Machine Learning from Veno-Venous Extracorporeal Membrane Oxygenation Identifies Factors Associated with Neurological Outcomes.

BACKGROUND: Neurological complications are common in patients receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO) support. We used machine learning (ML) algorithms to identify predictors for neurological outcomes for these patients. METHODS: All demographic, clinical, and circuit-related variables were extracted for adults with VV-ECMO support at a tertiary care center from 2016 to 2022. The primary outcome was good neurological outcome (GNO) at discharge defined as a modified Rankin Scale of 0-3. RESULTS: Of 99 total VV-ECMO patients (median age = 48 years; 65% male), 37% had a GNO. The best performing ML model achieved an area under the receiver operating characteristic curve of 0.87. Feature importance analysis identified down-trending gas/sweep/blender flow, FiO2, and pump speed as the most salient features for predicting GNO. CONCLUSION: Utilizing pre- as well as post-initiation variables, ML identified on-ECMO physiologic and pulmonary conditions that best predicted neurological outcomes.

Kidney Donation After Circulatory Death Using Thoracoabdominal Normothermic Regional Perfusion: The Largest Report of the United States Experience.

BACKGROUND: Thoracoabdominal normothermic regional perfusion (TA-NRP) has been increasingly used for donation after circulatory death (DCD) procurements in the United States. We present the largest report of outcomes of kidney transplants performed using DCD donor grafts perfused with TA-NRP. METHODS: Adult DCD kidney transplants between 2020 and 2022 in the United Network for Organ Sharing database were included. Donors with ≥50 min between asystole and aortic cross-clamp time in which the heart was also transplanted were considered TA-NRP donors. All other donors were considered direct recovery donors. Multivariable regressions were used to assess delayed graft function, as well as posttransplant survival and all-cause graft failure at 30, 90, and 180 d. A propensity-matched analysis of cohorts matched on donor Kidney Donor Profile Index was performed. RESULTS: Of the 16 140 total DCD kidney transplants performed during the study period, 306 (1.9%) used TA-NRP. TA-NRP donors were younger ( P < 0.001) and had lower Kidney Donor Profile Index ( P < 0.001) compared with direct recovery donors. Recipients receiving grafts recovered using TA-NRP were younger ( P < 0.001) and more likely to be blood group O ( P < 0.001). Transplants using TA-NRP had lower likelihood of delayed graft function (adjusted odds ratio 0.22 [95% confidence interval, 0.15-0.31], P < 0.001) but similar 180-d survival ( P = 0.8) and all-cause graft failure ( P = 0.3) as transplants using direct recovery grafts. These inferences were unchanged on propensity-matched analysis. CONCLUSIONS: Our results demonstrate that kidney transplants using TA-NRP DCD allografts have positive short-term mortality and graft survival outcomes, with significantly decreased rates of delayed graft function compared with direct recovery DCD grafts.

Debunking the July Effect in lung transplantation recipients.

Objective: The "July Effect" is a theory that the influx of trainees from July to September negatively impacts patient outcomes. We aimed to study this theoretical phenomenon in lung transplant recipients given the highly technical nature of thoracic procedures. Methods: Adult lung transplant hospitalizations were identified within the National Inpatient Sample (2005-2020). Recipients were categorized as academic Q1 (July to September) or Q2-Q4 (October to June). In-hospital mortality, operator-driven complications (pneumothorax, dehiscence including wound dehiscence, bronchial anastomosis, and others, and vocal cord/diaphragm paralysis, all 3 treated as a composite outcome), length of stay, and inflation-adjusted hospitalization charges were compared between both groups. Multivariable logistic regression was performed to assess the association between academic quarter and in-hospital mortality and operator-driven complications. The models were adjusted for recipient demographics and transplant characteristics. Subgroup analysis was performed between academic and nonacademic hospitals. Results: Of 30,788 lung transplants, 7838 occurred in Q1 and 22,950 occurred in Q2-Q4. Recipient demographic and clinical characteristics were similar between groups. Dehiscence (n = 922, 4% vs n = 236, 3%), post-transplant cardiac arrest (n = 532, 2% vs n = 113, 1%), and pulmonary embolism (n = 712, 3% vs n = 164, 2%) were more common in Q2-Q4 versus Q1 recipients (all P < .05). Other operator-driven complications, in-hospital mortality, and resource use were similar between groups (P > .05). These inferences remained unchanged in adjusted analyses and on subgroup analyses of academic versus nonacademic hospitals. Conclusions: The "July Effect" is not evident in US lung transplantation recipient outcomes during the transplant hospitalization. This suggests that current institutional monitoring systems for trainees across multiple specialties, including surgery, anesthesia, critical care, nursing, and others, are robust.

