Propofol Infusion Syndrome Following Endoscopic Tracheoplasty and Jet Ventilation: Case Report.

OBJECTIVE: We present a case of propofol infusion syndrome (PRIS) following jet ventilation. METHOD: Case report and review of literature. RESULTS: A 70-year-old man required CO2 laser endoscopic tracheoplasty for tracheal and subglottic stenosis due to A-frame deformity. Postoperatively, the patient was reintubated for respiratory distress and propofol was resumed. Over the next two days the patient developed acute kidney injury, leukocytosis, acute primary respiratory acidosis with high anion gap metabolic acidosis, multiple end organ damage, elevated cardiac markers, and worsening lactic acidosis. The patient was recognized as having propofol infusion syndrome and propofol was immediately discontinued and replaced with dexmedetomidine. Unfortunately the patient progressed to multi-organ failure complicated by rhabdomyolysis and distributive intravascular coagulopathy. CONCLUSIONS: Propofol is often used as an anesthetic for jet ventilation during otolaryngologic airway surgery. Propofol related infusion syndrome is an uncommon but life-threatening peri-operative complication that should be considered in any patient with an unusual post-operative recovery characterized by metabolic acidosis, ECG changes, end organ damage, and elevated lactate.

Cytomegalovirus Infection Facilitates the Costimulation of CD57+CD28- CD8 T Cells in HIV Infection and Atherosclerosis via the CD2-LFA-3 Axis.

CD8 T cells are emerging as important mediators in atherosclerosis and cardiovascular disease (CVD). Immune activation may play a particular role in people with HIV (PWH) who are at an increased risk of CVD, even after controlling for known CVD risk factors. Latent CMV infection is associated with increased CVD risk for both PWH and people without HIV, and human CMV-specific CD4 and CD8 T cells are enriched for an immunosenescent phenotype. We previously showed that CMV coinfection in PWH promotes vascular homing and activation of inflammatory CD4 T cells through the CD2-LFA-3 axis. However, the role of CD2/LFA3 costimulation of CD8 T cells in PWH with CMV has yet to be described. In the present study, we demonstrate that CD2 expression on CX3CR1+CD57+CD28- inflammescent CD8 T cells is increased on cells from CMV-seropositive PWH. In vitro CD2/LFA-3 costimulation enhances TCR-mediated activation of these inflammatory CD8 memory T cells. Finally, we show that LFA-3 is highly expressed in aortas of SIV-infected rhesus macaques and in atherosclerotic plaques of people without HIV. Our findings are consistent with a model in which CMV infection enhances CD2 expression on highly proinflammatory CD8 T cells that can then be stimulated by LFA-3 expressed in the vasculature, even in the absence of CD28 costimulation. This model, in which CMV infection exacerbates toxic cytokine and granzyme production by CD8 T cells within the vasculature, highlights a potential therapeutic target in atherosclerosis development and progression, especially for PWH.

Reference genomes for BALB/c Nude and NOD/SCID mouse models.

Mouse xenograft models play a vital role in tumor studies for research as well as for screening of drugs for the pharmaceutical industry. In particular, models with compromised immunity are favorable to increase the success of transplantation, such as, e.g. NOD/SCID and BALB/c Nude strains. The genomic sequence and alterations of many of these models still remain elusive and might hamper a model's further optimization or proper adapted usage. This can be in respect to treatments (e.g. NOD/SCID sensitivity to radiation), experiments or analysis of derived sequencing data of such models. Here we present the genome assemblies for the NOD/SCID and BALB/c Nude strains to overcome this short-coming for the future and improve our understanding of these models in the process. We highlight as well first insights into observed genomic differences for these models compared to the C57BL/6 reference genome. Genome assemblies for both are close to full-chromosome representations and provided with liftover annotations from the GRCm39 reference genome.

Nasopharyngeal cancer: Incidence and prognosis of human papillomavirus and Epstein-Barr virus association at a single North American institution.

