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Central anticholinergic syndrome (CAS) presents with central and/or peripheral neurological symptoms after exposure to anticholinergic medication. Pain management is a challenge for patients who have CAS and concurrent cancer-related pain. We present a patient who became lethargic and unresponsive after receiving butorphanol, with persistent symptoms despite administration of an opioid antagonist. This case report is the first to suggest a causal relationship between opioids and CAS without the presence of confounding anticholinergic medications. CAS should be considered for patients who develop neurological symptoms after opioid exposure and have an incomplete response to an opioid antagonist. Key words: central anticholinergic syndrome, butorphanol, opioids, cancer-related pain, anticholinergic toxicity, case report Abbreviations: CAS - Central Anticholinergic Syndrome; IV – intravenous; IM – intramuscular; ED - Emergency Department; WHO - World Health Organization; MRI - Magnetic Resonance Imaging; MED - Morphine Equivalent Dosing; ICU - Intensive Care Unit Citation: Choi A, Bui T, Pan EY, Ozcan M. Is central anticholinergic syndrome linked to opioid use for cervical cancer pain? Anaesth. pain intensive care 2022;26(6):826−830; DOI: 10.35975/apic.v26i6.2068

The gingiva is the target site for some topical drugs, but the permeability of human gingiva has not been systematically evaluated. Pigs are a common animal model for in vitro membrane transport studies. The objectives of this study were to: (a) determine the permeability coefficients of freshly excised human gingiva using model permeants, (b) compare the permeability coefficients of fresh human gingiva with those of fresh porcine gingiva, (c) evaluate the effect of freezing duration on the permeability of porcine gingiva, and (d) compare the permeability coefficients of fresh and cadaver (frozen) human gingiva. A goal was to examine the feasibility of using porcine gingiva as a surrogate for human gingiva. The potential of using frozen tissues in permeability studies of gingiva was also examined. Fresh and frozen porcine gingiva, fresh human gingiva, and frozen cadaver human gingiva were compared in the transport study with model polar and lipophilic permeants. The fresh porcine and human tissues showed similarities in the “permeability coefficient vs. octanol–water distribution coefficient” relationship. The porcine gingiva had a lower permeability than that of the human, with a moderate correlation between the permeability of the fresh porcine and fresh human tissues. The permeability of the porcine tissues for the model polar permeants increased significantly after the tissues were frozen in storage. Moreover, the frozen human cadaver tissue could not be utilized due to the high and indiscriminating permeability of the tissue for the permeants and large tissue sample-to-sample variabilities.

Background: Shivering is a common adverse effect of achieving and maintaining normothermia in neurocritical care patients. We compared the burden of shivering and shivering-related interventions between a novel trans-nasal temperature modulating device(tnTMD) and surface cooling temperature modulating devices(sTMDs) during the first 24 hours of targeted normothermia in mechanically ventilated febrile neurocritical care patients. Methods: This is a case: control study controlling for factors that impact shiver burden: age, sex, body surface area. All patients underwent transnasal cooling (COOLSTAT, KeyTech, Inc) as part of an ongoing multicenter clinical trial(NCT03360656). Patients undergoing treatment with sTMDs were selected from consecutively treated patients during the same time-period. Data collected included: core body temperature (every 2 hours), bedside shivering assessment scale(BSAS) score (every 2 hours), and administration of anti-shivering medication for BSAS>1.Time to normothermia(37.5 C(C*hr) were compared between groups using student’s t-test for mean differences. Proportion of patients requiring interventions as well as number of interventions per patient were compared using Chi-Square test. Significance was determined based on a P value < 0.05. Results: There were 10 tnTMD patients and 30 sTMD patients included in the analysis (mean age: 62+/-4, 30% women, BSA = 1.97+/-0.25). There were no differences between groups in temperature at cooling initiation (tnTMD: 38.5+/-0.2 C vs sTMD: 38.7+/-0.5 C, P=0.3), time to 37.5 (tnTMD:: -0.4 +/- 1.13 C*hr vs. sTMD median (IQR): -0.57 +/- 0.58 C*hr, P=0.67). The number of tnTMD patients who received pharmacologic shivering interventions was lower than the controls (20%vs.67%,p=0.01). tnTMD patients also had fewer shivering interventions per patient (0 (range: 0-3)vs.4(range: 0 – 23 ), p

