Search

Background: A trusting partnership between patient and surgeon lies at the core of a successful therapeutic relationship. However, there are conditions that can jeopardize this partnership and create an ethical dilemma for the surgeon, who is guided by a moral obligation to care for the patient without causing unnecessary harm. We present a discussion of several pathways to achieve ethical resolution to therapeutic relationships that have grown untenable with a focus on patients with comorbid psychiatric illness. The principal objective of these pathways is to prevent further delivery of futile interventions while avoiding patient abandonment., Methods: A review of the literature was performed, and principles of clinical ethics were applied to provide guidelines for care in situations of untenable patient-surgeon relationships., Results: There are no published ethical guidelines for resolving a therapeutic impasse in surgical patients suffering with psychiatric illness. We applied ethical principles of treatment futility, nonmaleficence, beneficence, and patient abandonment to develop a framework for navigating difficult post-operative patient relationships., Conclusions: Managing post-operative surgical patients with comorbid psychiatric conditions presents a unique challenge. In severe cases, therapeutic discharge may be ethically permissible and necessary to disrupt a maladaptive treatment cycle to prevent future patient harm. Specific precautions must be taken to avoid patient abandonment., Competing Interests: Financial disclosure statement: This research did not receive financial support. The authors do not have any conflicts of interest to disclose., (Copyright © 2024 by the American Society of Plastic Surgeons.)

AbstractCochlear implants can restore hearing in people with severe hearing loss and have a significant impact on communication, social integration, self-esteem, and quality of life. However, whether and how much clinical benefit is derived from cochlear implants varies significantly by patient and is influenced by the etiology and extent of hearing loss, medical comorbidities, and preexisting behavioral and psychosocial issues. In patients with underlying psychosis, concerns have been raised that the introduction of auditory stimuli could trigger hallucinations, worsen existing delusions, or exacerbate erratic behavior. This concern has made psychosis a relative contraindication to cochlear implant surgery. This is problematic because there is a lack of data describing this phenomenon and because the psychosocial benefits derived from improvement in auditory function may be a critical intervention for treating psychosis in some patients. The objective of this report is to provide an ethical framework for guiding clinical decision-making on cochlear implant surgery in the hearing impaired with psychosis.

Background: Autologous fat grafting (AFG) has emerged as a promising treatment option for Raynaud phenomenon. However, existing studies are limited by short follow-up, and there is little evidence regarding predictive factors for successful outcomes., Methods: A retrospective chart review and standardized phone interviews were performed for all patients (n = 17, 65% response rate) treated with AFG to the hands or feet at our institution for primary or secondary Raynaud from 2010 to 2021. Each occurrence of AFG was defined as a separate surgery (n = 23), with an average follow-up of 3.7 years., Results: At follow-up, patients reported a 31% reduction in cold attack frequency, a 45% reduction in the intensity of individual attacks, a 29% reduction in the duration of attacks, and a 40% improvement in overall Raynaud Condition Score (P < 0.01). Although initial AFG to an extremity significantly improved symptoms, subsequent attempts were not shown to statistically improve outcomes. Digital ulcers were present in 65% of cases, and AFG resulted in ulcer healing in 87% of those cases. Median duration of maximum symptom relief was 1 year postoperatively, with 74% of patients reporting diminishing symptom relief by 4 years postoperatively. Those with a BMI ≥25, with primary Raynaud phenomenon or without preoperative ulcers experienced significantly longer symptom relief (P < 0.05). Average patient satisfaction was 7.7 of 10, and 91% would recommend the procedure to others., Conclusions: Autologous fat grafting is an effective, albeit sometimes temporary, treatment for Raynaud and digital ulcers. Certain patients may be more likely to experience lasting symptom relief beyond 1 year., Competing Interests: Financial disclosure statement: The authors have no financial conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The integration of artificial intelligence technologies, such as large language models (LLMs), in health care holds potential for improved efficiency and decision support. However, ethical concerns must be addressed before widespread adoption. This article focuses on the ethical principles surrounding the use of Generative Pretrained Transformer-4 and its conversational model, ChatGPT, in healthcare settings. One concern is potential inaccuracies in generated content. LLMs can produce believable yet incorrect information, risking errors in medical records. Opacity of training data exacerbates this, hindering accuracy assessment. To mitigate, LLMs should train on precise, validated medical data sets. Model bias is another critical concern because LLMs may perpetuate biases from their training, leading to medically inaccurate and discriminatory responses. Sampling, programming, and compliance biases contribute necessitating careful consideration to avoid perpetuating harmful stereotypes. Privacy is paramount in health care, using public LLMs raises risks. Strict data-sharing agreements and Health Insurance Portability and Accountability Act (HIPAA)-compliant training protocols are necessary to protect patient privacy. Although artificial intelligence technologies offer promising opportunities in health care, careful consideration of ethical principles is crucial. Addressing concerns of inaccuracy, bias, and privacy will ensure responsible and patient-centered implementation, benefiting both healthcare professionals and patients., (Copyright © 2023 by the American Academy of Orthopaedic Surgeons.)