Transfection of hypoxia-inducible factor-1α mRNA upregulates the expression of genes encoding angiogenic growth factors.

Hypoxia-Inducible Factor-1α (HIF-1α) has presented a new direction for ischemic preconditioning of surgical flaps to promote their survival. In a previous study, we demonstrated the effectiveness of HIF-1a DNA plasmids in this application. In this study, to avoid complications associated with plasmid use, we sought to express HIF-1α through mRNA transfection and determine its biological activity by measuring the upregulation of downstream angiogenic genes. We transfected six different HIF-1a mRNAs-one predominant, three variant, and two novel mutant isoforms-into primary human dermal fibroblasts using Lipofectamine, and assessed mRNA levels using RT-qPCR. At all time points examined after transfection (3, 6, and 10 h), the levels of HIF-1α transcript were significantly higher in all HIF-1α transfected cells relative to the control (all p < 0.05, unpaired Student's T-test). Importantly, the expression of HIF-1α transcription response genes (VEGF, ANG-1, PGF, FLT1, and EDN1) was significantly higher in the cells transfected with all isoforms than with the control at six and/or ten hours post-transfection. All isoforms were transfected successfully into human fibroblast cells, resulting in the rapid upregulation of all five downstream angiogenic targets tested. These findings support the potential use of HIF-1α mRNA for protecting ischemic dermal flaps.

Outcomes of single vs double lung retransplantation in patients with cystic fibrosis.

BACKGROUND: Patients requiring lung transplant for cystic fibrosis (CF) may require retransplant due to limited graft survival and otherwise excellent life expectancy. Optimal transplant strategy for this population, including single vs double lung retransplant, has not been established. METHODS: We performed a retrospective analysis of the United Network for Organ Sharing/Organ Procurement and Transplant Network (UNOS/OPTN) database to identify adult lung retransplant recipients from 2005 to 2021 with a primary diagnosis of CF. Patients were stratified by retransplant type (single lung [re-SLTx] vs double lung [re-DLTx] retransplant). Descriptive statistics, Kaplan-Meier survival analysis, and multivariable Cox regression were performed. RESULTS: From 2005 to 2021, 384 recipients underwent retransplant after an initial transplant for an indication of CF; more recipients underwent re-DLTx (N = 337 [87.8%]) than re-SLTx (N = 47 [12.2%]). The median (IQR) time from initial transplant to retransplant was similar between re-SLTx and re-DLTx recipients (4.4 [2.9-8.6] vs 4.6 [2.6-7.4] years, p = 0.73). Ischemic time was shorter and lung allocation score was lower for re-SLTx than re-DLTx recipients. Median survival after retransplant was significantly shorter for re-SLTx vs re-DLTx recipients (2.0 [95% CI 1.2-3.5] vs 4.3 [95% CI 3.5-6.1] years post-retransplant, p = 0.008). Median survival for adults with CF undergoing primary transplant for CF in the same period was 9.1 (8.5-9.9) years. After adjusting for donor and recipient characteristics, re-SLTx in patients with CF was associated with 88% higher hazard of mortality than re-DLTx (aHR=1.88 [95% CI 1.28-2.78], p = 0.001). CONCLUSIONS: In this analysis of lung retransplant in recipients with CF, re-SLTx was associated with a higher hazard of mortality compared to re-DLTx, supporting re-DLTx as treatment for this population.

Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics.

