Cellular therapeutics and immunotherapies in wound healing - on the pulse of time?

Chronic, non-healing wounds represent a significant challenge for healthcare systems worldwide, often requiring significant human and financial resources. Chronic wounds arise from the complex interplay of underlying comorbidities, such as diabetes or vascular diseases, lifestyle factors, and genetic risk profiles which may predispose extremities to local ischemia. Injuries are further exacerbated by bacterial colonization and the formation of biofilms. Infection, consequently, perpetuates a chronic inflammatory microenvironment, preventing the progression and completion of normal wound healing. The current standard of care (SOC) for chronic wounds involves surgical debridement along with localized wound irrigation, which requires inpatient care under general anesthesia. This could be followed by, if necessary, defect coverage via a reconstructive ladder utilizing wound debridement along with skin graft, local, or free flap techniques once the wound conditions are stabilized and adequate blood supply is restored. To promote physiological wound healing, a variety of approaches have been subjected to translational research. Beyond conventional wound healing drugs and devices that currently supplement treatments, cellular and immunotherapies have emerged as promising therapeutics that can behave as tailored therapies with cell- or molecule-specific wound healing properties. However, in contrast to the clinical omnipresence of chronic wound healing disorders, there remains a shortage of studies condensing the current body of evidence on cellular therapies and immunotherapies for chronic wounds. This review provides a comprehensive exploration of current therapies, experimental approaches, and translational studies, offering insights into their efficacy and limitations. Ultimately, we hope this line of research may serve as an evidence-based foundation to guide further experimental and translational approaches and optimize patient care long-term.

Hard shell, soft core? Multi-disciplinary and multi-national insights into mental toughness among surgeons.

Background: With the prevalence of burnout among surgeons posing a significant threat to healthcare outcomes, the mental toughness of medical professionals has come to the fore. Mental toughness is pivotal for surgical performance and patient safety, yet research into its dynamics within a global and multi-specialty context remains scarce. This study aims to elucidate the factors contributing to mental toughness among surgeons and to understand how it correlates with surgical outcomes and personal well-being. Methods: Utilizing a cross-sectional design, this study surveyed 104 surgeons from English and German-speaking countries using the Mental Toughness Questionnaire (MTQ-18) along with additional queries about their surgical practice and general life satisfaction. Descriptive and inferential statistical analyses were applied to investigate the variations in mental toughness across different surgical domains and its correlation with professional and personal factors. Results: The study found a statistically significant higher level of mental toughness in micro-surgeons compared to macro-surgeons and a positive correlation between mental toughness and surgeons' intent to continue their careers. A strong association was also observed between general life satisfaction and mental toughness. No significant correlations were found between the application of psychological skills and mental toughness. Conclusion: Mental toughness varies significantly among surgeons from different specialties and is influenced by professional dedication and personal life satisfaction. These findings suggest the need for targeted interventions to foster mental toughness in the surgical community, potentially enhancing surgical performance and reducing burnout. Future research should continue to explore these correlations, with an emphasis on longitudinal data and the development of resilience-building programs.

Immune modulation in transplant medicine: a comprehensive review of cell therapy applications and future directions.

Balancing the immune response after solid organ transplantation (SOT) and vascularized composite allotransplantation (VCA) remains an ongoing clinical challenge. While immunosuppressants can effectively reduce acute rejection rates following transplant surgery, some patients still experience recurrent acute rejection episodes, which in turn may progress to chronic rejection. Furthermore, these immunosuppressive regimens are associated with an increased risk of malignancies and metabolic disorders. Despite significant advancements in the field, these IS related side effects persist as clinical hurdles, emphasizing the need for innovative therapeutic strategies to improve transplant survival and longevity. Cellular therapy, a novel therapeutic approach, has emerged as a potential pathway to promote immune tolerance while minimizing systemic side-effects of standard IS regiments. Various cell types, including chimeric antigen receptor T cells (CAR-T), mesenchymal stromal cells (MSCs), regulatory myeloid cells (RMCs) and regulatory T cells (Tregs), offer unique immunomodulatory properties that may help achieve improved outcomes in transplant patients. This review aims to elucidate the role of cellular therapies, particularly MSCs, T cells, Tregs, RMCs, macrophages, and dendritic cells in SOT and VCA. We explore the immunological features of each cell type, their capacity for immune regulation, and the prospective advantages and obstacles linked to their application in transplant patients. An in-depth outline of the current state of the technology may help SOT and VCA providers refine their perioperative treatment strategies while laying the foundation for further trials that investigate cellular therapeutics in transplantation surgery.

