Identification of a Regenerative Protocol for Recellularizing Human Auricular Cartilage Scaffolds.

OBJECTIVE: Utilizing biological scaffolds for cartilage tissue engineering is a promising tool for improving auricular reconstruction. Decellularized auricular scaffolds provide a means of regenerating cartilage for in vivo implantation, but identifying the ideal regenerative mix remains challenging. METHODS: Human cadaver auricular cartilage was decellularized and recellularized with either auricular chondrocytes alone, auricular chondrocytes with adipose-derived stem cells, or both cells with platelet-rich plasma. Confirmation of decellularization and recellularization was done by hematoxylin and eosin staining. Extracellular matrix preservation and production were determined by Masson's trichrome, Alcian blue, and Verhoeff-van Gieson staining. Collagen II assessments were made using immunohistochemistry. RESULTS: Decellularization of cadaver auricular cartilage was confirmed by the absence of cells, reduction in glycosaminoglycans, and the preservation of collagen and elastin. Recellularization was more efficient when chondrocytes were seeded with adipose-derived stem cells, which was enhanced by adding platelet-rich plasma. Coculture with platelet-rich plasma yielded better total collagen (56% increase) and glycosaminoglycan (47% increase) induction. Moreover, when platelet-rich plasma was added, collagen II induction was significantly increased (42%; P < 0.05). CONCLUSION: We identified a regenerative protocol that included auricular chondrocytes, adipose-derived stem cells, and platelet-rich plasma, which stimulated chondrogenesis on decellularized auricular cartilage. This finding provides a model to explore cartilage formation and the potential for improving auricular and cartilage-based reconstruction.

The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Results from a Randomized Phase I Pilot Study for Feasibility and Adherence.

PURPOSE: Chronic inflammation is integral to myeloproliferative neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among patients with MPN. EXPERIMENTAL DESIGN: We randomly assigned patients with MPN to either a Mediterranean diet or standard U.S. Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four timepoints during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome. RESULTS: The Mediterranean diet was as easy to follow for patients with MPN as the standard USDA diet. Approximately 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any timepoint. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention. CONCLUSIONS: With dietician counseling and written education, patients with MPN can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially incorporated into the management of other hematologic conditions. SIGNIFICANCE: Diet is a central tenant of management of chronic conditions characterized by subclinical inflammation, such as cardiovascular disease, but has not entered the treatment algorithm for clonal hematologic disorders. Here, we establish that a Mediterranean diet intervention is feasible in the MPN patient population and can improve symptom burden. These findings warrant large dietary interventions in patients with hematologic disorders to test the impact of diet on clinical outcomes.

Carboplatin and paclitaxel after anti-PD-1 or anti-PD-L1 antibody therapy in recurrent and/or metastatic squamous cell carcinoma of head and neck.

BACKGROUND: The impact of concurrent chemotherapy and immunotherapy has been well characterized in patients with recurrent and metastatic head and neck squamous cell carcinoma (RM-SCCHN). Here, we report outcomes in patients treated sequentially with immune checkpoint inhibition (ICI) followed by carboplatin and paclitaxel. METHODS: Patients with RM-SCCHN treated with ICI followed by carboplatin/paclitaxel at a single institution were identified retrospectively. ICI therapy history, p16, and PD-L1 status were collected. The best overall response was assessed by RECIST v1.1. RESULTS: Twelve patients met inclusion criteria. Eight patients received pembrolizumab, three durvalumab, and one nivolumab. The median duration of ICI was 3.44 months, median PFS was 5.8 months, and median OS was 15.2 months. 66.7% of patients had an objective response on carboplatin/paclitaxel. CONCLUSIONS: Carboplatin/paclitaxel can induce objective responses in patients with prior treatment with ICI and clinical outcomes in this small series compare favorably to those seen in ICI naïve patients.

Relationship between Body Mass Index and Outcomes in Microvascular Abdominally Based Autologous Breast Reconstruction.

