (3, 4a, 5a, 5b, and 5e) were toxic to one cell line, while two compounds (5c and 5d) were not cytotoxic to any of the three cell lines tested in the current study. Based on docking scores, MTT assay findings, and vascular endothelial growth factor receptor 2 (VEGFR-2) kinase activity data, Compound 4d was selected for further biological investigation. Flow cytometry was used to determine the mode of cell death (apoptosis vs. necrosis) and the effect on cell cycle progression. Compound 4d arrested HepG2 hepatocellular carcinoma cells in the G2/M phase and activated both the intrinsic and extrinsic apoptosis pathways. In conclusion, Compound 4d has shown promising results for future research as a potent VEGFR-2 tyrosine kinase inhibitor.

Antitumor activity of the new tyrphostin briva against BRAFV600E-mutant colorectal carcinoma cells.

Because of a reduced sensitivity of BRAF-mutant colorectal cancers to BRAF inhibitor treatment when compared with BRAF-mutant melanoma, it is essential to develop efficient drugs to cope with this disease. The new 2-(4-bromophenyl)-3-arylacrylonitrile compound Briva was prepared in one step from commercially available starting compounds. Briva and two known thiophene analogs (Thio-Iva and Thio-Dam) were tested for their cytotoxic activity against various tumor cell lines including colorectal and breast cancer cells. The antitumor activities of the test compounds were assessed in vitro via the MTT assay, DAPI staining of nuclei, RT-PCR and immunoblotting, wound healing, clonogenic assay, collagen I adhesion assay, and kinase inhibition assays. A selective activity of Briva was observed against BRAFV600E-mutant HT-29 and COLO-201 colorectal carcinoma (CRC) cells. Briva caused inhibition of HT-29 clonogenic tumor growth and was found to induce cytotoxicity by activating the intrinsic apoptosis pathway. In addition, Briva reduced HT-29 cell adhesion and migration. Kinase inhibition experiments revealed that Briva inhibits VEGFR2. Thus, Briva can be considered as a promising antitumor compound against BRAFV600E-mutant colon carcinoma by targeting VEGFR2 tyrosine kinase and consequently reducing cell adhesion and metastasis formation.

Neuraxial Anesthesia Significantly Reduces 30-Day Venous Thromboembolism Rate and Length of Hospital Stay in Primary Total Hip Arthroplasty: A Stratified Propensity Score-Matched Cohort Analysis.

BACKGROUND: General anesthesia (GA) has been the commonly used protocol for total hip arthroplasty (THA); however, neuraxial anesthesia (NA) has been increasingly performed. Our purpose was to compare NA and GA for 30-day postoperative outcomes in United States veterans undergoing primary THA. METHODS: A large veteran's database was utilized to identify patients undergoing primary THA between 1999 and 2019. A total of 6,244 patients had undergone THA and were included in our study. Of these, 44,780 (79.6%) had received GA, and 10,788 (19.2%) had received NA. Patients receiving NA or GA were compared for 30-day mortalities, cardiovascular, respiratory, and renal complications, and wound infections and hospital lengths of stay (LOS). Propensity score matching, multivariate regression analyses, and subgroup analyses by American Society of Anesthesiology classification were performed to control for selection bias and patient baseline characteristics. RESULTS: Upon propensity-adjusted multivariate analyses, NA was associated with decreased risks for deep venous thrombosis (odds ratio [OR] = 0.63; 95% CI = 0.4-0.9; P = .02), any respiratory complication (OR = 0.63; 95% CI = 0.5-0.9; P = .003), unplanned reintubation (OR = 0.51; 95% CI = 0.3-0.9; P = .009), and prolonged LOS (OR = 0.78; 95% CI = 0.72-0.84; P < .001). Subgroup analyses by American Society of Anesthesiology classes showed NA decreased 30-day venous thromboembolism rate in low-risk (class I/II) patients and decreased respiratory complications in high-risk (class III/IV) patients. CONCLUSION: Using a patient cohort obtained from a large national database, NA was associated with reduced risk of 30-day adverse events compared to GA in patients undergoing THA. Postoperative adverse events were decreased with NA administration with similar decreases observed across all patient preoperative risk levels. NA was also associated with a significant decrease in hospital LOS.

Sub-chondroplasty Reduces Pain, Improves Function and Delays the Conversion to Arthroplasty in Patients with Advanced Knee Osteoarthritis: A Stratified Meta-analysis and Quality Assessment.

