Hepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - ß-catenin cascade to promote liver tumorigenesis.

Hepatocellular carcinoma (HCC) is the 3rd most deadly malignancy. Activated hepatic stellate cells (aHSC) give rise to cancer-associated fibroblasts in HCC and are considered a potential therapeutic target. Here we report that selective ablation of stearoyl CoA desaturase-2 (Scd2) in aHSC globally suppresses nuclear CTNNB1 and YAP1 in tumors and tumor microenvironment and prevents liver tumorigenesis in male mice. Tumor suppression is associated with reduced leukotriene B4 receptor 2 (LTB4R2) and its high affinity oxylipin ligand, 12-hydroxyheptadecatrienoic acid (12-HHTrE). Genetic or pharmacological inhibition of LTB4R2 recapitulates CTNNB1 and YAP1 inactivation and tumor suppression in culture and in vivo. Single cell RNA sequencing identifies a subset of tumor-associated aHSC expressing Cyp1b1 but no other 12-HHTrE biosynthetic genes. aHSC release 12-HHTrE in a manner dependent on SCD and CYP1B1 and their conditioned medium reproduces the LTB4R2-mediated tumor-promoting effects of 12-HHTrE in HCC cells. CYP1B1-expressing aHSC are detected in proximity of LTB4R2-positive HCC cells and the growth of patient HCC organoids is blunted by LTB4R2 antagonism or knockdown. Collectively, our findings suggest aHSC-initiated 12-HHTrE-LTB4R2-CTNNB1-YAP1 pathway as a potential HCC therapeutic target.

The effect of intraoperative lidocaine administration in a disrupted erector spinae fascial plane on intercostal transcranial motor evoked potentials.

STUDY OBJECTIVE: Erector spinae plane (ESP) blocks have been recently described for postoperative pain management following spine surgery but their effects on intraoperative neuromonitoring are unknown. DESIGN: Retrospective cohort study. SETTING: Pediatric patients at a tertiary care center. PATIENTS: 26 pediatric patients who received bilateral surgically-placed ESP catheters for single-stage posterior spine fusion (PSF) from August 2020 to June 2021. INTERVENTIONS: Patients in this study did not receive any special interventions as part of this observational retrospective study. MEASUREMENTS: This retrospective study investigated the effects of local anesthesia administration through bilateral surgically-placed ESP catheters on intraoperative intercostal transcranial motor evoked potentials (tcMEPs) in the setting of a disrupted erector spinae fascial plane in pediatric patients undergoing single-stage posterior spine fusion. MAIN RESULTS: Of the 26 patients that received bilateral surgically-placed ESP catheters for pediatric posterior spine fusion surgery, none exhibited any changes in intercostal tcMEPs attributable to intraoperative lidocaine administration through the ESP catheters. CONCLUSIONS: The administration of a local anesthetic into a disrupted erector spinae fascial plane does not appear to interfere with intraoperative neuromonitoring of posterior spine fusion surgeries.

The impact of perioperative stroke and delirium on outcomes after surgical aortic valve replacement.

OBJECTIVE: The effects of stroke and delirium on postdischarge cognition and patient-centered health outcomes after surgical aortic valve replacement (SAVR) are not well characterized. Here, we assess the impact of postoperative stroke and delirium on these health outcomes in SAVR patients at 90 days. METHODS: Patients (N = 383) undergoing SAVR (41% received concomitant coronary artery bypass graft) enrolled in a randomized trial of embolic protection devices underwent serial neurologic and delirium evaluations at postoperative days 1, 3, and 7 and magnetic resonance imaging at day 7. Outcomes included 90-day functional status, neurocognitive decline from presurgical baseline, and quality of life. RESULTS: By postoperative day 7, 25 (6.6%) patients experienced clinical stroke and 103 (28.5%) manifested delirium. During index hospitalization, time to discharge was longer in patients experiencing stroke (hazard ratio, 0.62; 95% confidence interval [CI], 0.42-0.94; P = .02) and patients experiencing delirium (hazard ratio, 0.68; 95% CI, 0.54-0.86; P = .001). At day 90, patients experiencing stroke were more likely to have a modified Rankin score >2 (odds ratio [OR], 5.9; 95% CI, 1.7-20.1; P = .01), depression (OR, 5.3; 95% CI, 1.6-17.3; P = .006), a lower 12-Item Short Form Survey physical health score (adjusted mean difference -3.3 ± 1.9; P = .08), and neurocognitive decline (OR, 7.8; 95% CI, 2.3-26.4; P = .001). Delirium was associated with depression (OR, 2.2; 95% CI, 0.9-5.3; P = .08), lower 12-Item Short Form Survey physical health (adjusted mean difference -2.3 ± 1.1; P = .03), and neurocognitive decline (OR, 2.2; 95% CI, 1.2-4.0; P = .01). CONCLUSIONS: Stroke and delirium occur more frequently after SAVR than is commonly recognized, and these events are associated with disability, depression, cognitive decline, and poorer quality of life at 90 days postoperatively. These findings support the need for new interventions to reduce these events and improve patient-centered outcomes.

