Bridge-to-transplant temporary mechanical circulatory support and risk of allosensitization.

INTRODUCTION: Since the 2018 change in the US adult heart allocation policy, more patients are bridged-to-transplant on temporary mechanical circulatory support (tMCS). Previous studies indicate that durable left ventricular assist devices (LVAD) may lead to allosensitization. The goal of this study was to assess whether tMCS implantation is associated with changes in sensitization. METHODS: We included patients evaluated for heart transplants between 2015 and 2022 who had alloantibody measured before and after MCS implantation. Allosensitization was defined as development of new alloantibodies after tMCS implant. RESULTS: A total of 41 patients received tMCS before transplant. Nine (22.0%) patients developed alloantibodies following tMCS implantation: 3 (12.0%) in the intra-aortic balloon pump group (n = 25), 2 (28.6%) in the microaxial percutaneous LVAD group (n = 7), and 4 (44.4%) in the veno-arterial extra-corporeal membrane oxygenation group (n = 9)-p = .039. Sensitized patients were younger (44.7 ± 11.6 years vs. 54.3 ± 12.5 years, p = .044), were more likely to be sensitized at baseline - 3 of 9 (33.3%) compared to 2 out of 32 (6.3%) (p = .028) and received more transfusions with red blood cells (6 (66.6%) vs. 8 (25%), p = .02) and platelets (6 (66.6%) vs. 5 (15.6%), p = .002). There was no significant difference in tMCS median duration of support (4 [3,15] days vs. 8.5 [5,14.5] days, p = .57). Importantly, out of the 11 patients who received a durable LVAD after tMCS, 5 (45.5%) became sensitized, compared to 4 out of 30 patients (13.3%) who only had tMCS-p = .028. CONCLUSIONS: Our findings suggest that patients bridged-to-transplant with tMCS, without significant blood product transfusions and a subsequent durable LVAD implant, have a low risk of allosensitization. Further studies are needed to confirm our findings and determine whether risk of sensitization varies by type of tMCS and duration of support.

Assessing the Accessibility, Engagement, and Value of the Virtual Global Spine Conference as an Educational Platform for Spine: A Three-Year Review.

INTRODUCTION: The Coronavirus disease 2019 pandemic ushered a paradigm shift in medical education, accelerating the transition to virtual learning in select cases. The Virtual Global Spine Conference (VGSC), launched at the height of the pandemic, is a testament to this evolution, providing an independent educational series for spine care professionals worldwide. This study assesses VGSC's 3-year performance, focusing on accessibility, engagement, and educational value. METHODOLOGY: Through retrospective data analysis from April 2020 to August 2023, we examined our social media metrics to measure VGSC's reach and impact. RESULTS: Over the study period, VGSC's webinars successfully attracted 2337 unique participants, maintaining an average attendance of 47 individuals per session. The YouTube channel demonstrated significant growth, amassing over 2693 subscribers and releasing 168 videos. These videos collectively garnered 112,208 views and 15,823.3 hours of watch time. Viewer demographics reveal a predominant age group of 35-44 years, representing 56.81% of the audience, closely followed by the 25-34 age group at 40.2%. Male participants constituted 78.95% of the subscriber base. Geographically, the viewership primarily originates from the United States, with India, Canada, South Korea, and the United Kingdom also contributing substantial audience numbers. The VGSC's presence on the "X account" has grown to 2882 followers, significantly enlarging the digital community and fostering increased engagement. CONCLUSIONS: The VGSC has demonstrated significant value as a virtual educational tool in spine education. Its diverse content and ease of access will likely enable it to drive value well into the post-pandemic years. Maintaining and expanding engagement, beyond North America in particular, remains a priority.

Minimally Invasive Direct Aortic Implantation of Impella 5.5 As Bridge to Transplant: A Case Report.

The use of temporary mechanical circulatory support in cardiogenic shock (CS) is increasing. The Impella (Abiomed) is a percutaneous, microaxial ventricular assist device approved for short-term use in CS that can be implanted peripherally. Direct aortic placement is an alternative commonly performed when the sternum is open, for example, in post-cardiotomy shock or when the peripheral vasculature is of insufficient size or quality for implantation. Herein, we describe direct aortic implantation of the Impella 5.5 via right mini-thoracotomy for a patient in CS secondary to decompensated heart failure as a bridge to candidacy and, ultimately, transplantation.

