Tumor-derived hypoxic small extracellular vesicles promote endothelial cell migration and tube formation via ALS2/Rab5/ß-catenin signaling.

Tumor hypoxia has been associated with cancer progression, angiogenesis, and metastasis via modifications in the release and cargo composition of extracellular vesicles secreted by tumor cells. Indeed, hypoxic extracellular vesicles are known to trigger a variety of angiogenic responses via different mechanisms. We recently showed that hypoxia promotes endosomal signaling in tumor cells via HIF-1α-dependent induction of the guanine exchange factor ALS2, which activates Rab5, leading to downstream events involved in cell migration and invasion. Since Rab5-dependent signaling is required for endothelial cell migration and angiogenesis, we explored the possibility that hypoxia promotes the release of small extracellular vesicles containing ALS2, which in turn activate Rab5 in recipient endothelial cells leading to pro-angiogenic properties. In doing so, we found that hypoxia promoted ALS2 expression and incorporation as cargo within small extracellular vesicles, leading to subsequent transfer to recipient endothelial cells and promoting cell migration, tube formation, and downstream Rab5 activation. Consequently, ALS2-containing small extracellular vesicles increased early endosome size and number in recipient endothelial cells, which was followed by subsequent sequestration of components of the ß-catenin destruction complex within endosomal compartments, leading to stabilization and nuclear localization of ß-catenin. These events converged in the expression of ß-catenin target genes involved in angiogenesis. Knockdown of ALS2 in donor tumor cells precluded its incorporation into small extracellular vesicles, preventing Rab5-downstream events and endothelial cell responses, which depended on Rab5 activity and guanine exchange factor activity of ALS2. These findings indicate that vesicular ALS2, secreted in hypoxia, promotes endothelial cell events leading to angiogenesis. Finally, these events might explain how tumor angiogenesis proceeds in hypoxic conditions.

Use of Peripheral Nerve Blocks for Total hip Arthroplasty.

PURPOSE OF REVIEW: The purpose of this review is to summarize the recent literature regarding regional anesthesia (RA) techniques and outcomes for total hip arthroplasty (THA) in the face of changing surgical techniques and perioperative considerations. RECENT FINDINGS: Based on large meta-analyses, peripheral nerve blocks are indicated for THA. Each block has its own risks and benefits and data for outcomes for particular techniques are limited. New surgical techniques, improved use of multimodal analgesia, and improved ultrasound guided regional anesthetics lead to better pain control for patients undergoing THA with less associated risks. Block selection continues to be influenced by provider comfort, surgical approach, patient anatomy, and postoperative goals. Head-to-head studies of particular nerve blocks are warranted.

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.

Critical care innovations: navigating pain relief in intensive care: the role of regional anesthesia.

PURPOSE OF REVIEW: The purpose of this article is to provide an update of regional anesthesia and its applications in the critical care patient population. RECENT FINDINGS: Regional anesthesia including blocks of the abdomen and thorax, head and neck, as well as upper and lower extremities can be used to alleviate pain and assist in managing life-threatening conditions such as cerebral vasospasm and ventricular storm in the ICU population. There have been many advances in these techniques including ultrasound-guidance with innovative approaches that allow for more superficial procedures that are safer for critically ill patients. Regional anesthesia can decrease hospital length of stay (LOS), prevent ICU admission, shorten ICU LOS, and increase ventilator free days and may have mortality benefits. SUMMARY: Pain management in the ICU is an important and sometimes challenging aspect of patient care. Regional anesthetic techniques have more indications and are safe, versatile tools that should be incorporated into care of critically ill patients.

Assistive artificial intelligence for ultrasound image interpretation in regional anaesthesia: an external validation study.