Association of orthostatic blood pressure response with incident heart failure: The Framingham Heart Study.

IMPORTANCE: Orthostatic hypotension (OH) and hypertension (OHT) are aberrant blood pressure (BP) regulation conditions associated with higher cardiovascular disease risk. The relations of OH and OHT with heart failure (HF) risk in the community are unclear and there remains a paucity of data on the relations with HF subtypes [HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF)]. OBJECTIVE: Relate OH and OHT with HF risk and its subtypes. DESIGN: Prospective observational cohort. SETTING: Community-based individuals in the Framingham Heart Study Original Cohort. PARTICIPANTS: 1,914 participants (mean age 72 years; 1159 women) attending examination cycle 17 (1981-1984) followed until December 31, 2017 for incident HF or death. EXPOSURES: OH or OHT, defined as a decrease or increase, respectively, of ≥20/10 mmHg in systolic/diastolic BP upon standing from supine position. OUTCOMES AND MEASURES: At baseline, 1,241 participants had a normal BP response (749 women), 274 had OH (181 women), and 399 had OHT (229 women). Using Cox proportional hazards regression models, we related OH and OHT to risk of HF, HFrEF, and HFpEF compared to the absence of OH and OHT (reference), adjusting for age, sex, body mass index, systolic and diastolic BP, hypertension treatment, smoking, diabetes, and total cholesterol/high-density lipoprotein. RESULTS: On follow-up (median 13 years) we observed 492 HF events (292 in women; 134 HFrEF, 116 HFpEF, 242 HF indeterminate EF). Compared to the referent, participants with OH [n = 84/274 (31%) HF events] had a higher HF risk (Hazards Ratio [HR] 1.47, 95% CI 1.13-1.91). Moreover, OH was associated with a higher HFrEF risk (HR 2.21, 95% CI 1.34-3.67). OHT was not associated with HF risk. CONCLUSIONS AND RELEVANCE: Orthostatic BP response may serve as an early marker of HF risk. Findings suggest shared pathophysiology of BP regulation and HF, including HFrEF.

Rate of Post-Fertilization Mitotic Activity Predicts Embryonic Competence via Next Generation Sequencing: An Analysis of 39,301 Cleavage Stage Embryos.

OBJECTIVE: To investigate the association between cleavage stage development, embryonic competence, and euploidy in patients undergoing in vitro fertilization (IVF) with subsequent next generation sequencing. METHODS: The retrospective cohort study included patients at an academic fertility center who underwent IVF with at least one cleavage stage embryo from 2016 to 2019. Embryos were analyzed as slow (<6 cells), intermediate (6-8 cells), or fast (>8 cells); day 3 cell count was also analyzed as a continuous variable. Primary outcomes were blastulation rate, biopsied blastocyst rate, and euploid rate. Odds of blastulation, biopsy, and euploidy were also calculated. Additionally, we modeled the predicted probability of an embryo reaching blastulation, biopsy, and euploidy based on cleavage stage development. RESULTS: When compared with intermediate and slow cohorts, fast cleaving embryos had significantly higher rates of blastulation (82.70% vs. 75.13 vs. 42.48%), biopsy (55.04% vs. 44.00% vs. 14.98%), and euploidy (50.65% vs. 47.93% vs. 48.05%). After adjustment for covariates, there was a significant association between cleavage stage development and odds of blastulation (OR 1.38, 95% CI 1.29-1.48), biopsy (OR 1.42, 95% CI 1.34-1.51), and euploidy (OR 1.08, 95% CI 1.01-1.17). Finally, we observed significant associations between cleavage stage development and predicted probability of reaching blastulation (OR 1.29, 95% CI 1.27-1.32), biopsy (OR 1.24, 95% CI 1.22-1.26), and euploidy (OR 1.02, 95% CI 1.01-1.04). CONCLUSIONS: Cleavage stage embryos with greater mitotic activity perform as well as or better than intermediate or slower cleaving embryos. Rapidly cleaving embryos have high rates of euploidy and significant clinical potential.