BACKGROUND: The prognostication of Epstein-Barr virus (EBV) and human papillomavirus (HPV) status in nasopharyngeal cancer (NPC) is unclear. METHODS: This retrospective study analyzed NPC from 2000 to 2019. RESULTS: Seventy-eight patients were included: 43 EBV+ , 12 HPV+ , 23 EBV- /HPV- , and 0 EBV+ /HPV+ . All p16+ tumors were also positive for HPV-CISH. Baseline characteristics were not different between groups except age, N-classification, and Karnofsky Performance Scale (KPS) (p < 0.05). For EBV+ , HPV+ , and EBV- /HPV- respectively, 3-year overall survival (OS) was 89.9%, 69.8%, and 52.5% (p = 0.006). EBV- /HPV- status was significantly associated with worse OS but not freedom from progression (FFP) on univariate analysis, and did not remain a significant predictor of OS after adjusting for KPS, age, and group stage. CONCLUSIONS: EBV+ NPC tumors were seen in younger, healthier patients than HPV+ and EBV- tumors, and there were no cases of coinfection. The association of viral status with OS was insignificant after adjusting for KPS and age.

Creating Matched In vivo/In vitro Patient-Derived Model Pairs of PDX and PDX-Derived Organoids for Cancer Pharmacology Research.

Patient-derived tumor xenografts (PDXs) are considered the most predictive preclinical models, largely believed to be driven by cancer stem cells (CSC) for conventional cancer drug evaluation. A large library of PDXs is reflective of the diversity of patient populations and thus enables population based preclinical trials ("Phase II-like mouse clinical trials"); however, PDX have practical limitations of low throughput, high costs and long duration. Tumor organoids, also being patient-derived CSC-driven models, can be considered as the in vitro equivalent of PDX, overcoming certain PDX limitations for dealing with large libraries of organoids or compounds. This study describes a method to create PDX-derived organoids (PDXO), thus resulting in paired models for in vitro and in vivo pharmacology research. Subcutaneously-transplanted PDX-CR2110 tumors were collected from tumor-bearing mice when the tumors reached 200-800 mm3, per an approved autopsy procedure, followed by removal of the adjacent non-tumor tissues and dissociation into small tumor fragments. The small tumor fragments were washed and passed through a 100 µm cell strainer to remove the debris. Cell clusters were collected and suspended in basement membrane extract (BME) solution and plated in a 6-well plate as a solid droplet with surrounding liquid media for growth in a CO2 incubator. Organoid growth was monitored twice weekly under light microscopy and recorded by photography, followed by liquid medium change 2 or 3 times a week. The grown organoids were further passaged (7 days later) at a 1:2 ratio by disrupting the BME embedded organoids using mechanical shearing, aided by addition of trypsin and the addition of 10 µM Y-27632. Organoids were cryopreserved in cryo-tubes for long-term storage, after release from BME by centrifugation, and also sampled (e.g., DNA, RNA and FFPE block) for further characterization.

Utility of Transnasal Humidified Rapid Insufflation Ventilatory Exchange for Microlaryngeal Surgery.

