Low-intensity pulsed ultrasound improves myocardial ischaemia‒reperfusion injury via migrasome-mediated mitocytosis.

During myocardial ischaemia‒reperfusion injury (MIRI), the accumulation of damaged mitochondria could pose serious threats to the heart. The migrasomes, newly discovered mitocytosis-mediating organelles, selectively remove damaged mitochondria to provide mitochondrial quality control. Here, we utilised low-intensity pulsed ultrasound (LIPUS) on MIRI mice model and demonstrated that LIPUS reduced the infarcted area and improved cardiac dysfunction. Additionally, we found that LIPUS alleviated MIRI-induced mitochondrial dysfunction. We provided new evidence that LIPUS mechanical stimulation facilitated damaged mitochondrial excretion via migrasome-dependent mitocytosis. Inhibition the formation of migrasomes abolished the protective effect of LIPUS on MIRI. Mechanistically, LIPUS induced the formation of migrasomes by evoking the RhoA/Myosin II/F-actin pathway. Meanwhile, F-actin activated YAP nuclear translocation to transcriptionally activate the mitochondrial motor protein KIF5B and Drp1, which are indispensable for LIPUS-induced mitocytosis. These results revealed that LIPUS activates mitocytosis, a migrasome-dependent mitochondrial quality control mechanism, to protect against MIRI, underlining LIPUS as a safe and potentially non-invasive treatment for MIRI.

Ultrasound-guided suprainguinal fascia iliaca compartment block and early postoperative analgesia after total hip arthroplasty: a randomised controlled trial.

BACKGROUND: Hip replacement surgery can be painful; postoperative analgesia is crucial for comfort and to facilitate recovery. Regional anaesthesia can reduce pain and postoperative opioid requirements. The role of ultrasound-guided suprainguinal fascia iliaca block for analgesia after elective total hip arthroplasty is not well defined. This randomised trial evaluated its analgesic efficacy. METHODS: Consenting participants (134) scheduled for elective primary total hip arthroplasty under spinal anaesthesia were randomly allocated to receive ultrasound-guided fascia iliaca block with ropivacaine 0.5% or sham block with saline. The primary outcome was opioid consumption in the first 24 h after surgery. Additional outcomes included pain scores at 4, 8, 12, and 16 h, opioid-related side-effects (nausea, vomiting, pruritis), ability to perform physiotherapy on the first postoperative day, and physiotherapist-assessed quadriceps weakness. RESULTS: There were no significant differences in 24-h opioid consumption (block vs sham block, mean difference -3.2 mg oral morphine equivalent, 95% confidence interval -15.3 to 8.1 mg oral morphine equivalent, P=0.55) or any other prespecified outcomes. CONCLUSIONS: In patients undergoing primary total hip arthroplasty, ultrasound-guided suprainguinal fascia iliaca block with ropivacaine did not confer a significant opioid-sparing effect compared with sham block. There were no differences in other secondary outcomes including pain scores, opioid-related side-effects, or ability to perform physiotherapy on the first postoperative day. CLINICAL TRIAL REGISTRATION: www. CLINICALTRIALS: gov (NCT03069183).

Low-intensity pulsed ultrasound protects from inflammatory dilated cardiomyopathy through inciting extracellular vesicles.

AIMS: CD4+ T cells are activated during inflammatory dilated cardiomyopathy (iDCM) development to induce immunogenic responses that damage the myocardium. Low-intensity pulsed ultrasound (LIPUS), a novel physiotherapy for cardiovascular diseases, has recently been shown to modulate inflammatory responses. However, its efficacy in iDCM remains unknown. Here, we investigated whether LIPUS could improve the severity of iDCM by orchestrating immune responses and explored its therapeutic mechanisms. METHODS AND RESULTS: In iDCM mice, LIPUS treatment reduced cardiac remodelling and dysfunction. Additionally, CD4+ T-cell inflammatory responses were suppressed. LIPUS increased Treg cells while decreasing Th17 cells. LIPUS mechanically stimulates endothelial cells, resulting in increased secretion of extracellular vesicles (EVs), which are taken up by CD4+ T cells and alter their differentiation and metabolic patterns. Moreover, EVs selectively loaded with microRNA (miR)-99a are responsible for the therapeutic effects of LIPUS. The hnRNPA2B1 translocation from the nucleus to the cytoplasm and binding to caveolin-1 and miR-99a confirmed the upstream mechanism of miR-99a transport. This complex is loaded into EVs and taken up by CD4+ T cells, which further suppress mTOR and TRIB2 expression to modulate cellular differentiation. CONCLUSION: Our findings revealed that LIPUS uses an EVs-dependent molecular mechanism to protect against iDCM progression. Therefore, LIPUS is a promising new treatment option for iDCM.

