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BACKGROUND: Data demonstrating the clinical benefit of robotic cholecystectomy over the laparoscopic approach are lacking. Herein, we aim to evaluate whether robotic cholecystectomy is associated with improved surgical outcomes compared with laparoscopic cholecystectomy. STUDY DESIGN: This is a retrospective cohort study that used the American College of Surgeons National Surgical Quality Improvement Program to compare the outcomes of patients who underwent robotic or laparoscopic cholecystectomy for benign indications in 2022. RESULTS: Of the 59,216 patients identified, 53,746 underwent laparoscopic cholecystectomy and 5,470 robotic. Compared with the robotic cohort, the patients in the laparoscopic cholecystectomy group were older (50.4 vs 49.7 years), were of the male sex (32.7% vs 29.7%), and comprised a greater percentage of other races than White, African American, and Asian (28.6% vs 14.8%). Multivariable logistic regression revealed that robotic cholecystectomy compared with the laparoscopic approach was independently associated with a lower risk of Clavien-Dindo complications grade 3 or 4 (odds ratio, 0.82; 95% confidence interval, 0.69-0.98), a lower rate of conversion to open (odds ratio, 0.44; 95% confidence interval, 0.32-0.61), and lower odds of requiring hospitalization ≥24 hours (odds ratio, 0.76; 95% confidence interval, 0.71-0.81). There were no significant differences between the 2 approaches in terms of reoperation (odds ratio, 0.69; 95% confidence interval, 0.47-1.00) and readmission (odds ratio, 0.94; 95% confidence interval, 0.82-1.10). CONCLUSION: Robotic cholecystectomy was independently associated with a lower risk of serious complications, lower rate conversion to open, and hospitalization ≥24 hours compared with laparoscopic cholecystectomy. These findings suggest that new technologies might enhance the safety of minimally invasive surgery.

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Perineuronal nets (PNNs) are densely packed extracellular matrices that cover the cell body of fast-spiking inhibitory neurons. PNNs stabilize synapses inhibiting synaptic plasticity. Here we show that synaptic terminals of fast-spiking interneurons localize to holes in the PNNs in the adult mouse somatosensory cortex. Approximately 95% of holes in the PNNs contain synapses and astrocytic processes expressing Kir4.1, glutamate and GABA transporters. Hence, holes in the PNNs contain tripartite synapses. In the adult mouse brain, PNN degradation causes an expanded astrocytic coverage of the neuronal somata without altering the axon terminals. The loss of PNNs impairs astrocytic transmitter and potassium uptake, resulting in the spillage of glutamate into the extrasynaptic space. Our data show that PNNs and astrocytes cooperate to contain synaptically released signals in physiological conditions. Their combined action is altered in mouse models of Alzheimer's disease and epilepsy where PNNs are disrupted.

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OBJECTIVE: COVID-19 greatly influenced medical education and the residency match. As new guidelines were established to promote safety, travel was restricted, visiting rotations discontinued, and residency interviews turned virtual. The purpose of this study is to assess the geographic trends in distribution of successfully matched General Surgery applicants prior to and after the implementation of pandemic guidelines, and what we can learn from them as we move forward. DESIGN: This was a retrospective review of 129 Accreditation Council for Graduate Medical Education (ACGME) accredited, academic General Surgery Residency Programs across 46 states and the District of Columbia. Categorically matched residents' medical schools (i.e., home institutions), medical school states, and medical school regions as defined per the Association of American Medical Colleges (AAMC), were compared to the same geographic datapoints as their residency program. Preliminary residents were excluded. Residents in the 2018, 2019, and 2020 cycles were sub-categorized into the "pre-COVID" group and residents in the 2021 and 2022 applications cycles were sub-categorized into the "post-COVID" group. The percentages of residents who matched at their home institution, in-state, and in-region were examined. SETTING: Multiple ACGME-accredited, university-affiliated General Surgery Residency Programs across the United States of America. PARTICIPANTS: A total of 4033 categorical General Surgery residents were included. RESULTS: Of 4033 categorical residents who matched between 2018 and 2022, 56.1% (n = 2,263) were in the pre-COVID group and 43.9% (n = 1770) were in the post-COVID group. In the pre-COVID group 14.4% (n = 325) of residents remained in-home (IH), 24.4% (n = 553) in-state (IS), and 37.0% (n = 837) in- region (IR), compared to 18.8% IH (n = 333), 27.8% IS (n = 492), and 39.9% IR (n = 706) in the post-COVID group, respectively. Significant increases for IH and IS resident matching at 4.5% and 3.4%, respectively, were noted in the post-COVID period (p < 0.05). CONCLUSION: The COVID-19 pandemic, and the ensuing changes adopted to promote safety, significantly impacted medical student opportunities and the General Surgery residency application process. General Surgery match data over the last 5 years reveals a statistically significant increase in the percentage of applicants matching at in-home and in-state institutions after the pandemic.

