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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?'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.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.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.

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

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.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.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); p0.001]. 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.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.

The significance of lactate transporters has been recognized in various cancer types, but their role in urothelial carcinoma remains mostly unknown. The aim of this study was to investigate the functional importance of the monocarboxylate transporter (MCT) 4 in preclinical models of urothelial carcinoma and to assess its relevance in patient tumors. The association of MCT4 expression with molecular subtypes and outcome was determined in The Cancer Genome Atlas (TCGA) cohort and two independent cohorts of patients with urothelial carcinoma. Silencing of MCT4 was performed using siRNAs in urothelial carcinoma cell lines. Effects of MCT4 inhibition on cell growth, apoptosis, and production of reactive oxygen species (ROS) were assessed. Moreover, effects on lactate efflux were determined. The in vivo effects of MCT4 silencing were assessed in an orthotopic xenograft model. MCT4 expression was higher in the basal subtype. Decreased MCT4 methylation and increased RNA and protein expression were associated with worse overall survival (OS). Inhibition of MCT4 led to a reduction in cell growth, induction of apoptosis, and an increased synthesis of ROS. MCT4 inhibition resulted in intracellular accumulation of lactate. In vivo, stable knockdown of MCT4 reduced tumor growth. The expression of MCT4 in urothelial carcinoma is associated with features of aggressive tumor biology and portends a poor prognosis. Inhibition of MCT4 results in decreased tumor growth in vitro and in vivo. Targeting lactate metabolism via MCT4 therefore provides a promising therapeutic approach for invasive urothelial carcinoma, especially in the basal subtype.

Suppl. Table 1: Characteristics of the TCGA cohort; Suppl. Table 2: Characteristics of cohort A. CIS= carcinoma in situ; Suppl. Table 3: Characteristics of cohort B Suppl. Fig. 1. Correlation of degree of DNA methylation at CpG site cg10183885 in the SLC16A3 gene region (see Suppl. Table 4) and MCT4 mRNA expression; Suppl. Fig. 2. Correlation of gene expression and protein expression in cohort B. Suppl. Fig. 3. Representative H&E (upper panel) and immunohistochemical images in matched bladder cancer samples (each column is one patient). CD8 was used to stain T cells (middle panel) in comparison with MCT4 expression (lower panel). Suppl. Fig. 4. Protein expression of MCT4 in benign urothelium, primary tumor tissue and lymph node metastases (cohort A). Suppl. Fig. 5. Protein expression in primary tumors according to tumor stage (left) and lymph node involvement (right) (cohort A).; Suppl. Fig. 6. MCT4 mRNA expression correlates with molecular subtypes in the TCGA cohort using the updated TCGA nomenclature (n=408); Suppl. Fig. 7. MCT4 gene expression does not correlate with overall survival in a cohort of patients undergoing neoadjuvant chemotherapy; Suppl. Fig. 8. Expression of MCT4 in urothelial carcinoma cell lines detected by Western Blot (A) and qPCR (B); Suppl. Fig. 9. Effect of MCT4 silencing on cell growth in hypoxic conditions determined by MTT assay. Suppl. Fig. 10. Effect of inhibition of MCT4 using siRNA on cell growth of the MCT4 negative cell line RT4 determined by MTT assay; Suppl. Fig 11. Effect of MCT4 silencing on cell growth in glucose free conditions determined by MTT assay; Suppl.Fig. 12. Effect of different concentrations of MCT4 specific antisense olignucleotide (ASO) on cell growth determined by MTT assay. Suppl. Fig. 13. Oxygen consumption rates at baseline (A), following glucose injection (B) and following oligomycin injection (C) in cell lines treated with control siRNA or MCT4 specific siRNAs.

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.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).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.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.

BackgroundPubic 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 presentationA 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.ConclusionAnalgesia 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.