SF1: TGF-β1 promotes Twist1-induced epithelial dissemination without loss of adherens junction protein expression; SF2: Prkd1 inhibitors kb-NB142-70 and Gö-6976 block Twist1- induced dissemination dose-dependently; SF3: Dissemination defects in Twist1-On organoids resulting from Prkd1 inactivation; SF4: Twist1-induced epithelial cells express Prkd1 and maintain β-catenin expression; SF5: Limited toxicity observed in response to drug treatment of Twist1-induced organoids; SF6: Supporting data for Figure 6: SF7: Molecular model for Twist1-induced epithelial dissemination; ST1: List of inhibitors tested in Figure 1; ST2: List of antibodies used in the study; ST3: Phosphoantibody microarray data. Supplementary movie legends.

Dissemination is an essential early step in metastasis but its molecular basis remains incompletely understood. To define the essential targetable effectors of this process, we developed a 3D mammary epithelial culture model, in which dissemination is induced by overexpression of the transcription factor Twist1. Transcriptomic analysis and ChIP-PCR together demonstrated that protein kinase D1 (Prkd1) is a direct transcriptional target of Twist1 and is not expressed in the normal mammary epithelium. Pharmacologic and genetic inhibition of Prkd1 in the Twist1-induced dissemination model demonstrated that Prkd1 was required for cells to initiate extracellular matrix (ECM)–directed protrusions, release from the epithelium, and migrate through the ECM. Antibody-based protein profiling revealed that Prkd1 induced broad phosphorylation changes, including an inactivating phosphorylation of β-catenin and two microtubule depolymerizing phosphorylations of Tau, potentially explaining the release of cell–cell contacts and persistent activation of Prkd1. In patients with breast cancer, TWIST1 and PRKD1 expression correlated with metastatic recurrence, particularly in basal breast cancer. Prkd1 knockdown was sufficient to block dissemination of both murine and human mammary tumor organoids. Finally, Prkd1 knockdown in vivo blocked primary tumor invasion and distant metastasis in a mouse model of basal breast cancer. Collectively, these data identify Prkd1 as a novel and targetable signaling node downstream of Twist1 that is required for epithelial invasion and dissemination.Significance:Twist1 is a known regulator of metastatic cell behaviors but not directly targetable. This study provides a molecular explanation for how Twist1-induced dissemination works and demonstrates that it can be targeted.

This file contains the full blot images of all Western blots.

Early inhibition of Prkd1 blocks epithelial invasion into ECM and loss of cell-cell adhesion.

Late inhibition of Prkd1 after onset of dissemination prevents disseminated cell migration and prevents de novo dissemination.

SummaryInfection by hepatitis B virus (HBV) increases risk for liver cancer by inducing inflammation, cellular stress and cell death. To elucidate the molecular pathways by which HBV promotes cancer development and progression, we used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human host proteins in hepatocellular carcinoma (HCC). We find that viral proteins target host factors that are preferentially mutated in non-HBV-associated HCC, implicating cancer pathways whose interaction with HBV plays a role in HCC. Focusing on proteins that directly interact with the HBV oncoprotein X (HBx), we show that HBx remodels the PP2A phosphatase complex, altering its effect on tumor signaling. HBx excludes striatin-family regulatory subunits from PP2A, causing Hippo kinase activation and unmasking a requirement for mTOR complex 2 to maintain expression of the YAP oncoprotein in HCC. Thus, HBV rewires HCC to expose potentially targetable signaling dependencies.SignificancePrecision medicine has revolutionized cancer treatment but remains elusive for HCC. We used proteomics to define HBV/host interactions and integrated them with HCC mutations. The results implicate modifiers of HCC behavior via remodeling of host complexes and illuminate new biological mechanisms in advanced disease for therapeutic investigation.

