Impact of intra-operative ketamine on postoperative outcomes in abdominal surgery: a narrative review.

Background and Objective: Ketamine offers a promising solution to common postoperative issues in abdominal surgery, including pain, nausea, opioid use, and opioid-related side effects. The purpose of this literature review is to analyze the benefits and potential adverse effects associated with the intraoperative utilization of ketamine during abdominal surgeries. Methods: A comprehensive search of PubMed and Ovid MEDLINE was conducted by two independent reviewers. Studies were included if they targeted adult patients and evaluated intra-operative use of ketamine for abdominal operations. Key Content and Findings: We identified 13 studies of intraoperative use of ketamine in abdominal surgery. The results of these studies showed improved pain management as demonstrated by lower pain scores, decreased hyperalgesia, and a decreased need for additional analgesics. The results also demonstrated a decrease in opioid consumption during the critical 24-hour postoperative period. However, a few studies reported undesirable side effects such as hallucinations and delirium. Conclusions: The intraoperative use of ketamine holds promise as a valuable adjunct to anesthesia during abdominal surgeries. Studies support its use in improving post-operative pain and decreasing opioid consumption. Due to risks of adverse effects, further studies in larger patient populations may help identify which patients will benefit the most. This review offers a succinct selection of the pertinent literature.

De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression.

p16 is a tumor suppressor encoded by the CDKN2A gene whose expression is lost in approximately 50% of all human cancers. In its canonical role, p16 inhibits the G1-S-phase cell cycle progression through suppression of cyclin-dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway. However, the broader impact of p16/CDKN2A loss on other nucleotide metabolic pathways and potential therapeutic targets remains unexplored. Using CRISPR knockout libraries in isogenic human and mouse melanoma cell lines, we determined several nucleotide metabolism genes essential for the survival of cells with loss of p16/CDKN2A. Consistently, many of these genes are upregulated in melanoma cells with p16 knockdown or endogenously low CDKN2A expression. We determined that cells with low p16/CDKN2A expression are sensitive to multiple inhibitors of de novo purine synthesis, including antifolates. Finally, tumors with p16 knockdown were more sensitive to the antifolate methotrexate in vivo than control tumors. Together, our data provide evidence to reevaluate the utility of these drugs in patients with p16/CDKN2Alow tumors as loss of p16/CDKN2A may provide a therapeutic window for these agents. SIGNIFICANCE: Antimetabolites were the first chemotherapies, yet many have failed in the clinic due to toxicity and poor patient selection. Our data suggest that p16 loss provides a therapeutic window to kill cancer cells with widely-used antifolates with relatively little toxicity.

Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility.

Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye. To better understand this resistance, we comprehensively profile 100 human uveal melanoma metastases using clinicogenomics, transcriptomics, and tumor infiltrating lymphocyte potency assessment. We find that over half of these metastases harbor tumor infiltrating lymphocytes with potent autologous tumor specificity, despite low mutational burden and resistance to prior immunotherapies. However, we observe strikingly low intratumoral T cell receptor clonality within the tumor microenvironment even after prior immunotherapies. To harness these quiescent tumor infiltrating lymphocytes, we develop a transcriptomic biomarker to enable in vivo identification and ex vivo liberation to counter their growth suppression. Finally, we demonstrate that adoptive transfer of these transcriptomically selected tumor infiltrating lymphocytes can promote tumor immunity in patients with metastatic uveal melanoma when other immunotherapies are incapable.

The direction of theta and alpha travelling waves modulates human memory processing.