BACKGROUND: Ultrasonound is used to identify anatomical structures during regional anaesthesia and to guide needle insertion and injection of local anaesthetic. ScanNav Anatomy Peripheral Nerve Block (Intelligent Ultrasound, Cardiff, UK) is an artificial intelligence-based device that produces a colour overlay on real-time B-mode ultrasound to highlight anatomical structures of interest. We evaluated the accuracy of the artificial-intelligence colour overlay and its perceived influence on risk of adverse events or block failure. METHODS: Ultrasound-guided regional anaesthesia experts acquired 720 videos from 40 volunteers (across nine anatomical regions) without using the device. The artificial-intelligence colour overlay was subsequently applied. Three more experts independently reviewed each video (with the original unmodified video) to assess accuracy of the colour overlay in relation to key anatomical structures (true positive/negative and false positive/negative) and the potential for highlighting to modify perceived risk of adverse events (needle trauma to nerves, arteries, pleura, and peritoneum) or block failure. RESULTS: The artificial-intelligence models identified the structure of interest in 93.5% of cases (1519/1624), with a false-negative rate of 3.0% (48/1624) and a false-positive rate of 3.5% (57/1624). Highlighting was judged to reduce the risk of unwanted needle trauma to nerves, arteries, pleura, and peritoneum in 62.9-86.4% of cases (302/480 to 345/400), and to increase the risk in 0.0-1.7% (0/160 to 8/480). Risk of block failure was reported to be reduced in 81.3% of scans (585/720) and to be increased in 1.8% (13/720). CONCLUSIONS: Artificial intelligence-based devices can potentially aid image acquisition and interpretation in ultrasound-guided regional anaesthesia. Further studies are necessary to demonstrate their effectiveness in supporting training and clinical practice. CLINICAL TRIAL REGISTRATION: NCT04906018.

The Use of Peripheral Nerve Blockade in Laparoscopic and Robotic Surgery: Is There a Benefit?

PURPOSE OF REVIEW: The purpose of this review is to synthesize recent literature investigating the use of regional anesthesia for minimally invasive surgery. RECENT FINDINGS: Recent studies investigating the use of newer peripheral nerve blocks such as erector spinae plane (ESP) and quadratus lumborum (QL) block are very limited. Evidence supporting the use of peripheral nerve blockade in laparoscopic or robotic surgery is very limited and of low-moderate quality. While transverse abdominal plane (TAP) block may decrease opioid and pain scores after laparoscopic cholecystectomy, bariatric surgery, and colorectal surgery, the benefit of the block in the presence of multimodal analgesia remains to be clarified. Unilateral paravertebral block may be beneficial for percutaneous nephrolithotomy. ESP and rectus sheath blockade may enhance analgesia in laparoscopic surgery, but the magnitude of this benefit may not be clinically relevant. Limited evidence supports the use of QL block in laparoscopic urologic surgery. There is insufficient recent evidence to support the use of TAP or QL block for laparoscopic gynecologic surgery.

Mechanical Disturbance of Osteoclasts Induces ATP Release That Leads to Protein Synthesis in Skeletal Muscle through an Akt-mTOR Signaling Pathway.

Muscle and bone are tightly integrated through mechanical and biochemical signals. Osteoclasts are cells mostly related to pathological bone loss; however, they also start physiological bone remodeling. Therefore, osteoclast signals released during bone remodeling could improve both bone and skeletal muscle mass. Extracellular ATP is an autocrine/paracrine signaling molecule released by bone and muscle cells. Then, in the present work, it was hypothesized that ATP is a paracrine mediator released by osteoclasts and leads to skeletal muscle protein synthesis. RAW264.7-derived osteoclasts were co-cultured in Transwell® chambers with flexor digitorum brevis (FDB) muscle isolated from adult BalbC mice. The osteoclasts at the upper chamber were mechanically stimulated by controlled culture medium perturbation, resulting in a two-fold increase in protein synthesis in FDB muscle at the lower chamber. Osteoclasts released ATP to the extracellular medium in response to mechanical stimulation, proportional to the magnitude of the stimulus and partly dependent on the P2X7 receptor. On the other hand, exogenous ATP promoted Akt phosphorylation (S473) in isolated FDB muscle in a time- and concentration-dependent manner. ATP also induced phosphorylation of proteins downstream Akt: mTOR (S2448), p70S6K (T389) and 4E-BP1 (T37/46). Exogenous ATP increased the protein synthesis rate in FDB muscle 2.2-fold; this effect was blocked by Suramin (general P2X/P2Y antagonist), LY294002 (phosphatidylinositol 3 kinase inhibitor) and Rapamycin (mTOR inhibitor). These blockers, as well as apyrase (ATP metabolizing enzyme), also abolished the induction of FDB protein synthesis evoked by mechanical stimulation of osteoclasts in the co-culture model. Therefore, the present findings suggest that mechanically stimulated osteoclasts release ATP, leading to protein synthesis in isolated FDB muscle, by activating the P2-PI3K-Akt-mTOR pathway. These results open a new area for research and clinical interest in bone-to-muscle crosstalk in adaptive processes related to muscle use/disuse or in musculoskeletal pathologies.