Opioid-Free Postoperative Pain Management After Adenotonsillectomy With Nasal Turbinate Reduction Using Bilateral Suprazygomatic Infratemporal-Pterygopalatine Fossa Injections: A Case Report.

Adenotonsillectomies are one of the most common otolaryngologic surgeries performed to alleviate obstructive sleep-disordered breathing and apnea in children. The pain management following adenotonsillectomy continues to be a challenge for both pediatric anesthesiologists and otolaryngologists due to the mortality that stems from the use of opioid pain medications in children who have an increased baseline risk airway obstruction and apnea that is exacerbated by any exposure to opioids. We present a case utilizing bilateral suprazygomatic maxillary nerve (SZMN) blocks or, more accurately, suprazygomatic infratemporal-pterygopalatine fossa injections to achieve opioid-free perioperative analgesia for pediatric adenotonsillectomy with nasal turbinate reduction.

Fate and functional roles of Prominin 1+ cells in liver injury and cancer.

Prominin 1 (PROM1) is one of a few clinically relevant progenitor markers in human alcoholic hepatitis (AH) and hepatocellular carcinoma (HCC), and mouse liver tumor initiating stem cell-like cells (TICs). However, the origin, fate and functions of PROM1+ cells in AH and HCC are unknown. Here we show by genetic lineage tracing that PROM1+ cells are derived in part from hepatocytes in AH and become tumor cells in mice with diethyl nitrosamine (DEN)-initiated, Western alcohol diet-promoted liver tumorigenesis. Our RNA sequencing analysis of mouse PROM1+ cells, reveals transcriptomic landscapes indicative of their identities as ductular reaction progenitors (DRPs) and TICs. Indeed, single-cell RNA sequencing reveals two subpopulations of Prom1+ Afp- DRPs and Prom1+ Afp+ TICs in the DEN-WAD model. Integrated bioinformatic analysis identifies Discodin Domain Receptor 1 (DDR1) as a uniquely upregulated and patient-relevant gene in PROM1+ cells in AH and HCC. Translational relevance of DDR1 is supported by its marked elevation in HCC which is inversely associated with patient survival. Further, knockdown of Ddr1 suppresses the growth of TICs and TIC-derived tumor growth in mice. These results suggest the importance of PROM1+ cells in the evolution of liver cancer and DDR1 as a potential driver of this process.

Transesophageal probe placement increases endotracheal tube cuff pressure but is not associated with postoperative extubation failure after congenital cardiac surgery.

Context: The concomitant use of cuffed endotracheal tubes (ETT) and transesophageal echocardiography (TEE) probes increases ETT cuff pressures (CP), which may contribute to mucosal ischemia and perioperative complications such as failed extubation. Aims: To assess changes in ETT CP after TEE insertion in patients of different age groups undergoing congenital heart surgery and examine the relationship between ETT CP and postoperative extubation failure. Settings and Design: Single-center quality improvement project. Subjects and Methods: ETT CP was measured with a manometer following intubation and again after TEE insertion. Tracheal perfusion pressure was then calculated and postoperative extubation failures were recorded. Statistical Analysis: Chi-square testing, Fisher's-exact testing, one-way analysis of variance testing or Kruskal-Wallis testing with Dunn's pairwise, and student's t-test or Wilcoxon rank-sum testing were used to analyze the data. Results: Median ETT CP increased significantly after TEE insertion in each age group, with infants showing a smaller magnitude of increase (+2 [1-6] cm H2O, P < 0.001) than adults (+12 [8-14] cm H2O, P = 0.008) (intergroup comparison P = 0.002). Five patients (9%) failed extubation, all of which were infants. Within the infant subgroup, no significant difference existed between failed vs successful extubation regarding ETT CP during bypass (15 ± 1 vs 16 ± 2 mmHg, P = 0.206) or tracheal perfusion pressure pre-bypass (34 ± 9 vs 38 ± 11 mmHg, P = 0.518), during bypass (20 ± 9 vs 22 ± 6 mmHg, P = 0.697), or post-bypass (42 ± 9 vs 41 ± 9 mmHg, P = 0.923). There was a significant difference in cardiopulmonary bypass duration (151 ± 29 vs 85 ± 32 min, P < 0.001). Conclusion: Factors beyond intraoperative ETT CP likely play a larger role in postoperative extubation failure.