Objective: Thoracic outlet syndrome (TOS) is a rare disorder mostly seen in younger individuals. Although patient wellbeing is relevantly impaired, it often takes a long time before the diagnosis is made. Digital subtraction angiography (DSA) is routinely used despite its radiation exposure, which is a major concern in this young patient population. Moreover, DSA offers limited opportunities for functional assessment. By contrast, ultrasonography is widely accessible without causing radiation exposure and allows for flexible functional assessment. The main goal of the study was to investigate whether ultrasound (US) was a viable alternative to DSA in diagnosing arterial TOS (aTOS)., Methods: Patients, referred to a tertiary centre for evaluation of suspected TOS, were recruited into the study. DSA was routinely performed with the patient's arms both in the raised (abducted) and neutral (adducted) position. Two vascular surgeons and two radiologists assessed the resulting images for the presence of aTOS. Additionally, two examiners performed US according to a standardised protocol. The reference for presence of aTOS was the DSA based interdisciplinary vascular conference consensus. Inter-rater agreement and latent class analysis (LCA) were performed between assessors and diagnostic methods., Results: Fifty one consecutive patients (two thirds female) aged 39.3 ± 13.0 years were included within 11 months. US agreement was excellent at 0.94 (0.841-0.980), DSA agreement for vascular surgeons was good at 0.779 (0.479-1.000), whereas it was moderate at 0.546 (0.046-1.000) for radiologists. Results suggest that DSA is untenable as the gold standard for aTOS diagnosis. In LCA, US was shown to be a reliable diagnostic tool for the detection of aTOS., Conclusion: US examination is a valid test for the detection of haemodynamically relevant compression of arteries in the diagnostic work up of aTOS using a standardised protocol. The role of DSA as the gold standard should be reviewed and needs to be reconsidered., Competing Interests: None., (© 2024 The Author(s).)