The "Central Tendency Bias" in the assessment of facial attractiveness in group-based and individual ratings-A survey-based study in 727 volunteers.

BACKGROUND: The increasing number of esthetic procedures emphasizes the need for effective evaluation methods of outcomes. Current practices include the individual practitioners' judgment in conjunction with standardized scales, often relying on the comparison of before and after photographs. This study investigates whether comparative evaluations influence the perception of beauty and aims to enhance the accuracy of esthetic assessments in clinical and research settings. OBJECTIVE: To compare the evaluation of attractiveness and gender characteristics of faces in group-based versus individual ratings. METHODS: A sample of 727 volunteers (average age of 29.5 years) assessed 40 facial photographs (20 male, 20 female) for attractiveness, masculinity, and femininity using a 5-point Likert scale. Each face was digitally edited to display varying ratios in four lip-related proportions: vertical lip position, lip width, upper lip esthetics, and lower lip esthetics. Participants rated these images both in an image series (group-based) and individually. RESULTS: Differences in the perception of the most attractive/masculine/feminine ratios for each lip proportion were found in both the group-based and individual ratings. Group ratings exhibited a significant central tendency bias, with a preference for more average outcomes compared with individual ratings, with an average difference of 0.50 versus 1.00. (p = 0.033) CONCLUSION: A central tendency bias was noted in evaluations of attractiveness, masculinity, and femininity in group-based image presentation, indicating a bias toward more "average" features. Conversely, individual assessments displayed a preference for more pronounced, "non-average" appearances, thereby possibly pointing toward a malleable "intrinsic esthetic blueprint" shaped by comparative context.

The long-term intercorrelation between post-burn pain, anxiety, and depression: a post hoc analysis of the "RE-ENERGIZE" double-blind, randomized, multicenter placebo-controlled trial.

BACKGROUND: Despite the growing prevalence of burn survivors, a gap persists in our understanding of the correlation between acute burn trauma and the long-term impact on psychosocial health. This study set out to investigate the prevalence of long-term pain and symptoms of anxiety and depression in survivors of extensive burns, comparing this to the general population, and identify injury and demographic-related factors predisposing individuals to psychosocial compromise. METHODS: RE-ENERGIZE was an international, double-blinded, randomized-controlled trial that enrolled 1200 patients with partial- or full-thickness burns that required surgical treatment. For the post hoc analysis, we excluded participants who did not complete the Short Form Health Survey (SF-36) questionnaire. Normative data were taken from the 2021 National Health Interview Survey dataset. Propensity score matching was performed using the nearest-neighbor 1-to-1 method, and the two cohorts were compared in terms of chronic pain, and symptoms of anxiety and depression. A multivariable analysis was performed on the burns cohort to identify factors predicting post-discharge pain and symptoms of anxiety and depression. RESULTS: A total of 600 burn patients and 26,666 general population adults were included in this study. Following propensity score matching, both groups comprised 478 participants each, who were predominately male, white, overweight and between 20 and 60 years old. Compared to the general population, burn patients were significantly more likely to report the presence of moderate and a lot of pain (p = 0.002). Symptoms of anxiety were significantly higher in the burn population in two of four levels (most of the time; some of the time; p < 0.0001 for both). Responders in the burn population were significantly less likely to report the absence of depressive symptoms (p < 0.0001). Burn patients were also significantly more likely to report that their mental health affects their social life. TBSA, history of depression, and female sex were identified as independently associated factors for pain, anxiety, and depressive symptoms. The presence of chronic pain and anxiety symptoms independently predicted for symptoms of depression. CONCLUSIONS: Analyzing the largest multicenter cohort of patients with extensive burns, we find that burn injury is associated with chronic pain, and symptoms of anxiety and depression. In addition, TBSA-burned and history of depression directly correlate with the prevalence of chronic pain, and symptoms of anxiety and depression. Finally, pain, and symptoms of anxiety and depression are interrelated and may have interactive effects on the process of recovery following burn injury. Burn patients would, therefore, benefit from a multidisciplinary team approach with early mobilization of pain and mental health experts, in order to promptly prevent the development of psychosocial challenges and their consequences.