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Alterations in the extracellular matrix are common in patients with epilepsy and animal models of epilepsy, yet whether they are the cause or consequence of seizures and epilepsy development is unknown. Using Theiler's murine encephalomyelitis virus (TMEV) infection-induced model of acquired epilepsy, we found de novo expression of chondroitin sulfate proteoglycans (CSPGs), a major extracellular matrix component, in dentate gyrus (DG) and amygdala exclusively in mice with acute seizures. Preventing the synthesis of CSPGs specifically in DG and amygdala by deletion of the major CSPG aggrecan reduced seizure burden. Patch-clamp recordings from dentate granule cells revealed enhanced intrinsic and synaptic excitability in seizing mice that was significantly ameliorated by aggrecan deletion. In situ experiments suggested that dentate granule cell hyperexcitability results from negatively charged CSPGs increasing stationary cations on the membrane, thereby depolarizing neurons, increasing their intrinsic and synaptic excitability. These results show increased expression of CSPGs in the DG and amygdala as one of the causal factors for TMEV-induced acute seizures. We also show identical changes in CSPGs in pilocarpine-induced epilepsy, suggesting that enhanced CSPGs in the DG and amygdala may be a common ictogenic factor and potential therapeutic target.

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INTRODUCTION: Surgery remains the cornerstone treatment for gastric cancer. Previous studies have reported better lymphadenectomy with minimally invasive approaches. There is a paucity of data comparing robotic and laparoscopic gastrectomy in the US. Herein, we examined whether oncological adequacy differs between laparoscopic and robotic approaches. METHODS: The National Cancer Database was utilized to identify patients who underwent gastrectomy for adenocarcinoma between 2010 and 2019. A propensity score-matching analysis between robotic gastrectomy (RG) versus laparoscopic gastrectomy (LG) was performed. The primary outcomes were lymphadenectomy ≥ 16 nodes and surgical margins. RESULTS: A total of 11,173 patients underwent minimally invasive surgery for gastric adenocarcinoma between 2010 and 2019. Of those 8320 underwent LG and 2853 RG. Comparing the unmatched cohorts, RG was associated with a higher rate of adequate lymphadenectomy (63.5% vs 57.1%, p < .0.0001), higher rate of negative margins (93.8% vs 91.9%, p < 0.001), lower rate of prolonged length of stay (26.0% vs 29.6%, p < .0.001), lower 90-day mortality (3.7% vs 5.0%, p < 0.0001), and a better 5-year overall survival (OS) (56% vs 54%, p = 0.03). A propensity score-matching cohort with a 1:1 ratio was created utilizing the variables associated with lymphadenectomy ≥ 16 nodes. The matched analysis revealed that the rate of adequate lymphadenectomy was significantly higher for RG compared to LG, 63.5% vs 60.4% (p = 0.01), respectively. There was no longer a significant difference between RG and LG regarding the rate of negative margins, prolonged length of stay, 90-day mortality, rate of receipt of postoperative chemotherapy, and OS. CONCLUSIONS: This propensity score-matching analysis with a large US cohort shows that RG was associated with a higher rate of adequate lymphadenectomy compared to LR. RG and LG had a similar rate of negative margins, prolonged length of stay, receipt of postoperative chemotherapy, 90-day mortality, and OS, suggesting that RG is a comparable surgical approach, if not superior to LG.

