Effect of Preoperative Bilateral Ultrasound-guided Quadratus Lumborum Nerve Block on Quality of Recovery after Minimally Invasive Hysterectomy in an Enhanced Recovery after Surgery (ERAS) Setting.

STUDY OBJECTIVE: To assess the effect of preoperative bilateral ultrasound-guided quadratus lumborum nerve block (QLB) on quality of recovery after minimally invasive hysterectomy, in an enhanced recovery after surgery setting. DESIGN: Randomized, controlled, double-blinded trial (Canadian Task Force level I). SETTING: University-affiliated tertiary medical center. PATIENTS: All women undergoing an elective robotic or laparoscopic hysterectomy. Women with chronic pain, chronic anticoagulation, and body mass index >50 kg/m2 were excluded. INTERVENTION: Patients were randomized with a 1:1 allocation, to one of the following 2 arms, and stratified based on robotic versus laparoscopic approach. 1. QLB: QLB (bupivacaine) + sham local trocar sites infiltration (normal saline) 2. Local infiltration: sham QLB (normal saline) + local infiltration (bupivacaine) MEASUREMENTS AND MAIN RESULTS: The primary outcome was defined as the quality of recovery score based on the validated questionnaire Quality of Recovery, completed 24 hours postoperatively. Secondary outcomes included dynamic pain scores, accumulated opioid consumption up to 24 hours, postoperative nausea and vomiting, surgical complications, length of hospital stay, time to first pain medication administration in the postanesthesia care unit, and adverse events. A total of 76 women were included in the study. Demographic characteristics were similar in both groups. Median age was 44 years (interquartile range 39-50), 47% of the participants were African American, and mean body mass index was 32.8 kg/m2 (standard deviation [SD] 8.1). The mean Quality of Recovery score was 179.1 (SD ± 10.3) in the QLB and 175.6 (SD ± 9.7) for the local anesthesia group (p = .072). All secondary outcomes were comparable between groups. CONCLUSIONS: QLBs do not significantly improve quality of recovery after elective robotic or laparoscopic hysterectomy compared with local anesthetic port site infiltration.

Endothelial-specific telomerase inactivation causes telomere-independent cell senescence and multi-organ dysfunction characteristic of aging.

It has remained unclear how aging of endothelial cells (EC) contributes to pathophysiology of individual organs. Cell senescence results in part from inactivation of telomerase (TERT). Here, we analyzed mice with Tert knockout specifically in EC. Tert loss in EC induced transcriptional changes indicative of senescence and tissue hypoxia in EC and in other cells. We demonstrate that EC-Tert-KO mice have leaky blood vessels. The blood-brain barrier of EC-Tert-KO mice is compromised, and their cognitive function is impaired. EC-Tert-KO mice display reduced muscle endurance and decreased expression of enzymes responsible for oxidative metabolism. Our data indicate that Tert-KO EC have reduced mitochondrial content and function, which results in increased dependence on glycolysis. Consistent with this, EC-Tert-KO mice have metabolism changes indicative of increased glucose utilization. In EC-Tert-KO mice, expedited telomere attrition is observed for EC of adipose tissue (AT), while brain and skeletal muscle EC have normal telomere length but still display features of senescence. Our data indicate that the loss of Tert causes EC senescence in part through a telomere length-independent mechanism undermining mitochondrial function. We conclude that EC-Tert-KO mice is a model of expedited vascular senescence recapitulating the hallmarks aging, which can be useful for developing revitalization therapies.

Hepatic circadian and differentiation factors control liver susceptibility for fatty liver disease and tumorigenesis.

Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options for advanced HCC are limited, but improved tumor stratification could open the door to new treatment options. Previously, we demonstrated that the circadian regulator Aryl Hydrocarbon-Like Receptor Like 1 (ARNTL, or Bmal1) and the liver-enriched nuclear factor 4 alpha (HNF4α) are robustly co-expressed in healthy liver but incompatible in the context of HCC. Faulty circadian expression of HNF4α- either by isoform switching, or loss of expression- results in an increased risk for HCC, while BMAL1 gain-of-function in HNF4α-positive HCC results in apoptosis and tumor regression. We hypothesize that the transcriptional programs of HNF4α and BMAL1 are antagonistic in liver disease and HCC. Here, we study this antagonism by generating a mouse model with inducible loss of hepatic HNF4α and BMAL1 expression. The results reveal that simultaneous loss of HNF4α and BMAL1 is protective against fatty liver and HCC in carcinogen-induced liver injury and in the "STAM" model of liver disease. Furthermore, our results suggest that targeting Bmal1 expression in the absence of HNF4α inhibits HCC growth and progression. Specifically, pharmacological suppression of Bmal1 in HNF4α-deficient, BMAL1-positive HCC with REV-ERB agonist SR9009 impairs tumor cell proliferation and migration in a REV-ERB-dependent manner, while having no effect on healthy hepatocytes. Collectively, our results suggest that stratification of HCC based on HNF4α and BMAL1 expression may provide a new perspective on HCC properties and potential targeted therapeutics.

Cellular and physiological circadian mechanisms drive diurnal cell proliferation and expansion of white adipose tissue.

Hyperplastic expansion of white adipose tissue (WAT) relies in part on the proliferation of adipocyte precursor cells residing in the stromal vascular cell fraction (SVF) of WAT. This study reveals a circadian clock- and feeding-induced diurnal pattern of cell proliferation in the SVF of visceral and subcutaneous WAT in vivo, with higher proliferation of visceral adipocyte progenitor cells subsequent to feeding in lean mice. Fasting or loss of rhythmic feeding eliminates this diurnal proliferation, while high fat feeding or genetic disruption of the molecular circadian clock modifies the temporal expression of proliferation genes and impinges on diurnal SVF proliferation in eWAT. Surprisingly, high fat diet reversal, sufficient to reverse elevated SVF proliferation in eWAT, was insufficient in restoring diurnal patterns of SVF proliferation, suggesting that high fat diet induces a sustained disruption of the adipose circadian clock. In conclusion, the circadian clock and feeding simultaneously impart dynamic, regulatory control of adipocyte progenitor proliferation, which may be a critical determinant of adipose tissue expansion and health over time.