To support a range of behaviours, the brain must flexibly coordinate neural activity across widespread brain regions. One potential mechanism for this coordination is a travelling wave, in which a neural oscillation propagates across the brain while organizing the order and timing of activity across regions. Although travelling waves are present across the brain in various species, their potential functional relevance has remained unknown. Here, using rare direct human brain recordings, we demonstrate a distinct functional role for travelling waves of theta- and alpha-band (2-13 Hz) oscillations in the cortex. Travelling waves propagate in different directions during separate cognitive processes. In episodic memory, travelling waves tended to propagate in a posterior-to-anterior direction during successful memory encoding and in an anterior-to-posterior direction during recall. Because travelling waves of oscillations correspond to local neuronal spiking, these patterns indicate that rhythmic pulses of activity move across the brain in different directions for separate behaviours. More broadly, our results suggest a fundamental role for travelling waves and oscillations in dynamically coordinating neural connectivity, by flexibly organizing the timing and directionality of network interactions across the cortex to support cognition and behaviour.

Planning-to-binge: Time allocation for future media consumption.

The prevalence of streaming media has led firms to embrace the phenomenon of "binge-watching" by offering entire multipart series simultaneously. Such "on-demand" availability allows consumers to choose how to allocate future viewing time, but such decisions have received little attention in the literature. Across several studies, we show that individuals can plan binging in advance by allocating time in ways that aggregate episode consumption. Thus, we expand our understanding of media consumption to a new timepoint, distinct from "in-the-moment" viewing. We demonstrate that planning-to-binge preferences are flexible and shaped by perceptions of the media of interest. In particular, they are greater for content whose episodes are perceived as more sequential and connected, as opposed to independent. Since our framework focuses on the media's structural continuity, it applies across hedonic and utilitarian time use, motivations, and content, including "binge-learning" plans for online education. Furthermore, increased plans-to-binge can be triggered by merely framing content as more sequential versus independent. Finally, consumers are willing to spend both money and time for the future opportunity to binge, and more so for sequential content. These findings suggest ways media companies may strategically emphasize content structure to influence consumer decisions and media viewing styles. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Opioid Prescribing Patterns After Colorectal Resections in the United States of America.

Background The opioid epidemic is a significant source of morbidity and mortality in the United States of America. Minimizing opioid prescribing after operations has become an important component of post-operative care pathways. We hypothesized that opioid prescribing has decreased over time after colorectal resections. Methods This is a retrospective study from 2012 to 2019 using the Optum Clinformatics database (Eden Prairie, MN). We included patients aged 18 years or older who had an elective colorectal resection. Our primary outcome was the rate of opioid prescription at post-operative discharge. Secondary outcomes included the rates of gabapentinoid (GABA) prescribing post-operatively. Results Of 17,900 patients, the most common procedure was sigmoid colectomy (35%). Most procedures were open (N=10,626, 59.4%). The most common indication was benign disease (N=12,439, 69.5%). Post-operative opioid prescribing decreased from 64.4% in 2012 to 46.7% in 2019. In the adjusted model, the odds of post-operative opioid prescription were 37% lower in 2019 than in 2012 (OR, 0.63; 95% CI, 0.56-0.72; p<0.0001). At 60 days and one year post surgery, opioid prescribing decreased from 11.6% and 5.9% in 2012 to 7.2% and 5.2% in 2019 (p<0.0001). At 60 days, gabapentinoid prescribing increased from 2.3% in 2012 to 4.0% in 2019 (p=0.0016). Conclusions Our data show that opioid prescribing is common after colorectal surgery with an overall post-operative prescription rate of 55.8%. The modification of post-operative pathways to include guidance on opioid prescribing and non-opioid alternatives may curb opioid prescribing, decrease the number of new persistent opioid users, and decrease the number of opioids available for diversion.

De novo purine metabolism is a metabolic vulnerability of cancers with low p16 expression.