Let f ∈ Z [ x ] and l ∈ N . Consider the set of all ( a 0 , a 1 , … , a l ) ∈ N l + 1 with a i a i + 1 and f ( a i ) | f ( a i + 1 ) for all 0 ≤ i ≤ l − 1 . We say that f satisfies the gap principle of order l if lim ⁡ a l / a 0 = ∞ as a 0 → ∞ . We also define the gap order of f ( x ) to be the smallest positive integer l such that f ( x ) satisfies the gap principle of order l. If such l does not exist, we say that f ( x ) does not satisfy the gap principle. In this article, we prove a conjecture by Chan, Choi and Lam that f ( x ) does not satisfy the gap principle if and only if f ( x ) is in the form of f ( x ) = A ( B x + C ) n for some A , B , C ∈ Z . Moreover, we completely determine the gap order of any polynomial. We will show that if f ( x ) is not in the form of A ( B x + C ) n , then f ( x ) has gap order 2 if f ( x ) is a quadratic polynomial or a power of a quadratic polynomial; and has gap order 1 otherwise.

The REGAIN (Regional versus General Anesthesia for Promoting Independence after Hip Fracture) trial found similar ambulation and survival at 60 days with spinal versus general anesthesia for hip fracture surgery. Trial outcomes evaluating pain, prescription analgesic use, and patient satisfaction have not yet been reported.To compare pain, analgesic use, and satisfaction after hip fracture surgery with spinal versus general anesthesia.Preplanned secondary analysis of a pragmatic randomized trial. (ClinicalTrials.gov: NCT02507505).46 U.S. and Canadian hospitals.Patients aged 50 years or older undergoing hip fracture surgery.Spinal or general anesthesia.Pain on postoperative days 1 through 3; 60-, 180-, and 365-day pain and prescription analgesic use; and satisfaction with care.A total of 1600 patients were enrolled. The average age was 78 years, and 77% were women. A total of 73.5% (1050 of 1428) of patients reported severe pain during the first 24 hours after surgery. Worst pain over the first 24 hours after surgery was greater with spinal anesthesia (rated from 0 [no pain] to 10 [worst pain imaginable]; mean difference, 0.40 [95% CI, 0.12 to 0.68]). Pain did not differ across groups at other time points. Prescription analgesic use at 60 days occurred in 25% (141 of 563) and 18.8% (108 of 574) of patients assigned to spinal and general anesthesia, respectively (relative risk, 1.33 [CI, 1.06 to 1.65]). Satisfaction was similar across groups.Missing outcome data and multiple outcomes assessed.Severe pain is common after hip fracture. Spinal anesthesia was associated with more pain in the first 24 hours after surgery and more prescription analgesic use at 60 days compared with general anesthesia.Patient-Centered Outcomes Research Institute

Background Bupivacaine and ropivacaine are the preferred long-acting local anesthetics for peripheral nerve blocks as they provide prolonged analgesia in the postoperative period. No studies have directly compared the analgesic duration of these commonly used local anesthetics in the setting of low-volume ultrasound-guided interscalene block (US-ISB). This study was designed to determine which local anesthetic and concentration provides superior analgesia (duration and quality) for low-volume US-ISB. Methods Sixty eligible patients scheduled for arthroscopic shoulder surgery were randomized (1:1:1) to receive US-ISB (5 mL) with 0.5% bupivacaine with 1:200,000 epinephrine, 0.5% ropivacaine, or 1% ropivacaine. All individuals were blinded including study participants, anesthesiologists, surgeons, research personnel, and statistician. All participants received a standardized general anesthetic and multimodal analgesia. The primary outcome was duration of analgesia defined as the time from the end of injection to the time that the patients reported a significant increase in pain (>3 numeric rating scale [NRS]) at the surgical site. Results The mean duration of analgesia for 0.5% bupivacaine with 1:200,000 epinephrine, 0.5% ropivacaine, or 1% ropivacaine was 14.1 ± 7.4, 13.8 ± 4.5, and 15.8 ± 6.3 hours, respectively (analysis of variance [ANOVA], P = .51). There were no observed differences in analgesic duration or other secondary outcomes between the 3 groups with the exception of a difference in cumulative opioid consumption up to 20h00 on the day of surgery in favor of ropivacaine 0.5% over bupivacaine of minimal clinical significance. Conclusions In the context of single-injection low-volume US-ISB, we have demonstrated a similar efficacy between equal concentrations of ropivacaine and bupivacaine. In addition, increasing the concentration of ropivacaine from 0.5% to 1% did not prolong the duration of US-ISB.

