Improving Surgical Quality for Patients With Mental Illnesses: A Narrative Review.

OBJECTIVE: The aim of this study was to identify disparities in care for surgical patients with preexisting mental health diagnoses. SUMMARY BACKGROUND DATA: Mental illness affects approximately 6.7 million Canadians. For them, stigma, comorbid disorders, and sequelae of psychiatric diagnoses can be barriers to equitable health care. The goal of this review is to define inequities in surgical care for patients with preexisting mental illness. METHODS: We searched OVID Medline, Pubmed, EMBASE, and the Cochrane review files using a combination of search terms using a PICO (population, intervention, comparison, outcome) model focusing on surgical care for patients with mental illness. RESULTS: The literature on mental illness in surgical patients focused primarily on preoperative and postoperative disparities in surgical care between patients with and without a diagnosis of mental illness. Preoperatively, patients were 7.5% to 40% less likely to be deemed surgical candidates, were less likely to receive testing, and were more likely to present at later stages of their disease or have delayed surgical care. Similar themes arose in the postoperative period: patients with mental illness were more likely to require ICU admission, were up to 3 times more likely to have a prolonged length of hospital stay, had a 14% to 270% increased likelihood of having postoperative complications, and had significantly higher health care costs. CONCLUSIONS: Surgical patients with preexisting psychiatric diagnoses have a propensity for worse perioperative outcomes compared to patients without reported mental illness. Taking a thorough psychiatric history can potentially help surgical teams address disparities in access to care as well as anticipate and prevent adverse outcomes.

Dexmedetomidine Use in Intensive Care Unit Sedation and Postoperative Recovery in Elderly Patients Post-Cardiac Surgery (DIRECT).

OBJECTIVE: This study examined recovery, delirium, and neurocognitive outcome in elderly patients receiving dexmedetomidine or propofol sedation after undergoing cardiac surgery. DESIGN: Open-label randomized trial. SETTING: Single center. PARTICIPANTS: A total of 70 patients older than 75 years without English language limitations and Mini Mental State Examination scores >20. INTERVENTIONS: Patients received either propofol (group P) or dexmedetomidine (group D) postoperatively until normothermic and hemodynamically stable. MEASUREMENTS AND MAIN RESULTS: Quality of recovery (QoR) was measured by the QoR-40 questionnaire on postoperative day (POD) three. Secondary outcomes were incidence and duration of delirium, time to extubation, length of hospital stay, hospital mortality rate, postoperative quality of life (QoL; measured by SF-36 performed at baseline and six months postoperatively), and neurocognitive disorder (measured by Minnesota Cognitive Acuity Screen [MCAS] performed at baseline, POD5, and six months postoperatively). A total of sixty-seven patients completed the trial. There was no significant difference in QoR-40 scores (95% confidence interval [CI], -7.6081-to-10.9781; p = 1.000), incidence of delirium (group P, 42%; group D, 24%; p = 0.191), mean hospital stay (95% CI, -5.4838-to-1.5444; p = 0.297), mean time to extubation (95% CI, -19.2513-to-7.5561; p = 0.866), or mean duration of delirium (95% CI, -4.3065-to-1.067; p = 0.206) between groups. No patients died in the hospital. There were no significant differences in changes in SF-36 or MCAS scores over time between groups. There was a decline in MCAS score from preoperatively to POD5 in group P (95% CI, -8.95725-to- -2.61775; p = 0.0005), which was greater than that observed in group D. CONCLUSIONS: The authors' findings demonstrated that the use of dexmedetomidine compared with propofol in elderly patients undergoing cardiac surgery was unlikely to improve QoR/postoperative QoL. Although the study was underpowered to detect secondary outcomes, the results suggested no reductions in delirium, time to extubation, and hospital stay, but a potential decrease in delayed neurocognitive recovery.

Comparing rapid micro-induction and standard induction of buprenorphine/naloxone for treatment of opioid use disorder: protocol for an open-label, parallel-group, superiority, randomized controlled trial.