Research is an integral part of medical progress that leads to better understanding of disease processes and the development of therapies to improve patient care. The medical community has an obligation and societal responsibility to review its practices and advance its knowledge to optimize care for those who entrust it with their health and well-being. While ultimately intended to benefit patients specifically and society as a whole, every laboratory and clinical investigation inherently carries an element of uncertainty and has attendant risks. These can have unintended and, at times, harmful consequences that cannot justify the knowledge gained. In order to mitigate these risks and protect human subjects involved in clinical research studies, a basic framework of ethical principles has been developed to guide responsible experimental design, execution, and data dissemination. This article provides a review of these principles and the historical context from which they were derived and explores the persistent challenges and cognitive biases that can increase susceptibility to unethical research practices., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Summary: The use of high-fidelity stereolithographic models that accurately reflect patient-specific pathology has become commonplace in craniofacial surgery. Multiple studies have reported the use of commercially available three-dimensional (3D) printers that allow medical centers with limited resources to reconstruct 3D models comparable to industry-made counterparts. However, most models are printed using only a single filament, which portrays the surface craniofacial anatomy, but fails to highlight relevant intraosseous structures. This presents a significant limitation when used for preoperative planning and intraoperative guidance in surgical procedures requiring osteotomies, where knowledge of the precise location of critical structures is paramount to avoid injury. The authors report a novel technique for creating transparent 3D models of relevant intraosseous craniofacial anatomy at a cost that mitigates the financial burden of industrial 3D model or industrial 3D printer acquisition. Cases are presented to demonstrate the diverse applications of this technique, with accurate display of the tooth roots, the inferior alveolar nerve, and the optic nerve, to aid in preoperative planning of osteotomies. This technique enables production of low-cost, high-fidelity transparent 3D models with applications in preoperative planning for craniofacial surgery., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Siglec-7 regulates immune cell activity and is a promising target for immunomodulation. Here, we report the discovery of novel sialic acid derivatives binding to Siglec-7. Synthesis and affinity measurements are complemented by high-quality models of sialoside-Siglec-7 complexes based on molecular dynamics (MD) simulations on the microsecond time scale. We provide details for the predicted binding modes for the new ligands, e.g., that an extension of the carbon backbone leads to a different molecular interaction pattern with the receptor and the nearby water structure than found for known Siglec-7 ligands. Further on, we uncover some shortcomings of the GLYCAM06 and GAFF2 force fields when used for the simulation of sialoside-based glycomimetics. Our results open new opportunities for the rational design of Siglec-7 inhibitors. In addition, we provide strategies on how to use and visualize MD simulations to describe and investigate sialoside-Siglec complexes in general.

Adipose tissue is composed of a collection of cells with valuable structural and regenerative function. Taken as an autologous graft, these cells can be used to address soft tissue defects and irregularities, while also providing a reparative effect on the surrounding tissues. Adipose-derived stem or stromal cells are primarily responsible for this regenerative effect through direct differentiation into native cells and via secretion of numerous growth factors and cytokines that stimulate angiogenesis and disrupt pro-inflammatory pathways. Separating adipose tissue into its component parts, i.e., cells, scaffolds and proteins, has provided new regenerative therapies for skin and soft tissue pathology, including that resulting from radiation. Recent studies in both animal models and clinical trials have demonstrated the ability of autologous fat grafting to reverse radiation induced skin fibrosis. An improved understanding of the complex pathologic mechanism of RIF has allowed researchers to harness the specific function of the ASCs to engineer enriched fat graft constructs to improve the therapeutic effect of AFG.

Significant interest in the development of high-affinity ligands for Siglecs exists due to the various therapeutically relevant functions of these proteins. Here, we report a new strategy to develop and design Siglec ligands as disialyl-oligosaccharide mimetics exemplified on Siglec-2 (CD22). We report insights into development of dimeric ligands with high affinity and avidity to cell surface-expressed CD22, assay development, tool compounds, structure activity relationships, and biological data on calcium flux regulation in B-cells. The binding modes of selected ligands have been modeled based on state-of-the-art molecular dynamics simulations on the microsecond timescale, providing detailed views on ligand binding and opening a new perspective on drug design efforts for Siglecs. High-avidity dimeric ligands containing a linker opening the way towards bispecifics are presented as well.