BACKGROUND: Increasing body mass index (BMI) is a known risk factor for autologous microsurgical breast reconstruction. No prior studies have stratified outcomes across BMI ranges or defined the BMI at which complication rates dramatically increase. METHODS: The authors performed a retrospective chart review of all patients who underwent abdominally based autologous free flap breast reconstruction at their institution between 2004 and 2021. Clinical, surgical, and outcomes data were collected. Patients were stratified into five BMI categories: 25, 25.01 to 30, 30.01 to 35, 35.01 to 40, and greater than 40 kg/m 2 . Complication rates were analyzed across these groups, and a receiver-operating characteristic analysis was used to determine an optimal BMI cutoff point. RESULTS: A total of 365 patients (545 breasts) were included in this study. The rates of several breast complications significantly increased with increasing BMI at distinct levels, including any breast complication (BMI >30 kg/m 2 ), unplanned reoperation (BMI >35 kg/m 2 ), fat necrosis (BMI >40 kg/m 2 ), wound breakdown requiring re-operation (BMI >35 kg/m 2 ), any infection (BMI >30 kg/m 2 ), infection requiring oral antibiotics (BMI >25 kg/m 2 ), infection requiring intravenous antibiotics (BMI >35 kg/m 2 ), and mastectomy flap necrosis (BMI >35 kg/m 2 ). The rates of many abdominal complications significantly increased with increasing BMI at distinct levels as well, including delayed wound healing (BMI >30 kg/m 2 ), wound breakdown requiring re-operation (BMI >40 kg/m 2 ), any infection (BMI >25 kg/m 2 ), and infection requiring oral antibiotics (BMI >25 kg/m 2 ). Optimal BMI cutoffs of 32.7 and 30.0 kg/m 2 were determined to minimize the occurrence of any breast complication and any abdomen complication, respectively. CONCLUSIONS: Preoperative weight loss has great potential to alleviate surgical risk in overweight and obese patients pursuing autologous breast reconstruction. The authors' results quantify the risk reduction based on a patient's preoperative BMI. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Evaluating mesh use for abdominal donor site closure after deep inferior epigastric perforator flap breast reconstruction: A systematic review and meta-analysis.

BACKGROUND: Despite improvement in abdominal morbidity with deep inferior epigastric perforator (DIEP) flap breast reconstruction compared to prior abdominally-based free flap breast reconstruction, abdominal bulge, and hernia rates have been cited anywhere from 2% to 33%. As a result, some surgeons utilize mesh or other reinforcement upon donor-site closure, but its benefit in preventing abdominal wall morbidity has not been well-defined for DIEP flaps. The purpose of this systematic review is to evaluate DIEP donor-site closure techniques and the impact of mesh type and plane on abdominal-wall morbidity including hernia and bulge, relative to primary fascial closure. METHODS: MEDLINE, PubMED, Cochrane Library, and SCOPUS were systematically reviewed for studies evaluating DIEP flap breast reconstruction abdominal-donor site closure, where any mesh reinforcement or primary fascial closure was specified, and postoperative outcomes of hernia and/or abdominal bulge were reported. Analysis was performed in Review Manager (RevMan) evaluating mesh use, type, and plane relative to primary fascial closure, using the Mantel-Haenszel method to calculate odds ratios (ORs) of significance level p < .05, and a random effects model to account for inter-study heterogeneity. RESULTS: Of the 2791 DIEP patients across 11 studies, 1901 patients underwent primary closure and 890 were repaired with mesh. When hernia and/or bulge were combined into a single complication, the use of any mesh did not significantly reduce its odds compared to primary closure (OR = 0.69, p = .20). Similarly, the use of any mesh did not significantly reduce the odds of bulge alone compared to primary closure (OR = 0.62, p = .43). However, the odds of hernia alone were significantly reduced by 72% with any mesh use (OR = 0.28, p = .03). CONCLUSION: Mesh use was significantly associated with decreased odds of hernia alone with DIEP flap surgery, but there was no difference in bulge or combined hernia/bulge rates. As bulge is the more common abdominal morbidity after DIEP flap harvest in a patient with no prior abdominal surgery or risk factor for hernia, mesh use is not indicated in abdominal closure of all DIEP patients. Future prospective studies are warranted to characterize the specific indications for mesh use in the setting of DIEP flap surgery.