Comprehensive characterization of hepatocyte-derived extracellular vesicles identifies direct miRNA-based regulation of hepatic stellate cells and DAMP-based hepatic macrophage IL-1ß and IL-17 upregulation in alcoholic hepatitis mice.

Extracellular vesicles (EVs) have been growingly recognized as biomarkers and mediators of alcoholic liver disease (ALD) in human and mice. Here we characterized hepatocyte-derived EVs (HC-EVs) and their cargo for their biological functions in a novel murine model that closely resembles liver pathology observed in patients with alcoholic hepatitis (AH), the most severe spectrum of ALD. The numbers of circulating EVs and HC-EVs were significantly increased by 10-fold in AH mice compared with control mice. The miRNA (miR)-seq analysis detected 20 upregulated and 4 downregulated miRNAs (P < 0.001-0.05) in AH-HC-EVs. Treatment of murine primary hepatic stellate cells (HSCs) with AH-HC-EVs induced α-SMA (P < 0.05) and Col1a1 (P < 0.001). Smad7 and Nr1d2 genes, which were downregulated in HSCs from the AH mice, were predicted targets of 20 miRs upregulated in AH-HC-EVs. Among them were miR-27a and miR-181 which upon transfection in HSCs, indeed repressed Nr1d2, the quiescent HSC marker. AH-HC-EVs were also enriched with organelle proteins and mitochondrial DNA (10-fold, P < 0.05) and upregulated IL-1ß and IL-17 production by hepatic macrophages (HMs) from AH mice in a TLR9-dependent manner. These results demonstrate HC-EV release is intensified in AH and suggest that AH-HC-EVs orchestrate liver fibrogenesis by directly targeting the quiescent HSC transcripts via a unique set of miRNAs and by amplifying HSC activation via DAMP-based induction of profibrogenic IL-1ß and IL-17 by HMs. KEY MESSAGES: • Circulating EVs and HC-EVs were increased in AH mice compared with control mice • AH-HC-EVs were enriched in miRNAs, organelle proteins, and mitochondrial DNA • AH-HC-EVs increased cytokine production by AH-HMs in a TLR9-dependent manner.

Post-thyroidectomy emergency room visits and readmissions: Assessment from the Collaborative Endocrine Surgery Quality Improvement Program (CESQIP).

BACKGROUND: This study analyzed independent factors associated with post-thyroidectomy Emergency Room (ER) visits and Hospital Readmissions (HR). METHODS: This is a retrospective review from the CESQIP registry of 8381 thyroidectomy patients by 173 surgeons at 46 institutions. A total of 7142 ER visits and 7265 HR were analyzed. Multivariable logistic regression analysis was performed to determine the risk factors for an ER visit or HR. RESULTS: Within 30-days of surgery, rates of all ER visits were 3.4% (n = 250) and all HR were 2.3% (n = 170). Hypocalcemia was the reason for 21.9% of ER encounters and 36.4% of HR. BMI >40 kg/m2 was a risk factor for both ER visit (OR1.86) and HR (OR1.94). Surgical duration >3 h (OR2.63), and transection of recurrent laryngeal nerve (OR4.58) were risk factors for HR. CONCLUSIONS: Strategies to decrease hypocalcemia and improve perioperative care of patients with BMI >40 kg/m2 may improve post-thyroidectomy outcome.

Targeted next-generation sequencing of 565 neuro-oncology patients at UCLA: A single-institution experience.

