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Large Language Models (LLMs) like ChatGPT 4 (OpenAI), Claude 2 (Anthropic), and Llama 2 (Meta AI) have emerged as novel technologies to integrate artificial intelligence (AI) into everyday work. LLMs in particular, and AI in general, carry infinite potential to streamline clinical workflows, outsource resource-intensive tasks, and disburden the healthcare system. While a plethora of trials is elucidating the untapped capabilities of this technology, the sheer pace of scientific progress also takes its toll. Legal guidelines hold a key role in regulating upcoming technologies, safeguarding patients, and determining individual and institutional liabilities. To date, there is a paucity of research work delineating the legal regulations of Language Models and AI for clinical scenarios in plastic and reconstructive surgery. This knowledge gap poses the risk of lawsuits and penalties against plastic surgeons. Thus, we aim to provide the first overview of legal guidelines and pitfalls of LLMs and AI for plastic surgeons. Our analysis encompasses models like ChatGPT, Claude 2, and Llama 2, among others, regardless of their closed or open-source nature. Ultimately, this line of research may help clarify the legal responsibilities of plastic surgeons and seamlessly integrate such cutting-edge technologies into the field of PRS.
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Heart failure (HF) is a common disease associated with high morbidity and mortality rates despite advanced pharmacological therapies. Heart transplantation remains the gold standard therapy for end-stage heart failure; however, its application is curtailed by the persistent shortage of donor organs. Over the past two decades, mechanical circulatory support, notably Left Ventricular Assist Devices (LVADs), have been established as an option for patients waiting for a donor organ. This comprehensive review focuses on elucidating the benefits and barriers associated with this application. We provide an overview of landmark clinical trials that have evaluated the use of LVADs as a bridge to transplantation therapy, with a particular focus on post-transplant outcomes. We discuss the benefits of stabilizing patients with these systems, weighing associated complications and limitations. Further technical advancements and research on optimal implantation timing are critical to ultimately improve outcomes and securing quality of life. In a world where the availability of donor organs remains constrained, LVADs are an increasingly important piece of patient care, bridging the critical gap to transplantation in advanced heart failure management.
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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.
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Trasplante de Órganos , Humanos , Trasplante de Órganos/efectos adversos , Animales , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , InmunomodulaciónRESUMEN
Septic shock is characterized by an excessive inflammatory response depicted in a cytokine storm that results from invasive bacterial, fungi, protozoa, and viral infections. Non-canonical inflammasome activation is crucial in the development of septic shock promoting pyroptosis and proinflammatory cytokine production via caspase-11 and gasdermin D (GSDMD). Here, we show that NAD+ treatment protected mice toward bacterial and lipopolysaccharide (LPS)-induced endotoxic shock by blocking the non-canonical inflammasome specifically. NAD+ administration impeded systemic IL-1ß and IL-18 production and GSDMD-mediated pyroptosis of macrophages via the IFN-ß/STAT-1 signaling machinery. More importantly, NAD+ administration not only improved casp-11 KO (knockout) survival but rendered wild type (WT) mice completely resistant to septic shock via the IL-10 signaling pathway that was independent from the non-canonical inflammasome. Here, we delineated a two-sided effect of NAD+ blocking septic shock through a specific inhibition of the non-canonical inflammasome and promoting immune homeostasis via IL-10, underscoring its unique therapeutic potential.
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Citocinas , Choque Séptico , Animales , Ratones , Interleucina-10 , Inflamasomas , NAD , Choque Séptico/prevención & control , MacrófagosRESUMEN
Aging affects immunity broadly through changes caused by immunosenescence, clinically resulting in augmented susceptibility to infections, autoimmunity, and cancer. The most striking alterations associated with immunosenescence have been observed in the T-cell compartment with a significant shift toward a terminally differentiated memory phenotype taking on features of innate immune cells. At the same time, cellular senescence impairs T-cell activation, proliferation, and effector functions, compromising the effectiveness of immunity. In clinical transplantation, T-cell immunosenescence has been the main driver of less frequent acute rejections in older transplant recipients. This patient population, at the same time, suffers more frequently from the side effects of immunosuppressive therapy including higher rates of infections, malignancies, and chronic allograft failure. T-cell senescence has also been identified as an instigator of age-specific organ dysfunction through a process that has been coined "inflammaging," accelerating organ injury and potentially contributing to the limited lifetime of organ transplants. Here, we provide a summary of the latest evidence on molecular characteristics of T-cell senescence affecting alloimmunity and organ quality while dissecting the consequences of unspecific organ injury and immunosuppression on T-cell senescence. Rather than conceptualizing immunosenescence as a broad and general "weaker" alloimmune response, it appears critical to understand both mechanisms and clinical effects in detail as a basis to refine treatment.