The purpose of this systematic review and meta-analysis is to examine the effect of DEX on delayed dNCR (cognitive dysfunction ≥ 1 week postoperative) after cardiac surgery.DEX has salutary effects on cognitive outcomes following cardiac surgery, however, studies are limited by inconsistent assessment tools, timing, and definitions of dysfunction. It is imperative to identify accurate point estimates of effect of DEX on clinically relevant changes in cognitive function.Randomized trials of adults undergoing cardiac surgery comparing perioperative DEX to placebo or alternate sedation and assessing cognitive function ≥ 1 week postoperative were included. Data was abstracted by three reviewers independently and in parallel according to PRISMA guidelines. The primary outcome is dNCR. To classify as dNCR, cognitive function must decrease by at least the minimal clinically important difference or accepted alternate measure (eg, Reliable Change Index ≥1.96). Bias was assessed with the Cochrane Collaboration tool. Data was pooled using a random effects model.Nine trials (942 participants) were included in qualitative analysis, of which seven were included in the meta-analysis of dNCR. DEX reduced the incidence of dNCR (OR 0.39, 95% CI 0.25-0.61, P0.0001) compared to placebo/no DEX. There was no difference in the incidence of delirium (OR 0.69, 95% CI 0.35-1.34, P = 0.27) or incidence of hemodynamic instability (OR 1.14, 95% CI 0.59-2.18, P = 0.70) associated with perioperative DEX.DEX reduced the incidence of dNCR 1 week after cardiac surgery. Although this meta-analysis demonstrates short term cognitive outcomes are improved after cardiac surgery with perioperative DEX, future trials examining long term cognitive outcomes, using robust cognitive assessments, and new perioperative neurocognitive disorders nomenclature with objective diagnostic criteria are necessary.

Tranexamic acid reduces blood loss and transfusion requirements with no significant thrombotic adverse effects. Postoperative seizures have been seen in cardiac surgical patients in association with patient (advanced age, underlying neurologic disease, chronic kidney disease); surgical (open cardiac procedures, long bypass times); and drug (high tranexamic acid dose) risk factors. Tranexamic acid dosing regimens should be decreased in patients with chronic kidney dysfunction secondary to reduced clearance and drug accumulation. Optimal dosing for cardiac surgical patients has been recommended. Additional research is required to determine dosing regimens in major noncardiac surgery and plasma concentration levels associated with inducing seizures.

BACKGROUND Neuraxial anesthesia is conventionally performed using a landmark-based technique. Preprocedural ultrasound is often used in challenging clinical scenarios to identify an ideal needle path. The procedure is then carried out by the operator recreating the ultrasound needle path from memory. We suggest that a needle guidance system using the Microsoft HoloLens mixed reality headset, which projects a hologram of the ideal needle path, can assist operators in replicating the correct needle angulation and result in fewer needle passes. OBJECTIVE The objective of the study was to develop software for the mixed reality HoloLens headset, which could be used to augment the performance of neuraxial anesthesia, and establish its face validity in lumbar spine phantom models. METHODS We developed an ultrasound transducer marker and software for the HoloLens, which registers the position and angulation of the ultrasound transducer during preprocedural scans. Once an image of a clear path from skin to the intrathecal space is acquired, a hologram of the ideal needle path is projected onto the user’s visual field. The ultrasound probe is removed while the hologram remains in the correct spatial position to visualize the needle trajectory during the procedure as if conducting real-time ultrasound. User testing was performed using a lumbar spine phantom. RESULTS Preliminary work demonstrates that novice (2 anesthesia residents) and experienced operators (5 attending anesthesiologists) can rapidly learn to use mixed reality holograms to perform neuraxial anesthesia on lumbar spine phantoms. CONCLUSIONS Our study shows promising results for performing neuraxial anesthesia in phantoms using the HoloLens. Although this may have wide-ranging implications for image-guided therapies, further study is required to quantify the accuracy and safety benefit of using holographic guidance. CLINICALTRIAL ClinicalTrials.gov NCT04028284; https://clinicaltrials.gov/ct2/show/NCT04028284