OBJECTIVE: Microlaryngeal surgery typically requires oxygenation and ventilation via either an endotracheal tube (ETT), jet ventilation (JV), or intermittent apnea with an ETT. Transnasal Humidified Rapid Insufflation Ventilatory Exchange (THRIVE) delivered by high flow nasal cannula has been reported as an alternative technique. This method of apneic oxygenation and ventilation allows for stable, unobstructed visualization of immobile laryngeal structures. We aim to describe the technique and characterize intraoperative parameters related to its safety. STUDY DESIGN: Case Series. METHODS: The electronic medical record was reviewed for patients who underwent microlaryngoscopy using THRIVE technique. Patient demographics, procedural details, operative parameters, and anesthesia records were reviewed. Descriptive statistics were reported. RESULTS: A total of 53 patients underwent microlaryngoscopy using THRIVE as the sole method of ventilation, with 62% female. Median age was 51 years, and median BMI was 25 kg/m2 . Most patients were ASA class 2, and most had a Mallampati score of 2. The most common surgical indications were subglottic stenosis, vocal fold lesions, and vocal fold paralysis. Median apnea time was 16 minutes. At the end of case, median end tidal CO2 was 50 mmHg, and median minimum SpO2 was 95. Six cases required supplementation of THRIVE with JV or tracheal intubation for sustained oxygen desaturation. There was an increase in end tidal CO2 of 0.844 mmHg/min of apneic time. CONCLUSIONS: THRIVE is a safe and effective technique for oxygenation and ventilation in microlaryngeal, non-laser surgery in appropriately selected patients. To ensure safety, back-up plans such as jet ventilation and microlaryngeal ETT should be available. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:587-591, 2021.

CX3CL1 and IL-15 Promote CD8 T cell chemoattraction in HIV and in atherosclerosis.

Atherosclerotic cardiovascular disease (ASCVD) remains an important cause of morbidity in the general population and risk for ASCVD is increased approximately 2-fold in persons living with HIV infection (PLWH). This risk is linked to elevated CD8 T cell counts that are abundant in atherosclerotic plaques and have been implicated in disease pathogenesis yet the mechanisms driving T cell recruitment to and activation within plaques are poorly defined. Here we investigated the role of CD8 T cells in atherosclerosis in a non-human primate model of HIV infection and in the HIV-uninfected elderly; we sought to identify factors that promote the activation, function, and recruitment to endothelium of CX3CR1+ CD8 T cells. We measured elevated expression of CX3CL1 and IL-15, and increased CD8 T cell numbers in the aortas of rhesus macaques infected with SIV or SHIV, and demonstrated similar findings in atherosclerotic vessels of HIV-uninfected humans. We found that recombinant TNF enhanced the production and release of CX3CL1 and bioactive IL-15 from aortic endothelial cells, but not from aortic smooth muscle cells. IL-15 in turn promoted CX3CR1 surface expression on and TNF synthesis by CD8 T cells, and IL-15-treated CD8 T cells exhibited enhanced CX3CL1-dependent chemoattraction toward endothelial cells in vitro. Finally, we show that CD8 T cells in human atherosclerotic plaques have an activated, resident phenotype consistent with in vivo IL-15 and CX3CL1 exposure. In this report, we define a novel model of CD8 T cell involvement in atherosclerosis whereby CX3CL1 and IL-15 operate in tandem within the vascular endothelium to promote infiltration by activated CX3CR1+ memory CD8 T cells that drive further endothelial activation via TNF. We propose that these interactions are prevalent in aging and in PLWH, populations where circulating activated CX3CR1+ CD8 T cell numbers are often expanded.

Inflammescent CX3CR1+CD57+CD8+ T cells are generated and expanded by IL-15.

HIV infection is associated with an increase in the proportion of activated CD8+ memory T cells (Tmem) that express CX3CR1, but how these cells are generated and maintained in vivo is unclear. We demonstrate that increased CX3CR1 expression on CD8+ Tmem in people living with HIV (PLWH) is dependent on coinfection with human CMV, and CX3CR1+CD8+ Tmem are enriched for a putatively immunosenescent CD57+CD28- phenotype. The cytokine IL-15 promotes the phenotype, survival, and proliferation of CX3CR1+CD57+CD8+ Tmem in vitro, whereas T cell receptor stimulation leads to their death. IL-15-driven survival is dependent on STAT5 and Bcl-2 activity, and IL-15-induced proliferation requires STAT5 and mTORC1. Thus, we identify mechanistic pathways that could explain how "inflammescent" CX3CR1+CD57+ CD8+ Tmem dominate the overall memory T cell pool in CMV-seropositive PLWH and that support reevaluation of immune senescence as a nonproliferative dead end.