BACKGROUND: Buprenorphine/naloxone (Suboxone) is a current first-line treatment for opioid use disorder (OUD). The standard induction method of buprenorphine/naloxone requires patients to be abstinent from opioids and therefore experience withdrawal symptoms prior to induction, which can be a barrier in starting treatment. Rapid micro-induction (micro-dosing) involves the administration of small, frequent does of buprenorphine/naloxone and removes the need for a period of withdrawal prior to the start of treatment. This study aims to compare the effectiveness and safety of rapid micro-induction versus standard induction of buprenorphine/naloxone in patients with OUD. METHODS: This is a randomized, open-label, two-arm, superiority, controlled trial comparing the safety and effectiveness of rapid micro-induction versus standard induction of buprenorphine/naloxone for the treatment of OUD. A total of 50 participants with OUD will be randomized at one Canadian hospital. The primary outcome is the completion of buprenorphine/naloxone induction with low levels of withdrawal. Secondary outcomes are treatment retention, illicit drug use, self-reported drug use behaviour, craving, pain, physical health, safety, and client satisfaction. DISCUSSION: This is the first randomized controlled trial to compare the effectiveness and safety of rapid micro-induction versus standard induction of buprenorphine/naloxone. This study will thereby generate evidence for a novel induction method which eliminates substantial barriers to the use of buprenorphine/naloxone in the midst of the ongoing opioid crisis. Trial registration ClinicalTrials.gov, NCT04234191; date of registration: January 21, 2020; https://clinicaltrials.gov/ct2/show/NCT04234191.

Applying Serum Cytokine Levels to Predict Pain Severity in Cancer Patients.

BACKGROUND AND AIM: Cancers originating in the breast, lung and prostate often metastasize to the bone, frequently resulting in cancer-induced bone pain that can be challenging to manage despite conventional analgesic therapy. This exploratory study's aim was to identify potential biomarkers associated with cancer-induced pain by examining a sample population of breast cancer patients undergoing bisphosphonate therapy. METHODS: A secondary analysis of the primary study was performed to quantify serum cytokine levels for correlation to pain scores. Cytokines with statistically significant correlations were then input into a stepwise regression analysis to generate a predictive equation for a patient's pain severity. In an effort to find additional potential biomarkers, correlation analysis was performed between these factors and a more comprehensive panel of cytokines and chemokines from breast, lung, and prostate cancer patients. RESULTS: Statistical analysis identified nine cytokines (GM-CSF, IFNγ, IL-1ß, IL-2, IL-4, IL-5, IL-12p70, IL-17A, and IL-23) that had significant negative correlations with pain scores and they could best predict pain severity through a predictive equation generated for this specific evaluation. After performing a correlation analysis between these factors and a larger panel of cytokines and chemokines, samples from breast, lung and prostate patients showed distinct correlation profiles, highlighting the clinical challenge of applying pain-associated cytokines related to more defined nociceptive states, such as arthritis, to a cancer pain state. CONCLUSION: Exploratory analyses such as the ones presented here will be a beneficial tool to expand insights into potential cancer-specific nociceptive mechanisms and to develop novel therapeutics.

Evaluation of the preclinical analgesic efficacy of naturally derived, orally administered oil forms of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their 1:1 combination.

Chronic neuropathic pain (NP) is a growing clinical problem for which effective treatments, aside from non-steroidal anti-inflammatory drugs and opioids, are lacking. Cannabinoids are emerging as potentially promising agents to manage neuroimmune effects associated with nociception. In particular, Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination are being considered as therapeutic alternatives for treatment of NP. This study aimed to examine whether sex affects long-term outcomes on persistent mechanical hypersensitivity 7 weeks after ceasing cannabinoid administration. Clinically relevant low doses of THC, CBD, and a 1:1 combination of THC:CBD extracts, in medium chain triglyceride (MCT) oil, were orally gavaged for 14 consecutive days to age-matched groups of male and female sexually mature Sprague Dawley rats. Treatments commenced one day after surgically inducing a pro-nociceptive state using a peripheral sciatic nerve cuff. The analgesic efficacy of each phytocannabinoid was assessed relative to MCT oil using hind paw mechanical behavioural testing once a week for 9 weeks. In vivo intracellular electrophysiology was recorded at endpoint to characterize soma threshold changes in primary afferent sensory neurons within dorsal root ganglia (DRG) innervated by the affected sciatic nerve. The thymus, spleen, and DRG were collected post-sacrifice and analyzed for long-term effects on markers associated with T lymphocytes at the RNA level using qPCR. Administration of cannabinoids, particularly the 1:1 combination of THC, elicited a sustained mechanical anti-hypersensitive effect in males with persistent peripheral NP, which corresponded to beneficial changes in myelinated Aß mechanoreceptive fibers. Specific immune cell markers associated with T cell differentiation and pro-inflammatory cytokines, previously implicated in repair processes, were differentially up-regulated by cannabinoids in males treated with cannabinoids, but not in females, warranting further investigation into sexual dimorphisms that may underlie treatment outcomes.