Microsurgical Needle Retention Does Not Cause Pain or Neurovascular Injury in a Rat Model.

Approximately 20% of retained foreign bodies are surgical needles. Retained macro-needles may become symptomatic, but the effect of microsurgical needles is uncertain. We present the first animal model to simulate microsurgical needle retention. Given a lack of reported adverse outcomes associated with macro-needles and a smaller cutting area of microsurgical needles, we hypothesized that microsurgical needles in rats would not cause changes in health or neurovascular compromise. Methods: Male Sprague-Dawley rats (x̄ weight: 288.9 g) were implanted with a single, 9.0 needle (n = 8) or 8.0 needle (n = 8) orthogonal to the right femoral vessels and sutured in place. A control group (n = 8) underwent sham surgery. Weekly, a cumulative health score evaluating body weight, body condition score, physical appearance, and behavior for each rat was determined. Infrared thermography (°C, FLIR one) of each hindlimb and the difference was obtained on postoperative days 15, 30, 60, and 90. On day 90, animals were euthanatized, hindlimbs were imaged via fluoroscopy, and needles were explanted. Results: The mean, cumulative health score for all cohorts at each weekly timepoint was 0. The mean temperature difference was not significantly different on postoperative days 15 (P = 0.54), 30 (P = 0.97), 60 (P = 0.29), or 90 (P = 0.09). In seven of eight rats, 8.0 needles were recovered and visualized on fluoroscopy. In six of eight rats, 9.0 needles were recovered, but 0/8 needles were visualized on fluoroscopy. Conclusions: Microsurgical needle retention near neurovascular structures may be benign, and imaging for needles smaller than 8.0 may be futile. Further studies should explore microsurgical needle retention potentially through larger animal models.

A Comparison of Perioperative Complications of Hand and Wrist Arthroplasty for Osteoarthrosis by Orthopedic Versus Plastic Surgeons.

BACKGROUND: Arthroplasty is commonly performed in the management of osteoarthrosis of the hand and wrist by orthopedic or plastic surgeons with a fellowship in hand. The differences between operative outcomes between the 2 groups have not been described. Therefore, we analyzed a national database to determine acute outcomes between orthopedic and plastic surgery when performing arthroplasty for osteoarthrosis of the hand and wrist. METHODS: A retrospective cross-sectional analysis was performed by including patients with osteoarthrosis of the hand and wrist by International Classification of Diseases codes. Demographic, operative, and outcome variables were collected. Pearson χ2 and Fischer exact tests were used for categorical variables, while a Mann-Whitney U test was performed for continuous variables. Multivariate regression analysis was performed to determine strength of predictors. RESULTS: There were 3721 patients who received arthroplasty for osteoarthrosis of the hand and wrist from 2007 to 2020. Most cases were performed by orthopedic surgeons (82.7%); however, there were an increasing number of surgeries performed by plastic surgeons. Most cases were performed on the intercarpal or carpometacarpal joints (81.7%). The incidence of acute complications was low (1.9%) with superficial surgical site infections (SSIs) being the most common complication. Univariate analysis found that plastic surgery may result in higher chances of superficial SSIs, but multivariate analysis indicated that there were no significant differences between the 2 groups. CONCLUSION: There were no significant differences on multivariate regression analysis between plastic and orthopedic surgeons, suggesting that both can perform arthroplasty of the hand and wrist without safety concerns.

Targeting Myofibroblasts as a Treatment Modality for Dupuytren Disease.