BACKGROUND: After subarachnoid hemorrhage (SAH), early brain injury (EBI) and delayed cerebral ischemia (DCI) lead to poor outcomes. Discovery of biomarkers indicative of disease severity and predictive of DCI is important. We tested whether leucine-rich alpha-2-glycoprotein 1 (LRG1) is a marker of severity, DCI, and functional outcomes after SAH. METHODS: We performed untargeted proteomics using mass spectrometry in plasma samples collected at < 48 h of SAH in two independent discovery cohorts (n = 27 and n = 45) and identified LRG1 as a biomarker for DCI. To validate our findings, we used enzyme-linked immunosorbent assay and confirmed this finding in an internal validation cohort of plasma from 72 study participants with SAH (22 DCI and 50 non-DCI). Further, we investigated the relationship between LRG1 and markers of EBI, DCI, and poor functional outcomes (quantified by the modified Rankin Scale). We also measured cerebrospinal fluid (CSF) levels of LRG1 and investigated its relationship to EBI, DCI, and clinical outcomes. RESULTS: Untargeted proteomics revealed higher plasma LRG1 levels across EBI severity and DCI in both discovery cohorts. In the validation cohort, the levels of LRG1 were higher in the DCI group compared with the non-DCI group (mean (SD): 95 [44] vs. 72 [38] pg/ml, p < 0.05, Student’s t-test) and in study participants who proceeded to have poor functional outcomes (84 [39.3] vs. 72 [43.2] pg/ml, p < 0.05). Elevated plasma LRG1 levels were also associated with markers of EBI. However, CSF levels of LRG1 were not associated with EBI severity or the occurrence of DCI. CONCLUSIONS: Plasma LRG1 is a biomarker for EBI, DCI, and functional outcomes after SAH. Further studies to elucidate the role of LRG1 in the pathophysiology of SAH are needed.

Aneurysmal subarachnoid hemorrhage (aSAH) causes a robust inflammatory response which leads worse brain injury and poor outcomes. We investigated if stimulation of nicotinic acetylcholine α7 receptors (α7-AChR) (receptors shown to have anti-inflammatory effects) would reduce inflammation and improve outcomes. To investigate the level of peripheral inflammation after aSAH, inflammatory markers were measured in plasma samples collected in a cohort of aSAH patients. To study the effect of α7-AChR stimulation, SAH was induced in adult mice which were then treated with a α7-AChR agonist, galantamine, or vehicle. A battery of motor and cognitive tests were performed 24 h after subarachnoid hemorrhage. Mice were euthanized and tissue collected for analysis of markers of inflammation or activation of α7-AChR-mediated transduction cascades. A separate cohort of mice was allowed to survive for 28 days to assess long-term neurological deficits and histological outcome. Microglia cell culture subjected to hemoglobin toxicity was used to assess the effects of α7-AChR agonism. Analysis of eighty-two patient plasma samples confirmed enhanced systemic inflammation after aSAH. α7-AChR agonism reduced neuroinflammation at 24 h after SAH in male and female mice, which was associated with improved outcomes. This coincided with JAK2/STAT3 and IRAK-M activity modulations and a robust improvement in neurological/cognitive status that was effectively reversed by interfering with various components of these signaling pathways. Pharmacologic inhibition partially reversed the α7-AChR agonist’s benefits, supporting α7-AChR as a target of the agonist’s therapeutic effect. The cell culture experiment showed that α7-AChR agonism is directly beneficial to microglia. Our results demonstrate that activation of α7-AChR represents an attractive target for treatment of SAH. Our findings suggest that α7-AChR agonists, and specifically galantamine, might provide therapeutic benefit to aSAH patients.

Establishing goals of care (GOC) is a crucial component of a patient's treatment plan. The need for better physician-patient communication in this area has been recognized for decades, yet several gaps remain. Challenges exist for both physician and patient. Physicians should pursue a patient-led approach, exercise cultural competency, and use various communication techniques to guide patients when establishing GOC.

ObjectiveTo determine whether machine learning (ML) algorithms can improve the prediction of delayed cerebral ischemia (DCI) and functional outcomes after subarachnoid hemorrhage (SAH).MethodsML models and standard models (SMs) were trained to predict DCI and functional outcomes with data collected within 3 days of admission. Functional outcomes at discharge and at 3 months were quantified using the modified Rankin Scale (mRS) for neurologic disability (dichotomized as good [mRS ≤ 3] vs poor [mRS ≥ 4] outcomes). Concurrently, clinicians prospectively prognosticated 3-month outcomes of patients. The performance of ML, SMs, and clinicians were retrospectively compared.ResultsDCI status, discharge, and 3-month outcomes were available for 399, 393, and 240 participants, respectively. Prospective clinician (an attending, a fellow, and a nurse) prognostication of 3-month outcomes was available for 90 participants. ML models yielded predictions with the following area under the receiver operating characteristic curve (AUC) scores: 0.75 ± 0.07 (95% confidence interval [CI] 0.64–0.84) for DCI, 0.85 ± 0.05 (95% CI 0.75–0.92) for discharge outcome, and 0.89 ± 0.03 (95% CI 0.81–0.94) for 3-month outcome. ML outperformed SMs, improving AUC by 0.20 (95% CI −0.02 to 0.4) for DCI, by 0.07 ± 0.03 (95% CI −0.0018 to 0.14) for discharge outcomes, and by 0.14 (95% CI 0.03–0.24) for 3-month outcomes and matched physician's performance in predicting 3-month outcomes.ConclusionML models significantly outperform SMs in predicting DCI and functional outcomes and has the potential to improve SAH management.