Introduction: The objectives of this study are to analyze the impact of cleft palate (CP) on upper airway obstruction using polysomnography in patients with Pierre Robin Sequence (PRS) undergoing mandibular distraction osteogenesis (MDO) and subsequent CP repair., Methods: A single-surgeon, retrospective chart review was performed of all patients with nonsyndromic PRS treated with MDO. Severity of upper airway obstruction was evaluated pre- and post-distraction via polysomnography. Details of MDO and CP repair were collected and any complications recorded., Results: Twenty-one nonsyndromic PRS patients with CP and 6 patients without CP met inclusion criteria. There was no significant difference in predistraction apnea-hypopnea index between the 2 groups (53.4 ± 42.1 versus 34.4 ± 18.9; P = 0.3). Patients with CP had significantly higher predistraction SpO2 saturation (94.5 ± 1.6% versus 91.0% ± 4.8%; P = 0.01), SpO2 nadir (74.5% ± 9.1% versus 63.6% ± 11.6%; P = 0.03) and lower percentage time spent below 90% SpO2 (6.0% ± 7.2% versus 23.6% ± 29.9%; P = 0.04). The rate of oronasal fistulas formation was 38%. The time between MDO and CP repair was shorter for patients with complications (250.8 ± 3.3 versus 370.8 ± 191.9 days; P = 0.08). Five patients experienced relapse of respiratory difficulties after CP repair., Conclusions: The presence of CP in nonsyndromic PRS patients decreases the severity of obstructive sleep apnea by oxygen parameters on PSG. Palatal fistulas and relapse of respiratory distress are common complications of CP repair following MDO. Delaying CP repair may help to decrease complication rates., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by Mutaz B. Habal, MD.)

Background: Gentle and precise tissue dissection reduces collateral tissue damage and preserves its structural quality for optimizing healing. This is particularly true for peripheral nerve neurorrhaphy. Axon regeneration kinetics across the repair is dependent on the amount of intraneural fibrosis. The purpose of this study was to determine whether scalpel blade smoothness was a deterministic factor in the kinetics of postneurorrhaphy peripheral axon regeneration., Methods: Scalpel transection of the saphenous nerve was performed in 18 female Hartley guinea pigs either by a standard #15 stainless steel scalpel blade or a highly polished version of the same blade. Compound nerve action potential recordings and histochemical assay of neurofilament density proximal and 1 cm distal to the site of nerve transection were quantified postneurorrhaphy at postoperative weeks 5, 9, and 12., Results: There was no action potential transmission observed in the distal axons immediately after neurorrhaphy. A substantial acceleration of axonal conduction recovery was observed in nerves transected with polished scalpel blades observed by high compound nerve action potential amplitudes at postneurorrhaphy weeks 5 and 9 (P < .05). In addition, an increased recovery of intra-axonal neurofilament density in nerves transected with polished scalpel blades was observed by postoperative week 5 (P < .05)., Conclusion: The quality of the scalpel blade is an important determinate of postsurgical healing. Gentle handling of tissue matters., (© 2020 The Authors.)

Background: The COVID-19 crisis has brought many unique challenges to the health care system. Across the United States, social distancing measures have been put in place, including stay-at-home (SAH) orders, to combat the spread of this infection. This has impacted the type and volume of traumatic injuries sustained during this time. Meanwhile, steps have been taken in our health care system to assure that adequate resources are available to maintain a high standard of patient care while recognizing the importance of protecting health care providers. Using comparative data, we aim to describe the trends in traumatic injuries managed by our plastic surgery service and detail the changes in consultation policies made to minimize provider exposure., Methods: A retrospective chart review was performed of all plastic surgery emergencies at our institution during the 3 weeks preceding the issuance of SAH orders in Chicago and the 3 weeks after. The electronic medical record was queried for patient age, type and mechanism of injury, location where injury was sustained, presence of domestic violence, length of inpatient hospital stays, and treatment rendered. The two 3-week periods were then comparatively analyzed to determine differences and trends in these variables and treatment rendered. The 2 periods were then comparatively analyzed to determine differences and trends in these variables., Results: There was a significant decrease in trauma consults since the issuance of SAH (88 pre-SAH vs 62 post-SAH) with a marked decrease in trauma-related hand injuries. There was an increase in the percentage of assault-related injuries including those associated with domestic violence, whereas there was an overall decrease in motor vehicle collisions. There was no notable change in the location where injuries were sustained. Significantly fewer patients were seen by house staff in the emergency room, whereas those requiring surgical intervention were able to receive care without delay., Conclusions: Stay-at-home orders in Chicago have impacted traumatic injury patterns seen by the Section of Plastic and Reconstructive Surgery at a level I Trauma Center. Safe and timely care can continue to be provided with thorough communication, vigilance, and guidance from our colleagues.