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Alterations in the extracellular matrix (ECM) are common in epilepsy, yet whether they are cause or consequence of disease is unknow. Using Theiler's virus infection model of acquired epilepsy we find de novo expression of chondroitin sulfate proteoglycans (CSPGs), a major ECM component, in dentate gyrus (DG) and amygdala exclusively in mice with seizures. Preventing synthesis of CSPGs specifically in DG and amygdala by deletion of major CSPG aggrecan reduced seizure burden. Patch-clamp recordings from dentate granule cells (DGCs) revealed enhanced intrinsic and synaptic excitability in seizing mice that was normalized by aggrecan deletion. In situ experiments suggest that DGCs hyperexcitability results from negatively charged CSPGs increasing stationary cations (K+, Ca2+) on the membrane thereby depolarizing neurons, increasing their intrinsic and synaptic excitability. We show similar changes in CSPGs in pilocarpine-induced epilepsy suggesting enhanced CSPGs in the DG and amygdala may be a common ictogenic factor and novel therapeutic potential.

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BACKGROUND: The National Comprehensive Cancer Network guidelines recommend harvesting 16 or more lymph nodes for the adequate staging of gastric adenocarcinoma. This study examines the rate of adequate lymphadenectomy over recent years, its predictors, and its impact on overall survival(OS). STUDY DESIGN: The National Cancer Database was utilized to identify patients who underwent surgical treatment for gastric adenocarcinoma between 2006-2019. Trend analysis was performed for lymphadenectomy rates during the study period. Logistic regression, Kaplan-Meier survival plots, and Cox proportional hazard regression were utilized. RESULTS: A total of 57,039 patients who underwent surgical treatment for gastric adenocarcinoma were identified. Only 50.5% of the patients underwent a lymphadenectomy of ≥ 16 nodes. Trend analysis showed that this rate significantly improved over the years, from 35.1% in 2006 to 63.3% in 2019 (p < .0001). The main independent predictors of adequate lymphadenectomy included high-volume facility with ≥ 31 gastrectomies/year (OR: 2.71; 95%CI:2.46-2.99), surgery between 2015-2019 (OR: 1.68; 95%CI: 1.60-1.75), and preoperative chemotherapy (OR:1.49; 95%CI:1.41-1.58). Patients with adequate lymphadenectomy had better OS than patients who did not: median survival: 59 versus 43 months (Log-Rank: p < .0001). Adequate lymphadenectomy was independently associated with improved OS (HR:0.79; 95%CI:0.77-0.81). Laparoscopic and robotic gastrectomies were independently associated with adequate lymphadenectomy compared to open, OR: 1.11, 95%CI:1.05-1.18 and OR: 1.24, 95%CI:1.13-1.35, respectively. CONCLUSION: Although the rate of adequate lymphadenectomy improved over the study period, a large number of patients still lacked adequate lymph node dissection, negatively impacting their OS despite multimodality therapy. Laparoscopic and robotic surgeries were associated with a significantly higher rate of lymphadenectomy ≥ 16 nodes.

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BACKGROUND: Traumatic brain injury (TBI) remains a significant risk factor for post-traumatic epilepsy (PTE). The pathophysiological mechanisms underlying the injury-induced epileptogenesis are under investigation. The dentate gyrus-a structure that is highly susceptible to injury-has been implicated in the evolution of seizure development. METHODS: Utilizing the murine unilateral focal control cortical impact (CCI) injury, we evaluated seizure onset using 24/7 EEG video analysis at 2-4 months post-injury. Cellular changes in the dentate gyrus and hilus of the hippocampus were quantified by unbiased stereology and Imaris image analysis to evaluate Prox1-positive cell migration, astrocyte branching, and morphology, as well as neuronal loss at four months post-injury. Isolation of region-specific astrocytes and RNA-Seq were performed to determine differential gene expression in animals that developed post-traumatic epilepsy (PTE+) vs. those animals that did not (PTE-), which may be associated with epileptogenesis. RESULTS: CCI injury resulted in 37% PTE incidence, which increased with injury severity and hippocampal damage. Histological assessments uncovered a significant loss of hilar interneurons that coincided with aberrant migration of Prox1-positive granule cells and reduced astroglial branching in PTE+ compared to PTE- mice. We uniquely identified Cst3 as a PTE+-specific gene signature in astrocytes across all brain regions, which showed increased astroglial expression in the PTE+ hilus. CONCLUSIONS: These findings suggest that epileptogenesis may emerge following TBI due to distinct aberrant cellular remodeling events and key molecular changes in the dentate gyrus of the hippocampus.