There is an ongoing interest in alternatives to total knee arthroplasty, as a means to delay inevitable replacement. A possible, minimally invasive, alternative is a sub-chondroplasty, involving interosseous injection of bone substitute materials such as calcium phosphate (CaPo4), platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC) or Injectable demineralized bone matrix (iDBM) into the subchondral bone. Eleven clinical trials were found, investigating the effectiveness of sub-chondroplasties performed using CaPo4, PRP, BMAC, and iDBM. A non-stratified and stratified meta-analysis of the included studies were conducted to test for confounding variables across the trials. Non-stratified analysis, regardless of injectable type, revealed a significant improvement in the average Visual Analog Scale (VAS) score and postoperative Knee Injury and Osteoarthritis Outcome Score (KOOS) in patients post sub-chondroplasty, as compared to baseline. This analysis demonstrates that the sub-chondroplasty procedure reduces pain, improves function, and has lower risk of conversion to arthroplasty. (Journal of Surgical Orthopaedic Advances 32(2):065-074, 2023).

Pedestrian Trajectory Prediction for Real-Time Autonomous Systems via Context-Augmented Transformer Networks.

Forecasting the trajectory of pedestrians in shared urban traffic environments from non-invasive sensor modalities is still considered one of the challenging problems facing the development of autonomous vehicles (AVs). In the literature, this problem is often tackled using recurrent neural networks (RNNs). Despite the powerful capabilities of RNNs in capturing the temporal dependency in the pedestrians' motion trajectories, they were argued to be challenged when dealing with longer sequential data. Additionally, whilst the accommodation for contextual information (such as scene semantics and agents interactions) was shown to be effective for robust trajectory prediction, they can also impact the overall real-time performance of prediction system. Thus, in this work, we are introducing a framework based on the transformer networks that were demonstrated recently to be more efficient and outperformed RNNs in many sequential-based tasks. We relied on a fusion of sensor modalities, namely the past positional information, agent interactions information and scene physical semantics information as an input to our framework in order to not only provide a robust trajectory prediction of pedestrians, but also achieve real-time performance for multi-pedestrians' trajectory prediction. We have evaluated our framework on three real-life datasets of pedestrians in shared urban traffic environments and it has outperformed the compared baseline approaches in both short-term and long-term prediction horizons. For the short-term prediction horizon, our approach has achieved lower scores according to the average displacement error and the root-mean squared error (ADE/RMSE) of predictions over the state-of-the art (SOTA) approach by more than 11 cm and 23 cm, respectively. While for the long-term prediction horizon, our approach has achieved lower ADE and FDE over the SOTA approach by more than 62 cm and 165 cm, respectively. Additionally, our approach has achieved superior real time performance by scoring only 0.025 s (i.e., it can provide 40 individual trajectory predictions per second).

Recent trends in cholecystectomy in US veterans.

INTRODUCTION: We hypothesize that the recent trend in performing cholecystectomy in US Veterans shows wide adoption of the laparoscopic technique and improvement in the outcome following both laparoscopic (LC) and open cholecystectomy (OC). This study utilizes the Veterans Affairs Surgical Quality Improvement Program database to examine the status and outcome of cholecystectomy. METHODS: A retrospective review of veterans who underwent cholecystectomy between 2008 and 2015 was performed. Data analysis included patient demographics, operations, and postoperative outcomes. Cochran-Armitage trend analysis was used to assess significant changes in outcome over the study period. p ≤ 0.05 was considered significant. RESULTS: A total of 40,722 patients (average age of 61 years) were included in the study (males 85.6%). LC was performed in the majority of patients (86.4%). Patients in the OC group (13.6%) were more likely to have advanced age (≥ 65 years) (47.6% vs 32.0%, p < 0.001) and higher ASA class (III-V) (81.9% vs 65.4%, p < 0.001) than those in the LC group. Compared with LC, OC had higher mortality rates at 30 days (1.3% vs 0.3%; OR = 1.6, p = 0.03), 3 months (2.6% vs 0.7%; OR = 1.7, p < 0.001), 6 months (3.9% vs 1.1%; OR = 1.5, p < 0.001) and 1 year (5.7% vs 2.0%; OR = 1.5, p < 0.001); higher rates of morbidity, including pneumonia (OR = 1.9, p < 0.001), deep venous thrombosis (OR = 2.4, p = 0.02), reoperation (OR = 1.8, p < 0.001), and superficial (OR = 4.9, p < 0.001) and deep (OR = 1.5, p = 0.01) surgical site infections; and a longer length of stay (6.5 days vs 2.6 days, p < 0.001). Trend analysis showed a significant decrease in both mortality (p = 0.02) and morbidity (p < 0.001) for LC over the study period, but no improvement in mortality (p = 0.35) and a only a minimal improvement in morbidity (p = 0.04) for OC. CONCLUSION: In the recent era, LC has been widely performed in the VA with significant improvement in outcome. Efforts are needed to adopt alternative approaches to planned OC and to improve postoperative outcomes.