CD22 is a member of the Siglec family. Considerable attention has been drawn to the design and synthesis of new Siglec ligands to explore target biology and innovative therapies. In particular, CD22-ligand-targeted nanoparticles with therapeutic functions have proved successful in preclinical settings for blood cancers, autoimmune diseases, and tolerance induction. Here we report the design, synthesis and affinity evaluation of a new class of Siglec ligands: namely sialic acid derivatives with a triazole moiety replacing the natural glycoside oxygen atom. In addition, we describe important and surprising differences in binding to CD22 expressed at the cell surface for compounds with distinct valences. The new class of compounds might serve as a template for the design of ligands for other members of the Siglec family and next-generation CD22-ligand-based targeted therapies., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Natural killer cells are able to directly lyse tumor cells, thereby participating in the immune surveillance against cancer. Unfortunately, many cancer cells use immune evasion strategies to avoid their eradication by the immune system. A prominent escape strategy of malignant cells is to camouflage themselves with Siglec-7 ligands, thereby recruiting the inhibitory receptor Siglec-7 expressed on the NK cell surface which subsequently inhibits NK-cell-mediated lysis. Here we describe the synthesis and evaluation of the first, high-affinity low molecular weight Siglec-7 ligands to interfere with cancer cell immune evasion. The compounds are Sialic acid derivatives and bind with low micromolar K d values to Siglec-7. They display up to a 5000-fold enhanced affinity over the unmodified sialic acid scaffold αMe Neu5Ac, the smallest known natural Siglec-7 ligand. Our results provide a novel immuno-oncology strategy employing natural immunity in the fight against cancers, in particular blocking Siglec-7 with low molecular weight compounds.

A fragment library consisting of 3D-shaped, natural product-like fragments was assembled. Library construction was mainly performed by natural product degradation and natural product diversification reactions and was complemented by the identification of 3D-shaped, natural product like fragments available from commercial sources. In addition, during the course of these studies, novel rearrangements were discovered for Massarigenin C and Cytochalasin E. The obtained fragment library has an excellent 3D-shape and natural product likeness, covering a novel, unexplored and underrepresented chemical space in fragment based drug discovery (FBDD)., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Limited clinical site availability and an increased need for clinical training experiences often make it difficult for prehospital health care providers to complete new and annual training requirements. Medical simulation provides an alternative learning environment that provides trainees the opportunity to acquire and perfect new clinical skills without compromising patient care. The following is a detailed description of an air medical transport simulation of a neonate with hypoxic ischemic encephalopathy requiring transport to a higher level of care. Patient parameters were altered during flight to simulate potential complications unique to air medical transport. Use of this training strategy is particularly beneficial for low-volume, high-risk patients, and these lessons can be applied across all age patient groups, making the experience broadly applicable., (Copyright © 2016 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.)