Cytomegalovirus Coinfection Is Associated with Increased Vascular-Homing CD57+ CD4 T Cells in HIV Infection.

Cytotoxic CD4 T cells are linked to cardiovascular morbidities and accumulate in both HIV and CMV infections, both of which are associated with increased risk of cardiovascular disease (CVD). In this study, we identify CMV coinfection as a major driver of the cytotoxic phenotype, characterized by elevated CD57 expression and reduced CD28 expression, in circulating CD4 T cells from people living with HIV infection, and investigate potential mechanisms linking this cell population to CVD. We find that human CD57+ CD4 T cells express high levels of the costimulatory receptor CD2 and that CD2/LFA-3 costimulation results in a more robust and polyfunctional effector response to TCR signals, compared with CD28-mediated costimulation. CD57+ CD4 T cells also express the vascular endothelium-homing receptor CX3CR1 and migrate toward CX3CL1-expressing endothelial cells in vitro. IL-15 promotes the cytotoxic phenotype, elevates CX3CR1 expression, and enhances the trafficking of CD57+ CD4 T cells to endothelium and may therefore be important in linking these cells to cardiovascular complications. Finally, we demonstrate the presence of activated CD57+ CD4 T cells and expression of CX3CL1 and LFA-3 in atherosclerotic plaque tissues from HIV-uninfected donors. Our findings are consistent with a model in which cytotoxic CD4 T cells contribute to CVD in HIV/CMV coinfection and in atherosclerosis via CX3CR1-mediated trafficking and CD2/LFA-3-mediated costimulation. This study identifies several targets for therapeutic interventions and may help bridge the gap in understanding how CMV infection and immunity are linked to increased cardiovascular risk in people living with HIV infection.

CD8+ T-Cell-Derived Tumor Necrosis Factor Can Induce Tissue Factor Expression on Monocytes.

Circulating CD8+ T cells and monocytes are activated during human immunodeficiency virus (HIV) infection and colocalize in the aortas of simian immunodeficiency virus-infected nonhuman primates. We hypothesized that CD8+ T cells could exert a proatherosclerotic effect via paracrine actions on monocytes. We found that T-cell receptor-stimulated CD8+ T cells induce monocytes to express tissue factor, a potent activator of coagulation. Tumor necrosis factor was both necessary and sufficient for this effect.

Subjective social status and functional decline in older adults.

BACKGROUND: It is unknown whether subjective assessment of social status predicts health outcomes in older adults. OBJECTIVE: To describe the relationship between subjective social status and functional decline in older adults. DESIGN: Longitudinal cohort study. SETTING: The Health and Retirement Study, a nationally representative survey of community-dwelling older adults (2004-2008). PARTICIPANTS: Two thousand five hundred and twenty-three community-dwelling older adults. MAIN MEASURES: Self-report of social status (SSS), categorized into three groups, reported by participants who marked a 10-rung ladder to represent where they stand in society. Four-year functional decline (new difficulty in any of five activities of daily living, mobility decline and/or death) KEY RESULTS: Mean age was 64; 46% were male, 85% were white. At baseline, lower SSS was associated with being younger, unmarried, of nonwhite race/ethnicity, higher rates of chronic medical conditions and ADL impairment (P < 0.01). Over 4 years, 50% in the lowest SSS group declined in function, compared to the middle and highest groups (28% and 26%), P-trend <0.001. Those in the lowest rungs of SSS were at increased risk of 4-year functional decline (unadjusted RR = 1.91, CI 1.-9-2.46). The relationship between a subjective belief that one is worse off than others and functional decline persisted after serial adjustment for demographics, objective SES measures, and baseline health and functional status (RR 1.36, CI 1.08-1.73). CONCLUSIONS: In older adults, the belief that one is in the lowest rungs of social status is a measure of socioeconomic distress and of significant risk for functional decline. These findings suggest that self-report of low subjective social status may give clinicians additional information about which older adults are at high risk for future functional decline.