A Comparison of Neuraxial and General Anesthesia for Thirty-Day Postoperative Outcomes in United States Veterans Undergoing Total Knee Arthroplasty.

BACKGROUND: The aim of this study is to investigate which anesthetic technique is superior on 30-day outcomes after primary total knee arthroplasty (TKA) in United States veteran patients. To our knowledge, this is the first account from the Veterans Health Administration comparing the effects of different anesthesia modalities in patients undergoing TKA. METHODS: The Veterans Affairs Surgical Quality Improvement Program database was utilized to analyze patients undergoing primary TKA during the period of 2008-2015. Subjects were divided into 2 cohorts based on the method of surgical anesthesia used: general anesthesia or neuraxial anesthesia. Propensity score matching was utilized to avoid possible selection bias between the 2 cohorts when assessing patient demographics and comorbidities. The 2 groups were analyzed for 30-day postoperative complications, using multivariable logistic regression techniques to evaluate independent associations between anesthetic method and postoperative outcomes. RESULTS: All Veterans Affairs patients undergoing primary TKA under general anesthesia (n = 32,363) and neuraxial anesthesia (n = 14,395) within the study period were included in this study. Following propensity score matching, multivariable analysis revealed significantly lower risks of cardiovascular (adjusted odds ratio [AOR] 0.74, 95% confidence interval [CI] 0.6-0.88, P < .001), respiratory (AOR 0.75, 95% CI 0.57-0.97, P = .03), and renal complications (AOR 0.62, 95% CI 0.4-0.9, P = .01) in patients receiving neuraxial anesthesia compared to those receiving general anesthesia. Neuraxial anesthesia was also associated with reduced hospital stay and lower odds of prolonged hospitalization (AOR 0.85, 95% CI 0.8-0.9, P < .001). CONCLUSION: Veteran patients undergoing TKA under neuraxial anesthesia had reduced postoperative complications and decreased hospitalization stay compared to patients undergoing general anesthesia.

In Vitro Release of 5-Fluorouracil and Methotrexate from Different Thermosensitive Chitosan Hydrogel Systems.

5-Fluorouracil is a member of cytotoxic drugs with poor selectivity to cancer cells. Currently, systemic administration of this anti-cancer drug (oral or injection) exposes normal tissues to the drug-induced toxicity. Nowadays, attention has been greatly directed towards in situ gel-forming systems that can be injected into the affected tissues in its sol form with a minimally invasive technique. More specifically, chitosan hydrogel systems were in focus due to their antibacterial effect as well as their biodegradable, biocompatible, and mucoadhesive properties. In the present work, 5-fluorouracil was loaded on various thermosensitive chitosan hydrogel systems cross linked with different linking agents like ß-glycerophosphate, pluronic F127, and hydroxyapatite. Also, methotrexate was added to 5-fluorouracil in order to gain its previously reported synergistic effects. Firstly, a compatibility study was performed using UV-spectrophotometric, infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) techniques to exclude the possibility of any physical or chemical interactions between the selected drugs and excipients. The prepared hydrogel systems were characterized for their physicochemical properties including organoleptic, pH, syringeability and injectability, viscosity, and gelation temperature (Tgel) by various analysis techniques. Moreover, the in vitro release behavior of 5-fluorouracil and methotrexate was determined with a modified analytical method. The results indicated that chitosan hydrogel system cross-linked with a combination of ß- glycerophosphate, and 10 % pluronicF127 (F4) showed the most suitable physicochemical properties and release profile. Accordingly, this formula can be considered as a missionary system for localized sustained delivery of cytotoxic drugs.

The Joint Utilization Management Program-Implementation of a Bundle Payment Model and Comparison Between Year 1 and 2 Results.