Increased soluble endoglin (sENG) has been observed in human brain arteriovenous malformations (bAVMs). In addition, the overexpression of sENG in concurrence with vascular endothelial growth factor (VEGF)-A has been shown to induce dysplastic vessel formation in mouse brains. However, the underlying mechanism of sENG-induced vascular malformations is not clear. The evidence suggests the role of sENG as a pro-inflammatory modulator, and increased microglial accumulation and inflammation have been observed in bAVMs. Therefore, we hypothesized that microglia mediate sENG-induced inflammation and endothelial cell (EC) dysfunction in bAVMs. In this study, we confirmed that the presence of sENG along with VEGF-A overexpression induced dysplastic vessel formation. Remarkably, we observed increased microglial activation around dysplastic vessels with the expression of NLRP3, an inflammasome marker. We found that sENG increased the gene expression of VEGF-A, pro-inflammatory cytokines/inflammasome mediators (TNF-α, IL-6, NLRP3, ASC, Caspase-1, and IL-1β), and proteolytic enzyme (MMP-9) in BV2 microglia. The conditioned media from sENG-treated BV2 (BV2-sENG-CM) significantly increased levels of angiogenic factors (Notch-1 and TGFβ) and pERK1/2 in ECs but it decreased the level of IL-17RD, an anti-angiogenic mediator. Finally, the BV2-sENG-CM significantly increased EC migration and tube formation. Together, our study demonstrates that sENG provokes microglia to express angiogenic/inflammatory molecules which may be involved in EC dysfunction. Our study corroborates the contribution of microglia to the pathology of sENG-associated vascular malformations.

Chronic neuropathic pain is an incapacitating secondary consequence of spinal cord injury occurring in 40%–70% of injured people. There is no clear injury characteristic or patient phenotype that predicts who will develop neuropathic pain. However, promising work is ongoing to combine objective laboratory-based assays, standardized testing, and clinical factors to predict, identify, and/or monitor neuropathic pain. Biomarkers prognostic of neuropathic pain may allow for early intervention and identify novel mechanism-based treatments. In this chapter we discuss current biomarker discovery approaches and elaborate on some of the promising biomarker candidates.

Spontaneous intracerebral hemorrhage (ICH) is the second most prevalent subtype of stroke and has high mortality and morbidity. The utility of radiographic features to predict secondary brain injury related to hematoma expansion (HE) or increased intracranial pressure has been highlighted in patients with ICH, including the computed tomographic angiography (CTA) spot sign and intraventricular hemorrhage (IVH). Understanding the pathophysiology of spot sign and IVH may help identify optimal therapeutic strategies. We examined factors related to the spot sign and IVH, including coagulation status, hematoma size, and location, and evaluated their prognostic value in patients with ICH.Prospectively collected data from a single center between 2012 and 2015 were analyzed. Patients who underwent thromboelastography within 24 h of symptom onset and completed follow-up brain imaging and CTA within 48 h after onset were included for analysis. Multivariate logistic regression analyses were performed to identify determinants of the spot sign and IVH and their predictive value for HE, early neurological deterioration (END), in-hospital mortality, and functional outcome at discharge.Of 161 patients, 50 (31.1%) had a spot sign and 93 (57.8%) had IVH. In multivariable analysis, the spot sign was associated with greater hematoma volume (odds ratio [OR] 1.02; 95% confidence interval [CI] 1.00-1.03), decreased white blood cell count (OR 0.88; 95% CI 0.79-0.98), and prolonged activated partial thromboplastin time (OR 1.14; 95% CI 1.06-1.23). IVH was associated with greater hematoma volume (OR 1.02; 95% CI 1.01-1.04) and nonlobar location of hematoma (OR 0.23; 95% CI 0.09-0.61). The spot sign was associated with greater risk of all adverse outcomes. IVH was associated with an increased risk of END and reduced HE, without significant impact on mortality or functional outcome.The spot sign and IVH are associated with specific hematoma characteristics, such as size and location, but are related differently to coagulation status and clinical course. A combined analysis of the spot sign and IVH can improve the understanding of pathophysiology and risk stratification after ICH.