Prevention of persistent pain with lidocaine infusions in breast cancer surgery (PLAN): study protocol for a multicenter randomized controlled trial.

BACKGROUND: Persistent pain is a common yet debilitating complication after breast cancer surgery. Given the pervasive effects of this pain disorder on the patient and healthcare system, post-mastectomy pain syndrome (PMPS) is becoming a larger population health problem, especially as the prognosis and survivorship of breast cancer increases. Interventions that prevent persistent pain after breast surgery are needed to improve the quality of life of breast cancer survivors. An intraoperative intravenous lidocaine infusion has emerged as a potential intervention to decrease the incidence of PMPS. We aim to determine the definitive effects of this intervention in patients undergoing breast cancer surgery. METHODS: PLAN will be a multicenter, parallel-group, blinded, 1:1 randomized, placebo-controlled trial of 1,602 patients undergoing breast cancer surgery. Adult patients scheduled for a lumpectomy or mastectomy will be randomized to receive an intravenous 2% lidocaine bolus of 1.5 mg/kg with induction of anesthesia, followed by a 2.0 mg/kg/h infusion until the end of surgery, or placebo solution (normal saline) at the same volume. The primary outcome will be the incidence of persistent pain at 3 months. Secondary outcomes include the incidence of pain and opioid consumption at 1 h, 1-3 days, and 12 months after surgery, as well as emotional, physical, and functional parameters, and cost-effectiveness. DISCUSSION: This trial aims to provide definitive evidence on an intervention that could potentially prevent persistent pain after breast cancer surgery. If this trial is successful, lidocaine infusion would be integrated as standard of care in breast cancer management. This inexpensive, widely available, and easily administered intervention has the potential to reduce pain and suffering in an already afflicted patient population, decrease the substantial costs of chronic pain management, potentially decrease opioid use, and improve the quality of life in patients. TRIAL REGISTRATION: This trial has been registered on clinicaltrials.gov (NCT04874038, Dr. James Khan. Date of registration: May 5, 2021).

Randomized control trial of a holographic needle guidance technique for thoracic epidural placement.

INTRODUCTION: The Microsoft HoloLens is a head-mounted mixed reality device, which allows for overlaying hologram-like computer-generated elements onto the real world. This technology can be combined with preprocedural ultrasound during thoracic epidural placement to create a visual of the ideal needle angulation and trajectory in the users' field of view. This could result in a technically easier and potentially safer alternative to traditional blind landmark techniques. METHODS: Patients were randomly assigned to one of two groups: (1) HoloLens-assisted thoracic epidural technique (intervention-group H) or (2) traditional thoracic epidural technique (control-group C). The primary outcome was needling time (defined as skin puncture to insertion of epidural catheter) during the procedure. The secondary outcomes were number of needle punctures, number of needle movements, number of bone contacts, and epidural failure. Procedural pain and recovery room pain levels were also evaluated. RESULTS: Eighty-three patients were included in this study. The primary outcome of procedure time was reduced in the HoloLens group compared with control (4.5 min vs 7.3 min, p=0.02, 95% CI), as was the number of needle movements required (7.2 vs 14.4, p=0.01), respectively. There was no difference in intraprocedure or postprocedure pain, bone contacts, or total number of needle punctures. Three patients in the control group experienced epidural failure versus one patient in the HoloLens group. CONCLUSIONS: This study shows that thoracic epidural placement may be facilitated by using a guidance hologram and may be more technically efficient. TRIAL REGISTRATION NUMBER: NCT04028284.

Protective effect of low-intensity pulsed ultrasound on immune checkpoint inhibitor-related myocarditis via fine-tuning CD4+ T-cell differentiation.