PURPOSE: Currently, no treatment corrects the contractile nature of Dupuytren myofibroblasts (DMFs) or prevents recurrence following surgery. Antifibrotic and proadipogenic growth factors are released when adipose-derived stem cells (ASCs) are cultured with platelet-rich plasma (PRP), a platelet concentration from whole blood. Reprograming myofibroblasts into adipocytes via growth factors is proposed as a powerful potential tool to target fibrosis. We aimed to assess whether the combination of ASCs and PRP reprograms DMFs into adipocytes in vitro and alters their contractile nature in vivo. METHODS: Normal human dermal fibroblasts (NHDFs) and DMFs from Dupuytren patients were isolated and cocultured with ASCs and PRP either alone or together. Adipocytes were detected by Oil Red O and perilipin staining. DMFs and NHDFs were transplanted into the forepaws of rats (Rowett Nude [rnu/rnu]) and treated with saline, PRP+ASCs, or collagenase Clostridium histolyticum (clinical comparison) 2 months later. After 2 weeks, the tissue was harvested and subjected to Masson trichrome staining, and collagen I and III and alpha-smooth muscle actin detection by immunohistochemistry. RESULTS: Myofibroblasts transform into adipocytes upon coculture with PRP+ASCs. DMFs show increased alpha-smooth muscle actin expression in vivo compared with NHDFs, which is significantly decreased after PRP+ASCs and collagenase Clostridium histolyticum treatments. DMFs induce collagen I and III expressions in rat paws compared with NHDFs, with a type III to I ratio increase. Treatment with PRP+ASC reduced the ratio, but collagenase Clostridium histolyticum did not. CONCLUSIONS: Treating DMFs with PRP+ASCs provides factors that induce myofibroblast to adipocyte transformation. This treatment reduces the contractile phenotype and fibrosis markers in vivo. Future studies should detail the mechanism of this conversion. CLINICAL RELEVANCE: The combination of PRP and ASCs to induce the differentiation of DMFs into adipocytes may serve to limit surgery to a percutaneous contracture release and biological injection, rather than a moderate or radical fasciectomy, and reduce the recurrence of Dupuytren contracture.

Evaluation of Microvascular Autologous Breast Reconstruction in Patients Older Than 60 Years.

BACKGROUND: While free-flap breast reconstruction becomes more common, it is still approached with caution in older patients. Outcomes in the elderly population have not been well characterized, especially with regard to donor-site sequalae. This study compares microvascular autologous breast reconstruction outcomes in patients older and younger 60 years. METHODS: A single-institution retrospective review was performed for microvascular autologous breast reconstruction from January 2004 through January 2021. Demographic, intraoperative, and postoperative variables, including breast flap and donor-site complications, were evaluated. RESULTS: Five hundred forty-five breast free flaps were identified, of which 478 (87.8%) were performed on patients younger than 60 years (mean, 46.2 years) and 67 (12.2%) older than 60 years (mean, 64.8 years; P = 0.000). Hyperlipidemia was significantly higher in older patients (19.4% vs 9.6%, P = 0.016). Mean operative time was 46.3 minutes faster in the older cohort ( P = 0.030). There were no significant differences in free-flap loss, venous congestion, takeback, hematoma, seroma, wound healing, or infection. Interestingly, there were significantly more total breast flap complications (28.5% vs 16.4%, P = 0.038) and higher rates of fat necrosis (9.6% vs 1.5%, P = 0.026) in the younger cohort. Significantly more abdominal donor-site complications (43.3% vs 21.3%, P = 0.000) were seen in the older people, with increased wound breakdown ( P = 0.000) and any return to the operating room (20.9% vs 9.8%, P = 0.007). Older patients were also significantly more likely to require surgical correction of an abdominal bulge or hernia (10.4% vs 4%, P = 0.020). The mean follow-up was 1.8 years. CONCLUSIONS: Our data showed no worsening of individual breast flap outcomes in the older people. However, there were significantly more abdominal complications including surgical correction of abdominal bulge and hernia. This may be related to the inherent qualities of tissue aging and should be taken into consideration for flap selection. These results support autologous breast reconstruction in patients older than 60 years, but patients should be counseled regarding potentially increased abdominal donor-site sequelae.