BACKGROUND: Health care spending is projected to increase throughout the next decade alongside the number of total joint arthroplasties (TJAs) performed. Such growth places significant financial burden on the economic system. To address these concerns, Bundled Payments for Care Improvement (BPCI) is becoming a favorable reimbursement model. The aim of this study is to present the outcomes with BPCI model focused on the post-acute care (PAC) phase and compare the outcomes between years 1 and 2 of implementation. METHODS: The Joint Utilization Management Program (JUMP) was implemented in January 2014. Inclusion criteria were Medicare patients undergoing primary unilateral in-patient TJA procedures, outpatient procedures that resulted in an in-hospital admission, and trauma episodes that required TJA. Scorecards monitoring surgeons' performance and tracking length of stay (LOS) in the PAC setting were established. The data generated from these scorecards guided percentage sum-allocation from the total gain-shared sum among the participating providers. RESULTS: A total of 683 JUMP patients were assessed over two years. PAC utilization decreased between 2014 and 2015. The average LOS was longer in year 1 than year 2 (4.50 vs 3.19 days). In-patient rehabilitation (IPR) decreased from 6.45% to 3.22%, with a decrease in IPR average LOS of 1.47 days. The rate of 30-day readmission was lower for JUMP patients in 2015 than 2014 (8.77% vs 10.56%), with day of readmission being earlier (11.91 days vs 13.71 days) in 2014. CONCLUSION: Under the BPCI program, our experience with the JUMP model demonstrates higher efficiency of care in the PAC setting through reduced LOS, IPR admission rates, and 30-day readmission rate.

Effective Vehicle-Based Kangaroo Detection for Collision Warning Systems Using Region-Based Convolutional Networks.

Traffic collisions between kangaroos and motorists are on the rise on Australian roads. According to a recent report, it was estimated that there were more than 20,000 kangaroo vehicle collisions that occurred only during the year 2015 in Australia. In this work, we are proposing a vehicle-based framework for kangaroo detection in urban and highway traffic environment that could be used for collision warning systems. Our proposed framework is based on region-based convolutional neural networks (RCNN). Given the scarcity of labeled data of kangaroos in traffic environments, we utilized our state-of-the-art data generation pipeline to generate 17,000 synthetic depth images of traffic scenes with kangaroo instances annotated in them. We trained our proposed RCNN-based framework on a subset of the generated synthetic depth images dataset. The proposed framework achieved a higher average precision (AP) score of 92% over all the testing synthetic depth image datasets. We compared our proposed framework against other baseline approaches and we outperformed it with more than 37% in AP score over all the testing datasets. Additionally, we evaluated the generalization performance of the proposed framework on real live data and we achieved a resilient detection accuracy without any further fine-tuning of our proposed RCNN-based framework.

Prevention and Diagnosis of Periprosthetic Knee Infection.

Total knee arthroplasty (TKA) has become an increasingly common treatment option for patients who have debilitating knee arthritis. TKA is a relatively safe and efficient procedure that results in promising outcomes and has a positive effect on a patient's quality of life. More TKAs are being performed annually because the procedure substantially reduces pain and improves functionality; however, as the number of TKAs continues to rise, there is concern for potential complications that may result in prosthetic joint failure. Primary TKA failure may result in revision procedures that have high costs and an increased risk for additional complications. Infection is the second most common cause of primary TKA failure and the single most common cause of revision TKA failure. Surgeons who have a better understanding of the epidemiology, risk factors, and diagnostic modalities associated with periprosthetic knee infection will be able to implement preventive measures and treat patients in whom such a complication occurs.

Single-Stage Revision Total Knee Arthroplasty in the Setting of Periprosthetic Knee Infection: Indications, Contraindications, and Postoperative Outcomes.

Single-stage revision total knee arthroplasty has become an increasingly common treatment option for patients with failed knee prostheses. Periprosthetic knee infection is the leading and most devastating cause of revision total knee arthroplasty. Although periprosthetic knee infection has been extensively studied in the orthopaedic literature, the role of single-stage revision total knee arthroplasty for the treatment of periprosthetic knee infection warrants further research. As healthcare reform shifts from a volume-based to a value-based system, it is imperative that orthopaedic surgeons understand the procedural indications, risks, and benefits of single-stage revision total knee arthroplasty.

Two-Stage Revision Total Knee Arthroplasty in the Setting of Periprosthetic Knee Infection.

Two-stage revision total knee arthroplasty (TKA) is the standard of care for patients who require a revision procedure for the mangement of a late or chronic periprosthetic knee infection. A careful examination of two-stage revision TKA is warranted as the number of patients who require revision TKA in the United States continues to rise. Surgeons should understand the intricacies involved in two-stage revision TKA, including the indications, procedural variations, and current deliberations on two-stage revision TKA in the literature. Surgeons also should understand the alternative treatments for periprosthetic knee infections.

Using a Comanagement Model to Develop a Hip Fracture Integrated Care Pathway.