We prospectively studied SARS-CoV-2 transmission at schools in an era of Variants of Concern (VoCs), offering all close contacts serial viral asymptomatic testing up to 14 days. Of 229 school close contacts, 3 tested positive (1.3%), of which 2 were detected through asymptomatic testing. Most secondary transmission (90%) occurred in households. Routine asymptomatic testing of close contacts should be examined in the context of local testing rates, preventive measures, programmatic costs, and health impacts of asymptomatic transmission.

COVID-19 is an ongoing pandemic with a devastating impact on public health. Acute neurological symptoms have been reported after a COVID-19 diagnosis, however, the long-term neurological symptoms including pain is not well established. Using a prospective registry of hospitalized COVID-19 patients, we assessed pain and neurological function (including functional, cognitive and psychiatric assessments) of several hospitalized patients at 3 months. Our main finding is that 60% of the patients report pain symptoms. 71% of the patients still experienced neurological symptoms at 3 months and the most common symptoms being fatigue (42%) and PTSD (25%). Cognitive symptoms were found in 12%. Our preliminary findings suggests the importance of investigating long-term outcomes and rationalizes the need for further studies investigating the neurologic outcomes and symptoms of pain after COVID-19.

Objective Although COVID-19 is a respiratory disease, all organs can be affected including the brain. To date, specific investigations of brain injury markers (BIM) and endothelial injury markers (EIM) have been limited. Additionally, a male bias in disease severity and mortality after COVID-19 is evident globally. Sex differences in the immune response to COVID-19 may mediate this disparity. We investigated BIM, EIM and inflammatory cytokine/chemokine (CC) levels after COVID-19 and in across sexes. Methods Plasma samples from 57 subjects at Results Three BIMs: MAP2, NSE and S100B, two EIMs: sICAM1 and sVCAM1 and seven CCs: GRO IL10, sCD40L, IP10, IL1Ra, MCP1 and TNFα were significantly (p p Conclusion The acute elevation of BIMs, CCs, and EIMs and the robust associations among them at COVID-19 hospitalization are suggestive of brain and endothelial injury. Higher BIM and inflammatory markers in men additionally suggest that men are more susceptible to the risk compared to women.

Background: A previous study suggested an association between low caloric intake(CI), negative nitrogen balance, and poor outcome after subarachnoid hemorrhage(SAH). Objective of this multinational, multicenter study was to investigate whether clinical outcomes vary by protein intake(PI) or CI in SAH patients adjusting for the nutritional risk as judged by the modified NUTrition Risk in the Critically Ill (mNUTRIC) score. Methods: The International Nutrition Survey(INS) 2007-2014 was utilized to describe the characteristics, outcomes and nutrition use. A subgroup of patients from 2013 and 2014(when NUTRIC score was captured) examined the association between CI and PI and time to discharge alive(TTDA) from hospital using Cox regression models, adjusting for nutrition risk classified by the mNUTRIC score as low(0-4) or high(5-9). Results: There were 489 SAH patients(57% female with a mean ± SD age 57.5 ± 13.9 years, BMI of 25.9 ± 5.3 kg/m2 and APACHE-2 score 19.4 ± 7.0. Majority(85%) received enteral nutrition(EN) only, with a time to initiation of EN of 35.4 ± 35.2 hours. 64% had EN interrupted. Patients received a CI of 14.6 ± 7.1 calories/kg/day and PI 0.7 ± 0.3 grams/kg/day corresponding to 59% and 55% of total prescribed CI and PI respectively. In the 2013 and 2014 subgroup there were 226 SAH patients with a mNUTRIC score of 3.4 ± 1.8. Increased CI and PI were associated with faster TTDA among high mNUTRIC patients(HR per 20% of prescription received = 1.34[95% CI,1.03 -1.76] for CI and 1.44[1.07 -1.93] for PI), but not low mNUTRIC patients(CI: HR = 0.95[0.77 -1.16] PI:0.95[0.78 -1.16]). Conclusions: Results from this multicenter study found that SAH patients received under 60% of their prescribed CI and PI. Further, achieving greater CI and PI in hi risk SAH patients was associated with improved TTDA. mNUTRIC serves to identify SAH patients that benefit most from artificial nutrition and efforts to optimize protein and caloric delivery in this subpopulation should be maximized.