Effect of the COVID-19 Pandemic on Global Interest in Plastic Surgery.

Introduction: Due to the SARS-CoV-2 (COVID-19) pandemic, many elective surgeries were canceled, including most aesthetic plastic surgery procedures. Although studies have shown COVID-19's effect on plastic surgery in the United States, no study to date has examined the international interest in plastic surgery procedures after the start of the COVID-19 pandemic. Thus, we sought to find this effect using the Google Trends tool. Material and Methods: The most common cosmetic procedures and top countries with the highest plastic surgery volume were selected from the International Society of Plastic Surgeons report and used as the search terms for Google Trends. Weekly search data from each procedure and country were collected from March 18, 2018 to March 13, 2022, split into 2 periods according to the start of the US COVID-19 lockdown, and compared. Results: Among the countries, the United States had the most plastic surgery interest after the COVID-19 pandemic, with India and Mexico closely following. On the other hand, Russia and Japan had the fewest changes in procedure interest. Regarding specific procedures, interest in breast augmentation, forehead lift, injectable filler, laser hair removal, liposuction, microdermabrasion, and rhytidectomy increased in all countries after the COVID-19 pandemic. Conclusions: After COVID-19, there has been increasing interest in almost all plastic surgery procedures globally, especially nonsurgical procedures and facial plastic surgery, with the greatest increases in the United States, India, and Mexico. These results can help inform plastic surgeons which procedures to focus on and which devices or technologies to invest in that are specific to their country.

Modifiable Post-Mastectomy Radiation Therapy Factors and Impact on Implant-Based Breast Reconstruction Outcomes.

INTRODUCTION: Intensity modulated radiation therapy (IMRT) and other modifiable radiation factors have been associated with decreased radiation toxicity. These factors could allow for improved reconstructive outcomes in patients requiring post-mastectomy radiation therapy (PMRT). However, they have not yet been well-studied in implant-based breast reconstruction (IBBR). METHODS: We performed a retrospective chart review of patients who underwent mastectomy with immediate tissue expander placement followed by PMRT. Radiation characteristics were collected, including radiation technique, bolus regimen, X-ray energy, fractionation, maximum radiation hot spot (DMax), and tissue volume receiving >105% (V105%) or >107% (V107%) of the prescription dose. Reconstructive complications occurring after initiation of PMRT were analyzed with respect to these radiation characteristics. RESULTS: 68 patients (70 breasts) were included in this study. The overall complication rate was 28.6%, with infection being the most common complication (24.3%), requiring removal of the tissue expander or implant in greater than half of infections (15.7%). DMax was greater in patients who required explant after PMRT, and this approached statistical significance (114.5+/-7.2% v. 111.4+/-4.4%, p=0.059). V105% and V107% were also greater in patients who required explant after PMRT (42.1+/-17.1% v. 33.0+/-20.9% and 16.4+/-14.5% v. 11.3+/-14.6%, respectively), however this was not statistically significant (p=0.176 and p=0.313, respectively). There were no significant differences in complication rates between patients with respect to radiation technique or other radiation characteristics studied. CONCLUSIONS: Minimizing the radiation hot spots and volumes of tissue receiving greater than the prescription dose of radiation may improve reconstructive outcomes in patients undergoing IBBR followed by PMRT.

Immediate Versus Delayed-Immediate Autologous Breast Reconstruction After Nipple-Sparing Mastectomy.