EXECUTIVE SUMMARY: Hip fracture care represents a service line that profoundly affects patients' quality of life. As hospitals and physicians are motivated to improve quality, reduce costs, and maximize efficiency of care, several alignment models have been proposed under new healthcare legislation. Evaluation of such models as they pertain to hip fracture care warrants further investigation. In this article, we identify the current model of operations present in large healthcare organizations, examine the reasoning behind hospital-physician alignment, and describe specific comanagement principles that are common in healthcare settings. Furthermore, the effects of a comanagement model on a hip fracture integrated care pathway will be demonstrated through a case study. A comanagement team was formed at a Level I academic trauma center to create an integrated care pathway for the hip fracture service line. An internal data review of hip fracture cases before and after implementation of the pathway was undertaken to assess the impact of this model in terms of postoperative outcomes and resource utilization. The postimplementation group displayed more observant care while consuming fewer resources. Thus, the comanagement model described in this article serves as a powerful tool, allowing hospitals and physicians to improve the quality of care. This study provides recommendations based on our success in the hip fracture setting that may be extrapolated to improve service lines and healthcare efficiency nationally.

A Novel Technique Utilizing a Vastus Lateralis Anchor in Treatment of Chronic Patellar Dislocation After Total Knee Arthroplasty.

Extensor mechanism complications involving the patella frequently result in total knee arthroplasty (TKA) failure. Postoperative patellar dislocation may be caused by soft tissue imbalance, improper sizing, and position of the prosthesis. This report describes a case of revision TKA requiring several rounds of soft tissue releases in an effort to treat the patient's chronic patellar dislocation. In the process, a novel surgical approach was developed for the surgical management of refractory chronic patellar dislocations. Postoperative follow-up at 1, 2, 6, 12, and 24 months indicated no complaints of patellar subluxation or dislocation. Plain films also demonstrated no effusion, fracture, or patellar dislocation on sunrise, anteroposterior, and lateral views. This novel anatomic repositioning of the vastus lateralis around the quadriceps tendon converted a pathologic lateralizing force into a medial stabilizer. On follow-up evaluations, successful patellar tracking without dislocation has been demonstrated. (Journal of Surgical Orthopaedic Advances.

Influence of Hydroalcoholic Vehicle on In Vitro Transport of 4-Hydroxy Tamoxifen Through the Mammary Papilla (Nipple).

Majority of breast cancers originate from epithelial cells in the duct and lobules in the breast. Current systemic treatments for breast cancer are associated with significant systemic side effects, thus warranting localized drug delivery approaches. The aim of this study was to investigate the influence of hydroalcoholic vehicle on topical delivery of 4-hydroxy tamoxifen (4-HT) through the mammary papilla (nipple). The in vitro permeability of 4-HT through porcine mammary papilla was studied using different hydroalcoholic vehicles (0, 33.33, and 66.66% alcohol). Nile red was used as a model lipophilic dye to characterize the drug transport pathway in the mammary papilla. The penetration of 4-HT through the mammary papilla increased with increase in alcohol concentration in the vehicle. The solubility of 4-HT was enhanced by increasing alcohol concentration in the vehicle. On the other hand, the epidermis/vehicle partition coefficient decreased with increase in alcohol concentration. The mammary papilla served as a depot and slowly released 4-HT into the receptor medium. Highest drug penetration was observed with saturated drug solution in 66.66% alcohol, and 4-HT levels were comparable to IC50 value of 4-HT. Results from this study demonstrate the possibility of using mammary papilla as a potential route for direct delivery of 4-HT to the breast.

Cardiovascular Considerations for Joint Replacement Surgery.

Heart disease is the leading cause of death in the United States. Cardiovascular complications are associated with higher morbidity and mortality rates for patients who undergo orthopaedic surgery. Therefore, the clinical importance of a comprehensive preoperative evaluation and medical clearance is crucial and may substantially improve postoperative outcomes. A thorough knowledge of cardiovascular perioperative planning and management can enable healthcare professionals to identify patients who are potentially at risk for cardiovascular complications, and eventually improve both short- and long-term patient outcomes and satisfaction.

Perioperative Treatment of Patients with Rheumatoid Arthritis.

Rheumatoid arthritis is an autoimmune disease mediated by a widespread, chronic, and systematic inflammatory process that causes joint deterioration, which leads to pain, disability, and poor quality of life. The increased use of disease-modifying antirheumatic drugs has been shown to markedly slow disease progression, which has translated into a decrease in the need for orthopaedic intervention in this population. However, in a substantial percentage of patients with the disease, optimal pharmacologic treatment fails and surgical intervention is required. A thorough understanding of medical considerations in these patients and improved knowledge of the medical complications caused by the disease process and the pharmacologic therapy used to treat it may lead to improved preoperative planning and medical clearance, which may ultimately improve the overall postoperative outcome.