Objective Anticoagulant therapy (ACT) after traumatic intracranial hemorrhage may lead to progression of hemorrhage, but in the presence of thromboembolic events, the clinician must decide if the benefits outweigh the risks. Currently, no data exist to guide therapy in the acute setting. Methods We retrospectively identified all patients admitted to our institution with traumatic intracranial hemorrhage that received intravenous heparin, full-dose enoxaparin, or warfarin during their initial hospitalization over a 3-year period. We reviewed their demographics, hospital course, clinical indication and timing for initiation of ACT, and complications. Results A total of 112 patients were identified. The median age and Glasgow Coma Scale score of these patients was 50.5 years and 9.5, respectively. Twenty-two patients required neurosurgical procedures for their presenting injury, including intracranial pressure monitors and/or open surgeries. Fifty-four patients had deep vein thrombosis or pulmonary embolism prior to initiation, and the remaining 20 patients had preexisting conditions or other indications for initiating ACT. The median time from injury to starting ACT was 8 days. Immediate complications occurred in 6 patients; however, none of these patients required a neurosurgical intervention. Delayed complications included progression of acute to chronic subdural hematoma that required intervention in 2 patients. One patient died from delayed hemorrhage. Conclusions For this patient population, the risk of immediate and delayed intracranial hemorrhages from initiating ACT therapy in intracranial injury must be weighed against the morbidity of delaying treatment. Although further studies are needed, our review provides the first rates of complications for this patient population.

Although precision medicine has revolutionized the treatment for other solid tumors, comprehensive genome profiling of hepatocellular carcinoma (HCC) has demonstrated that there are few oncogenic mutational drivers. HCC arises nearly universally in the context of co-morbid hepatitis, driven by hepatitis C virus or hepatitis B virus (HBV). Previous work has highlighted the effects of HBV protein X (HBx) on signaling and proliferation. However, it remains unclear how these signaling changes interact with the stress imposed by HBV replication. We hypothesize that HBV replication and maintenance of HBV proteins like HBx creates specific vulnerabilities that can be uncovered and exploited. We performed whole-genome clustered regularly interspaced short palindromic repeat interference (CRISPRi) screening in two engineered, patient-derived HBV+ cell models, Hep3B and SNU-368, with cellular proliferation as the readout. A conditional induction of HBx was used to overexpress HBx in each cell model for the whole genome CRISPRi screen. Genes where HBx expression was significantly associated with a more negative dependency score were classified as HBV differential dependencies. 37 genes were identified as shared HBV-induced dependencies across both cell lines. Of these, 16 were also differentially expressed in HCC specimens with ongoing HBV replication vs. non-HBV expressing tumors collected in The Cancer Genome Atlas (TCGA), suggesting in vivo selective pressure to alter the expression of these genes. We focused on Zinc Fingers and Homeoboxes 2 (ZHX2) and methionine adenosyltransferase 2A (MAT2A). ZHX2 was identified as an HCC tumor suppressor, and data from TCGA showed differential gene expression of ZHX2 in HBV+HCC. Validation of ZHX2 sgRNA knockdown confirmed that ZHX2 knockdown preferentially reduced cell proliferation in the presence of HBx, consistent with an HBV-induced dependency. ZHX2 also can activate the HIF pathway; we identified alterations of HIF targets with ZHX2 knockdown and HBx expression. Similarly, MAT2A knockdown in HBV+HCC cell lines showed decreased cell proliferation with HBx expression. MAT2A is an emerging therapeutic target, with sensitivity to MAT2A inhibitors conferred by deletions in methylthioadenosine phosphorylase (MTAP), seen in 3% of HCC. Ongoing investigations include alteration of splicing and cell cycle changes with depletion of MAT2A in the presence of HBx. With small molecule inhibitors of MAT2A in clinical development, this finding may be therapeutically actionable. Thus, using functional genomics to interrogate HBV-associated gene dependencies has illuminated the biology of HCC and identified candidate therapeutic targets for pre-clinical validation. Citation Format: Rigney E Turnham, Huat Chye Lim, Lucille Ferret, Katherine Lo, LeeAnn Wang, Alex Choi, John D Gordan. Uncovering hepatitis B virus-induced signaling changes in hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO023.