Siglecs (sialic acid recognizing immunoglobulin like lectins) are a family of lectins with specificity for sialic acid containing carbohydrates. Synthetic sialic acid derivatives with high affinity proved useful to unravel the biological role of the ligand binding domain, although many of their functions in immunity remain unknown. Here we present design, synthesis, affinity evaluation and molecular modeling of novel 9-N-oxamoyl modified sialosides as Siglec-7 ligands., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: An emergent open thoracotomy (OT) is a high-risk, low-frequency procedure uniquely suited for simulation training. We developed a cost-effective Cardiothoracic (CT) Surgery trainer and assessed its potential for improving technical and interprofessional skills during an emergent simulated OT., Materials and Methods: We modified a commercially available mannequin torso with artificial tissue models to create a custom CT Surgery trainer. The trainer's feasibility for simulating emergent OT was tested using a multidisciplinary CT team in three consecutive in situ simulations. Five discretely observable milestones were identified as requisite steps in carrying out an emergent OT; namely (1) diagnosis and declaration of a code situation, (2) arrival of the code cart, (3) arrival of the thoracotomy tray, (4) initiation of the thoracotomy incision, and (5) defibrillation of a simulated heart. The time required for a team to achieve each discrete step was measured by an independent observer over the course of each OT simulation trial and compared., Results: Over the course of the three OT simulation trials conducted in the coronary care unit, there was an average reduction of 29.5% (P < 0.05) in the times required to achieve the five critical milestones. The time required to complete the whole OT procedure improved by 7 min and 31 s from the initial to the final trial-an overall improvement of 40%., Conclusions: In our preliminary evaluation, the CT Surgery trainer appears to be useful for improving team performance during a simulated emergent bedside OT in the coronary care unit., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Telepresence is emerging in clinical and educational settings as a potential modality to provide expert guidance during remote airway management. This study aimed to compare the effectiveness of telepresent versus in-person supervision of tracheal intubation., Materials and Methods: A randomized, crossover study was performed in a university medical simulation center with 48 first- and second-year medical students with no formal procedural training in tracheal intubation. Each participant was assigned to receive each of four study arms in random sequence: (1) direct laryngoscopy (DL) with in-person supervision, (2) DL with telepresent supervision, (3) videolaryngoscopy (VL) with in-person supervision, and (4) VL with telepresent supervision. Telepresence was established with a smartphone (Apple [Cupertino, CA] iPhone(®)) via FaceTime(®) connection. The primary outcome measure was the time to successful intubation. Secondary outcome measures included first pass success rate and the number of blade and tube attempts., Results: There was no significant difference between in-person and telepresent supervision for any of the outcomes. The median difference (in-person versus telepresent) for time to intubation was -3 s (95% confidence interval [CI], -20 to 14 s). The odds ratio for first attempt success was 0.7 (95% CI, 0.3-1.3), and the rate ratio for extra number of blade attempts (i.e., attempts in addition to first) was 1.1 (95% CI, 0.7-1.7) and 1.4 (95% CI, 0.9-2.2) for extra number of tube attempts., Conclusions: In this study population of procedurally naive medical students, telepresent supervision was as effective as in-person supervision for tracheal intubation.

Introduction: The objective of this study was to determine whether or not a navigation grid (NG) with a coordinate system overlaid on a laparoscopic display might allow attending surgeons to more easily and precisely direct their assistants' instruments to specific sites in a simulated laparoscopic field., Materials and Methods: In this randomized, crossover study, we evaluated the impact of the NG on an individual's performance in a target identification task. One hundred thirty pins served as targets in a standard laparoscopic box trainer. An instructor guided 30 naive subjects to locate five randomly selected targets each, either with verbal instructions alone or with verbal instructions supplemented by a localizing NG. The NG appeared on both the instructor's and the participants' monitors, but the randomly selected targets were visible only to the instructor. Each participant performed 10 trials alternating between with and without the NG. The outcome measure was the interval (in seconds) from when the laparoscopic instrument was first visible in the field to when the subject grasped the correct target with forceps., Results: The mean time to identify each selected target was significantly shorter with the NG (9.150±3.43 seconds) than without (12.53±4.89 seconds) (P<.0001). This effect was sustained throughout the learning curve., Conclusions: The use of the NG appears to improve efficiency in guiding an instrument to randomly identified targets within a laparoscopic field. The use of an NG may reduce the time required to move instruments to specific sites during surgery.

Sialic acids are abundant in higher domains of life and lectins recognizing sialosaccharides are heavily involved in the regulation of the human immune system. Modified sialosides are useful tools to explore the functions of those lectins, especially members of the Siglec (sialic acid binding immunoglobulin like lectin) family. Here we report design, synthesis, and affinity evaluation of novel sialoside classes with combined modification at positions 2, 4, and 9 or 2, 3, 4, and 9 of the sialic acid scaffold as human CD22 (human Siglec-2) ligands. They display up to 7.5 × 10(5)-fold increased affinity over αMe Neu5Ac (the minimal Siglec ligand). CD22 is a negative regulating coreceptor of the B-cell receptor (BCR). In vitro experiments with a human B-lymphocyte cell line showed functional blocking of CD22 upon B-cell receptor (BCR) stimulation in the presence of nanomolar concentrations of the novel ligands. The observed increased Ca(2+) response corresponds to enhanced cell activation, providing an opportunity to therapeutically modulate B-lymphocyte responses, e.g., in immune deficiencies and infections.

