Integration of Electrospun Scaffolds and Biological Polymers for Enhancing the Delivery and Efficacy of Mesenchymal Stem/Stromal Cell Therapies.

Mesenchymal stem/stromal cells (MSCs) have emerged as a promising therapeutic approach for a variety of diseases due to their immunomodulatory and tissue regeneration capabilities. Despite their potential, the clinical application of MSC therapies is hindered by limited cell retention and engraftment at the target sites. Electrospun scaffolds, with their high surface area-to-volume ratio and tunable physicochemical properties, can be used as platforms for MSC delivery. However, synthetic polymers often lack the bioactive cues necessary for optimal cell-scaffold interactions. Integrating electrospun scaffolds and biological polymers, such as polysaccharides, proteins, and composites, combines the mechanical integrity of synthetic materials with the bioactivity of natural polymers and represents a strategic approach to enhance cell-scaffold interactions. The molecular interactions between MSCs and blended or functionalized scaffolds have been examined in recent studies, and it has been shown that integration can enhance MSC adhesion, proliferation, and paracrine secretion through the activation of multiple signaling pathways, such as FAK/Src, MAPK, PI3K/Akt, Wnt/ß-catenin, and YAP/TAZ. Preclinical studies on small animals also reveal that the integration of electrospun scaffolds and natural polymers represents a promising approach to enhancing the delivery and efficacy of MSCs in the context of regenerating bone, cartilage, muscle, cardiac, vascular, and nervous tissues. Future research should concentrate on identifying the distinct characteristics of the MSC niche, investigating the processes involved in MSC-scaffold interactions, and applying new technologies in stem cell treatment and biofabrication to enhance scaffold design. Research on large animal models and collaboration among materials scientists, engineers, and physicians are crucial to translating these advancements into clinical use.

Evaluating Chat Generative Pre-trained Transformer Responses to Common Pediatric In-toeing Questions.

OBJECTIVE: Chat generative pre-trained transformer (ChatGPT) has garnered attention in health care for its potential to reshape patient interactions. As patients increasingly rely on artificial intelligence platforms, concerns about information accuracy arise. In-toeing, a common lower extremity variation, often leads to pediatric orthopaedic referrals despite observation being the primary treatment. Our study aims to assess ChatGPT's responses to pediatric in-toeing questions, contributing to discussions on health care innovation and technology in patient education. METHODS: We compiled a list of 34 common in-toeing questions from the "Frequently Asked Questions" sections of 9 health care-affiliated websites, identifying 25 as the most encountered. On January 17, 2024, we queried ChatGPT 3.5 in separate sessions and recorded the responses. These 25 questions were posed again on January 21, 2024, to assess its reproducibility. Two pediatric orthopaedic surgeons evaluated responses using a scale of "excellent (no clarification)" to "unsatisfactory (substantial clarification)." Average ratings were used when evaluators' grades were within one level of each other. In discordant cases, the senior author provided a decisive rating. RESULTS: We found 46% of ChatGPT responses were "excellent" and 44% "satisfactory (minimal clarification)." In addition, 8% of cases were "satisfactory (moderate clarification)" and 2% were "unsatisfactory." Questions had appropriate readability, with an average Flesch-Kincaid Grade Level of 4.9 (±2.1). However, ChatGPT's responses were at a collegiate level, averaging 12.7 (±1.4). No significant differences in ratings were observed between question topics. Furthermore, ChatGPT exhibited moderate consistency after repeated queries, evidenced by a Spearman rho coefficient of 0.55 (P = 0.005). The chatbot appropriately described in-toeing as normal or spontaneously resolving in 62% of responses and consistently recommended evaluation by a health care provider in 100%. CONCLUSION: The chatbot presented a serviceable, though not perfect, representation of the diagnosis and management of pediatric in-toeing while demonstrating a moderate level of reproducibility in its responses. ChatGPT's utility could be enhanced by improving readability and consistency and incorporating evidence-based guidelines. LEVEL OF EVIDENCE: Level IV-diagnostic.

The Novel Use of the Lateral Scanogram to Detect Cruciate Deficiency in Children With Congenital Femoral Deficiency.