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Well over 100 different viruses can infect the brain and cause brain inflammation. In the developing world, brain inflammation is a leading cause for epilepsy and often refractory to established anti-seizure drugs. Epilepsy generally results from an imbalance in excitatory glutamatergic and inhibitory GABAergic neurotransmission. GABAergic inhibition is determined by the intracellular Cl- concentration which is established through the opposing action of two cation chloride cotransporters namely NKCC1 and KCC2. Brain-derived neurotrophic factor (BDNF) signaling is known to regulate expression of KCC2. Hence we hypothesized that viral induced epilepsy may result from aberrant BDNF signaling. We tested this hypothesis using a mouse model of Theiler's murine encephalomyelitis virus (TMEV) infection-induced epilepsy. We found that BDNF levels in the hippocampus from TMEV-infected mice with seizures was increased at the onset of acute seizures and continued to increase during the peak of acute seizure as well as in latent and chronic phases of epilepsy. During the acute phase of epilepsy, we found significant reduction in the expression of KCC2 in hippocampus, whereas the level of NKCC1 was unaltered. Importantly, inhibiting BDNF using scavenging bodies of BDNF in live brain slices from TMEV-infected mice with seizures normalized the level of KCC2 in hippocampus. Our results suggest that BDNF can directly decrease the relative expression of NKCC1 and KCC2 such as to favor accumulation of chloride intracellularly which in turn causes hyperexcitability by reversing GABA-mediated inhibition. Although our attempt to inhibit the BDNF signaling mediated through tyrosine kinase B-phospholipase Cγ1 (TrkB-PLCγ1) using a small peptide did not change the course of seizure development following TMEV infection, alternative strategies for controlling the BDNF signaling could be useful in preventing seizure generation and development of epilepsy in this model.

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Glioblastoma multiforme (GBM) is a deadly brain tumor with a large unmet therapeutic need. Here, we tested the hypothesis that wild-type p53 is a negative transcriptional regulator of SLC7A11, the gene encoding the System xc- (SXC) catalytic subunit, xCT, in GBM. We demonstrate that xCT expression is inversely correlated with p53 expression in patient tissue. Using representative patient derived (PDX) tumor xenolines with wild-type, null, and mutant p53 we show that p53 expression negatively correlates with xCT expression. Using chromatin immunoprecipitation studies, we present a molecular interaction whereby p53 binds to the SLC7A11 promoter, suppressing gene expression in PDX GBM cells. Accordingly, genetic knockdown of p53 increases SLC7A11 transcript levels; conversely, over-expressing p53 in p53-null GBM cells downregulates xCT expression and glutamate release. Proof of principal studies in mice with flank gliomas demonstrate that daily treatment with the mutant p53 reactivator, PRIMA-1Met, results in reduced tumor growth associated with reduced xCT expression. These findings suggest that p53 is a molecular switch for GBM glutamate biology, with potential therapeutic utility.

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OBJECTIVE: A growing body of evidence indicates a potential role for the gut-brain axis as a novel therapeutic target in treating seizures. The present study sought to characterize the gut microbiome in Theiler murine encephalomyelitis virus (TMEV)-induced seizures, and to evaluate the effect of microbial metabolite S-equol on neuronal physiology as well as TMEV-induced neuronal hyperexcitability ex vivo. METHODS: We infected C57BL/6J mice with TMEV and monitored the development of acute behavioral seizures 0-7 days postinfection (dpi). Fecal samples were collected at 5-7 dpi and processed for 16S sequencing, and bioinformatics were performed with QIIME2. Finally, we conducted whole-cell patch-clamp recordings in cortical neurons to investigate the effect of exogenous S-equol on cell intrinsic properties and neuronal hyperexcitability. RESULTS: We demonstrated that gut microbiota diversity is significantly altered in TMEV-infected mice at 5-7 dpi, exhibiting separation in beta diversity in TMEV-infected mice dependent on seizure phenotype, and lower abundance of genus Allobaculum in TMEV-infected mice regardless of seizure phenotype. In contrast, we identified specific loss of S-equol-producing genus Adlercreutzia as a microbial hallmark of seizure phenotype following TMEV infection. Electrophysiological recordings indicated that exogenous S-equol alters cortical neuronal physiology. We found that entorhinal cortex neurons are hyperexcitable in TMEV-infected mice, and exogenous application of microbial-derived S-equol ameliorated this TMEV-induced hyperexcitability. SIGNIFICANCE: Our study presents the first evidence of microbial-derived metabolite S-equol as a potential mechanism for alteration of TMEV-induced neuronal excitability. These findings provide new insight for the novel role of S-equol and the gut-brain axis in epilepsy treatment.