PURPOSE: Immune checkpoint inhibitors (ICIs) have transformed traditional cancer treatments. Specifically, ICI-related myocarditis is an immune-related adverse event (irAE) with high mortality. ICIs activate CD4+ T-lymphocyte reprogramming, causing an imbalance between Th17 and Treg cell differentiation, ultimately leading to myocardial inflammatory damage. Low-intensity pulsed ultrasound (LIPUS) can limit inflammatory responses, with positive therapeutic effects across various cardiovascular inflammatory diseases; however, its role in the pathogenesis of ICI-related myocarditis and CD4+ T-cell dysfunction remains unclear. Accordingly, this study investigated whether LIPUS can alleviate ICI-related myocarditis inflammatory damage and, if so, aimed to elucidate the beneficial effects of LIPUS and its underlying molecular mechanisms. METHODS: An in vivo model of ICI-related myocarditis was obtained by intraperitonially injecting male A/J mice with an InVivoPlus anti-mouse PD-1 inhibitor. LIPUS treatment was performed via an ultrasound-guided application to the heart via the chest wall. The echocardiographic parameters were observed and cardiac function was assessed using an in vivo imaging system. The expression of core components of the HIPPO pathway was analyzed via western blotting. RESULTS: LIPUS treatment reduced cardiac immune responses and inflammatory cardiac injury. Further, LIPUS treatment alleviated the inflammatory response in mice with ICI-related myocarditis. Mechanistically, in the HIPPO pathway, the activation of Mst1-TAZ axis improved autoimmune inflammation by altering the interaction between the transcription factors FOXP3 and RORγt and regulating the differentiation of Treg and Th17 cells. CONCLUSION: LIPUS therapy was shown to reduce ICI-related myocarditis inflammatory damage and improve cardiac function, representing an exciting finding for irAEs treatment.

Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium (B-Free): A Protocol for a Multi-centre Randomized Cluster Crossover Trial.

Delirium is common after cardiac surgery and is associated with adverse outcomes. Administration of benzodiazepines before and after cardiac surgery is associated with delirium; guidelines recommend minimizing their use. Benzodiazepine administration during cardiac surgery remains common because of its recognized benefits. The Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium (B-Free) trial is a randomized cluster crossover trial evaluating whether an institutional policy of restricting intraoperative benzodiazepine administration (ie, ≥ 90% of patients do not receive benzodiazepines during cardiac surgery), as compared with a policy of liberal intraoperative benzodiazepine administration (ie, ≥ 90% of patients receive ≥ 0.03 mg/kg midazolam equivalent), reduces delirium. Hospitals performing ≥ 250 cardiac surgeries a year are included if their cardiac anesthesia group agrees to apply both benzodiazepine policies per their randomization, and patients are assessed for postoperative delirium every 12 hours in routine clinical care. Hospitals apply the restricted or liberal benzodiazepine policy during 12 to 18 crossover periods of 4 weeks each. Randomization for all periods takes place in advance of site startup; sites are notified of their allocated policy during the last week of each crossover period. Policies are applied to all patients undergoing cardiac surgery during the trial period. The primary outcome is the incidence of delirium at up to 72 hours after surgery. The B-Free trial will enroll ≥ 18,000 patients undergoing cardiac surgery at 20 hospitals across North America. Delirium is common after cardiac surgery, and benzodiazepines are associated with the occurrence of delirium. The B-Free trial will determine whether an institutional policy restricting the administration of benzodiazepines during cardiac surgery reduces the incidence of delirium after cardiac surgery. Clinicaltrials.gov registration number: NCT03928236 (First registered April 26, 2019).