BACKGROUND: Targeted next-generation sequencing (NGS) is frequently obtained at the University of California, Los Angeles (UCLA) for clinical characterization of CNS tumors. In this study, we describe the diagnostic reliability of the Foundation Medicine (FM) targeted NGS platform and its ability to explore and identify tumor characteristics of prognostic significance in gliomas. METHODS: Neuro-oncology patients seen at UCLA who have received FM testing between August 2012 and March 2019 were included in this study, and all mutations from FM test reports were recorded. Initial tumor diagnoses and diagnostic markers found via standard clinical methods were obtained from pathology reports. With overall and progression-free survival data, elastic net regularized Cox regression and Cox proportional hazards models were used to determine whether any mutations of unknown significance detected by FM could predict patient outcome in glioblastoma (GBM). RESULTS: Six hundred and three samples tested by FM from 565 distinct patients were identified. Concordance of diagnostic markers was high between standard clinical testing methods and FM. Oligodendroglial markers detected via FM were highly correlated with 1p19q codeletion in IDH mutated gliomas. FM testing of multiple tumor samples from the same patient demonstrated temporal and spatial mutational heterogeneity. Mutations in BCORL1, ERBB4, and PALB2, which are mutations of unknown significance in GBM, were shown to be statistically significant in predicting patient outcome. CONCLUSIONS: In our large cohort, we found that targeted NGS can both reliably and efficiently detect important diagnostic markers in CNS tumors.

Impact of Aortic Atherosclerosis Burden on Outcomes of Surgical Aortic Valve Replacement.

BACKGROUND: Epiaortic ultrasound detects and localizes ascending aortic atherosclerosis. In this analysis we investigated the association between epiaortic ultrasound-based atheroma grade during surgical aortic valve replacement (SAVR) and perioperative adverse outcomes. METHODS: SAVR patients in a randomized trial of 2 embolic protection devices underwent a protocol-defined 5-view epiaortic ultrasound read at a core laboratory. Aortic atherosclerosis was quantified with the Katz atheroma grade, and patients were categorized as mild (grade I-II) or moderate/severe (grade III-V). Multivariable logistic regression was used to estimate associations between atheroma grade and adverse outcomes, including death, clinically apparent stroke, cerebral infarction on diffusion-weighted magnetic resonance imaging, delirium, and acute kidney injury (AKI) by 7 and 30 days. RESULTS: Precannulation epiaortic ultrasound data were available for 326 of 383 randomized patients (85.1%). Of these, 106 (32.5%) had moderate/severe Katz atheroma grade at any segment of the ascending aorta. Although differences in the composite of death, stroke, or cerebral infarction on diffusion-weighted magnetic resonance imaging by 7 days were not statistically significant, moderate/severe atheroma grade was associated with a greater risk of AKI by 7 days (adjusted odds ratio, 2.63; 95% confidence interval, 1.24-5.58; P = .01). At 30 days, patients with moderate/severe atheroma grade had a greater risk of death, stroke, or AKI (adjusted odds ratio, 1.97; 95% confidence interval, 1.04-3.71; P = .04). CONCLUSIONS: Moderate/severe aortic atherosclerosis was associated with an increased risk of adverse events after SAVR. Epiaortic ultrasound may serve as a useful adjunct for identifying patients who may benefit from strategies to reduce atheroembolic complications during SAVR.

ICU Risk Stratification Models Feasible for Use in Sub-Saharan Africa Show Poor Discrimination in Malawi: A Prospective Cohort Study.

BACKGROUND: Critical illness disproportionately affects people in low-income countries (LICs). Efforts to improve critical care in LICs must account for differences in demographics and infrastructure compared to high-income settings. Part of this effort includes the development and validation of intensive care unit (ICU) risk stratification models feasible for use in LICs. The purpose of this study was to validate and compare the performance of ICU mortality models developed for use in sub-Saharan Africa. MATERIALS AND METHODS: This was a prospective, observational cohort study of ICU patients in a referral hospital in Malawi. Models were selected for comparison based on a Medline search for studies which developed ICU mortality models based on cohorts in sub-Saharan Africa. Model discrimination was evaluated using the area under the curve with 95% confidence intervals (CI). RESULTS: During the study, 499 patients were admitted to the study ICU, and after exclusions, there were 319 patients. The cohort was 62% female, with the mean age 31 years (IQR: 23-41), and 74% had surgery preceding ICU admission. Discrimination for hospital mortality ranged from 0.54 (95% CI 0.48, 0.60) for the Universal Vital Assessment (UVA) to 0.72 (95% CI 0.66, 0.78) for the Malawi Intensive care Mortality Evaluation (MIME). After tenfold cross-validation, these results were unchanged. CONCLUSIONS: The MIME outperformed other models in this prospective study. Most ICU models developed for LICs had poor to modest discrimination for hospital mortality. Future research may contribute to a better risk stratification model for LICs by refining and enhancing the MIME.