Lymphadenopathy and lymph node rejection following facial vascularized composite allotransplantation.

BACKGROUND: Apart from the skin, little is known about the immunological processes in deeper tissues, which are typically not accessible to biopsy and inspection, of vascularized composite allografts (VCAs). Face transplant patients develop prominent adenopathy shortly after transplantation that resolves over time. The mechanisms underlying this process are not understood. MATERIALS AND METHODS: A retrospective cohort study was conducted on 9 patients who underwent 10 facial VCAs at the Brigham and Women's Hospital, Boston, MA, between April 2009 and July 2019. Clinical, radiological, and histological data related to lymphadenopathy of the head and neck were reviewed. RESULTS: Patients who received donor-derived lymph nodes (LNs) developed bilateral lymphadenopathy of the submental or submandibular superficial LNs. Median time of presentation was POD18 (range POD6-POM3). Notably, bilateral adenopathy of the neck was not observed in later stages of follow-up (mean follow-up, 115 months). Histology of 3 LNs showed increased histiocytes and apoptosis, with the features reminiscent of necrotizing histiocytic lymphadenitis, and B and T lymphocytes (mostly CD8 + T) admixed with CD163 + histiocytes and dendritic cells. Molecular chimerism analysis in one case showed the coexistence of donor (81%) and recipient (19%) derived lymphocytes. Granzyme B (GZMB) expression confirmed the presence of increased cytotoxic T cells in this LN sample. CONCLUSION: Our data suggested the involvement of an immunological process within the donor-derived LNs after facial allotransplantation between the recipient and donor cells. GZMB expression suggested LN rejection that can occurred independently of skin rejection. This finding supports the need to better define the role of donor-derived immune cells in the context of allograft rejection.

Increasing Precision When Targeting the Depressor Anguli Oris (DAO) Muscle With Neuromodulators - An Ultrasound-Based Investigation.

BACKGROUND: Neuromodulator treatments of the perioral region are increasingly popular and aim to modulate the position of the modiolus. The predominantly targeted muscle is the depressor anguli oris (DAO) which allows for the modiolus to reposition cranially once temporarily relaxed. OBJECTIVES: To identify the precise anatomic position of the DAO in relation to the Marionette Line for increasing precision and reducing adverse events during neuromodulator treatments. METHODS: A total of n = 80 DAO muscles were investigated in n = 40 healthy, toxin naïve volunteers (11 males, 29 females) having a mean age of 48.15 (15) years and a mean body mass index of 24.07 (3.7) kg/m2. The location of the DAO in relation to the labiomandibular sulcus (LMS), its depth, extent, and thickness were investigated with high frequency ultrasound imaging. RESULTS: The skin surface projection of the LMS separates the DAO into medial and lateral portions. The distance between skin surface and muscle surface was on average 4.4 mm with males having a greater distance (p < 0.001) and higher BMI being an important influencing factor for a greater distance (p < 0.001). The thickness of the DAO was on average 3.5 mm with a range of 2.8-4.8 mm and with females having thinner muscles when compared to men (p < 0.001). The most favorable injection depth was calculated to be 6.1 mm for intra-muscular product placement. CONCLUSIONS: Understanding the perioral anatomy and the influence of age, sex, and BMI will potentially allow the injectors to increase efficacy and duration of neuromodulator treatments while expertly managing adverse events.

Gynecomastia Surgery in 4996 Male Patients Over 14 Years: A Retrospective Analysis of Surgical Trends, Predictive Risk Factors, and Short-Term Outcomes.