L'état confusionnel est fréquent après une chirurgie cardiaque et il est associé à des complications. L'administration de benzodiazépines avant et après une chirurgie cardiaque est associée à l'état confusionnel; dans les lignes directrices, on recommande de réduire leur utilisation au minimum. L'administration de benzodiazépines pendant une chirurgie cardiaque demeure fréquente, en raison des leurs bienfaits reconnus. L'essai B-Free (Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium ou l'anesthésie sans benzodiazépine en contexte de chirurgie cardiaque pour la réduction de l'état confusionnel postopératoire) est un essai à répartition aléatoire par grappes et avec permutation, visant à évaluer si une politique institutionnelle de restriction de l'administration peropératoire de benzodiazépines (c.-à-d. que ≥ 90 % des patients ne reçoivent pas de benzodiazépines durant une chirurgie cardiaque) réduit l'état confusionnel, comparativement à une politique d'administration peropératoire libérale de benzodiazépines (c.-à-d. que ≥ 90 % des patients reçoivent ≥ 0,03 mg/kg d'équivalent du midazolam). Des hôpitaux effectuant au moins 250 chirurgies cardiaques par année sont inclus dans l'essai si leurs équipes d'anesthésie cardiaque acceptent d'appliquer les deux politiques relatives aux benzodiazépines en vertu de la répartition aléatoire et si les patients sont évalués toutes les 12 heures, en ce qui a trait à l'état confusionnel postopératoire, dans le cadre des soins cliniques habituels. Les hôpitaux mettent en œuvre la politique d'administration restreinte ou libérale de benzodiazépines durant 12 à 18 périodes de permutation de 4 semaines chacune. La répartition aléatoire de l'ensemble des périodes a lieu avant le début de l'essai à l'hôpital; les établissements sont avisés de la politique qui leur est attribuée au cours de la dernière semaine de chaque période de permutation. Les politiques sont appliquées à tous les patients qui subissent une chirurgie cardiaque durant la période de l'essai. Le critère d'évaluation principal est l'incidence de l'état confusionnel dans les 72 heures suivant l'intervention chirurgicale. L'étude B-Free inclura au moins 18 000 patients qui subiront une chirurgie cardiaque dans 20 hôpitaux en l'Amérique du Nord. L'état confusionnel est fréquent après une chirurgie cardiaque, et les benzodiazépines sont associées à la survenue de l'état confusionnel. L'essai B-Free permettra de déterminer si une politique institutionnelle de restriction de l'administration de benzodiazépines durant une chirurgie cardiaque réduit l'incidence de l'état confusionnel après une telle chirurgie.Clinicaltrials.gov registration number: NCT03928236 (First registered April 26, 2019).

Preoperative assessment of postoperative delirium: a cross-sectional study of patients and anesthesiologists in Canada.

PURPOSE: We sought to evaluate 1) patient- and anesthesiologist-reported rates of postoperative delirium (POD) risk discussion during preoperative meetings, 2) patients' and anesthesiologists' ratings of the importance of POD, and 3) predictors of patient-reported discussion of POD risk during preoperative meetings. METHODS: In this multicentre two-part cross-sectional survey study, patients ≥ 65 yr scheduled to undergo elective noncardiac surgery completed a five-minute survey after preoperative anesthesia consultation. Patients were asked about their perception of POD importance, and whether they discussed or were assessed for POD risk. Anesthesiologists were surveyed using self-administered surveys circulated via institutional email lists. Anesthesiologists were asked about the frequency of POD risk assessment and discussion in older adults, tools used, and perception of POD-screening barriers. RESULTS: Four hundred and twelve (of 510 approached) patients (50% male; mean age, 73 yr) and 267 anesthesiologists (of 1,205 invited via e-mail) participated in this study conducted in five Canadian hospitals. Postoperative delirium screening and discussion was reported by 88/412 (22%) patients and 229/267 (86%) anesthesiologists. Postoperative delirium was rated as "somewhat-extremely" important by 64% of patients. A previous history of delirium, higher education, the number of daily medications, and longer surgical duration were associated with POD discussion. On average, anesthesiologists rated the importance of POD at 8/10, and 42% ranked "patient risk factors" as the top reason prompting discussion. CONCLUSION: The combined evaluation of patients' and anesthesiologists' perspectives provides valuable information on preoperative POD screening and risk assessment, and highlights areas for improvement in the current practice. Most factors we identified to be associated with higher odds of POD discussion are recognized risk factors of POD.