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Inmunosenescencia , Trasplante de Órganos , Humanos , Anciano , Senescencia de Células T , Envejecimiento/fisiología , Inmunosenescencia/fisiología , Senescencia Celular , Trasplante de Órganos/efectos adversos , Inflamación/etiologíaRESUMEN
In clinical organ transplantation, donor and recipient ages may differ substantially. Old donor organs accumulate senescent cells that have the capacity to induce senescence in naïve cells. We hypothesized that the engraftment of old organs may induce senescence in younger recipients, promoting age-related pathologies. When performing isogeneic cardiac transplants between age-mismatched C57BL/6 old donor (18 months) mice and young and middle-aged C57BL/6 (3- or 12- month-old) recipients , we observed augmented frequencies of senescent cells in draining lymph nodes, adipose tissue, livers, and hindlimb muscles 30 days after transplantation. These observations went along with compromised physical performance and impaired spatial learning and memory abilities. Systemic levels of the senescence-associated secretory phenotype factors, including mitochondrial DNA (mt-DNA), were elevated in recipients. Of mechanistic relevance, injections of mt-DNA phenocopied effects of age-mismatched organ transplantation on accelerating aging. Single treatment of old donor animals with senolytics prior to transplantation attenuated mt-DNA release and improved physical capacities in young recipients. Collectively, we show that transplanting older organs induces senescence in transplant recipients, resulting in compromised physical and cognitive capacities. Depleting senescent cells with senolytics, in turn, represents a promising approach to improve outcomes of older organs.
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Senescencia Celular , Trasplante de Órganos , Animales , Ratones , Senoterapéuticos , Ratones Endogámicos C57BL , Trasplante de Órganos/efectos adversos , ADN/farmacología , Envejecimiento/fisiologíaRESUMEN
Mitral valve prolapse (MVP) is common among heart valve disease patients, causing severe mitral regurgitation (MR). Although complications such as cardiac arrhythmias and sudden cardiac death are rare, the high prevalence of the condition leads to a significant number of such events. Through next-generation gene sequencing approaches, predisposing genetic components have been shown to play a crucial role in the development of MVP. After the discovery of the X-linked inheritance of filamin A, autosomal inherited genes were identified. In addition, the study of sporadic MVP identified several genes, including DZIP1, TNS1, LMCD1, GLIS1, PTPRJ, FLYWCH, and MMP2. The early screening of these genetic predispositions may help to determine the patient population at risk for severe complications of MVP and impact the timing of reconstructive surgery. Surgical mitral valve repair is an effective treatment option for MVP, resulting in excellent short- and long-term outcomes. Repair rates in excess of 95% and low complication rates have been consistently reported for minimally invasive mitral valve repair performed in high-volume centers. We therefore conceptualize a potential preventive surgical strategy for the treatment of MVP in patients with genetic predisposition, which is currently not considered in guideline recommendations. Further genetic studies on MVP pathology and large prospective clinical trials will be required to support such an approach.
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Introduction: Following heart transplantation, a cascade of immunological responses is initiated influencing the clinical outcome and long-term survival of the transplanted patients. The anti-inflammatory cytokine interleukin-10 (IL-10) was shown to be elevated in the blood of heart transplant recipients directly after transplantation but the releasing cell populations and the composition of lymphocyte subsets following transplantation have not been thoroughly studied. Methods: We identified immune cells by immunophenotyping and analyzed intracellular IL-10 production in peripheral blood mononuclear cells (PBMC) of heart transplanted patients (n= 17) before, directly after and 24h post heart transplantation. The cells were stimulated with lipopolysaccharide or PMA/Ionomycin to enhance cytokine production within leukocytes in vitro. Results and discussion: We demonstrate that intermediate monocytes (CD14highCD16+), but not CD8+ T cells, CD4+ T cells, CD56+ NK cells or CD20+ B cells appeared to be the major IL-10 producers within patients PBMC following heart transplantation. Consequently, the absolute monocyte count and the ratio of intermediate monocytes to classical monocytes (CD14+CD16-) were specifically increased in comparison to pre transplant levels. Hence, this population of monocytes, which has not been in the focus of heart transplantation so far, may be an important modulator of clinical outcome and long-term survival of heart transplant recipients. Alteration of blood-circulating monocytes towards a CD14highCD16+ phenotype could therefore shift the pro-inflammatory immune response towards induction of graft tolerance, and may pave the way for the optimization of immunosuppression.