BACKGROUND: The high prevalence of benign male breast tissue enlargement (gynecomastia) has resulted in a marked increase of gynecomastia cases. While about one third of male adults experience some form of gynecomastia, gynecomastia surgery (GS) outcome research is limited to small study populations and single-center/-surgeon databases. In this study, we aimed to access the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database to identify preoperative risk factors for complications and investigate postoperative outcomes of GS. METHODS: In this retrospective study, we queried the ACS-NSQIP database from 2008 to 2021 to identify male adult patients who underwent GS. Postoperative outcomes involved the occurrence of any, surgical and medical complications, as well as reoperation, readmission, and mortality within a 30-day postoperative time period. Univariable and multivariable assessment were performed to identify risk factors for complications while adjusting for possible confounders. RESULTS: The study included 4,996 GS patients with a mean age of 33.7 ± 15 years and BMI of 28.2 ± 5.1 kg/m2. White patients constituted 54% (n = 2713) of the cohort, and 27% (n = 1346) were obese. Except for 2020, there was a steady increase in GS cases over the study period. Outpatient surgeries were most common at 95% (n = 4730), while general surgeons performed the majority of GS (n = 3580; 72%). Postoperatively, 91% (n = 4538) of patients were discharged home; 4.4% (n = 222) experienced any complications. Multivariable analysis identified inpatient setting (p < 0.001), BMI (p = 0.023), prior sepsis (p = 0.018), and bleeding disorders (p = 0.047) as independent risk factors for complications. CONCLUSION: In this study, we analyzed 4996 male adult GS patients from the ACS-NSQIP database, revealing an increased caseload and significant general surgeon involvement. Risk factors like bleeding disorders, inpatient status, and prior sepsis were linked to postoperative complications, while BMI was crucial for predicting adverse events. Overall, our findings may aid in enhancing patient care through advanced preoperative screening and closer perioperative management. LEVEL OF EVIDENCE III: 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 .

ChatGPT's Response Consistency: A Study on Repeated Queries of Medical Examination Questions.

(1) Background: As the field of artificial intelligence (AI) evolves, tools like ChatGPT are increasingly integrated into various domains of medicine, including medical education and research. Given the critical nature of medicine, it is of paramount importance that AI tools offer a high degree of reliability in the information they provide. (2) Methods: A total of n = 450 medical examination questions were manually entered into ChatGPT thrice, each for ChatGPT 3.5 and ChatGPT 4. The responses were collected, and their accuracy and consistency were statistically analyzed throughout the series of entries. (3) Results: ChatGPT 4 displayed a statistically significantly improved accuracy with 85.7% compared to that of 57.7% of ChatGPT 3.5 (p < 0.001). Furthermore, ChatGPT 4 was more consistent, correctly answering 77.8% across all rounds, a significant increase from the 44.9% observed from ChatGPT 3.5 (p < 0.001). (4) Conclusions: The findings underscore the increased accuracy and dependability of ChatGPT 4 in the context of medical education and potential clinical decision making. Nonetheless, the research emphasizes the indispensable nature of human-delivered healthcare and the vital role of continuous assessment in leveraging AI in medicine.

Surface modification of PEEK implants for craniofacial reconstruction and aesthetic augmentation-fiction or reality?

Facial implantology, a crucial facet of plastic and reconstructive surgery, focuses on optimizing implant materials for facial augmentation and reconstruction. This manuscript explores the use of Polyetheretherketone (PEEK) implants in craniofacial surgery, highlighting the challenges and advancements in this field. While PEEK offers mechanical resilience, durability, and compatibility with imaging modalities, its biologically inert nature hinders integration with the host tissue, which may lead to complications. In this systematic review, our aim was to assess the current state of knowledge regarding the clinical evaluation of Polyetheretherketone (PEEK) implants in facial implantology, with a focus on craniofacial augmentation and reconstruction in human studies. Additionally, we explore and discuss surface and structural modifications that may enhance bioreactivity and reduce complications in PEEK implants. A systematic review identified 32 articles detailing the use of PEEK Patient-Specific Implants (PSIs) in 194 patients for both reconstructive and aesthetic purposes. Complications, including infections and implant failures, were reported in 18% of cases, suggesting the need for improved implant materials. The discussion delves into the limitations of PEEK, prompting the exploration of surface and structural modifications to enhance its bioreactivity. Strategies, such as hydroxyapatite coating, titanium coating, and porous structures show promise in improving osseointegration and reducing complications. However, the literature review did not reveal reports of coated or modified PEEK in facial reconstructive or aesthetic surgery. In conclusion, although PEEK implants have been successfully used in craniofacial reconstruction, their biological inertness poses challenges. Surface modifications, particularly hydroxyapatite coatings, provide opportunities to promote osseointegration. Future research should focus on prospective long-term studies, especially in craniofacial surgery, to investigate the stability of uncoated PEEK implants and the potential benefits of surface modifications in clinical applications. Patient-specific PEEK implants hold promise for achieving durable craniofacial reconstruction and augmentation.