RéSUMé: OBJECTIF: Nous avons cherché à évaluer 1) les taux de discussion concernant le risque de delirium postopératoire (DPO) déclarés par les patient·es et les anesthésiologistes lors des rencontres préopératoires, 2) les évaluations des patient·es et des anesthésiologistes de l'importance de DPO, et 3) les prédicteurs d'une discussion telle que rapportée par les patient·es sur le risque de DPO pendant les rencontres préopératoires. MéTHODE: Dans ce sondage transversal multicentrique en deux parties, les patient·es ≥ 65 ans devant subir une chirurgie non cardiaque non urgente ont rempli un sondage de cinq minutes après la consultation d'anesthésie préopératoire. Les patient·es ont été interrogé·es sur leur perception de l'importance du DPO et si leur risque de DPO avait été discuté ou évalué. Des sondages auto-administrés ont été distribués aux anesthésiologistes via les listes de courriels institutionnelles. Ce sondage interrogeait les anesthésiologistes quant à la fréquence de l'évaluation et de la discussion des risques de DPO chez les personnes âgées, aux outils utilisés et à la perception des obstacles au dépistage de DPO. RéSULTATS: Quatre cent douze (des 510 personnes approchées) patient·es (50 % d'hommes; âge moyen, 73 ans) et 267 anesthésiologistes (sur 1205 invité·es par courriel) ont participé à cette étude menée dans cinq hôpitaux canadiens. Le dépistage et la discussion sur le delirium postopératoire ont été signalés par 88/412 (22 %) des patient·es et 229/267 (86 %) des anesthésiologistes. Le delirium postopératoire a été jugé « assez ­ extrêmement ¼ important par 64 % des patient·es. Des antécédents de delirium, des études supérieures, le nombre de médicaments quotidiens et une durée chirurgicale plus longue ont été associés à la discussion sur le DPO. En moyenne, les anesthésiologistes ont évalué l'importance du DPO à 8/10, et 42 % ont classé les « facteurs de risque liés au/à la patient·e ¼ comme la principale raison suscitant la discussion. CONCLUSION: L'évaluation combinée des points de vue des patient·es et des anesthésiologistes fournit des informations précieuses sur le dépistage préopératoire des DPO et l'évaluation des risques, et met en évidence les domaines à améliorer dans la pratique actuelle. La plupart des facteurs que nous avons identifiés comme étant associés à des probabilités plus élevées de discussion sur le DPO sont des facteurs de risque reconnus de DPO.

General versus loco-regional anesthesia for endovascular aortic aneurysm repair.

BACKGROUND: Aortic aneurysms occur when the aorta, the body's largest artery, grows in size, and can occur in the thoracic or abdominal aorta. The approaches to repair aortic aneurysms include directly exposing the aorta and replacing the diseased segment via open repair, or endovascular repair. Endovascular repair uses fluoroscopic-guidance to access the aorta and deliver a device to exclude the aneurysmal aortic segment without requiring a large surgical incision. Endovascular repair can be performed under a general anesthetic, during which the unconscious patient is paralyzed and reliant on an anesthetic machine to maintain the airway and provide oxygen to the lungs, or a loco-regional anesethetic, for which medications are administered to provide the person with sufficient sedation and pain control without requiring a general anesthetic. While people undergoing general anesthesia are more likely to remain still during surgery and have a well-controlled airway in the event of unanticipated complications, loco-regional anesthesia is associated with fewer postoperative complications in some studies. It remains unclear which anesthetic technique is associated with better outcomes following the endovascular repair of aortic aneurysms. OBJECTIVES: To evaluate the benefits and harms of general anesthesia compared to loco-regional anesthesia for endovascular aortic aneurysm repair. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search was 11 March 2022. SELECTION CRITERIA: We searched for all randomized controlled trials that assessed the effects of general anesthesia compared to loco-regional anesthesia for endovascular aortic aneurysm repairs. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were: all-cause mortality, length of hospital stay, length of intensive care unit stay. Our secondary outcomes were: incidence of endoleaks, requirement for re-intervention, incidence of myocardial infarction, quality of life, incidence of respiratory complications, incidence of pulmonary embolism, incidence of deep vein thrombosis, and length of procedure. We planned to use GRADE methodology to assess the certainty of evidence for each outcome. MAIN RESULTS: We found no studies, published or ongoing, that met our inclusion criteria. AUTHORS' CONCLUSIONS: We did not identify any randomized controlled trials that compared general versus loco-regional anesthesia for endovascular aortic aneurysm repair. There is currently insufficient high-quality evidence to determine the benefits or harms of either anesthetic approach during endovascular aortic aneurysm repair. Well-designed prospective randomized trials with relevant clinical outcomes are needed to adequately address this.

Genomic alterations in neuroendocrine prostate cancer: A systematic review and meta-analysis.