Heart Transplant and Donors After Circulatory Death: A Clinical-Preclinical Systematic Review.

INTRODUCTION: Heart transplantation is the treatment of choice for end-stage heart failure. There is a mismatch between the number of donor hearts available and the number of patients awaiting transplantation. Expanding the donor pool is critically important. The use of hearts donated following circulatory death is one approach to increasing the number of available donor hearts. MATERIALS AND METHODS: A systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines utilizing Pubmed/MEDLINE and Embase. Articles including adult human studies and preclinical animal studies of heart transplantation following donation after circulatory death were included. Studies of pediatric populations or including organs other than heart were excluded. RESULTS: Clinical experience and preclinical studies are reviewed. Clinical experience with direct procurement, normothermic regional perfusion, and machine perfusion are included. Preclinical studies addressing organ function assessment and enhancement of performance of marginal organs through preischemic, procurement, preservation, and reperfusion maneuvers are included. Articles addressing the ethical considerations of thoracic transplantation following circulatory death are also reviewed. CONCLUSIONS: Heart transplantation utilizing organs procured following circulatory death is a promising method to increase the donor pool and offer life-saving transplantation to patients on the waitlist living with end-stage heart failure. There is robust ongoing preclinical and clinical research to optimize this technique and improve organ yield. There are also ongoing ethical considerations that must be addressed by consensus before wide adoption of this approach.

Feasibility and Acceptability of a Preoperative Multimodal Mobile Health Assessment in Spine Surgery Candidates.

BACKGROUND: Rapid growth in smartphone use has expanded opportunities to use mobile health (mHealth) technology to collect real-time patient-reported and objective biometric data. These data may have important implication for personalized treatments of degenerative spine disease. However, no large-scale study has examined the feasibility and acceptability of these methods in spine surgery patients. OBJECTIVE: To evaluate the feasibility and acceptability of a multimodal preoperative mHealth assessment in patients with degenerative spine disease. METHODS: Adults undergoing elective spine surgery were provided with Fitbit trackers and sent preoperative ecological momentary assessments (EMAs) assessing pain, disability, mood, and catastrophizing 5 times daily for 3 weeks. Objective adherence rates and a subjective acceptability survey were used to evaluate feasibility of these methods. RESULTS: The 77 included participants completed an average of 82 EMAs each, with an average completion rate of 86%. Younger age and chronic pulmonary disease were significantly associated with lower EMA adherence. Seventy-two (93%) participants completed Fitbit monitoring and wore the Fitbits for an average of 247 hours each. On average, participants wore the Fitbits for at least 12 hours per day for 15 days. Only worse mood scores were independently associated with lower Fitbit adherence. Most participants endorsed positive experiences with the study protocol, including 91% who said they would be willing to complete EMAs to improve their preoperative surgical guidance. CONCLUSION: Spine fusion candidates successfully completed a preoperative multimodal mHealth assessment with high acceptability. The intensive longitudinal data collected may provide new insights that improve patient selection and treatment guidance.

Continuous renal replacement therapy and extracorporeal membrane oxygenation: implications in the COVID-19 era.

The novel severe acute respiratory syndrome coronavirus 2, SARS-CoV-2 (coronavirus Disease 19 (COVID-19)) was identified as the causative agent of viral pneumonias in Wuhan, China in December 2019, and has emerged as a pandemic causing acute respiratory distress syndrome (ARDS) and multiple organ dysfunction. Interim guidance by the World Health Organization states that extracorporeal membrane oxygenation (ECMO) should be considered as a rescue therapy in COVID-19-related ARDS. International registries tracking ECMO in COVID-19 patients reveal a 21%-70% incidence of acute renal injury requiring renal replacement therapy (RRT) during ECMO support. The indications for initiating RRT in patients on ECMO are similar to those for patients not requiring ECMO. RRT can be administered during ECMO via a temporary dialysis catheter, placement of a circuit in-line hemofilter, or direct connection of continuous RRT in-line with the ECMO circuit. Here we review methods for RRT during ECMO, RRT initiation and timing during ECMO, anticoagulation strategies, and novel cytokine filtration approaches to minimize COVID-19's pathophysiological impact.