An evaluation of the anti-hyperalgesic effects of cannabidiolic acid-methyl ester in a preclinical model of peripheral neuropathic pain.

BACKGROUND AND PURPOSE: Chronic neuropathic pain (NEP) is associated with growing therapeutic cannabis use. To promote quality of life without psychotropic effects, cannabinoids other than Δ9-tetrahydrocannabidiol, including cannabidiol and its precursor cannabidiolic acid (CBDA), are being evaluated. Due to its instability, CBDA has been understudied, particularly as an anti-nociceptive agent. Adding a methyl ester group (CBDA-ME) significantly enhances its stability, facilitating analyses of its analgesic effects in vivo. This study examines early treatment efficacy of CBDA-ME in a rat model of peripherally induced NEP and evaluates sex as a biological variable. EXPERIMENTAL APPROACH: After 14 consecutive days of intraperitoneal CBDA-ME administration at 0.01, 0.1 and 1 µg·kg-1 , commencing 1 day after surgically implanting a sciatic nerve-constricting cuff to induce NEP, the anti-nociceptive efficacy of this cannabinoid was assessed in male and female Sprague-Dawley rats relative to vehicle-treated counterparts. In females, 2 and 4 µg·kg-1 daily doses of CBDA-ME were also evaluated. Behavioural tests were performed for hind paw mechanical and thermal withdrawal thresholds once a week for 8 weeks. At endpoint, in vivo electrophysiological recordings were obtained to characterize soma threshold changes in primary sensory neurons. KEY RESULTS: In males, CBDA-ME elicited a significant concentration-dependent chronic anti-hyperalgesic effect, also influencing both nociceptive and non-nociceptive mechanoreceptors, which were not observed in females at any of the concentrations tested. CONCLUSION AND IMPLICATIONS: Initiating treatment of a peripheral nerve injury with CBDA-ME at an early stage post-surgery provides anti-nociception in males, warranting further investigation into potential sexual dimorphisms underlying this response.

Tumor-targeting domains for chimeric antigen receptor T cells.

Immunotherapy with chimeric antigen receptor (CAR) T cells has been advancing steadily in clinical trials. Since the ability of engineered T cells to recognize intended tumor-associated targets is crucial for the therapeutic success, antigen-binding domains play an important role in shaping T-cell responses. Single-chain antibody and T-cell receptor fragments, natural ligands, repeat proteins, combinations of the above and universal tag-specific domains have all been used in the antigen-binding moiety of chimeric receptors. Here we outline the advantages and disadvantages of different domains, discuss the concepts of affinity and specificity, and highlight the recent progress of each targeting strategy.

High levels of estradiol impair spatial performance in the Morris water maze and increase 'depressive-like' behaviors in the female meadow vole.

The present study investigated sex differences and the effect of a high level of estradiol in the female meadow vole on performance in the forced swim test (FST) and the Morris water maze in meadow voles. Female meadow voles were ovariectomized (OVX) and administered either vehicle (sesame oil) or estradiol for 2 days prior to performing the FST. Four days following the FST, all animals were run in the Morris water maze. Results indicated that estradiol-injected female meadow voles showed more 'depressive-like' behaviors in the FST (greater time spent immobile and less time spent swimming) than vehicle-treated female or male meadow voles. In addition, estradiol-treated females had impaired performance (greater latencies and distance swam to reach the hidden platform) than both vehicle-treated female and male meadow voles, consistent with previous data. Despite the fact that estradiol administration increased 'depressive-like' behaviors in the FST and impaired performance in the Morris water maze, there was no correlation between the two behaviors indicating that 'depressive-like' behaviors did not account for the differences seen in spatial performance in the Morris water maze. To our knowledge, this is the first demonstration in rodents indicating that estradiol-mediated changes in behavior in the FST is not indicative of subsequent performance in the Morris water maze.