Background: Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. We performed a systematic review and meta-analysis to evaluate the prevalence of genomic alterations in NEPC and better understand its molecular features to potentially inform precision medicine. Methods: EMBASE, PubMed, and Cochrane Central Register of Controlled Trials databases were searched for eligible studies until March 2022. Study qualities were assessed using the Q-genie tool. The prevalence of gene mutations and copy number alterations (CNAs) were extracted, and meta-analysis was performed using R Studio with meta package. Results: A total of 14 studies with 449 NEPC patients were included in this meta-analysis. The most frequently mutated gene in NEPC was TP53 (49.8%), and the prevalence of deleterious mutations in ATM/BRCA was 16.8%. Common CNAs in NEPC included RB1 loss (58.3%), TP53 loss (42.8%), PTEN loss (37.0%), AURKA amplification (28.2%), and MYCN amplification (22.9%). RB1/TP53 alterations and concurrent RB1 and TP53 alterations were remarkably common in NEPC, with a prevalence of 83.8% and 43.9%, respectively. Comparative analyses indicated that the prevalence of (concurrent) RB1/TP53 alterations was significantly higher in de novo NEPC than in treatment-emergent NEPC (t-NEPC). Conclusions: This study presents the comprehensive prevalence of common genomic alterations and potentially actionable targets in NEPC and reveals the genomic differences between de novo NEPC and t-NEPC. Our findings highlight the importance of genomic testing in patients for precision medicine and provide insights into future studies exploring different NEPC subtypes.

Tranexamic acid for the prevention of postpartum haemorrhage: the TAPPH-1 pilot randomized trial and lessons learned for trials in Canadian obstetrics.

Postpartum haemorrhage (PPH) is a leading cause of maternal morbidity and mortality. While tranexamic acid (TXA) reduces bleeding and transfusion requirements in established PPH, we sought to determine the feasibility of conducting a fully powered trial assessing the effect of prophylactic tranexamic acid, prior to PPH onset, in a Canadian Obstetric setting. With institutional and Health Canada approval, consenting, eligible parturients (singleton, > 32 weeks gestation, vaginal or caesarian delivery) were randomly assigned to receive TXA (1 g intravenously) or placebo (0.9% saline) prior to delivery. Participants, investigators, data collectors/adjudicators, and analysis was blinded. The primary outcome was administration of study intervention to > 85% of randomized individuals. Secondary outcomes included recruitment rate (feasibility) and safety outcomes. Over 8 months, 611 were approached, 35 consented, and 27 randomized (14 TXA, 13 placebo). 89% of randomized participants received the assigned intervention. Recruitment fell below feasibility (23% target). No serious adverse outcomes occurred. Our pilot trial in a Canadian Obstetric setting was unable to demonstrate feasibility to conduct a large, multicentre trial to examine prophylactic use of tranexamic for PPH secondary to the complex regulatory requirements associated with a trial for an off-label, but commonly utilized intervention. These challenges should inform stakeholders on the resources and challenges of conducting future trials using off-label interventions.Trial registration: www.clinicaltrials.gov , NCT03069859 (03/03/2017).

Hollow CoP@N-Carbon Nanospheres: Heterostructure and Glucose-Enhanced Charge Separation for Sonodynamic/Starvation Therapy.

Sonodynamic therapy (SDT) can be described as ultrasonic (US) catalysis. Adequate charge separation is considered as effective means to promote reactive oxygen species (ROS). Here, hollow CoP@N-carbon@PEG (CPCs@PEG) nanospheres (∼60 nm) are prepared as sonosensitizers, showing greater ROS generation than pure CoP@PEG under US irradiation. Both 1O2 and ·O2- are activation species that are determined by O2 and electrons. The great SDT performance of CPCs@PEG is ascribed to the heterostructure which promotes the separation and transfer for US-generated electrons and holes. In addition, holes can be further captured by endogenous glucose that is in favor of electron aggregation and ROS generation. Moreover, the consumption of glucose would decrease intracellular ATP for starvation therapy. Given the higher oxidation ability of Co3+, CPCs@PEG nanospheres possess catalase (CAT) activity to convert H2O2 into O2 for assisting ROS generation. Moreover, they also can oxidize glutathione (GSH) as a mimic GSH oxidase to break intratumor redox balance, facilitating oxidative stress. More importantly, the nanocomposites reveal good degradation ability dominated by the oxidation from insoluble phosphide into soluble phosphate, accelerating elimination via urine and feces within 14 days. CPCs@PEG nanospheres integrate the above effects not only to reveal great tumor inhibition ability but also to excite immune activation for anticancer.

Proof-of-concept randomized controlled trial of single-session nitrous oxide treatment for refractory bipolar depression: Focus on cerebrovascular target engagement.