Spinal Tumors: Diagnosis and Treatment.

Tumors that present in or around the spine can be challenging to diagnose and treat. A proper workup involves a complete history and physical examination, appropriate staging studies, appropriate imaging of the entire spine, and a tissue biopsy. The biopsy defines the lesion and guides treatment, but in some rare instances, rapid neurological decline may lead to urgent or emergent surgery before it can be analyzed. "Enneking-appropriate" margins should remain the goal for primary tumors while adequate debulking/separation/stabilization are often the goals in metastatic disease. Primary tumors of the spine are rare and often complex tumors to operate on-achieving Enneking-appropriate margins provides the greatest chance of survival while decreasing the chance of local recurrence. Metastatic tumors of the spine are increasingly more common, and timing of surgery must be considered within the greater framework of the patient and the patient's disease, deficits, stability, and other treatments available. The specific tumor type will dictate what other multidisciplinary approaches are available, allowing for chemotherapy and radiation as needed.

Why X-rays? The importance of radiographs in spine surgery.

Despite the advances made in high-resolution spinal imaging, plain films (radiographs or x-rays) remain a cornerstone of evaluating and caring for spine patients in the preoperative, intraoperative, and postoperative settings. Although often undervalued when compared with more advanced imaging such as MRIs or CT scans, plain films provide surgeons invaluable information that other imaging modalities oftentimes cannot. In addition to their use during surgery for localization or evaluation of hardware placement, x-rays provide an overall image of a patient's spine, are useful in evaluating hardware complications, allow detailed assessment of alignment and stability and allow for repeated images in clinic during follow-up. Plain films continue to provide critical information that cannot be obtained with other imaging modalities, and they remain central to providing optimal care for spine patients.

Low Cancer Incidence in Naked Mole-Rats May Be Related to Their Inability to Express the Warburg Effect.

Metabolic flexibility in mammals enables stressed tissues to generate additional ATP by converting large amounts of glucose into lactic acid; however, this process can cause transient local or systemic acidosis. Certain mammals are adapted to extreme environments and are capable of enhanced metabolic flexibility as a specialized adaptation to challenging habitat niches. For example, naked mole-rats (NMRs) are a fossorial and hypoxia-tolerant mammal whose metabolic responses to environmental stressors markedly differ from most other mammals. When exposed to hypoxia, NMRs exhibit robust hypometabolism but develop minimal acidosis. Furthermore, and despite a very long lifespan relative to other rodents, NMRs have a remarkably low cancer incidence. Most advanced cancers in mammals display increased production of lactic acid from glucose, irrespective of oxygen availability. This hallmark of cancer is known as the Warburg effect (WE). Most malignancies acquire this metabolic phenotype during their somatic evolution, as the WE benefits tumor growth in several ways. We propose that the peculiar metabolism of the NMR makes development of the WE inherently difficult, which might contribute to the extraordinarily low cancer rate in NMRs. Such an adaptation of NMRs to their subterranean environment may have been facilitated by modified biochemical responses with a stronger inhibition of the production of CO2 and lactic acid by a decreased extracellular pH. Since this pH-inhibition could be deeply hard-wired in their metabolic make-up, it may be difficult for malignant cells in NMRs to acquire the WE-phenotype that facilitates cancer growth in other mammals. In the present commentary, we discuss this idea and propose experimental tests of our hypothesis.

Attitudes and trends in the use of radiolucent spinal implants: A survey of the North American Spine Society section of spinal oncology.

