Alterations in glutamate, arginine, and energy metabolism characterize cerebrospinal fluid and plasma metabolome of persons with HIV-associated dementia.

OBJECTIVES: HIV-associated dementia (HAD) is the most severe clinical expression of HIV-mediated neuropathology, and the processes underlying its development remain poorly understood. We aimed to exploit high-dimensional metabolic profiling to gain insights into the pathological mechanisms associated to HAD. DESIGN: In this cross-sectional study, we utilized metabolomics to profile matched cerebrospinal fluid (CSF) and plasma samples of HAD individuals ( n  = 20) compared with neurologically asymptomatic people with HIV (ASYM, n  = 20) and healthy controls (NEG, n  = 20). METHODS: Identification of plasma and CSF metabolites was performed by liquid-chromatography or gas-chromatography following a validated experimental pipeline. The resulting metabolic profiles were analyzed by machine-learning algorithms, and altered pathways were identified by comparison with KEGG pathway database. RESULTS: In CSF, HAD patients displayed an imbalance in glutamine/glutamate ratio, decreased levels of isocitrate and arginine, and increased oxidative stress when compared with ASYM or NEG. These changes were confirmed in matched plasma samples, which in addition revealed an accumulation of eicosanoids and unsaturated fatty acids in HAD individuals. Pathway analysis in both biological fluids suggested that alterations in several metabolic processes, including protein biosynthesis, glutamate and arginine metabolism, and energy metabolism, in association to a perturbed eicosanoid metabolism in plasma, may represent the metabolic signature associated to HAD. CONCLUSION: These findings show that HAD may be associated with metabolic modifications in CSF and plasma. These preliminary data may be useful to identify novel metabolic biomarkers and therapeutic targets in HIV-associated neurological impairment.

Anesthetic Considerations for Patients With Mitral Stenosis Undergoing Orthotopic Liver Transplant.

A 70-year-old male presented for an orthotopic liver transplant (OLT) with co-existing moderate-severe mitral valve stenosis. The hemodynamic goals of managing mitral stenosis posed a significant additional challenge to this patient's care. Intraoperative transesophageal echocardiography (TEE) was critical in guiding volume status and resuscitation. In addition, the patient's valvulopathy guided our vasoactive medication selection and arrhythmia prevention. In this article, we describe the multidisciplinary discussions regarding preoperative valvular intervention as well as the intraoperative techniques used to preserve cardiac output while avoiding coagulopathy and arrhythmias. We discuss the pathophysiology of valvular disease in the context of liver failure and the guidelines by which this disease process is classified. In addition, we discuss the benefits and limitations of intraoperative TEE in evaluating this unique physiology.

A Case of Severe Tricuspid Valve Regurgitation in a Patient Undergoing Orthotopic Liver Transplantation: Whether to Proceed, or Not.

A 38-year-old male presented for orthotopic liver transplantation complicated by new-onset torrential tricuspid regurgitation before incision. Subclinical volume overload and functional tricuspid regurgitation created a challenging scenario in which the benefits of expeditious transplant were weighed against the risks of allograft congestion and failure. Intraoperative transesophageal echocardiography proved critical in diagnosing severe tricuspid regurgitation and guided clinical decision making. In this article, we describe the intraoperative presentation of acutely elevated right heart pressures and the subsequent management of this patient prior to ultimately successful liver transplantation.

Transfusion-Related Acute Lung Injury During Liver Transplantation: A Scoping Review.

Liver transplantation is associated with significant blood loss, often requiring massive blood product transfusion. Transfusion-related acute lung injury (TRALI) is a devastating cause of transfusion-related deaths. While reports have investigated the general incidence of TRALI, the incidence of TRALI specifically following transfusion during liver transplant remains unclear. This scoping review summarizes existing literature regarding TRALI during the liver transplantation perioperative period. Databases were searched for all articles and abstracts reporting on TRALI after liver transplantation. Data collected included number of patients studied, patient characteristics, incidences of TRALI, TRALI characteristics, and patient outcomes. The primary outcome investigated was the incidence of TRALI in the setting of liver transplantation. Thirteen full-text citations were included in this review. The incidence of TRALI post-liver transplant was 0.68% (65 of 9,554). Based on reported transfusion data, patients diagnosed with TRALI received an average of 10.92 ± 10.81 units of packed red blood cells (pRBC), 20.05 ± 15.72 units of fresh frozen plasma, and 5.75 ± 10.00 units of platelets. Common interventions following TRALI diagnosis included mechanical ventilation with positive end-expiratory pressure, inhaled high-flow oxygen, inhaled pulmonary vasodilator, and pharmacologic treatment using pressors or inotropes, corticosteroids, or diuretics. Based on reported mortality data, 26.67% of patients (12 of 45) diagnosed with TRALI died during the postoperative period. This scoping review underscores the importance of better understanding the incidence and presentation of TRALI after liver transplant surgery. The clinical implications of these results warrant the development of identification and management strategies for liver transplant patients at increased risk for developing TRALI.