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Given the important functions that glutamate serves in excitatory neurotransmission, understanding the regulation of glutamate in physiological and pathological states is critical to devising novel therapies to treat epilepsy. Exclusive expression of pyruvate carboxylase and glutamine synthetase in astrocytes positions astrocytes as essential regulators of glutamate in the central nervous system (CNS). Additionally, astrocytes can significantly alter the volume of the extracellular space (ECS) in the CNS due to their expression of the bi-directional water channel, aquaporin-4, which are enriched at perivascular endfeet. Rapid ECS shrinkage has been observed following epileptiform activity and can inherently concentrate ions and neurotransmitters including glutamate. This review highlights our emerging knowledge on the various potential contributions of astrocytes to epilepsy, particularly supporting the notion that astrocytes may be involved in seizure initiation via failure of homeostatic responses that lead to increased ambient glutamate. We also review the mechanisms whereby ambient glutamate can influence neuronal excitability, including via generation of the glutamate receptor subunit GluN2B-mediated slow inward currents, as well as indirectly affect neuronal excitability via actions on metabotropic glutamate receptors that can potentiate GluN2B currents and influence neuronal glutamate release probabilities. Additionally, we discuss evidence for upregulation of System x c - , a cystine/glutamate antiporter expressed on astrocytes, in epileptic tissue and changes in expression patterns of glutamate receptors.

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Understanding the cytoarchitecture and wiring of the brain requires improved methods to record and stimulate large groups of neurons with cellular specificity. This requires miniaturized neural interfaces that integrate into brain tissue without altering its properties. Existing neural interface technologies have been shown to provide high-resolution electrophysiological recording with high signal-to-noise ratio. However, with single implantation, the physical properties of these devices limit their access to one, small brain region. To overcome this limitation, we developed a platform that provides three-dimensional coverage of brain tissue through multisite multifunctional fiber-based neural probes guided in a helical scaffold. Chronic recordings from the spatially expandable fiber probes demonstrate the ability of these fiber probes capturing brain activities with a single-unit resolution for long observation times. Furthermore, using Thy1-ChR2-YFP mice we demonstrate the application of our probes in simultaneous recording and optical/chemical modulation of brain activities across distant regions. Similarly, varying electrographic brain activities from different brain regions were detected by our customizable probes in a mouse model of epilepsy, suggesting the potential of using these probes for the investigation of brain disorders such as epilepsy. Ultimately, this technique enables three-dimensional manipulation and mapping of brain activities across distant regions in the deep brain with minimal tissue damage, which can bring new insights for deciphering complex brain functions and dynamics in the near future.

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BACKGROUND: We compared the Emergency General Surgery Specific Frailty Index (EGSFI), Risk Analysis Index (RAI-C) and the Katz Index (KI) at assessing frailty in acute care surgery (ACS). METHODS: A prospective cohort of ACS patients was stratified into frail or non-frail by the EGSFI, RAI-C and KI. The agreement between scales were compared. RESULTS: Of 272 eligible patients, 72, 75, and 56 were categorized as frail by the EGSFI, RAI-C, and KI respectively. There was weak to no agreement between instruments and consensus among all three scales was 59.4%. CONCLUSION: Between 21 and 28% of patients seen in this ACS cohort were categorized as frail using the EGSFI, RAI-C and KI. These frailty tools have different measures of what constitutes frailty and there was poor agreement between them. Only the KI definition of frailty was associated with a longer LOS. The KI may be more useful for assessing ACS patients in a tertiary care facility.