Congenital femoral deficiency (CFD) is often associated with cruciate ligament deficiency. The lateral scanogram may be a potential solution to some limitations for detecting instability associated with cruciate ligament deficiency. This qualitative case study identified two children with congenital femoral deficiency who were assessed with a lateral scanogram and had their results correlated to the clinical examination and MRI. Both cases identified a child with congenital femoral deficiency, one with a total leg length discrepancy (LLD) of 12 cm and the next with 6.5 cm. The weight-bearing lateral scanogram revealed anterior tibial translation, indicating knee instability. Both patients will undergo anterior cruciate ligament (ACL) reconstruction prior to limb lengthening. The lateral scanogram is a useful imaging modality that is capable of detecting anterior tibial translation, and thereby knee instability, in children with congenital femoral deficiency. Larger studies utilizing and evaluating the benefits of lateral scanograms are warranted.

A Novel Mouse Model for SNP in Steroid Receptor Co-Activator-1 Reveals Role in Bone Density and Breast Cancer Metastasis.

The steroid receptor coactivator-1 (SRC-1) is a nuclear receptor co-activator, known to play key roles in both estrogen response in bone and in breast cancer metastases. We previously demonstrated that the P1272S single nucleotide polymorphism (SNP; P1272S; rs1804645) in SRC-1 decreases the activity of estrogen receptor in the presence of selective estrogen receptor modulators (SERMs) and that it is associated with a decrease in bone mineral density (BMD) after tamoxifen therapy, suggesting it may disrupt the agonist action of tamoxifen. Given such dual roles of SRC-1 in the bone microenvironment and in tumor cell-intrinsic phenotypes, we hypothesized that SRC-1 and a naturally occurring genetic variant, P1272S, may promote breast cancer bone metastases. We developed a syngeneic, knock-in mouse model to study if the SRC-1 SNP is critical for normal bone homeostasis and bone metastasis. Our data surprisingly reveal that the homozygous SRC-1 SNP knock-in increases tamoxifen-induced bone protection after ovariectomy. The presence of the SRC-1 SNP in mammary glands resulted in decreased expression levels of SRC-1 and reduced tumor burden after orthotopic injection of breast cancer cells not bearing the SRC-1 SNP, but increased metastases to the lungs in our syngeneic mouse model. Interestingly, the P1272S SNP identified in a small, exploratory cohort of bone metastases from breast cancer patients was significantly associated with earlier development of bone metastasis. This study demonstrates the importance of the P1272S SNP in both the effect of SERMs on BMD and the development of tumor in the bone.

Coagulation, inflammation, and CD46 transgene expression in neonatal porcine islet xenotransplantation.

BACKGROUND: Thrombosis is a known consequence of intraportal islet transplantation, particularly for xenogeneic islets. To define the origins of thrombosis after islet xenotransplantation and relate it to early inflammation, we examined porcine islets transplanted into non-human primates using a dual-transplant model to directly compare islet characteristics. METHODS: α1,3-Galactosyltransferase gene-knockout (GTKO) islets with and without expression of the human complement regulatory transgene CD46 (hCD46) were studied. Biologically inert polyethylene microspheres were used to examine the generic pro-thrombotic effects of particle embolization. Immunohistochemistry was performed 1 and 24 hours after transplantation. RESULTS: Xeno-islet transplantation activated both extrinsic and intrinsic coagulation pathways. The intrinsic pathway was also initiated by microsphere embolization, while extrinsic pathway tissue factor (TF) and platelet aggregation were more specific to engrafted islets. hCD46 expression significantly reduced TF, platelet, fibrin, and factor XIIIa accumulation in and around islets but did not alter intrinsic factor activation. Layers of TF+ cells emerged around islets within 24 hours, particularly co-localized with vimentin, and identified as CD3+ and CD68+ cells inflammatory cells. CONCLUSIONS: These findings detail the origins of thrombosis following islet xenotransplantation, relate it to early immune activation, and suggest a role for transgenic hCD46 expression in its mitigation. Layers of TF-positive inflammatory cells and fibroblasts around islets at 24 hours may have important roles in the progressive events of thrombosis, inflammatory cell recruitment, rejection, and the ultimate outcome of transplanted grafts. These suggest that the strategies targeting these elements could yield more progress toward successful xenogeneic islet engraftment and survival.