Combined Liver Kidney Transplant in Adult Patient With Alagille Syndrome and Pulmonary Hypertension.

In this article, we describe a case of a 33-year-old female with Alagille syndrome complicated by bilateral branch pulmonary artery stenosis resulting in moderate pulmonary hypertension, end-stage liver disease complicated by portal hypertension, and chronic renal disease who presented for combined liver-kidney transplant. Alagille syndrome is an autosomal dominant disease affecting the liver, heart, and kidneys. Multidisciplinary preoperative evaluation was performed with a team consisting of a congenital heart disease cardiologist, a cardiac anesthesiologist, a nephrologist, and a transplant surgeon. We describe Alagille syndrome and our intraoperative management. To our knowledge, this is the first description of a combined liver-kidney transplant in an adult patient with Alagille syndrome.

Evaluating the Impact of Pulmonary Artery Obstruction After Lung Transplant Surgery: A Systematic Review and Meta-analysis.

BACKGROUND: Pulmonary artery obstruction is an uncommon but significant complication after lung transplantation. Although numerous reports have documented its occurrence, the hemodynamic parameters associated with its presentation and diagnostic considerations remain ill-defined. This systematic review summarizes evidence in the literature surrounding pulmonary artery obstruction after lung transplantation surgery. METHODS: Databases were searched for all articles and abstracts reporting on pulmonary artery obstruction. Data collected included the number of patients studied, patient characteristics, incidences of pulmonary artery obstruction, and timing and imaging modality used for diagnosis. RESULTS: Thirty-four full-text citations were included in this review. The point prevalence of pulmonary artery obstruction was 3.66%. The peak pulmonary artery velocity associated with obstruction was found to be 2.60 ± 0.58 m/s. The diameter of the obstructed pulmonary artery predictive of poor outcomes was noted to be 0.78 ± 0.40 cm. The majority of diagnoses were made in the late postoperative period using pulmonary angiogram and transesophageal echocardiography. Overall, 76% of patients (47 of 62) required emergent procedural reintervention, and 23% of patients (14 of 62) diagnosed with pulmonary artery obstruction died during their hospital stay. CONCLUSIONS: This systematic review underscores the importance of identifying pulmonary artery obstruction immediately after lung transplant surgery. The clinical implications of these results warrant the development of identification and management strategies for early detection of irregularities in pulmonary artery anastomosis in lung transplant patients.

New or Worsened Mitral Regurgitation After Surgical Aortic Valve Replacement: A Systematic Review.

BACKGROUND: New or worsened mitral regurgitation (MR) is an uncommon yet serious complication after surgical aortic valve replacement (SAVR). While there have been numerous reports of its occurrence, there is little consensus regarding its presentation and management. This systematic review summarizes the evidence in the current literature surrounding new or worsened MR after SAVR and analyzes its potential implications. METHODS: Databases were examined for all articles and abstracts reporting on new or worsened MR after SAVR. Data collected included number of patients studied; patient characteristics; incidences of new or worsened MR; timing of diagnosis; and treatment. RESULTS: Thirty-six full-text citations were included in this review. The prevalence of new or worsened MR after SAVR was 8.4%. Sixteen percent of new MR occurrences were from an organic etiology, and 83% of new MR occurrences were that of a functional etiology. Most diagnoses were made in the late or unspecified postoperative period using echocardiography (range: 0 minutes to 18 years postoperatively). While no patients died from this complication, 7.7% of patients (16 out of 207) required emergent procedural re-intervention. CONCLUSIONS: This systematic review underscores the importance of identifying new or worsened MR following SAVR and accurate scoring of MR severity to guide treatment. It also outlines the associated clinical measures commonly documented following this complication, and the usefulness of transesophageal echocardiography for the detection of significant MR. These results reflect the current, limited state of the literature on this topic and warrant further investigation into MR detection and management strategies in SAVR patients.

Feasibility and safety of same day subcutaneous defibrillator implantation and send home (DASH) strategy.