Background: In a disease that has only existed for 18 months, it is difficult to be fully informed of the long-term sequelae of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Evidence is growing that most organ systems can be affected by the virus, causing severe disabilities in survivors. The extent of the aftermath will declare itself over the next 5–10 years, but it is likely to be substantial with profound socio-economic impact on society.Methods: This is an international multi-center, prospective long-term follow-up study of patients who developed severe coronavirus disease-2019 (COVID-19) and were admitted to Intensive Care Units (ICUs). The study will be conducted at international tertiary hospitals. Patients will be monitored from time of ICU discharge up to 24 months. Information will be collected on demographics, co-existing illnesses before ICU admission, severity of illness during ICU admission and post-ICU quality of life as well as organ dysfunction and recovery. Statistical analysis will consist of patient trajectories over time for the key variables of quality of life and organ function. Using latent class analysis, we will determine if there are distinct patterns of patients in terms of recovery. Multivariable regression analyses will be used to examine associations between baseline characteristics and severity variables upon admission and discharge in the ICU, and how these impact outcomes at all follow-up time points up to 2 years.Ethics and Dissemination: The core study team and local principal investigators will ensure that the study adheres to all relevant national and local regulations, and that the necessary approvals are in place before a site may enroll patients.Clinical Trial Registration:anzctr.org.au: ACTRN12620000799954.

Objective: Current guidelines recommend active surveillance with serial magnetic resonance angiography (MRA) for management of small, asymptomatic unruptured anterior circulation aneurysms (UIAs). We sought to determine the cost-effectiveness of active surveillance compared to immediate surgery. Methods: We developed a Markov cost-effectiveness model simulating patients with small (Results: Immediate surgical treatment was the most cost-effective management strategy for small UIAs with ICER of USD 45,772 relative to active surveillance. Sensitivity analysis demonstrated immediate surgery was the preferred strategy, if rupture rate was >0.1%/year and if the diagnosis age was 11%. Probabilistic sensitivity analysis demonstrated that at a willingness-to-pay of USD 100,000/QALY, immediate surgical treatment was the most cost-effective strategy in 64% of iterations. Conclusion: Immediate surgical treatment is a cost-effective strategy for initial management of small UIAs in patients

ObjectiveTo investigate brain injury markers (BIM), endothelial injury markers (EIM) and cytokine/chemokine (CC) markers of systemic inflammation in coronavirus disease 2019 (COVID-19) and across sex.MethodsPlasma samples from 57 subjects at ResultsThree BIMs: MAP2, NSE and S100B, two EIMs: sICAM1 and sVCAM1 and seven CCs: GRO IL10, sCD40L, IP10, IL1Ra, MCP1 and TNFα were significantly (pConclusionThe acute elevation of BIMs, CCs, and EIMs and the robust associations among them at COVID-19 hospitalization suggest that brain injury is mediated by endotheliopathy and inflammation. Higher BIM and inflammatory markers in men additionally suggest that men are more susceptible to the risk compared to women.

Aneurysmal subarachnoid hemorrhage (aSAH) causes a robust inflammatory response which leads worse brain injury and poor outcomes. We investigated if stimulation of nicotinic acetylcholine α(7) receptors (α(7)-AChR) (receptors shown to have anti-inflammatory effects) would reduce inflammation and improve outcomes. To investigate the level of peripheral inflammation after aSAH, inflammatory markers were measured in plasma samples collected in a cohort of aSAH patients. To study the effect of α(7)-AChR stimulation, SAH was induced in adult mice which were then treated with a α(7)-AChR agonist, galantamine, or vehicle. A battery of motor and cognitive tests were performed 24 h after subarachnoid hemorrhage. Mice were euthanized and tissue collected for analysis of markers of inflammation or activation of α(7)-AChR-mediated transduction cascades. A separate cohort of mice was allowed to survive for 28 days to assess long-term neurological deficits and histological outcome. Microglia cell culture subjected to hemoglobin toxicity was used to assess the effects of α(7)-AChR agonism. Analysis of eighty-two patient plasma samples confirmed enhanced systemic inflammation after aSAH. α(7)-AChR agonism reduced neuroinflammation at 24 h after SAH in male and female mice, which was associated with improved outcomes. This coincided with JAK2/STAT3 and IRAK-M activity modulations and a robust improvement in neurological/cognitive status that was effectively reversed by interfering with various components of these signaling pathways. Pharmacologic inhibition partially reversed the α(7)-AChR agonist’s benefits, supporting α(7)-AChR as a target of the agonist’s therapeutic effect. The cell culture experiment showed that α(7)-AChR agonism is directly beneficial to microglia. Our results demonstrate that activation of α(7)-AChR represents an attractive target for treatment of SAH. Our findings suggest that α(7)-AChR agonists, and specifically galantamine, might provide therapeutic benefit to aSAH patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01052-3.