Biliary reconstruction options for bile duct stricture in patients with prior Roux-en-Y reconstruction.

Comprehensive description with illustrations of the 4 biliary reconstruction options for bile duct injury in patients with history of Roux-en-Y gastric bypass.

Reconstruction Options for Pancreaticoduodenectomy in Patients with Prior Roux-en-Y Gastric Bypass.

BACKGROUND: Patients with prior Roux-en-Y gastric bypass (RYGB) operations for weight loss present reconstruction challenges during a pancreaticoduodenectomy (PD). With over 60,000 RYGB performed annually, the increasing odds of encountering such patients during a PD make it imperative to understand the RYGB anatomy and anticipate reconstruction options. This article describes the possible reconstruction options and their rationale. METHODS: We reviewed our PD reconstruction options, compared them to what have been described in the literature, and derived a consensus from internal conferences comprising bariatric and hepatopancreatobiliary surgeons to describe known reconstruction options. RESULTS: In general, reconstruction options can include one of three options: (1) remnant gastrectomy, (2) preservation of gastric remnant, or (3) reversal of gastric bypass. CONCLUSION: This article describes individualized reconstruction options for RYGB patients undergoing PD. The reconstruction options can be tailored to the needs of the patient.

Lymph node dissection for stage III melanoma.

Locoregional spread of melanoma to its draining lymph node basin is the strongest negative prognostic factor for patients. Exclusive of clinical trials, patients with sentinel lymph node-positive (microscopic) or clinically palpable (macroscopic) nodal disease should undergo lymphadenectomy. This article reviews the management and technical aspects of surgical care for regional metastases. Adjunct therapies (immunotherapy, targeted therapy, and radiation) may supplement lymphadenectomy in certain patient populations. Surgical morbidity after lymphadenectomy can be substantial, creating opportunities for improvement via minimally invasive techniques or refined patient selection.

Islet cell xenotransplantation: a serious look toward the clinic.

Type I diabetes remains a significant clinical problem in need of a reliable, generally applicable solution. Both whole organ pancreas and islet allotransplantation have been shown to grant patients insulin independence, but organ availability has restricted these procedures to an exceptionally small subset of the diabetic population. Porcine islet xenotransplantation has been pursued as a potential means of overcoming the limits of allotransplantation, and several preclinical studies have achieved near-physiologic function and year-long survival in clinically relevant pig-to-primate model systems. These proof-of-concept studies have suggested that xenogeneic islets may be poised for use in clinical trials. In this review, we examine recent progress in islet xenotransplantation, with a critical eye toward the gaps between the current state of the art and the state required for appropriate clinical investigation.

Hypophosphataemia after major hepatectomy and the risk of post-operative hepatic insufficiency and mortality: an analysis of 719 patients.

BACKGROUND: Hypophosphataemia after a hepatectomy suggests hepatic regeneration. It was hypothesized that the absence of hypophosphataemia is associated with post-operative hepatic insufficiency (PHI) and complications. METHODS: Patients who underwent a major hepatectomy from 2000-2012 at a single institution were identified. Post-operative serum phosphorus levels were assessed. Primary outcomes were PHI (peak bilirubin >7 mg/dl), major complications, and 30- and 90-day mortality. RESULTS: Seven hundred and nineteen out of 749 patients had post-operative phosphorus levels available. PHI and major complications occurred in 63 (8.8%) and 169 (23.5%) patients, respectively. Thirty- and 90-day mortality were 4.0% and 5.4%, respectively. The median phosphorus level on post-operative-day (POD) 2 was 2.2 mg/dl; 231 patients (32.1%) had phosphorus >2.4 on POD2. Patients with POD2 phosphorus >2.4 had a significantly higher incidence of PHI, major complications and mortality. On multivariate analysis, POD2 phosphorus >2.4 remained a significant risk factor for PHI [(hazard ratio HR):1.78; 95% confidence interval (CI):1.02-3.17; P = 0.048], major complications (HR:1.57; 95%CI:1.02-2.47; P = 0.049), 30-day mortality (HR:2.70; 95%CI:1.08-6.76; P = 0.034) and 90-day mortality (HR:2.51; 95%CI:1.03-6.15; P = 0.044). Similarly, patients whose phosphorus level reached nadir after POD3 had higher PHI, major complications and mortality. CONCLUSION: Elevated POD2 phosphorus levels >2.4 mg/dl and a delayed nadir in phosphorus beyond POD3 are associated with increased post-operative hepatic insufficiency, major complications and early mortality. Failure to develop hypophosphataemia within 72 h after a major hepatectomy may reflect insufficient liver remnant regeneration.