p16 is a tumor suppressor encoded by the CDKN2A gene whose expression is lost in ~50% of all human cancers. In its canonical role, p16 inhibits the G1-S phase cell cycle progression through suppression of cyclin dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway. Whether other nucleotide metabolic genes and pathways are affected by p16/CDKN2A loss and if these can be specifically targeted in p16/CDKN2A-low tumors has not been previously explored. Using CRISPR KO libraries in multiple isogenic human and mouse melanoma cell lines, we determined that many nucleotide metabolism genes are negatively enriched in p16/CDKN2A knockdown cells compared to controls. Indeed, many of the genes that are required for survival in the context of low p16/CDKN2A expression based on our CRISPR screens are upregulated in p16 knockdown melanoma cells and those with endogenously low CDKN2A expression. We determined that cells with low p16/Cdkn2a expression are sensitive to multiple inhibitors of de novo purine synthesis, including anti-folates. Tumors with p16 knockdown were more sensitive to the anti-folate methotrexate in vivo than control tumors. Together, our data provide evidence to reevaluate the utility of these drugs in patients with p16/CDKN2A-low tumors as loss of p16/CDKN2A may provide a therapeutic window for these agents.

Melanoma-associated repair-like Schwann cells suppress anti-tumor T-cells via 12/15-LOX/COX2-associated eicosanoid production.

Peripheral glia, specifically the Schwann cells (SCs), have been implicated in the formation of the tumor microenvironment (TME) and in cancer progression. However, in vivo and ex vivo analyses of how cancers reprogram SC functions in different organs of tumor-bearing mice are lacking. We generated Plp1-CreERT/tdTomato mice which harbor fluorescently labeled myelinated and non-myelin forming SCs. We show that this model enables the isolation of the SCs with high purity from the skin and multiple other organs. We used this model to study phenotypic and functional reprogramming of the SCs in the skin adjacent to melanoma tumors. Transcriptomic analyses of the peritumoral skin SCs versus skin SCs from tumor-free mice revealed that the former existed in a repair-like state typically activated during nerve and tissue injury. Peritumoral skin SCs also downregulated pro-inflammatory genes and pathways related to protective anti-tumor responses. In vivo and ex vivo functional assays confirmed immunosuppressive activities of the peritumoral skin SCs. Specifically, melanoma-reprogrammed SCs upregulated 12/15-lipoxygenase (12/15-LOX) and cyclooxygenase (COX)-2, and increased production of anti-inflammatory polyunsaturated fatty acid (PUFA) metabolites prostaglandin E2 (PGE2) and lipoxins A4/B4. Inhibition of 12/15-LOX or COX2 in SCs, or EP4 receptor on lymphocytes reversed SC-dependent suppression of anti-tumor T-cell activation. Therefore, SCs within the skin adjacent to melanoma tumors demonstrate functional switching to repair-like immunosuppressive cells with dysregulated lipid oxidation. Our study suggests the involvement of the melanoma-associated repair-like peritumoral SCs in the modulation of locoregional and systemic anti-tumor immune responses.

Gender differences in "optimistic" information processing in uncertain decisions.

Decision-makers often are faced with uncertain situations in which they have incomplete information. While risky decisions include the probabilities of the possible outcomes, ambiguous decisions involve both unknown probabilities and unknown outcomes. Prior research has suggested that there are differences in how men and women evaluate risk, but evidence related to gender and ambiguity is mixed. The present work approaches this problem from a novel angle, focusing on the use of information that is present rather than the impact of information that is absent. It examines how individuals assign value in uncertain decisions based on the partial information they do have. While a main effect of gender on value is not observed, there is an enhanced "optimism bias" in how both favorable and unfavorable information influences the subjective value of ambiguous financial prospects for male compared to female participants. Unpacking these effects suggests multiple mechanisms, including a significant contribution of risk processing. Specifically, favorable and unfavorable information are over- and underweighted respectively in male participants' estimated likelihood of a winning outcome, and unfavorable information is underweighted in estimating certainty. There also is an interaction of gender and risk preferences, such that value increases more for male participants as the subjectively estimated likelihood of winning increases. A second experiment demonstrates this risk interaction effect is also observed for objective probabilities of winning, suggesting that the relationship between value and risk uses similar mechanisms across layers of uncertainty.

Neuronal activity in the human amygdala and hippocampus enhances emotional memory encoding.