INTRODUCTION: Autologous reconstruction following nipple-sparing mastectomy (NSM) is either performed in a delayed-immediate fashion, with a tissue expander placed initially at the time of mastectomy and autologous reconstruction performed later, or immediately at the time of NSM. It has not been determined which method of reconstruction leads to more favorable patient outcomes and lower complication rates. METHODS: We performed a retrospective chart review of all patients who underwent autologous abdomen-based free flap breast reconstruction after NSM between January 2004 and September 2021. Patients were stratified into 2 groups by timing of reconstruction (immediate and delayed-immediate). All surgical complications were analyzed. RESULTS: One hundred one patients (151 breasts) underwent NSM followed by autologous abdomen-based free flap breast reconstruction during the defined time period. Fifty-nine patients (89 breasts) underwent immediate reconstruction, whereas 42 patients (62 breasts) underwent delayed-immediate reconstruction. Considering only the autologous stage of reconstruction in both groups, the immediate reconstruction group experienced significantly more delayed wound healing, wounds requiring reoperation, mastectomy skin flap necrosis, and nipple-areolar complex necrosis. Analysis of cumulative complications from all reconstructive surgeries revealed that the immediate reconstruction group still experienced significantly greater cumulative rates of mastectomy skin flap necrosis. However, the delayed-immediate reconstruction group experienced significantly greater cumulative rates of readmission, any infection, infection requiring PO antibiotics, and infection requiring IV antibiotics. CONCLUSIONS: Immediate autologous breast reconstruction after NSM alleviates many issues seen with tissue expanders and delayed autologous reconstruction. Although mastectomy skin flap necrosis occurs at a significantly greater rate after immediate autologous reconstruction, it can often be managed conservatively.

The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Feasibility Phase.

Purpose: Chronic inflammation is integral to Myeloproliferative Neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among MPN patients. Experimental Design: We randomly assigned participants to either a Mediterranean diet or standard US Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four time points during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome. Results: The Mediterranean diet was as easy to follow for MPN patients as the standard USDA diet. Over 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any time point. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention. Conclusions: With dietician counseling and written education MPN patients can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially even be incorporated into the management of other chronic clonal hematologic conditions.

Changing Aesthetic Surgery Interest in Men: An 18-Year Analysis.

BACKGROUND: Historically, men have been shamed if they cared seemingly too much about their appearance and especially, if they pursued aesthetic surgery. However, due to the changing landscape of the culture, this stigma has seemed to decrease. Men have diverse and quickly changing interests in particular procedures that have not been readily explored in the currently available reports. To examine this, we analyzed interest in specific plastic surgery procedures in men over the last two decades using the Google Trends tool. METHODS: The most common cosmetic procedures were chosen from the American Society of Plastic Surgeons website and served as the search terms for the Google Trends tool from 2004 to 2021. All 19 procedures were examined for overall trends and for changes in the last decade through comparing the data in bisected time periods. RESULTS: Interest in all plastic surgery procedures in men increased since 2004 except for breast reduction. Most notably, jawline filler, Botox, microneedling, lip filler, chemical peel, CoolSculpting, and butt lift had the largest trend increases. In the last decade, all procedures showed a significant increase in interest. CONCLUSIONS: While surgical volume data are valuable, our study shows that Google Trends is a beneficial tool to predict quickly changing and specific trends, especially as the patient population of plastic surgery grows with increased diversity and generational changes. Our study shows that there is an increase in male-centered plastic surgery procedures, especially nonsurgical facial procedures. Male interest in plastic surgery will continue to increase with time. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors   www.springer.com/00266 .

Non-typhoidal Salmonella soft-tissue infection after gender affirming subcutaneous mastectomy case report.

We present a case of a 32-year-old transgender male who underwent chest masculinization, complicated by purulent soft tissue infection of bilateral chest incisions. Cultures tested positive for non-typhoidal Salmonella, methicillin-resistant Staphylococcus aureus, and Pseudomonas aeruginosa. Herein, we discuss multiple factors contributing to the complexity of treating this patient's clinical course.