Early identification of patients at increased risk for hepatic insufficiency, complications and mortality after major hepatectomy.

OBJECTIVE: Total bilirubin (TB) of >7 mg/dl is an accepted definition of postoperative hepatic insufficiency (PHI) given its association with the occurrence of complications and mortality after hepatectomy. The aim of this study was to identify a surrogate marker for PHI early in the postoperative course. METHODS: A single-institution database of patients undergoing major hepatectomy (three or more segments) during 2000-2012 was retrospectively reviewed. Demographic, clinicopathologic and perioperative factors were assessed for their association with PHI, defined as postoperative TB of >7 mg/dl or new ascites. Secondary outcomes included complications, major complications (Clavien-Dindo Grades III-V) and 90-day mortality. RESULTS: A total of 607 patients undergoing major hepatectomy without bile duct reconstruction were identified. Postoperative hepatic insufficiency occurred in 60 (9.9%) patients. A postoperative day 3 (PoD 3) TB level of ≥3 mg/dl was the only early perioperative factor associated with the development of PHI on multivariate analysis [hazard ratio (HR) = 7.81, 95% confidence interval (CI) 3.74-16.31; P < 0.001]. A PoD 3 TB of ≥3 mg/dl was associated with increased risk for postoperative complications (75.7% versus 53.9%), major complications (45.6% versus 17.6%), and 90-day mortality (15.5% versus 2.3%). This association persisted on multivariate analysis for any complications (HR = 1.98, 95% CI 1.10-3.54; P = 0.022), major complications (HR = 3.18, 95% CI 1.90-5.32; P < 0.001), and 90-day mortality (HR = 8.11, 95% CI 3.00-21.92; P < 0.001). CONCLUSIONS: Total bilirubin of ≥3 mg/dl on PoD 3 after major hepatectomy is associated with PHI, increased complications, major complications and 90-day mortality. This marker may serve as an early postoperative predictor of hepatic insufficiency.

Oncologic outcomes of patients undergoing videoscopic inguinal lymphadenectomy for metastatic melanoma.

BACKGROUND: Open inguinal lymphadenectomy for regionally metastatic melanoma is associated with a high wound-related morbidity. Videoscopic inguinal lymphadenectomy (VIL) is a minimally invasive approach with fewer wound-related complications, yet its adoption has been hindered by a lack of oncologic outcomes data. STUDY DESIGN: Data were prospectively collected on all VILs performed for melanoma from 2008 to 2012 (n = 40) and compared with a retrospective cohort of open superficial inguinal lymphadenectomies from 2005 to 2012 (n = 40). Continuous variables were analyzed with Student's t-test, binomial variables with chi-square, and survival curves using log-rank comparison. RESULTS: Median follow-up for patients undergoing VIL was 19.1 months compared with 33.9 months in the open inguinal lymphadenectomy group. There were no statistical differences in demographics (age, sex, body mass index, smoking status, Charlson comorbidity index) or clinicopathologic features (primary site, stage, Breslow depth, ulceration). Lymph node yield was similar (VIL, 12.6; open, 14.2; p = 0.131). Overall recurrence rates were also similar: 27.5% in the VIL group and 30.0% in the open group (p = 0.805). One patient in the VIL group and 2 in the open group suffered recurrence in the nodal basin. Although median survival was not reached in the VIL group, Kaplan-Meier estimates of disease-free survival (p = 0.226) and overall survival (p = 0.308) were similar. In a comprehensive analysis of wound complications including infection, skin necrosis, and seroma, patients undergoing VIL had markedly less morbidity (VIL, 47.5%; open, 80.0%; p = 0.002). CONCLUSIONS: Videoscopic inguinal lymphadenectomy is associated with similar oncologic outcomes and markedly reduced wound complications when compared with open inguinal lymphadenectomy. The minimally invasive procedure may be the preferred method for inguinal lymphadenectomy in melanoma.