Background: In spinal oncology, titanium implants pose several challenges including artifact on advanced imaging and therapeutic radiation perturbation. To mitigate these effects, there has been increased interest in radiolucent carbon fiber (CF) and CF-reinforced polyetheretherketone (CFR-PEEK) implants as an alternative for spinal reconstruction. This study surveyed the members of the North American Spine Society (NASS) section of Spinal Oncology to query their perspectives regarding the clinical utility, current practice patterns, and recommended future directions of radiolucent spinal implants. Methods: In February 2021, an anonymous survey was administered to the physicians of the NASS section of Spinal Oncology. Participation in the survey was optional. The survey contained 38 items including demographic questions as well as multiple-choice, yes/no questions, Likert rating scales, and short free-text responses pertaining to the "clinical concept", "efficacy", "problems/complications", "practice pattern", and "future directions" of radiolucent spinal implants. Results: Fifteen responses were received (71.4% response rate). Six of the participants (40%) were neurosurgeons, eight (53.3%) were orthopedic surgeons, and one was a spinal radiation oncologist. Overall, there were mixed opinions among the specialists. While several believed that radiolucent spinal implants provide substantial benefits for the detection of disease recurrence and radiation therapy options, others remained less convinced. Ongoing concerns included high costs, low availability, limited cervical and percutaneous options, and suboptimal screw and rod designs. As such, participants estimated that they currently utilize these implants for 27.3% of anterior and 14.7% of all posterior reconstructions after tumor resection. Conclusion: A survey of the NASS section of Spinal Oncology found a lack of consensus with regards to the imaging and radiation benefits, and several ongoing concerns about currently available options. Therefore, routine utilization of these implants for anterior and posterior spinal reconstructions remains low. Future investigations are warranted to practically validate these devices' theoretical risks and benefits.

Minimally Invasive versus Full Sternotomy SAVR in the Era of TAVR: An Institutional Review.

In the era of advancing transcatheter aortic valve replacement (TAVR) technology, traditional open surgery remains a valuable intervention for patients who are not TAVR candidates. We sought to compare perioperative variables and postoperative outcomes of minimally invasive and full sternotomy surgical aortic valve replacement (SAVR) at a single institution. A retrospective analysis of 113 patients who underwent isolated SAVR via full sternotomy or upper hemi-sternotomy between January 2015 and December 2019 at the University of Utah Hospital was performed. Preoperative comorbidities and demographic information were not different among groups, with the exception of diabetes, which was significantly more common in the full sternotomy group (p = 0.01). Median procedure length was numerically shorter in the minimally invasive group but was not significant following the Bonferroni correction (p = 0.047). Other perioperative variables were not significantly different. The two groups showed no difference in the incidence of postoperative adverse events (p = 0.879). As such, minimally invasive SAVR via hemi-sternotomy remains a safe and effective alternative to full sternotomy for patients who meet the criteria for aortic valve replacement.

Mitochondrial lactate metabolism: history and implications for exercise and disease.

Mitochondrial structures were probably observed microscopically in the 1840s, but the idea of oxidative phosphorylation (OXPHOS) within mitochondria did not appear until the 1930s. The foundation for research into energetics arose from Meyerhof's experiments on oxidation of lactate in isolated muscles recovering from electrical contractions in an O2 atmosphere. Today, we know that mitochondria are actually reticula and that the energy released from electron pairs being passed along the electron transport chain from NADH to O2 generates a membrane potential and pH gradient of protons that can enter the molecular machine of ATP synthase to resynthesize ATP. Lactate stands at the crossroads of glycolytic and oxidative energy metabolism. Based on reported research and our own modelling in silico, we contend that lactate is not directly oxidized in the mitochondrial matrix. Instead, the interim glycolytic products (pyruvate and NADH) are held in cytosolic equilibrium with the products of the lactate dehydrogenase (LDH) reaction and the intermediates of the malate-aspartate and glycerol 3-phosphate shuttles. This equilibrium supplies the glycolytic products to the mitochondrial matrix for OXPHOS. LDH in the mitochondrial matrix is not compatible with the cytoplasmic/matrix redox gradient; its presence would drain matrix reducing power and substantially dissipate the proton motive force. OXPHOS requires O2 as the final electron acceptor, but O2 supply is sufficient in most situations, including exercise and often acute illness. Recent studies suggest that atmospheric normoxia may constitute a cellular hyperoxia in mitochondrial disease. As research proceeds appropriate oxygenation levels should be carefully considered.