Emotional events comprise our strongest and most valuable memories. Here we examined how the brain prioritizes emotional information for storage using direct brain recording and deep brain stimulation. First, 148 participants undergoing intracranial electroencephalographic (iEEG) recording performed an episodic memory task. Participants were most successful at remembering emotionally arousing stimuli. High-frequency activity (HFA), a correlate of neuronal spiking activity, increased in both the hippocampus and the amygdala when participants successfully encoded emotional stimuli. Next, in a subset of participants (N = 19), we show that applying high-frequency electrical stimulation to the hippocampus selectively diminished memory for emotional stimuli and specifically decreased HFA. Finally, we show that individuals with depression (N = 19) also exhibit diminished emotion-mediated memory and HFA. By demonstrating how direct stimulation and symptoms of depression unlink HFA, emotion and memory, we show the causal and translational potential of neural activity in the amygdalohippocampal circuit for prioritizing emotionally arousing memories.

A phenylpropanoid dimer from the leaves of Piper betle.

Phytochemical analyses of the chloroform extract of Piper betle L. var. Sanchi, Piperaceae, leaves led to the isolation of a new phenylpropanoid analogue for the first time: hydroxychavicol dimer, 2-(γ'-hydroxychavicol)-hydroxychavicol (S1), on the basis of spectroscopic data 1 D (1H and 13C) and 2 D (1H-1H COSY and HMBC) NMR, as well as ESI-MS, FT-IR, HR-ESI-MS and LC-ESI-MS. Compound S1 exhibited excellent antioxidant DPPH radical scavenging activity with IC50 values of 9.07 µg/mL, compared to ascorbic acid as a standard antioxidant drug with IC50 value of 3.41 µg/mL. Evaluation of cytotoxic activity against two human colon cancer cell lines (HT 29 and COLO-205) showed significant effect with GI50 values of 73.81 and 64.02 µmol/L, compared to Doxorubicin® as a standard cytotoxic drug with GI50 value of <10 µmol/L.

Combined thioredoxin reductase and glutaminase inhibition exerts synergistic anti-tumor activity in MYC-high high-grade serous ovarian carcinoma.

Approximately 50%-55% of high-grade serous ovarian carcinoma (HGSOC) patients have MYC oncogenic pathway activation. Because MYC is not directly targetable, we have analyzed molecular pathways enriched in MYC-high HGSOC tumors to identify potential therapeutic targets. Here, we report that MYC-high HGSOC tumors show enrichment in genes controlled by NRF2, an antioxidant signaling pathway, along with increased thioredoxin redox activity. Treatment of MYC-high HGSOC tumors cells with US Food and Drug Administration (FDA)-approved thioredoxin reductase 1 (TrxR1) inhibitor auranofin resulted in significant growth suppression and apoptosis in MYC-high HGSOC cells in vitro and also significantly reduced tumor growth in an MYC-high HGSOC patient-derived tumor xenograft. We found that auranofin treatment inhibited glycolysis in MYC-high cells via oxidation-induced GAPDH inhibition. Interestingly, in response to auranofin-induced glycolysis inhibition, MYC-high HGSOC cells switched to glutamine metabolism for survival. Depletion of glutamine with either glutamine starvation or glutaminase (GLS1) inhibitor CB-839 exerted synergistic anti-tumor activity with auranofin in HGSOC cells and OVCAR-8 cell line xenograft. These findings suggest that applying a combined therapy of GLS1 inhibitor and TrxR1 inhibitor could effectively treat MYC-high HGSOC patients.

The unlikelihood effect: When knowing more creates the perception of less.

People face increasingly detailed information related to a range of risky decisions. To aid individuals in thinking through such risks, various forms of policy and health messaging often enumerate their causes. Whereas some prior literature suggests that adding information about causes of an outcome increases its perceived likelihood, we identify a novel mechanism through which the opposite regularly occurs. Across seven primary and six supplementary experiments, we find that the estimated likelihood of an outcome decreases when people learn about the (by- definition lower) probabilities of the pathways that lead to that outcome. This "unlikelihood" bias exists despite explicit communication of the outcome's total objective probability and occurs for both positive and negative outcomes. Indeed, awareness of a low-probability pathway decreases subjective perceptions of the outcome's likelihood even when its addition objectively increases the outcome's actual probability. These findings advance the current understanding of how people integrate information under uncertainty and derive subjective perceptions of risk. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Sensory Nerves Impede the Formation of Tertiary Lymphoid Structures and Development of Protective Antimelanoma Immune Responses.