Designing an ethics curriculum to support global health experiences in surgery.

BACKGROUND: The field of global health is rapidly expanding in many medical centers across the US. As a result, medical students have increasing opportunities to incorporate global health experiences (GHEs) into their medical education. Ethics is a critical component of global health curricula, yet little literature exists to direct the further development of didactic training. Therefore, we sought to define ethical encounters experienced by medical students participating in short-term surgical GHEs and create a framework for the design of ethics curriculum specific to global surgery. MATERIALS AND METHODS: Emory University Departments of Surgery, Urology, and Anesthesia, in partnership with the non-profit organization Project Medishare, have taken annual humanitarian surgical trips to Hinche, Haiti. All medical students returning from the trips in 2011 and 2012 received a 35-question survey to assess demographic data, extent of prior ethics education, frequency of exposure and situational confidence to ethical subject matter, as well as ethical conflicts involved in surgical GHEs. The same comparative data were also collected for domestic clinical clerkships. RESULTS: Seventeen out of 21 medical students completed the survey. Nearly all (88.3%) students had previous formal ethics training as an undergraduate or in medical school. Ethical issues were commonly encountered during domestic clinical encounters and volunteerism. However, students reported enhanced exposure to the professional obligation of surgeons (P = 0.025) and truth-telling/surgeon-patient relationships (P = 0.044) during surgical volunteerism. Despite increased exposure, situational confidence did not change. CONCLUSIONS: Ethical issues are commonly confronted during GHEs in surgery and differ from domestic clinical encounters. Healthcare ethics curriculum should be designed to meet the needs of medical students involved in global health.

Minimizing morbidity in melanoma surgery.

The selection of a treatment modality involves a balance between risk and benefit. Surgical decision making is intrinsically dependent on potential morbidity; therefore, the desire to minimize adverse outcomes remains paramount in the effort to provide patients with the widest range of therapeutic options. The adoption of sentinel lymph node biopsy for the evaluation of regionally metastatic melanoma has reduced the number of complete lymphadenectomies and their attendant comorbidities. For patients who require completion lymphadenectomy, selective lymphadenectomy and, more recently, videoscopic inguinal lymphadenectomy have been shown to further reduce wound-related complications, while maintaining equivalent regional control and lymph node yield, respectively. Finally, in carefully selected patients laparoscopic metastasectomy can increase survival with less impact on quality of life than open extirpation. Ongoing trials, such as the Multicenter Selective Lymphadenectomy Trial II (MSLT-II), and research into gene profiling may improve the selection of patients for surgery. Obviating the need for surgery may offer the greatest reduction in morbidity of all.

Videoscopic inguinal lymphadenectomy for metastatic melanoma.

BACKGROUND: The standard treatment of care for melanoma metastatic to the inguinal lymph node basin is lymphadenectomy. However, up to 50% of patients forgo the operation partly due to concerns about morbidity. Videoscopic inguinal lymphadenectomy (VIL) is a minimally invasive technique designed to minimize wound complications while achieving comparable oncological control. METHODS: We reviewed pertinent literature related to open inguinal lymphadenectomy and VIL specific to melanoma, offering personal experience where appropriate. RESULTS: Despite efforts to minimize the complications of open inguinal lymphadenectomy, approximately 50% of patients experience a wound-related complication. However, performing minimally invasive VIL has led to a significant decrease in length of hospital stay, a decrease in complications, and equivalent or superior lymph node retrieval in patients with metastatic melanoma to the inguinal basin. CONCLUSIONS: VIL is an alternative to open inguinal lymphadenectomy for patients with melanoma and regional metastases.