COVID-19 is an ongoing pandemic with a devastating impact on public health. Acute neurological symptoms have been reported after a COVID-19 diagnosis, however there is no data available on the long-term neurological symptoms. Using a prospective registry of hospitalized COVID-19 patients, we assessed the neurological assessments (including functional, cognitive and psychiatric assessments) of several hospitalized patients at 3 months. Our main finding is that 71% of the patients still experienced neurological symptoms at 3 months and the most common symptoms being fatigue (42%) and PTSD (29%). 64% of the patients report pain symptoms we well. Cognitive symptoms were found in 12%. Our preliminary findings suggests the importance of investigating long-term and rationalizes the need for further studies investigating the neurologic outcomes after COVID-19.

Background Electronic nicotine delivery systems (ENDSs), including electronic cigarettes (e-cigarettes), are rapidly gaining popularity. The aim of this study was to use poison centre data to describe epidemiological trends in ENDS-related exposures. Methods We conducted an observational case series study using records containing both coded fields and free-text narratives from the British Columbia Drug and Poison Information Centre for all calls involving exposure to ENDS received from 2012 to 2017. We described trends in exposures and exposed people, as well as clinical effects. Results A total of 243 calls were recorded for 186 unique exposures to ENDS devices, e-juice, e-cigarette cartridges and other associated paraphernalia over the study period. Calls related to ENDS exposures increased nearly sixfold between 2013 and 2014 and did not decline subsequently. Exposures were most frequently documented in children aged 4 years or less (81 [43.5%]), with 58 (31.0%) in 1- and 2-year-olds. Seventy-two exposures (89%) in children aged 4 years or less were due to accidental ingestion, whereas adults aged 25 years or more called the poison centre following ENDS malfunctions (7 [23%], spills (4 [13%]) and exposure to e-juice mistaken for other substances (4 [13%]). Of the 186 exposed people, 87 (46.8%) reported symptoms. Interpretation British Columbia experienced a sixfold increase in ENDS-related calls to the provincial poison centre between 2012 and 2017, driven by ingestions in young children. Regulatory approaches aimed at minimizing children's access to ENDS, clear labelling of nicotine concentration, and packaging that reduces the likelihood of spills, product confusion and malfunction should be considered.

The gut microbiome is fundamental in neurogenesis processes. Alterations in microbial constituents promote inflammation and immunosuppression. Recently, in immune-oncology, specific microbial taxa have been described to enhance the effects of therapeutic modalities. However, the effects of microbial dysbiosis on glioma are still unknown. The aim of this study was to explore the effects of glioma development and Temozolomide (TMZ) on fecal microbiome in mice and humans. C57BL/6 mice were implanted with GL261/Sham and given TMZ/Saline. Fecal samples were collected longitudinally and analyzed by 16S rRNA sequencing. Fecal samples were collected from healthy controls as well as glioma patients at diagnosis, before and after chemoradiation. Compared to healthy controls, mice and glioma patients demonstrated significant differences in beta diversity, Firmicutes/Bacteroides (F/B) ratio, and increase of Verrucomicrobia phylum and Akkermansia genus. These changes were not observed following TMZ in mice. TMZ treatment in the non-tumor bearing mouse-model diminished the F/B ratio, increase Muribaculaceae family and decrease Ruminococcaceae family. Nevertheless, there were no changes in Verrucomicrobia/Akkermansia. Glioma development leads to gut dysbiosis in a mouse-model, which was not observed in the setting of TMZ. These findings seem translational to humans and warrant further study.