Peripheral neurons comprise a critical component of the tumor microenvironment (TME). The role of the autonomic innervation in cancer has been firmly established. However, the effect of the afferent (sensory) neurons on tumor progression remains unclear. Utilizing surgical and chemical skin sensory denervation methods, we showed that afferent neurons supported the growth of melanoma tumors in vivo and demonstrated that sensory innervation limited the activation of effective antitumor immune responses. Specifically, sensory ablation led to improved leukocyte recruitment into tumors, with decreased presence of lymphoid and myeloid immunosuppressive cells and increased activation of T-effector cells within the TME. Cutaneous sensory nerves hindered the maturation of intratumoral high endothelial venules and limited the formation of mature tertiary lymphoid-like structures containing organized clusters of CD4+ T cells and B cells. Denervation further increased T-cell clonality and expanded the B-cell repertoire in the TME. Importantly, CD8a depletion prevented denervation-dependent antitumor effects. Finally, we observed that gene signatures of inflammation and the content of neuron-associated transcripts inversely correlated in human primary cutaneous melanomas, with the latter representing a negative prognostic marker of patient overall survival. Our results suggest that tumor-associated sensory neurons negatively regulate the development of protective antitumor immune responses within the TME, thereby defining a novel target for therapeutic intervention in the melanoma setting.

Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis.

The triggers that drive interferon-γ (IFNγ)-producing CD8 T cell (Tc1 cell)-mediated autoimmune hepatitis (AIH) remain obscure. Here, we show that lack of hematopoietic Tet methylcytosine dioxygenase 2 (Tet2), an epigenetic regulator associated with autoimmunity, results in the development of microbiota-dependent AIH-like pathology, accompanied by hepatic enrichment of aryl hydrocarbon receptor (AhR) ligand-producing pathobionts and rampant Tc1 cell immunity. We report that AIH-like disease development is dependent on both IFNγ and AhR signaling, as blocking either reverts ongoing AIH-like pathology. Illustrating the critical role of AhR-ligand-producing pathobionts in this condition, hepatic translocation of the AhR ligand indole-3-aldehyde (I3A)-releasing Lactobacillus reuteri is sufficient to trigger AIH-like pathology. Finally, we demonstrate that I3A is required for L. reuteri-induced Tc1 cell differentiation in vitro and AIH-like pathology in vivo, both of which are restrained by Tet2 within CD8 T cells. This AIH-disease model may contribute to the development of therapeutics to alleviate AIH.

Addition of Local Anesthetic Epidural Infusion Catheter to Intravenous Opioid Analgesia for Postoperative Pain Control in Children Undergoing Video Assisted Thoracoscopic Surgery (VATS).

PURPOSE: Postoperative analgesia following minimally invasive video assisted thoracoscopic surgery (VATS) in pediatric patients may involve intravenous opioid analgesics and continuous local anesthetic infusions via an epidural infusion catheter. The use of epidural catheters may avoid systemic side effects of intravenous opioids in this vulnerable population. DESIGN: Our primary aim was to compare total morphine equivalents (MEQ) required, and pain scores between local anesthetic epidural infusion catheters combined with intravenous opioids, versus intravenous opioids alone in pediatric patients following VATS procedure. METHODS: Following Institutional Review Board approval, we performed a retrospective chart review of children (ages 1 month to 18 years) who underwent VATS procedure for noncardiac thoracic surgery. Based on the postoperative analgesic technique used, the study population was divided into two groups that is, epidural group and nonepidural group. Both groups received intravenous systemic opioids. The primary outcome variables were total MEQ required and pain scores in the perioperative period. FINDINGS: Ninety-two patients were included in the study. Of these, 22 patients belonged to the epidural group versus 70 patients to the nonepidural group. There was no statistical difference in MEQ requirements or pain scores between the groups intraoperatively (P = .304), in the postanesthesia care unit (P = .166), or at postoperative time intervals of 24 hours (P = .805) and 48 hours (P = .844). The presence of infection or empyema was a significant factor for the avoidance of epidural placement by providers (P = .003). CONCLUSIONS: There was no significant difference in the perioperative MEQ or postoperative pain scores between the epidural catheter group and the nonepidural group. More research is necessary to determine if this could be due to epidural catheter malposition and/or inadequate dermatomal coverage of surgical chest tubes.