Purpose of Review:Perioperative neurocognitive disorders are common following surgery and have serious socioeconomic impacts. Despite this, these disorders remain under recognized and underdiagnosed. To facilitate detection and direct patients towards appropriate preventative interventions, assessment of cognition during the perioperative period is of critical importance. However, there are considerable barriers to the widespread clinical implementation of cognitive assessments, including a lack of consensus regarding the optimal tool for use in specific clinical scenarios.Recent Findings:We provide an overview of the most widely used and validated cognitive assessment tools, including those that permit telemedicine-enabled patient encounters.Summary:No single tool is optimal for all contexts. This narrative review can help clinicians to identify the appropriate cognitive screening tool for their needs by describing the advantages and disadvantages of several available tools, thereby enabling the identification of patients at risk of cognitive decline and facilitating optimization of patient-focused perioperative care.

To the Editor: Acute kidney injury (AKI) is a lesser-known complication of hip fracture that may come about owing to decreased kidney perfusion and heightened inflammation from trauma, pain, bleeding, and fasting. Approximately 15%-20% of patients undergoing surgery for a hip fracture develop AKI, with 0.5%-1.8% receiving dialysis. [...]

BACKGROUND Consensus recommendations regarding the threshold levels of cardiac troponin elevations for the definition of perioperative myocardial infarction and clinically important periprocedural myocardial injury in patients undergoing cardiac surgery range widely (from >10 times to >= 70 times the upper reference limit for the assay). Limited evidence is available to support these recommendations. METHODS We undertook an international prospective cohort study involving patients 18 years of age or older who underwent cardiac surgery. High-sensitivity cardiac troponin I measurements (upper reference limit, 26 ng per liter) were obtained 3 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We performed Cox analyses using a regression spline that explored the relationship between peak troponin measurements and 30-day mortality, adjusting for scores on the European System for Cardiac Operative Risk Evaluation II (which estimates the risk of death after cardiac surgery on the basis of 18 variables, including age and sex). RESULTS Of 13,862 patients included in the study, 296 (2.1%) died within 30 days after surgery. Among patients who underwent isolated coronary-artery bypass grafting or aortic-valve replacement or repair, the threshold troponin level, measured within 1 day after surgery, that was associated with an adjusted hazard ratio of more than 1.00 for death within 30 days was 5670 ng per liter (95% confidence interval [CI], 1045 to 8260), a level 218 times the upper reference limit. Among patients who underwent other cardiac surgery, the corresponding threshold troponin level was 12,981 ng per liter (95% CI, 2673 to 16,591), a level 499 times the upper reference limit. CONCLUSIONS The levels of high-sensitivity troponin I after cardiac surgery that were associated with an increased risk of death within 30 days were substantially higher than levels currently recommended to define clinically important periprocedural myocardial injury. (Funded by the Canadian Institutes of Health Research and others; VISION Cardiac Surgery ClinicalTrials.gov number, NCT01842568.)

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, I2= 74%) and day 2 (standardized mean differences -0.63, 95% CI -0.91 to -0.35, I2= 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, I2= 96%) and (mean differences -0.89, 95% CI -1.45, -0.33, I2= 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.

"With a rapidly aging world population, it is critical for physicians of every specialty to adapt the ways they provide medical and perioperative care to patients. Older adults represent the largest population of health care users, and they have very different needs and preferences compared with their younger counterparts. In this article, the authors discuss some of the current gaps in geriatric anesthesia and perioperative care, as they elaborate on what can be expected in the near future at different levels of the health care system: the patient, the environment, and the anesthesia specialty."