Axillary Impella insertion under regional nerve block: A case report.

Percutaneous coronary interventions with the Impella (Abiomed, MA) catheter-based, micro-axial mechanical left ventricular assist device is a safe option for patients undergoing higher risk interventions. However, severe peripheral arterial disease limits vascular access for Impella insertion. Upper extremity arterial access has been traditionally obtained under general anesthesia. We present the first case, to our knowledge, of using peripheral nerve blocks for Impella 3.5 CP insertion into the axillary artery.

The pupil: a window on social automatic processing in autism spectrum disorder children.

BACKGROUND: Faces are crucial social stimuli, eliciting automatic processing associated with increased physiological arousal in observers. The level of arousal can be indexed by pupil diameter (the 'Event-Related Pupil Dilation', ERPD). However, many parameters could influence the arousal evoked by a face and its social saliency (e.g. virtual vs. real, neutral vs. emotional, static vs. dynamic). A few studies have shown an atypical ERPD in autism spectrum disorder (ASD) patients using several kinds of faces but no study has focused on identifying which parameter of the stimulus is the most interfering with face processing in ASD. METHODS: In order to disentangle the influence of these parameters, we propose an original paradigm including stimuli along an ecological social saliency gradient: from static objects to virtual faces to dynamic emotional faces. This strategy was applied to 186 children (78 ASD and 108 typically developing (TD) children) in two pupillometric studies (22 ASD and 47 TD children in the study 1 and 56 ASD and 61 TD children in the study 2). RESULTS: Strikingly, the ERPD in ASD children is insensitive to any of the parameters tested: the ERPD was similar for objects, static faces or dynamic faces. On the opposite, the ERPD in TD children is sensitive to all the parameters tested: the humanoid, biological, dynamic and emotional quality of the stimuli. Moreover, ERPD had a good discriminative power between ASD and TD children: ASD had a larger ERPD than TD in response to virtual faces, while TD had a larger ERPD than ASD for dynamic faces. CONCLUSIONS: This novel approach evidences an abnormal physiological adjustment to socially relevant stimuli in ASD.

Case Report: Treatment of Refractory Post-Surgical Neuralgia With Erector Spinae Plane Block.

BACKGROUND: Peripheral nerve blocks (PNBs) are used for a wide spectrum of headache and facial pain disorders. The objective of this case report is to highlight the erector spinae plane (ESP) block, which has recently been reported to successfully treat headache. CASE PRESENTATION: A 70-year-old man with a history of mild to moderate headaches, previously ruptured aneurysm, and right pterional craniotomy and clipping of an anterior communicating artery aneurysm presented with exacerbation of chronic post-surgical scalp pain and severe headache with nausea. Results of the physical examination were not consistent with cellulitis of the scalp, complete blood count and chemistry panel results were unremarkable, and imaging revealed an intact aneurysm clip. Given the severe unilateral throbbing pain with associated nausea, he was treated with a variety of migraine abortives and other pain medications without significant relief. ESP block was performed. He tolerated the procedure well without complications. His pain decreased to 2/10 from a baseline of 9 to 10/10 30 minutes after the procedure, and he was pain free the next day. Follow-up revealed a return of his pain 1 to 2 weeks after the procedure, which prompted follow-up with an outpatient pain management specialist. CONCLUSION: PNBs, ESP block in our case, can be a useful modality in managing chronic neuralgiform pain for treatment-refractory patients. It can provide improvement in quality of life and spare the patient from medication side effects. In an inpatient setting, it can decrease length of stay that would otherwise be extended due to a trial of multiple medications until the pain was controlled. PNBs are used for a wide spectrum of headache and facial pain disorders. This case report highlights successful management of chronic neuralgiform pain with the ESP block, which has recently been reported to successfully treat headache. ESP block provided relief to the patient's neuralgiform pain that was refractory to multiple medications, resulting in decreased length of stay, fewer medication side effects, and improved quality of life. It also provided a window for initiation of long-term pain medications.