Complete lymph node dissection in cutaneous melanoma patients with positive sentinel lymph node: Outcome and predictors in a retrospective cohort study over 16 years.

BACKGROUND: In melanoma treatment, complete lymph node dissection (CLND) has been considered the therapeutic gold standard in patients with positive sentinel lymph node biopsy (SLNB). This long-held approach was revised in 2017, with recent evidence questioning the therapeutic benefit of CLND in malignant melanoma (MM) therapy. In this study, we aimed to fill this knowledge gap by retrospectively analyzing the impact of CLND on MM patients' survival. METHODS: We retrospectively analyzed the multi-center population-based Clinical Cancer Registry at the Tumor Center Regensburg (TUDOK) database (2004-2020) to identify patients who had been diagnosed with SLN-positive MM and underwent (non)invasive management thereof. Patient cohorts were subdivided according to the treatment received (CLND and waiving CLND). Primary outcomes included overall survival (OS), recurrence-free survival (RFS), and cumulative recurrence rate. RESULTS: We identified 1143 MM patients, of whom 126 (11.0%) had positive SLN status. CLND was waived in the majority of SLN-positive MM cases (n = 71; 56.3%), with 55 (43.7%) patients undergoing CLND. Univariable and multivariable Cox regression revealed no significant advantage for CLND patients compared to non-CLND patients in OS (HR=0.970, p = 0.915 and HR=1.295, p = 0.479, respectively), RFS (HR=1.050, p = 0.849 and HR=1.220, p = 0.544, respectively), and cumulative recurrence rate (HR=1.234, p = 0.441 and HR=1.220, p = 0.544), respectively). CONCLUSION: We found that CLND had no significant impact on patient survival and MM recurrence rate, thus corroborating the validity of current clinical guidelines.

Early outcomes and risk factors for complications after facial alloplastic implant surgery: An ACS-NSQIP study.

BACKGROUND: Facial implantology (FI) is a growing field in facial surgery that focuses on harmonizing and balancing facial features. Despite its increasing popularity, larger-scale studies on FI outcomes and risks are scarce. METHODS: The ACS-NSQIP (2008-2021) was queried to identify patients who underwent combined/isolated alloplastic FI surgery of the malar/mandibular region. Based on CPT codes (21125; 21270), procedures were subdivided into combined or isolated FI surgery of the malar or the mandibular region. RESULTS: The study population included 84 patients, of which n = 19 (23%), n = 10 (12%), n = 33 (39%), and n = 22 (26%) underwent combined malar, isolated malar, combined mandibular, and isolated mandibular FI surgery, respectively. Isolated malar (total n = 10) and mandibular FI surgery (total n = 22) patients had relatively high comorbidity rates with up to n = 6 (60%) active smokers and n = 9 (41%) with hypertension, respectively. Combined malar (n = 19) and mandibular FI surgeries (n = 33) had the highest complication rates with n = 3 (16%) and n = 5 (15%) patients experiencing any complications. For both isolated malar and mandibular FI procedures, n = 1 (10% and 4.5%) patient reported any complications. CONCLUSION: In this study, we accessed the ACS-NSQIP database and found alloplastic augmentation for zygoma and mandible to be safe. Patients who underwent combined procedures and mandibular augmentation were more likely to show complications or require inpatient stay. Most alloplastic augmentations of mandible or zygoma were combined with other procedures (62%) which suggests that alloplastic facial implants (in the academic setting) are often used as an adjunct in the treatment of complex craniofacial disorders.

Integrated Molecular and Histological Insights for Targeted Therapies in Mesenchymal Sinonasal Tract Tumors.