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Trasplante de Corazón , Monocitos , Humanos , Leucocitos Mononucleares , Interleucina-10 , Receptores de Lipopolisacáridos , Receptores de IgG , CitocinasRESUMEN
Ex vivo machine perfusion (EVMP) is an emerging technique for preserving explanted solid organs with primary application in allogeneic organ transplantation. EVMP has been established as an alternative to the standard of care static-cold preservation, allowing for prolonged preservation and real-time monitoring of organ quality while reducing/preventing ischemia-reperfusion injury. Moreover, it has paved the way to involve expanded criteria donors, e.g., after circulatory death, thus expanding the donor organ pool. Ongoing improvements in EVMP protocols, especially expanding the duration of preservation, paved the way for its broader application, in particular for reconditioning and modification of diseased organs and tumor and infection therapies and regenerative approaches. Moreover, implementing EVMP for in vivo-like preclinical studies improving disease modeling raises significant interest, while providing an ideal interface for bioengineering and genetic manipulation. These approaches can be applied not only in an allogeneic and xenogeneic transplant setting but also in an autologous setting, where patients can be on temporary organ support while the diseased organs are treated ex vivo, followed by reimplantation of the cured organ. This review provides a comprehensive overview of the differences and similarities in abdominal (kidney and liver) and thoracic (lung and heart) EVMP, focusing on the organ-specific components and preservation techniques, specifically on the composition of perfusion solutions and their supplements and perfusion temperatures and flow conditions. Novel treatment opportunities beyond organ transplantation and limitations of abdominal and thoracic EVMP are delineated to identify complementary interdisciplinary approaches for the application and development of this technique.
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Objectives: Stethoscopes carry a significant risk for pathogen transmission. Here, the safe use and performance of a new, non-sterile, single-use stethoscope cover (SC), that is impermeable for pathogens, was investigated by different healthcare professionals (HCPs) in the postoperative care setting of an intensive care unit (ICU). Methods: Fifty-four patients underwent routine auscultations with the use of the SC (Stethoglove®, Stethoglove GmbH, Hamburg, Germany). The participating HCPs (n = 34) rated each auscultation with the SC on a 5-point Likert scale. The mean ratings of acoustic quality and the SC handling were defined as primary and secondary performance endpoint. Results: 534 auscultations with the SC were performed (average 15.7/user) on the lungs (36.1%), the abdomen (33.2%), the heart (28.8%), or other body-sites (1.9%). No adverse device-effects occurred. The acoustic quality was rated at 4.2 ± 0.7 (mean) with a total of 86.1% of all auscultations being rated at least as 4/5, and with no rating as below 2. The SC handling was rated at 3.7 ± 0.8 (mean) with a total of 96.4% of all auscultations being rated at least 3/5. Conclusion: Using a real-world setting, this study demonstrates that the SC can be safely and effectively used as cover for stethoscopes during auscultation. The SC may therefore represent a useful and easy-to-implement tool for preventing stethoscope-mediated infections.Study Registration: EUDAMED no. CIV-21-09-037762.
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Myeloid-derived suppressor cells (MDSCs) are naturally occurring leukocytes that develop from immature myeloid cells under inflammatory conditions that were discovered initially in the context of tumor immunity. Because of their robust immune inhibitory activities, there has been growing interest in MDSC-based cellular therapies for transplant tolerance induction. Indeed, various pre-clinical studies have introduced in vivo expansion or adoptive transfer of MDSC as a promising therapeutic strategy leading to a profound extension of allograft survival due to suppression of alloreactive T cells. However, several limitations of cellular therapies using MDSCs remain to be addressed, including their heterogeneous nature and limited expansion capacity. Metabolic reprogramming plays a crucial role for differentiation, proliferation and effector function of immune cells. Notably, recent reports have focused on a distinct metabolic phenotype underlying the differentiation of MDSCs in an inflammatory microenvironment representing a regulatory target. A better understanding of the metabolic reprogramming of MDSCs may thus provide novel insights for MDSC-based treatment approaches in transplantation. In this review, we will summarize recent, interdisciplinary findings on MDSCs metabolic reprogramming, dissect the underlying molecular mechanisms and discuss the relevance for potential treatment approaches in solid-organ transplantation.