Initiation of extracorporeal membrane oxygenation (ECMO) is stressful, especially for inexperienced extracorporeal life support providers. The main objective of this study was to create a novel, reusable mannequin for high-fidelity simulation of ECMO initiation. We modified a Laerdal neonatal mannequin (SimNewB; Stavanger, Norway) so that it could be used to simulate an ECMO initiation. A simulation of a neonatal patient suffering from meconium aspiration was performed in the pediatric intensive care unit, and participants included new extracorporeal life support specialists in addition to the composition of the clinical ECMO team. A total of 17 individuals participated in the neonatal ECMO initiation simulation. Questionnaire results showed that 88% of participants felt better prepared to assist in an ECMO initiation after the simulation. All participants (100%) agreed that the modified mannequin and the environment were realistic and that this simulation helps teamwork and communication in future initiations of ECMO. Simulation can be used for the prevention, identification, and reduction of anxiety-related crisis situations that novice providers may infrequently encounter during routine clinical use of mechanical circulatory support. Use of a reusable, high-fidelity mannequin may be beneficial for effective team training of complex pediatric ECMO-related procedures.

CD22 is an inhibitory co-receptor of the B-cell receptor (BCR) on B cells. Since CD22 is ubiquitously expressed in the B-cell lineage and CD22 endocytosis can be triggered efficiently, antibodies and antibody-based immunotoxins against CD22 are used to target B cells both in B-cell lymphomas and leukemias, as well as in autoimmune diseases. CD22 recognizes α2,6-linked sialic acids as endogenous ligands. We have developed new synthetic sialosides as ligands for human CD22. These sialosides bind CD22 on human B cells with high affinity and can efficiently enhance IgM-triggered Ca(2+) signaling. We coupled these sialosides to Pseudomonas exotoxin A to generate a novel CD22 ligand-based immunotoxin. This sialoside-exotoxin-A construct can specifically kill CD22-positive B-cell lymphoma cells. It binds specifically to CD22-positive B-cell lymphoma cells and is dominant over endogenous cis-ligands on the B-cell surface. The sialoside-exotoxin-A construct is efficiently internalized by endocytosis into B-cell lymphoma cell lines. Thus we show the development of a new therapeutic compound for targeting CD22 on human B cells, both for B-cell lymphoma, as well as for B-cell-mediated autoimmune diseases., (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Secondary active transporters from the SLC17 protein family are required for excitatory and purinergic synaptic transmission, sialic acid metabolism, and renal function, and several members are associated with inherited neurological or metabolic diseases. However, molecular tools to investigate their function or correct their genetic defects are limited or absent. Using structure-activity, homology modeling, molecular docking, and mutagenesis studies, we have located the substrate-binding site of sialin (SLC17A5), a lysosomal sialic acid exporter also recently implicated in exocytotic release of aspartate. Human sialin is defective in two inherited sialic acid storage diseases and is responsible for metabolic incorporation of the dietary nonhuman sialic acid N-glycolylneuraminic acid. We built cytosol-open and lumen-open three-dimensional models of sialin based on weak, but significant, sequence similarity with the glycerol-3-phosphate and fucose permeases from Escherichia coli, respectively. Molecular docking of 31 synthetic sialic acid analogues to both models was consistent with inhibition studies. Narrowing the sialic acid-binding site in the cytosol-open state by two phenylalanine to tyrosine mutations abrogated recognition of the most active analogue without impairing neuraminic acid transport. Moreover, a pilot virtual high-throughput screening of the cytosol-open model could identify a pseudopeptide competitive inhibitor showing >100-fold higher affinity than the natural substrate. This validated model of human sialin and sialin-guided models of other SLC17 transporters should pave the way for the identification of inhibitors, glycoengineering tools, pharmacological chaperones, and fluorescent false neurotransmitters targeted to these proteins.