PURPOSE OF REVIEW: This review aims to provide a comprehensive overview of mesenchymal sinonasal tract tumors (STTs), a distinct subset of STTs. Despite their rarity, mesenchymal STTs represent a unique clinical challenge, characterized by their rarity, often slow progression, and frequently subtle or overlooked symptoms. The complex anatomy of the sinonasal area, which includes critical structures such as the orbit, brain, and cranial nerves, further complicates surgical treatment options. This underscores an urgent need for more advanced and specialized therapeutic approaches. RECENT FINDINGS: Advancements in molecular diagnostics, particularly in next-generation sequencing, have significantly enhanced our understanding of STTs. Consequently, the World Health Organization has updated its tumor classification to better reflect the distinct histological and molecular profiles of these tumors, as well as to categorize mesenchymal STTs with greater accuracy. The growing understanding of the molecular characteristics of mesenchymal STTs opens new possibilities for targeted therapeutic interventions, marking a significant shift in treatment paradigms. This review article concentrates on mesenchymal STTs, specifically addressing sinonasal tract angiofibroma, sinonasal glomangiopericytoma, biphenotypic sinonasal sarcoma, and skull base chordoma. These entities are marked by unique histopathological and molecular features, which challenge conventional treatment approaches and simultaneously open avenues for novel targeted therapies. Our discussion is geared towards delineating the molecular underpinnings of mesenchymal STTs, with the objective of enhancing therapeutic strategies and addressing the existing shortcomings in the management of these intricate tumors.

Isolated and combined breast augmentation in transgender patients: Multi-institutional insights into early outcomes and risk factors.

BACKGROUND: The increasing demand for gender-affirming surgery (GAS) in transgender and gender-diverse healthcare highlights the importance of breast augmentation surgery (BAS) for transfeminine patients. Despite its significance, there is a lack of research on postoperative outcomes of BAS. METHODS: We analyzed the multi-institutional American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) (2008-2021) database to identify female transgender individuals (TGIs) who underwent BAS surgery, both isolated and combined with concurrent GAS procedures. We evaluated 30-day outcomes, including the incidence of mortality, reoperation, readmission as well as surgical and medical complication occurrence. RESULTS: Of 1699 female TGIs, 92% underwent isolated BAS and 7.7% underwent combined BAS. The mean age and body mass index (BMI) were 36 ± 12 years and 27 ± 6.6 kg/m2, respectively. Isolated BAS showed a 2.8% complication rate, while combined BAS had a higher rate with 9.1%. Specifically, all complications occurred in patients undergoing BAS with concurrent genitourinary surgery (n = 85; 14%), whereas no adverse events were recorded after combined BAS and facial feminization (n = 19) or chondrolaryngoplasty (n = 19). In patients seeking combined BAS, advanced age (p = 0.05) and nicotine abuse (p = 0.004) were identified as risk factors predisposing to adverse events, whereas American Society of Anesthesiology class 1 was found to be protective (p = 0.02). CONCLUSIONS: Isolated BAS in TGIs demonstrates a positive safety profile. Combined surgeries, particularly with genitourinary procedures, pose higher risks. Identifying risk factors such as smoking and advanced age is crucial for patient selection and surgical planning. These findings can aid in refining patient eligibility and inform surgical decision-making for BAS.

Balancing beauty and science: a review of facial implant materials in craniofacial surgery.

Facial reconstruction and augmentation, integral in facial plastic surgery, address defects related to trauma, tumors infections, and congenital skeletal deficiencies. Aesthetic considerations, including age-related facial changes, involve volume loss and diminished projection, often associated with predictable changes in the facial skeleton. Autologous, allogeneic, and alloplastic implants are used to address these concerns. Autologous materials such as bone, cartilage, and fat, while longstanding options, have limitations, including unpredictability and resorption rates. Alloplastic materials, including metals, polymers, and ceramics, offer alternatives. Metals like titanium are biocompatible and used primarily in fracture fixation. Polymers, such as silicone and polyethylene, are widely used, with silicone presenting migration, bony resorption, and visibility issues. Polyethylene, particularly porous polyethylene (MedPor), was reported to have one of the lowest infection rates while it becomes incorporated into the host. Polyether-ether-ketone (PEEK) exhibits mechanical strength and compatibility with imaging modalities, with custom PEEK implants providing stable results. Acrylic materials, like poly-methylmethacrylate (PMMA), offer strength and is thus mostly used in the case of cranioplasty. Bioceramics, notably hydroxyapatite (HaP), offer osteoconductive and inductive properties, and HaP granules demonstrate stable volume retention in facial aesthetic augmentation. Combining HaP with other materials, such as PLA, may enhance mechanical stability. 3D bioprinting with HaP-based bioinks presents a promising avenue for customizable and biocompatible implants. In conclusion, various materials have been used for craniofacial augmentation, but none have definitively demonstrated superiority. Larger randomized controlled trials are essential to evaluate short- and long-term complications comprehensively, potentially revolutionizing facial balancing surgery.