PURPOSE: To assess the feasibility and safety of same-day discharge after S-ICD implantation by implementing a specific analgesia protocol and phone follow-up. METHODS: Consecutive patients presenting for outpatient S-ICD implantation were enrolled between 1/1/2018 and 4/30/2019. An analgesia protocol included pre-operative acetaminophen and oxycodone, intraoperative local bupivacaine, and limited use of oxycodone-acetaminophen at discharge. The primary outcome was successful same-day discharge. Numerical Pain Rating Scale (NPRS) on postoperative day (POD) 1, 3, 14, and 30 and any unplanned health care visits during the 1-month follow-up period were assessed. RESULTS: Out of 53 potentially eligible S-ICD patients, 49 patients (92.5%) were enrolled and successfully discharged on the same day. Mean age of these 49 patients was 47 ± 14 years. There were no acute procedural complications. Severe pain (NPRS ≥ 8) on POD 0, 1, and 3 was present in 14.3%, 14.3%, and 8.2% of patients, respectively. The total in-hospital stay was 534 ± 80 min. Four unplanned visits (8%) due to cardiac or device-related issues occurred during 1-month follow-up, including 2 patients with heart failure exacerbation, one patient with an incisional infection, and one patient with inappropriate shocks. CONCLUSIONS: With the appropriate institutional protocol including specific analgesics and phone follow-up, same-day discharge after outpatient S-ICD implantation is feasible and appears safe for most patients.. Device-related pain can be severe in the first 3 days post-implantation and can be successfully treated with limited supply of narcotic medications.

Implantation of subcutaneous defibrillator is feasible and safe with monitored anesthesia care.

BACKGROUND: The perioperative anesthesia care during subcutaneous implantable cardioverter-defibrillator (S-ICD) implantation is still evolving. OBJECTIVE: To assess the feasibility and safety of S-ICD implantation with monitored anesthesia care (MAC) versus general anesthesia (GA) in a tertiary care center. METHODS: This is a single-center retrospective study of patients undergoing S-ICD implantation between October 2012 and May 2019. Patients were categorized into MAC and GA group based on the mode of anesthesia. Procedural success without escalation to GA was the primary endpoint of the study, whereas intraprocedural hemodynamics, need of pharmacological support for hypotension and bradycardia, length of the procedure, stay in the post-anesthesia care unit, and postoperative pain were assessed as secondary endpoints. RESULTS: The study comprises 287 patients with MAC in 111 and GA in 176 patients. Compared to MAC, patients in GA group were younger and had a higher body mass index. All patients had successful S-ICD implantation. Only one patient (0.9%) in the MAC group was converted to GA. Despite a similar baseline heart rate (HR) and mean arterial blood pressure (MAP) in both groups, patients with GA had significantly lower HR and MAP during the procedure and more frequently required pharmacological hemodynamic support. Length of the procedure, stay in the postanesthesia care unit, and postoperative pain was similar in both groups. CONCLUSION: This retrospective experience suggests that implantation of S-ICD is feasible and safe with MAC. Use of GA is associated with more frequent administration of hemodynamic drugs during S-ICD implantation.

Physical Processes in Polymeric Filters Used for Dialysis.

The key physical processes in polymeric filters used for the blood purification include transport across the capillary wall and the interaction of blood cells with the polymer membrane surface. Theoretical modeling of membrane transport is an important tool which provides researchers with a quantification of the complex phenomena involved in dialysis. In the paper, we present a dense review of the most successful theoretical approaches to the description of transport across the polymeric membrane wall as well as the cell⁻polymer surface interaction, and refer to the corresponding experimental methods while studying these phenomena in dialyzing filters.

Pulmonary cuff dysfunction after lung transplant surgery: A systematic review of the evidence and analysis of its clinical implications.

BACKGROUND: Pulmonary cuff dysfunction, either due to pulmonary vein obstruction, pulmonary vein stenosis, or pulmonary vein thrombosis, is an uncommon, yet serious complication after lung transplantation. Although there have been numerous reports of its occurrence, there is little consensus regarding the hemodynamic parameters associated with its presentation and diagnostic considerations. This systematic review summarizes the evidence surrounding pulmonary cuff dysfunction after lung transplantation surgery and empirically analyzes its implications. METHODS: Databases were examined for all articles and abstracts reporting on pulmonary cuff dysfunction. Data collected included: number of patients studied; patients' characteristics; incidences of pulmonary vein stenosis and pulmonary vein thrombosis; and timing and imaging modality utilized for diagnosis. RESULTS: Thirty-four full-text citations were included in this review. The point prevalence of pulmonary vein stenosis and thrombosis were 1.4% and 2.5%, respectively. The peak pulmonary cuff velocity associated with dysfunction was found to be 1.59 ± 0.66 m/sec. The diameter of the dysfunctional pulmonary vein was noted to be 0.48 ± 0.20 cm. The majority of diagnoses were made in the early post-operative period using transesophageal echocardiography. Overall, 41.3% of patients (26 of 63) required emergent procedural reintervention, and 32% of patients (20 of 63) diagnosed with pulmonary cuff dysfunction died during their hospital stay. CONCLUSIONS: This systematic review underscores the importance of identifying pulmonary cuff dysfunction after lung transplant surgery, and the usefulness of transesophageal echocardiography for detection of this complication. The clinical implications of these results warrant the further development of identification and management strategies for lung transplant patients.

A Phase 1 Trial of CNDO-109-Activated Natural Killer Cells in Patients with High-Risk Acute Myeloid Leukemia.