Antibody binding to native cytomegalovirus glycoprotein B predicts efficacy of the gB/MF59 vaccine in humans.

Human cytomegalovirus (CMV) is the most common infectious cause of infant brain damage and posttransplant complications worldwide. Despite the high global burden of disease, vaccine development to prevent infection remains hampered by challenges in generating protective immunity. The most efficacious CMV vaccine candidate tested to date is a soluble glycoprotein B (gB) subunit vaccine with MF59 adjuvant (gB/MF59), which achieved 50% protection in multiple historical phase 2 clinical trials. The vaccine-elicited immune responses that conferred this protection have remained unclear. We investigated the humoral immune correlates of protection from CMV acquisition in populations of CMV-seronegative adolescent and postpartum women who received the gB/MF59 vaccine. We found that gB/MF59 immunization elicited distinct CMV-specific immunoglobulin G (IgG)-binding profiles and IgG-mediated functional responses in adolescent and postpartum vaccinees, with heterologous CMV strain neutralization observed primarily in adolescent vaccinees. Using penalized multiple logistic regression analysis, we determined that protection against primary CMV infection in both cohorts was associated with serum IgG binding to gB present on a cell surface but not binding to the soluble vaccine antigen, suggesting that IgG binding to cell-associated gB is an immune correlate of vaccine efficacy. Supporting this, we identified gB-specific monoclonal antibodies that differentially recognized soluble or cell-associated gB, revealing that there are structural differences in cell-associated and soluble gB are relevant to the generation of protective immunity. Our results highlight the importance of the native, cell-associated gB conformation in future CMV vaccine design.

Lactate-Protected Hypoglycemia (LPH).

Here, we provide an overview of the concept of a lactate-protected hypoglycemia ("LPH"), originally proposed as lowering glucose while simultaneously increasing lactate concentration as a method by which tumors might be targeted. Central to this hypothesis is that lactate can act as a critical salvage fuel for the central nervous system, allowing for wide perturbations in whole body and central nervous system glucose concentrations. Further, many tumors exhibit "the Warburg" effect, consuming glucose and producing and exporting lactate despite adequate oxygenation. While some recent data have provided evidence for a "reverse-Warburg," where some tumors may preferentially consume lactate, many of these experimental methods rely on a significant elevation in lactate in the tumor microenvironment. To date it remains unclear how various tumors behave in vivo, and how they might respond to perturbations in lactate and glucose concentrations or transport inhibition. By exploiting and targeting lactate transport and metabolism in tumors (with a combination of changes in lactate and glucose concentrations, transport inhibitors, etc.), we can begin developing novel methods for targeting otherwise difficult to treat pathologies in the brain and spinal cord. Here we discuss evidence both experimental and observational, and provide direction for next steps in developing therapies based on these concepts.

Specificity and effector functions of non-neutralizing gB-specific monoclonal antibodies isolated from healthy individuals with human cytomegalovirus infection.

Human cytomegalovirus (HCMV) is the most common congenital infection. A glycoprotein B (gB) subunit vaccine (gB/MF59) is the most efficacious clinically tested to date, having achieved 50% protection against primary infection of HCMV-seronegative women. We previously identified that gB/MF59 vaccination primarily elicits non-neutralizing antibody responses, with variable binding to gB genotypes, and protection associated with binding to membrane-associated gB. We hypothesized that gB-specific non-neutralizing antibody binding breadth and function are dependent on epitope and genotype specificity, and ability to interact with membrane-associated gB. We mapped twenty-four gB-specific monoclonal antibodies (mAbs) from naturally HCMV-infected individuals for gB domain specificity, genotype preference, and ability to mediate phagocytosis or NK cell activation. gB-specific mAbs were primarily specific for Domain II and demonstrated variable binding to gB genotypes. Two mAbs facilitated phagocytosis with binding specificities of Domain II and AD2. This investigation provides novel understanding on the relationship between gB domain specificity and antigenic variability on gB-specific antibody effector functions.