The Multifaceted Functions of TRPV4 and Calcium Oscillations in Tissue Repair.

The transient receptor potential vanilloid 4 (TRPV4) specifically functions as a mechanosensitive ion channel and is responsible for conveying changes in physical stimuli such as mechanical stress, osmotic pressure, and temperature. TRPV4 enables the entry of cation ions, particularly calcium ions, into the cell. Activation of TRPV4 channels initiates calcium oscillations, which trigger intracellular signaling pathways involved in a plethora of cellular processes, including tissue repair. Widely expressed throughout the body, TRPV4 can be activated by a wide array of physicochemical stimuli, thus contributing to sensory and physiological functions in multiple organs. This review focuses on how TRPV4 senses environmental cues and thereby initiates and maintains calcium oscillations, critical for responses to organ injury, tissue repair, and fibrosis. We provide a summary of TRPV4-induced calcium oscillations in distinct organ systems, along with the upstream and downstream signaling pathways involved. In addition, we delineate current animal and disease models supporting TRPV4 research and shed light on potential therapeutic targets for modulating TRPV4-induced calcium oscillation to promote tissue repair while reducing tissue fibrosis.

Copper incorporated biomaterial-based technologies for multifunctional wound repair.

The treatment of wounds is a worldwide challenge, and wound infection can affect the effectiveness of wound treatment and further increase the disease burden. Copper is an essential trace element that has been shown to have broad-spectrum antibacterial effects and to be involved in the inflammation, proliferation, and remodeling stages of wound healing. Compared to treatments such as bioactive factors and skin grafts, copper has the advantage of being low-cost and easily available, and has received a lot of attention in wound healing. Recently, biomaterials made by incorporating copper into bioactive glasses, polymeric scaffolds and hydrogels have been used to promote wound healing by the release of copper ions. In addition, copper-incorporated biomaterials with catalytic, photothermal, and photosensitive properties can also accelerate wound healing through antibacterial and wound microenvironment regulation. This review summarizes the antibacterial mechanisms of copper- incorporated biomaterials and their roles in wound healing, and discusses the current challenges. A comprehensive understanding of the role of copper in wounds will help to facilitate new preclinical and clinical studies, thus leading to the development of novel therapeutic tools.

Patient-reported Outcomes Utilizing the Breast-Q Questionnaire After Breast Conserving Surgery With and Without Oncoplastic Breast Surgery: A Systematic Review and Meta-analysis.

Oncoplastic breast surgery (OBS) arose to decrease the deformity following breast conserving surgery (BCS) for breast cancer. In this meta-analysis (MA), we pool Breast-Q™ questionnaire data to compare quality of life (QOL) in breast cancer patients who received BCS alone or in combination with Level I or II oncoplastic breast surgery (BCS+OBS). All relevant databases were searched following the PRISMA and QUOROM guidelines. All prospective or retrospective studies with a BCS or BCS+OBS cohort that reported QOL as assessed with the Breast-Q™ questionnaire were eligible. Fifty-five studies (75 distinct patient cohorts; 11,186 patients) were included in the MA, with 12 studies reporting both pre- and postoperative values and eligible for a pairwise MA. The pairwise MA showed a significant postoperative improvement in the overall satisfaction with the breast (MD +8.0%, p=0.003) and in the psychosocial well-being (MD +9.2%, 3.5-14.8, p=0.001) of the entire cohort (BCS and BCS+OBS). A subgroup MA of proportions highlighted a superiority of BCS+OBS to BCS in terms of overall satisfaction with the breast (72.0%, 68.0-76.1, versus 62.9%, 58.3-67.5; p=0.02) and psychosocial well-being (78.9%, 71.5-86.4, versus 73.3%, 67.3-76.5, p=0.0001). A leave-one-out sensitivity analysis confirmed the results of the pairwise MA and the MA of proportions. Oncoplastic breast surgery effectively improves QoL based on the patient-reported outcomes assessed using the Breast-Q™ questionnaire. The improvements were associated with acceptable complication rates, further supporting the use of BCS followed by OBS where mastectomy would otherwise be necessary.

Pure Wisdom or Potemkin Villages? A Comparison of ChatGPT 3.5 and ChatGPT 4 on USMLE Step 3 Style Questions: Quantitative Analysis.