The development of long-term symptoms of coronavirus disease 2019 (COVID-19) more than four weeks after primary infection, termed "long COVID" or post-acute sequela of COVID-19 (PASC), can implicate persistent neurological complications in up to one third of patients and present as fatigue, "brain fog", headaches, cognitive impairment, dysautonomia, neuropsychiatric symptoms, anosmia, hypogeusia, and peripheral neuropathy. Pathogenic mechanisms of these symptoms of long COVID remain largely unclear; however, several hypotheses implicate both nervous system and systemic pathogenic mechanisms such as SARS-CoV2 viral persistence and neuroinvasion, abnormal immunological response, autoimmunity, coagulopathies, and endotheliopathy. Outside of the CNS, SARS-CoV-2 can invade the support and stem cells of the olfactory epithelium leading to persistent alterations to olfactory function. SARS-CoV-2 infection may induce abnormalities in innate and adaptive immunity including monocyte expansion, T-cell exhaustion, and prolonged cytokine release, which may cause neuroinflammatory responses and microglia activation, white matter abnormalities, and microvascular changes. Additionally, microvascular clot formation can occlude capillaries and endotheliopathy, due to SARS-CoV-2 protease activity and complement activation, can contribute to hypoxic neuronal injury and blood-brain barrier dysfunction, respectively. Current therapeutics target pathological mechanisms by employing antivirals, decreasing inflammation, and promoting olfactory epithelium regeneration. Thus, from laboratory evidence and clinical trials in the literature, we sought to synthesize the pathophysiological pathways underlying neurological symptoms of long COVID and potential therapeutics.

Outcomes Comparison of Robot-Assisted and Video-Assisted Thoracoscopic Cardiac Sympathetic Denervation.

OBJECTIVE: Cardiac sympathetic denervation (CSD) is a surgical antiadrenergic procedure that can reduce sustained ventricular tachyarrhythmia (VT). Video-assisted thoracoscopic surgery (VATS) is currently the standard approach used in CSD, and the practicality for robot-assisted thoracoscopic surgery (RATS) has yet to be investigated. METHODS: We conducted a single-center retrospective study of all adult patients (N = 67) who underwent CSD from 2015 to 2021. We compared short-term outcomes of those treated with RATS versus VATS thoracic sympathectomy. For patients with VT, we examined the effectiveness of a RATS approach in reducing implantable cardioverter defibrillator (ICD) shock burden. RESULTS: A total of 34 patients underwent RATS cardiac denervation, and 33 underwent VATS cardiac denervation. Those undergoing RATS denervation had a significantly shorter procedure duration with a median of 129 min (P = 0.008). Patients receiving the VATS approach were significantly more complicated by pneumothorax (P = 0.004) and overall complications (P = 0.01) when compared with the RATS approach. At 1 year after surgery, both groups had significant reductions in ICD shocks compared with before surgery, both decreasing from a median of 4 to 0 shocks (P < 0.001). In addition, at 1 year after surgery, the percentage of patients with persistent ICD shocks and the median of ICD shocks were similar between the groups. CONCLUSIONS: The RATS approach to cardiac denervation has similar 1-year follow-up outcomes in reducing recurrent VT as the VATS approach. However, patients undergoing RATS denervation experienced better perioperative outcomes. This shows promise for robotic CSD to be an effective and safe therapeutic option for patients with malignant arrhythmias.

Small-molecule modulation of the p75 neurotrophin receptor inhibits a wide range of tau molecular pathologies and their sequelae in P301S tauopathy mice.

In tauopathies, phosphorylation, acetylation, cleavage and other modifications of tau drive intracellular generation of diverse forms of toxic tau aggregates and associated seeding activity, which have been implicated in subsequent synaptic failure and neurodegeneration. Suppression of this wide range of pathogenic species, seeding and toxicity mechanisms, while preserving the physiological roles of tau, presents a key therapeutic goal. Identification and targeting of signaling networks that influence a broad spectrum of tau pathogenic mechanisms might prevent or reverse synaptic degeneration and modify disease outcomes. The p75 neurotrophin receptor (p75NTR) modulates such networks, including activation of multiple tau kinases, calpain and rhoA-cofilin activity. The orally bioavailable small-molecule p75NTR modulator, LM11A-31, was administered to tauP301S mice for 3 months starting at 6 months of age, when tau pathology was well established. LM11A-31 was found to reduce: excess activation of hippocampal cdk5 and JNK kinases and calpain; excess cofilin phosphorylation, tau phosphorylation, acetylation and cleavage; accumulation of multiple forms of insoluble tau aggregates and filaments; and, microglial activation. Hippocampal extracts from treated mice had substantially reduced tau seeding activity. LM11A-31 treatment also led to a reversal of pyramidal neuron dendritic spine loss, decreased loss of dendritic complexity and improvement in performance of hippocampal behaviors. These studies identify a therapeutically tractable upstream signaling module regulating a wide spectrum of basic mechanisms underlying tauopathies.