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OBJECTIVE: C57BL/6J mice infected with Theiler's murine encephalomyelitis virus (TMEV) develop acute behavioral seizures in the first week of infection and later develop chronic epilepsy. The TMEV model provides a useful platform to test novel antiseizure therapeutics. The present study was designed to test the efficacy of cannabidiol (CBD) in reducing acute seizures induced by viral infection. METHODS: C57BL/6J mice were infected intracortically with 2 × 105 plaque-forming units of TMEV. Mice were divided into two treatment groups-1) CBD-treated mice and 2) vehicle-treated mice. Frequency and severity of acute seizures were evaluated by video-monitoring the mice four times daily by the experimenter blinded to the treatment group. RESULTS: Cannabidiol (180 mg/kg; 360 mg/kg/day) decreased both the frequency and severity of acute behavioral seizures following TMEV infection, but 150 mg/kg of CBD did not improve overall seizure outcome. The time to peak effect (TPE) of CBD in the 6 Hz 32 mA psychomotor seizure test using C57BL/6J mice was observed at 2 hours post-CBD treatment. Interestingly, CBD (150 mg/kg) significantly reduced frequency and severity of TMEV-induced acute seizures at 2 hours post-CBD treatment. These results suggest that CBD could be effective in decreasing TMEV-induced acute seizures when the seizure test is conducted at the TPE of CBD. SIGNIFICANCE: Cannabinoids are increasingly studied for their potential antiseizure effects. Several preclinical and clinical studies provide evidence that CBD could be an effective therapy for intractable epilepsies. The present study corroborates those previous findings and provides an opportunity to investigate pharmacokinetics, pharmacodynamics, and mechanism(s) of antiseizure effects of CBD in the TMEV model, which may help to design future clinical studies more effectively.

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BACKGROUND AND OBJECTIVES: Etiologies, levels, and associated factors of psychological distress in cancer patients facing surgery are poorly defined. We conducted a prospective comparative study of perioperative anxiety and depression in patients undergoing abdominal surgery for either malignant or benign disease. METHODS: With Institutional Review Board approval, patients consenting for surgery at our institution were enrolled. Surveys were completed at a preoperative visit and within 2 weeks of a postoperative appointment. Participants listed their top three sources of anxiety, and completed the Patient Health Questionnaire-9 and the General Anxiety Disorder-7. RESULTS: A total of 79 patients completed the preoperative assessment and 44 (58.7%) finished the postoperative survey. Forty-one were male (51.9%), 12 (15.2%) had a psychiatric comorbidity (PSYHx), and 47 (59.5%) had cancer. Perioperative anxiety and depression did not differ by malignancy status. Patients were most concerned about surgery (22.5%) preoperatively and finances (27.9%) postoperatively. PSYHx, frailty, insurance status, and opioid use were all associated with perioperative psychological distress. CONCLUSIONS: Cancer patients did not have significantly higher levels of perioperative psychological distress compared with benign controls. Socioeconomic worries are prevalent throughout the perioperative period, and efforts to alleviate distress should focus on providing adequate counseling.

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Epilepsy is a neurological disorder afflicting ~65 million people worldwide. It is caused by aberrant synchronized firing of populations of neurons primarily due to imbalance between excitatory and inhibitory neurotransmission. Hence, the historical focus of epilepsy research has been neurocentric. However, the past two decades have enjoyed an explosion of research into the role of glia in supporting and modulating neuronal activity, providing compelling evidence of glial involvement in the pathophysiology of epilepsy. The mechanisms by which glia, particularly astrocytes and microglia, may contribute to epilepsy and consequently could be harnessed therapeutically are discussed in this Review.

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Brain tumor patients commonly present with epileptic seizures. We show that tumor-associated seizures are the consequence of impaired GABAergic inhibition due to an overall loss of peritumoral fast spiking interneurons (FSNs) concomitant with a significantly reduced firing rate of those that remain. The reduced firing is due to the degradation of perineuronal nets (PNNs) that surround FSNs. We show that PNNs decrease specific membrane capacitance of FSNs permitting them to fire action potentials at supra-physiological frequencies. Tumor-released proteolytic enzymes degrade PNNs, resulting in increased membrane capacitance, reduced firing, and hence decreased GABA release. These studies uncovered a hitherto unknown role of PNNs as an electrostatic insulator that reduces specific membrane capacitance, functionally akin to myelin sheaths around axons, thereby permitting FSNs to exceed physiological firing rates. Disruption of PNNs may similarly account for excitation-inhibition imbalances in other forms of epilepsy and PNN protection through proteolytic inhibition may provide therapeutic benefits.

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