BACKGROUND: There remain few efficacious treatments for bipolar depression, which dominates the course of bipolar disorder (BD). Despite multiple studies reporting associations between depression and cerebral blood flow (CBF), little is known regarding CBF as a treatment target, or predictor and/or indicator of treatment response, in BD. Nitrous oxide, an anesthetic gas with vasoactive and putative antidepressant properties, has a long history as a neuroimaging probe. We undertook an experimental medicine paradigm, coupling in-scanner single-session nitrous oxide treatment of bipolar depression with repeated measures of CBF. METHODS: In this double-blind randomized controlled trial, 25 adults with BD I/II and current treatment-refractory depression received either: (1) nitrous oxide (20 min at 25% concentration) plus intravenous saline (n = 12), or (2) medical air plus intravenous midazolam (2 mg total; n = 13). Study outcomes included changes in depression severity (Montgomery-Asberg Depression Rating Scale scores, primary) and changes in CBF (via arterial spin labeling magnetic resonance imaging). RESULTS: There were no significant between-group differences in 24-h post-treatment MADRS change or treatment response. However, the nitrous oxide group had significantly greater same-day reductions in depression severity. Lower baseline regional CBF predicted greater 24-h post-treatment MADRS reductions with nitrous oxide but not midazolam. In region-of-interest and voxel-wise analyses, there was a pattern of regional CBF reductions following treatment with midazolam versus nitrous oxide. CONCLUSIONS: Present findings, while tentative and based on secondary endpoints, suggest differential associations of nitrous oxide versus midazolam with bipolar depression severity and cerebral hemodynamics. Larger studies integrating neuroimaging targets and repeated nitrous oxide treatment sessions are warranted.

Novel use of continuous pericapsular nerve group (PENG) block technique for traumatic superior and inferior pubic rami fractures: a case report.

BACKGROUND: Pubic rami fractures are painful injuries more commonly seen in the elderly with osteoporosis after high velocity trauma. In the most cases, management is conservative and non-operative with the goal to provide optimal pain relief to facilitate early mobilization and hospital discharge. Unfortunately, opioids remain the mainstay analgesic option and regional anesthesia techniques are limited but may include lumbar epidural anesthesia. CASE PRESENTATION: A female patient in her 80s presented to the emergency department of a level 1 trauma center following a high-speed motor vehicle collision. The patient suffered multiple non-life-threatening injuries. Notably, the patient was experiencing severe right groin and leg pain secondary to superior and inferior pubic rami fractures. Due to the severity of this pain, the patient was unable to mobilize or participate with physiotherapy. A lumbar epidural anesthesia technique was not deemed suitable and instead, we inserted a continuous pericapsular nerve group (PENG) block with a programmed intermittent bolus regimen. Immediate relief of pain was achieved and 48 hours later, the patient still reported satisfactory pain control and started to independently mobilize. CONCLUSION: Analgesia options are limited in pubic rami fractures. We present the first published case of a novel use of the PENG block with a continuous catheter technique for the analgesic management of a traumatic superior and inferior pubic rami fracture. The clinical utility of this technique in pubic ramus fractures warrants further clinical investigation.

Cognitive deficits after general anaesthesia in animal models: a scoping review.

BACKGROUND: It remains controversial whether general anaesthetic drugs contribute to perioperative neurocognitive disorders in adult patients. Preclinical studies have generated conflicting results, likely because of differing animal models, study protocols, and measured outcomes. This scoping review of preclinical studies addressed the question: 'Do general anaesthetic drugs cause cognitive deficits in adult animals that persist after the drugs have been eliminated from the brain?' METHODS: Reports of preclinical studies in the MEDLINE database published from 1953 to 2021 were examined. A structured review process was used to assess original studies of cognitive behaviours, which were measured after treatment (≥24 h) with commonly used general anaesthetic drugs in adult animals. RESULTS: The initial search yielded 380 articles, of which 106 were fully analysed. The most frequently studied animal model was male (81%; n=86/106) rodents (n=106/106) between 2-3 months or 18-20 months of age. Volatile anaesthetic drugs were more frequently studied than injected drugs, and common outcomes were memory behaviours assessed using the Morris water maze and fear conditioning assays. Cognitive deficits were detected in 77% of studies (n=82/106) and were more frequent in studies of older animals (89%), after inhaled anaesthetics, and longer drug treatments. Limitations of the studies included a lack of physiological monitoring, mortality data, and risk of bias attributable to the absence of randomisation and blinding. CONCLUSIONS: Most studies reported cognitive deficits after general anaesthesia, with age, use of volatile anaesthetic drugs, and duration of anaesthesia as risk factors. Recommendations to improve study design and guide future research are presented.