The role of doxycycline in the management of chronic rhinosinusitis with nasal polyps.

INTRODUCTION: Many theories on the pathophysiology of chronic rhinosinusitis with nasal polyposis (CRSwNP) exist. The most effective management of CRSwNP has not been elucidated. Doxycycline, which has anti-inflammatory and anti-bacterial properties, has shown durable effects; however, its efficacy in combination with standard therapy has not been examined. We hypothesized that its addition to the standard anti-inflammatory regimen would improve patient outcomes. METHODS: We performed a double-blind, placebo-controlled trial at a tertiary level institution. Patients with moderate or severe CRSwNP were randomized into two groups, each receiving a 20-day course of oral corticosteroids and doxycycline or placebo. The 22-item Sinonasal Outcome Test (SNOT-22), nasal polyp scores, and visual analog scale (VAS) scores were recorded at the initial, 3-, 8- and 12-week visits. RESULTS: 49 patients were enrolled, 24 in the experimental and 25 in the placebo group with 3 moderate disease patients in each group. There were 12 dropouts in the treatment group and 14 in the placebo group. The most common reasons for dropout were severe CRS and asthma exacerbations. There was no significant difference in SNOT-22 scores, nasal polyp scores, and VAS scores between the two arms. CONCLUSIONS: Non-surgical management of patients with CRSwNP remains challenging. Our conclusions are limited given the high dropout rate and thus, limited sample size with inadequate power. This study is important, however, because a high dropout rate of mostly severe disease patients may illustrate that this patient population may not be optimally managed with medical therapy alone.

Intraoperative Mortality in Malawi.

BACKGROUND: Surgical care is essential to improving population health, but metrics to monitor and evaluate the continuum of surgical care delivery have rarely been applied in low-resource settings, and improved efforts at benchmarking progress are needed. The objective of this study was to measure the intraoperative mortality at a Central Referral Hospital in Malawi, evaluate whether there have been changes in intraoperative mortality between 2 time periods, and assess factors associated with intraoperative mortality. METHODS: This was a retrospective cohort study of patients undergoing surgery at Kamuzu Central Hospital in Lilongwe, Malawi. Data describing daily consecutive operative cases were collected prospectively during 2 time periods: 2004-2006 (early cohort) and 2015-2016 (late cohort). The primary outcome was intraoperative mortality. Inverse probability of treatment weighting was used to analyze the association of intraoperative mortality with time using logistic regression models. Multivariable logistic models were performed to evaluate factors associated with intraoperative mortality. RESULTS: There were 21,090 surgeries performed during the 2 time periods, with 15,846 (75%) and 5244 (25%) completed from 2004 to 2006 and 2015 to 2016, respectively. Intraoperative mortality in the early cohort was 57 deaths per 100,000 surgeries (95% confidence interval [CI], 26-108) and in the late cohort was 133 per 100,000 surgeries (95% CI, 56-286), with 76 per 100,000 surgeries (95% CI, 44-124) overall. After applying inverse probability of treatment weighting, there was no evidence of an association between time periods and intraoperative mortality (odds ratio [OR], 1.6; 95% CI, 0.9-2.8; P = .08). Factors associated with intraoperative mortality, adjusting for demographics, included American Society of Anesthesiology physical status III or IV versus I or II (OR, 4.4; 95% CI, 1.5-12.5; P = .006) and emergency versus elective surgery (OR, 7.7; 95% CI, 2.5-23.6; P < .001). CONCLUSIONS: Intraoperative mortality in the study hospital in Malawi is high and has not improved over time. These data demonstrate an urgent need to improve the safety and quality of perioperative care in developing countries and integrate perioperative care into global health efforts.