Natural killer (NK) cells are an emerging immunotherapy approach to acute myeloid leukemia (AML); however, the optimal approach to activate NK cells before adoptive transfer remains unclear. Human NK cells that are primed with the CTV-1 leukemia cell line lysate CNDO-109 exhibit enhanced cytotoxicity against NK cell-resistant cell lines. To translate this finding to the clinic, CNDO-109-activated NK cells (CNDO-109-NK cells) isolated from related HLA-haploidentical donors were evaluated in a phase 1 dose-escalation trial at doses of 3 × 105 (n = 3), 1 × 106 (n = 3), and 3 × 106 (n = 6) cells/kg in patients with AML in first complete remission (CR1) at high risk for recurrence. Before CNDO-109-NK cell administration, patients were treated with lymphodepleting fludarabine/cyclophosphamide. CNDO-109-NK cells were well tolerated, and no dose-limiting toxicities were observed at the highest tested dose. The median relapse-free survival (RFS) by dose level was 105 (3 × 105), 156 (1 × 106), and 337 (3 × 106) days. Two patients remained relapse-free in post-trial follow-up, with RFS durations exceeding 42.5 months. Donor NK cell microchimerism was detected on day 7 in 10 of 12 patients, with 3 patients having evidence of donor cells on day 14 or later. This trial establishes that CNDO-109-NK cells generated from related HLA haploidentical donors, cryopreserved, and then safely administered to AML patients with transient persistence without exogenous cytokine support. Three durable complete remissions of 32.6 to 47.6+ months were observed, suggesting additional clinical investigation of CNDO-109-NK cells for patients with myeloid malignancies, alone or in combination with additional immunotherapy strategies, is warranted.

Distribution and Quantity of Sites of John Cunningham Virus Persistence in Immunologically Healthy Patients: Correlation With John Cunningham Virus Antibody and Urine John Cunningham Virus DNA.

Importance: Although seroepidemiological studies indicate that greater than 50% of the population has been infected with John Cunningham virus (JCV), the sites of JCV persistence remain incompletely characterized. Objective: To determine sites of JCV persistence in immunologically healthy individuals. Design, Setting, and Participants: Tissue specimens from multiple sites including brain, renal, and nonrenal tissues were obtained at autopsy performed in the Department of Pathology at the University of Kentucky from 12 immunologically healthy patients between February 9, 2011, and November 27, 2012. Quantitative polymerase chain reaction was performed on the tissue specimens and urine. Serum JCV antibody status was determined by enzyme-linked immunosorbent assay. Main Outcomes and Measures: The detection and quantification of JCV from the tissues by quantitative polymerase chain reaction illuminated sites of viral persistence. These results were correlated with JCV antibody levels. Results: Autopsies were performed on 12 individuals, 10 men and 2 women, ranging in age from 25 to 75 years (mean, 55.3 years). Seven of 12 individuals were JCV antibody seropositive based on absorbance units. Serostatus was associated with amounts of JCV DNA in urine and its tissue distribution. John Cunningham virus DNA was found in 75% of genitourinary tissue samples from donors (18 of 24) with high JCV antibody levels, 13.3% of donors with low levels i(4 of 30), and 0% of seronegative persons (0 of 32). In nongenitourinary tissues, JCV DNA was detected in 45.1% of tissue samples of donors (32 of 71) with high JCV, 2.2% of donors with low JCV serostatus (2 of 93), and 0% of seronegative persons (0 of 43). Genitourinary tissues had higher copy numbers than other sites. John Cunningham virus DNA was detected in urine of seronegative individuals in a research-grade assay. Conclusions and Relevance: Persistent (latent or actively replicating) JCV infection mostly predominates in genitourinary tissues but distributes in other tissues at low copy number. The distribution and copy numbers of the virus appear to correlate with urinary JCV shedding and serostatus.

Anesthetic Management for Multiple Family Members with Myotonic Dystrophy for Interventional Cardiac Procedures-A Case Series.

Myotonic muscular dystrophy (MMD) is a rare autosomal dominant disorder that can complicate anesthetic management of patients. MMD is characterized by progressively worsening muscle loss and weakness, cardiac conduction abnormalities, cardiomyopathy, restrictive lung disease, obstructive sleep apnea, and delayed gastric emptying. Patients presenting with MMD for any surgical procedure present a management challenge to the anesthesiologist. Several reports of airway loss due to medication-mediated respiratory depression, sudden death due to dysrhythmias, aspiration of stomach contents, and prolonged intubation have been reported. We present a case series of three family members with MMD type 1 who presented for electrophysiologic assessment of the cardiac conduction system and possible pacemaker insertion. While there are reports of anesthetic management of patients with myotonic dystrophy for various procedures, our report is unique in that we were able to demonstrate variations of anesthetic management based on the procedure and variation in disease phenotype-differing severity between family members.