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Células Supresoras de Origen Mieloide , Trasplante de Órganos , Células Supresoras de Origen Mieloide/metabolismo , Células Mieloides , Tolerancia Inmunológica , Linfocitos TRESUMEN
Early kinetics of lymphocyte subsets involved in tolerance and rejection following heart transplantation (HTx) are barely defined. Here, we aimed to delineate the early alloimmune response immediately after HTx. Therefore, blood samples from 23 heart-transplanted patients were collected before (pre-), immediately (T0), 24 hours (T24), and 3 weeks (3 wks) after HTx. Immunophenotyping was performed using flow cytometry. A significant increase was detected for terminally differentiated (TEMRA) CD4+ or CD8+ T cells and CD56dim CD16+ NK cells immediately after HTx linked to a decrease in naïve CD8+ and CM CD4+ T as well as CD56bright CD16- NK cells, returning to baseline levels at T24. More detailed analyses revealed increased CD69+ CD25- and diminished CD69- CD25- CD4+ or CD8+ T-cell proportions at T0 associated with decreasing S1PR1 expression. Passenger T and NK cells were found at low frequencies only in several patients at T0 and did not correlate with lymphocyte alterations. Collectively, these results suggest an immediate, transient shift toward memory T and NK cells following HTx. Opposite migratory properties of naïve versus memory T and NK cells occurring in the early phase after HTx could underlie these observations and may impinge on the development of allo-specific immune responses.
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Linfocitos T CD8-positivos , Trasplante de Corazón , Humanos , Células Asesinas Naturales , Subgrupos Linfocitarios , Inmunofenotipificación , Antígeno CD56/metabolismoRESUMEN
BACKGROUND: Perioperative stroke remains a devastating complication in the operative treatment of acute type A aortic dissection. To reduce the risk of perioperative stroke, different perfusion techniques can be applied. A consensus on the preferred cerebral protection strategy does not exist. METHODS: To provide an overview about the different cerebral protection strategies, literature research on Medline/PubMed was performed. All available original articles reporting on cerebral protection in surgery for acute type A aortic dissection and neurologic outcomes since 2010 were included. RESULTS: Antegrade and retrograde cerebral perfusion may provide similar neurological outcomes while outperforming deep hypothermic circulatory arrest. The choice of arterial cannulation site and chosen level of hypothermia are influencing factors for perioperative stroke. CONCLUSIONS: Deep hypothermic circulatory arrest is not recommended as the sole cerebral protection technique. Antegrade and retrograde cerebral perfusion are today's standard to provide cerebral protection during aortic surgery. Bilateral antegrade cerebral perfusion potentially leads to superior outcomes during prolonged circulatory arrest times between 30 and 50 min. Arterial cannulation sites with antegrade perfusion (axillary, central or carotid artery) in combination with moderate hypothermia seem to be advantageous. Every concept should be complemented by adequate intraoperative neuromonitoring.
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In this backstory, researchers from Swiss Federal Institute of Technology (ETH Zurich) who initiated an interdisciplinary program to generate innovative solutions for different cardiovascular diseases, such as myocardial infarction, valvular replacement, and movement-based rehabilitation therapy, discuss the benefits and challenges of interdisciplinary research.
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PURPOSE OF REVIEW: Ex-situ machine perfusion for both heart (HTx) and lung transplantation (LuTx) reduces ischemia-reperfusion injury (IRI), allows for greater flexibility in geographical donor management, continuous monitoring, organ assessment for extended evaluation, and potential reconditioning of marginal organs. In this review, we will delineate the impact of machine perfusion, characterize novel opportunities, and outline potential challenges lying ahead to improve further implementation. RECENT FINDINGS: Due to the success of several randomized controlled trials (RCT), comparing cold storage to machine perfusion in HTx and LuTx, implementation and innovation continues. Indeed, it represents a promising interface for organ-specific therapies targeting IRI, allo-immune responses, and graft reconditioning. These mostly experimental efforts range from genetic approaches and nanotechnology to cellular therapies, involving mesenchymal stem cell application. Despite tremendous potential, prior to clinical transition, more data is needed. SUMMARY: Collectively, machine perfusion constitutes the vanguard in thoracic organ transplantation research with extensive potential for expanding the donor pool, enhancing transplant outcomes as well as developing novel therapy approaches.