BACKGROUND: The United States Medical Licensing Examination (USMLE) has been critical in medical education since 1992, testing various aspects of a medical student's knowledge and skills through different steps, based on their training level. Artificial intelligence (AI) tools, including chatbots like ChatGPT, are emerging technologies with potential applications in medicine. However, comprehensive studies analyzing ChatGPT's performance on USMLE Step 3 in large-scale scenarios and comparing different versions of ChatGPT are limited. OBJECTIVE: This paper aimed to analyze ChatGPT's performance on USMLE Step 3 practice test questions to better elucidate the strengths and weaknesses of AI use in medical education and deduce evidence-based strategies to counteract AI cheating. METHODS: A total of 2069 USMLE Step 3 practice questions were extracted from the AMBOSS study platform. After including 229 image-based questions, a total of 1840 text-based questions were further categorized and entered into ChatGPT 3.5, while a subset of 229 questions were entered into ChatGPT 4. Responses were recorded, and the accuracy of ChatGPT answers as well as its performance in different test question categories and for different difficulty levels were compared between both versions. RESULTS: Overall, ChatGPT 4 demonstrated a statistically significant superior performance compared to ChatGPT 3.5, achieving an accuracy of 84.7% (194/229) and 56.9% (1047/1840), respectively. A noteworthy correlation was observed between the length of test questions and the performance of ChatGPT 3.5 (ρ=-0.069; P=.003), which was absent in ChatGPT 4 (P=.87). Additionally, the difficulty of test questions, as categorized by AMBOSS hammer ratings, showed a statistically significant correlation with performance for both ChatGPT versions, with ρ=-0.289 for ChatGPT 3.5 and ρ=-0.344 for ChatGPT 4. ChatGPT 4 surpassed ChatGPT 3.5 in all levels of test question difficulty, except for the 2 highest difficulty tiers (4 and 5 hammers), where statistical significance was not reached. CONCLUSIONS: In this study, ChatGPT 4 demonstrated remarkable proficiency in taking the USMLE Step 3, with an accuracy rate of 84.7% (194/229), outshining ChatGPT 3.5 with an accuracy rate of 56.9% (1047/1840). Although ChatGPT 4 performed exceptionally, it encountered difficulties in questions requiring the application of theoretical concepts, particularly in cardiology and neurology. These insights are pivotal for the development of examination strategies that are resilient to AI and underline the promising role of AI in the realm of medical education and diagnostics.

Bone-targeting engineered small extracellular vesicles carrying anti-miR-6359-CGGGAGC prevent valproic acid-induced bone loss.

The clinical role and underlying mechanisms of valproic acid (VPA) on bone homeostasis remain controversial. Herein, we confirmed that VPA treatment was associated with decreased bone mass and bone mineral density (BMD) in both patients and mice. This effect was attributed to VPA-induced elevation in osteoclast formation and activity. Through RNA-sequencing, we observed a significant rise in precursor miR-6359 expression in VPA-treated osteoclast precursors in vitro, and further, a marked upregulation of mature miR-6359 (miR-6359) in vivo was demonstrated using quantitative real-time PCR (qRT-PCR) and miR-6359 fluorescent in situ hybridization (miR-6359-FISH). Specifically, the miR-6359 was predominantly increased in osteoclast precursors and macrophages but not in neutrophils, T lymphocytes, monocytes and bone marrow-derived mesenchymal stem cells (BMSCs) following VPA stimulation, which influenced osteoclast differentiation and bone-resorptive activity. Additionally, VPA-induced miR-6359 enrichment in osteoclast precursors enhanced reactive oxygen species (ROS) production by silencing the SIRT3 protein expression, followed by activation of the MAPK signaling pathway, which enhanced osteoclast formation and activity, thereby accelerating bone loss. Currently, there are no medications that can effectively treat VPA-induced bone loss. Therefore, we constructed engineered small extracellular vesicles (E-sEVs) targeting osteoclast precursors in bone and naturally carrying anti-miR-6359 by introducing of EXOmotif (CGGGAGC) in the 3'-end of the anti-miR-6359 sequence. We confirmed that the E-sEVs exhibited decent bone/osteoclast precursor targeting and exerted protective therapeutic effects on VPA-induced bone loss, but not on ovariectomy (OVX) and glucocorticoid-induced osteoporotic models, deepening our understanding of the underlying mechanism and treatment strategies for VPA-induced bone loss.