Jose Delgado: A controversial trailblazer in neuromodulation.

Dr. Jose Delgado performed audacious demonstrations utilizing brain stimulation to instantly change behavior in animals. These feats spark ethical debates to this day. However, behind his controversial career is an important legacy of neurological discoveries and technological innovation. Delgado pioneered techniques in causally manipulating brain patterns and behavior with electrical stimulation and developed innovative, closed-loop neural devices. His inventive devices and techniques were ahead of his time and remain relevant to the field of neuromodulation today.

Association between number of abnormal glucose values and severity of fasting plasma glucose in IADPSG criteria and maternal outcomes in women with gestational diabetes mellitus.

AIMS: The International Association for Diabetes in Pregnancy Study Group (IADPSG) criteria recommend a single-step diagnostic oral glucose tolerance test (OGTT) for diagnosis of gestational diabetes mellitus (GDM). The aim of this study was to examine the association between the number of abnormal glucose values and levels of FPG with pregnancy outcomes. METHODS: Pregnant women (n=1,044) were screened for GDM at maternity centers in South India using IADPSG criteria. OGTTs were classified based on the number of abnormal glucose values (any one value or more than one value high) and fasting plasma glucose (FPG) values (<92mg/dl,92-100mg/dl,>100mg/dl) and correlated with pregnancy outcomes. Odds ratio were adjusted for age, BMI, gestational week at diagnosis, family history of diabetes, previous history of GDM, gestational week at delivery and birth weight. For macrosomia and large for gestation age, birth weight was excluded from the model. RESULTS: Risk of caesarean section was significantly higher in women with any one abnormal glucose value (OR: 1.49; 95%CI: 1.07-2.09). This further increased in those with >1 value (OR: 1.35; 95%CI: 0.87-2.10), when compared to women with all values normal. Risk of large for gestation age (LGA) was higher in women with FPG 92-100mg/dl (OR: 1.37; 95%CI: 0.80-2.35) and in those with FPG >100mg/dl (OR: 1.87; 95%CI: 1.04-3.35), compared to those with FPG <92mg/dl. CONCLUSIONS: The risk for poor pregnancy outcomes starts in those with one abnormal value in the OGTT or with FPG >92mg/dl but becomes significantly higher in those with higher abnormal values.

Expression of Tim-3 drives phenotypic and functional changes in Treg cells in secondary lymphoid organs and the tumor microenvironment.

Regulatory T cells (Treg cells) are critical mediators of self-tolerance, but they can also limit effective anti-tumor immunity. Although under homeostasis a small fraction of Treg cells in lymphoid organs express the putative checkpoint molecule Tim-3, this protein is expressed by a much larger proportion of tumor-infiltrating Treg cells. Using a mouse model that drives cell-type-specific inducible Tim-3 expression, we show that expression of Tim-3 by Treg cells is sufficient to drive Treg cells to a more effector-like phenotype, resulting in increases in suppressive activity, effector T cell exhaustion, and tumor growth. We also show that T-reg-cell-specific inducible deletion of Tim-3 enhances anti-tumor immunity. Enhancement of Treg cell function by Tim-3 is strongly correlated with increased expression of interleukin-10 (IL-10) and a shift to a more glycolytic metabolic phenotype. Our data demonstrate that Tim-3+ Treg cells may be a relevant therapeutic target cell type for the treatment of cancer.