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Trasplante de Pulmón , Trasplante de Órganos , Humanos , Preservación de Órganos , Trasplante de Órganos/efectos adversos , Perfusión , Donantes de TejidosRESUMEN
Obesity initiates a chronic inflammatory network linked to perioperative complications and increased acute rejection rates in organ transplantation. Bariatric surgery is the most effective treatment of obesity recommended for morbidly obese transplant recipients. Here, we delineated the effects of obesity and bariatric surgery on alloimmunity and transplant outcomes in diet-induced obese (DIO) mice. Allograft survival was significantly shorter in DIO-mice. When performing sleeve gastrectomies (SGx) prior to transplantation, we found attenuated T cell-derived alloimmune responses resulting in prolonged allograft survival. Administering taurodeoxycholic acid (TDCA) and valine, metabolites depleted in DIO-mice and restored through SGx, prolonged graft survival in DIO-mice comparable with SGx an dampened Th1 and Th17 alloimmune responses while Treg frequencies and CD4+ T cell-derived IL-10 production were augmented. Moreover, in recipient animals treated with TDCA/valine, levels of donor-specific antibodies had been reduced. Mechanistically, TDCA/valine restrained inflammatory M1-macrophage polarization through TGR5 that compromised cAMP signaling and inhibited macrophage-derived T cell activation. Consistently, administering a TGR5 agonist to DIO-mice prolonged allograft survival. Overall, we provide novel insights into obesity-induced inflammation and its impact on alloimmunity. Furthermore, we introduce TDCA/valine as a noninvasive alternative treatment for obese transplant patients.
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Trasplante de Corazón , Obesidad Mórbida , Aloinjertos , Animales , Rechazo de Injerto/etiología , Supervivencia de Injerto , Trasplante de Corazón/efectos adversos , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ácido Taurodesoxicólico , ValinaRESUMEN
Older organs provide a substantial unrealized potential with the capacity to close the gap between demand and supply in organ transplantation. The potential of senolytics in improving age-related conditions has been shown in various experimental studies and early clinical trials. Those encouraging data may also be of relevance for transplantation. As age-differences between donor and recipients are not uncommon, aging may be accelerated in recipients when transplanting older organs; young organs may, at least in theory, have the potential to 'rejuvenate' old recipients. Here, we review the relevance of senescent cells and the effects of senolytics on organ quality, alloimmune responses and outcomes in solid organ transplantation. This article is part of the Special Issue - Senolytics - Edited by Joao Passos and Diana Jurk.
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Trasplante de Órganos/métodos , Senoterapéuticos/farmacología , Envejecimiento Prematuro/prevención & control , Senescencia Celular/efectos de los fármacos , Humanos , Supervivencia Tisular/fisiologíaRESUMEN
Allogeneic lung transplantation (LuTx) is considered the treatment of choice for a broad range of advanced, progressive lung diseases resistant to conventional treatment regimens. Ischemia reperfusion injury (IRI) occurring upon reperfusion of the explanted, ischemic lung during implantation remains a crucial mediator of primary graft dysfunction (PGD) and early allo-immune responses. Ex vivo lung perfusion (EVLP) displays an advanced technique aiming at improving lung procurement and preservation. Indeed, previous clinical trials have demonstrated a reduced incidence of PGD following LuTx utilizing EVLP, while long-term outcomes are yet to be evaluated. Mechanistically, EVLP may alleviate donor lung inflammation through reconditioning the injured lung and diminishing IRI through storing the explanted lung in a non-ischemic, perfused, and ventilated status. In this work, we review potential mechanisms of EVLP that may attenuate IRI and improve organ quality. Moreover, we dissect experimental treatment approaches during EVLP that may further attenuate inflammatory events deriving from tissue ischemia, shear forces or allograft rejection associated with LuTx.