The Effect of Cryotherapy Application on Postoperative Pain: A Systematic Review and Meta-analysis.

OBJECTIVE: To systematically review and meta-analyze whether the application of cryotherapy on closed incisions reduces postoperative pain and opioid consumption. BACKGROUND: Reduction of acute pain and opioid use is important in the postoperative phase of patient care. ''Cryotherapy'' refers to the use of low temperatures for therapeutic purposes. METHODS: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Online registries of clinical trial were search until October 2019. RCT that examined postoperative application of cryotherapy over surgical incisions in adults compared to no cryotherapy were eligible. Selection, extraction, and risk of bias appraisal were completed in duplicate. Data were synthesized using random effects meta-analyses. The outcomes of interest were postoperative pain, opioid use, hospital length of stay (LOS) and surgical site infection (SSI). RESULTS: Fifty-one RCTs (N = 3425 patients) were included. With moderate certainty evidence, patients treated with cryotherapy experienced a reduction in pain on postoperative day 1 (standardized mean differences -0.50, 95% CI -0.71 to -0.29, l 2= 74%) and day 2 (standardized mean differences -0.63, 95% CI -0.91 to -0.35, I 2 = 83%) relative to without cryotherapy application. With moderate certainty of evidence, cryotherapy reduces opioid consumption in morphine milliequivalents and morphine milliequivalents/kg, (mean differences -7.43, 95% CI -12.42, -2.44, I 2 = 96%) and (mean differences -0.89, 95% CI -1.45, -0.33, I 2 = 99%), respectively. With low certainty evidence, cryotherapy does not affect hospital LOS or rate of SSI. CONCLUSION: Cryotherapy is a pragmatic, noncostly intervention that reduces postoperative pain and opioid consumption with no effect on SSI rate or hospital LOS.

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer.

There is an urgent need for exploring new actionable targets other than androgen receptor to improve outcome from lethal castration-resistant prostate cancer. Tumor metabolism has reemerged as a hallmark of cancer that drives and supports oncogenesis. In this regard, it is important to understand the relationship between distinctive metabolic features, androgen receptor signaling, genetic drivers in prostate cancer, and the tumor microenvironment (symbiotic and competitive metabolic interactions) to identify metabolic vulnerabilities. We explore the links between metabolism and gene regulation, and thus the unique metabolic signatures that define the malignant phenotypes at given stages of prostate tumor progression. We also provide an overview of current metabolism-based pharmacological strategies to be developed or repurposed for metabolism-based therapeutics for castration-resistant prostate cancer.

Opioid consumption and pain in patients with gynecological cancer who underwent spinal anesthesia vs. general anesthesia for interstitial brachytherapy.

AIMS: Interstitial brachytherapy (ISBT) is an effective option for delivering conformal high dose radiation to the target volume with better organ-at risk sparing but is thought to be more invasive and painful than other methods. This study investigated pain levels and opioid consumption in patients who received spinal anesthesia (SA) or general anesthesia (GA) for their ISBT. MATERIALS AND METHODS: Patients that underwent ISBT from April 2014 to September 2018 were analyzed from a prospective institutional database. The most prevalent malignancies were cervical (45%), recurrent endometrial (27%) and vaginal (20%) cancers. Baseline patient characteristics, radiation treatment details, anesthesia records, and inpatient charts were obtained. Opioid consumption was quantified as oral morphine equivalent per day (OMEq/day) from implantation until removal. Pain score levels were collected by using an 11-point scoring system. RESULTS: Ninety nine patients received GA and 40 patients received SA as their anesthesia for ISBT. During their first admission, 76 patients (55%) required intravenous opioids. Patients receiving SA had significantly lower mean pain scores on the morning of their procedure 6 (Interquartile range [IQR] 2-8) vs. 0 (IQR: 0-1); p < 0.001]. Pain did not significantly differ between cohorts at any other time. During the first admission, SA patients had a lower median opioid usage of 23 (IQR: 9-47) mg/day compared to GA patients at 38 (IQR: 21-71) mg/day (p = 0.011). No difference in opioid consumption was seen during subsequent admissions. CONCLUSIONS: In patients undergoing ISBT, SA provides better immediate pain control post insertion compared to GA. Patients who received SA used lower amounts of opioids during their first ISBT insertion.