Tranexamic Acid in Patients Undergoing Liver Resection: The HeLiX Randomized Clinical Trial.

Importance: Tranexamic acid reduces bleeding and blood transfusion in many types of surgery, but its effect in patients undergoing liver resection for a cancer-related indication remains unclear. Objective: To determine whether tranexamic acid reduces red blood cell transfusion within 7 days of liver resection. Design, Setting, and Participants: Multicenter randomized clinical trial of tranexamic acid vs placebo conducted from December 1, 2014, to November 8, 2022, at 10 hepatopancreaticobiliary sites in Canada and 1 site in the United States, with 90-day follow-up. Participants, clinicians, and data collectors were blinded to allocation. A volunteer sample of 1384 patients undergoing liver resection for a cancer-related indication met eligibility criteria and consented to randomization. Interventions: Tranexamic acid (1-g bolus followed by 1-g infusion over 8 hours; n = 619) or matching placebo (n = 626) beginning at induction of anesthesia. Main Outcomes and Measures: The primary outcome was receipt of red blood cell transfusion within 7 days of surgery. Results: The primary analysis included 1245 participants (mean age, 63.2 years; 39.8% female; 56.1% with a diagnosis of colorectal liver metastases). Perioperative characteristics were similar between groups. Red blood cell transfusion occurred in 16.3% of participants (n = 101) in the tranexamic acid group and 14.5% (n = 91) in the placebo group (odds ratio, 1.15 [95% CI, 0.84-1.56]; P = .38; absolute difference, 2% [95% CI, -2% to 6%]). Measured intraoperative blood loss (tranexamic acid, 817.3 mL; placebo, 836.7 mL; P = .75) and total estimated blood loss over 7 days (tranexamic acid, 1504.0 mL; placebo, 1551.2 mL; P = .38) were similar between groups. Participants receiving tranexamic acid experienced significantly more complications compared with placebo (odds ratio, 1.28 [95% CI, 1.02-1.60]; P = .03), with no significant difference in venous thromboembolism (odds ratio, 1.68 [95% CI, 0.95-3.07]; P = .08). Conclusions and Relevance: Among patients undergoing liver resection for a cancer-related indication, tranexamic acid did not reduce bleeding or blood transfusion but increased perioperative complications. Trial Registration: ClinicalTrials.gov Identifier: NCT02261415.

Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer.

Small cell lung cancers (SCLCs) are composed of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLCs, ∼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes as top dependencies specific to POU2F3-positive SCLC. Notably, chemical disruption of mSWI/SNF ATPase activity attenuates proliferation of all POU2F3-positive SCLCs, while disruption of non-canonical BAF (ncBAF) via BRD9 degradation is effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF targets to and maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, clinical-grade pharmacologic disruption of SMARCA4/2 ATPases and BRD9 decreases POU2F3-SCLC tumor growth and increases survival in vivo. These results demonstrate mSWI/SNF-mediated governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for POU2F3-positive SCLCs.

Hepatopancreaticobiliary Resection Arginine Immunomodulation (PRIMe) trial: protocol for a randomised phase II trial of the impact of perioperative immunomodulation on immune function following resection for hepatopancreaticobiliary malignancy.

INTRODUCTION: Surgical stress results in immune dysfunction, predisposing patients to infections in the postoperative period and potentially increasing the risk of cancer recurrence. Perioperative immunonutrition with arginine-enhanced diets has been found to potentially improve short-term and cancer outcomes. This study seeks to measure the impact of perioperative immunomodulation on biomarkers of the immune response and perioperative outcomes following hepatopancreaticobiliary surgery. METHODS AND ANALYSIS: This is a 1:1:1 randomised, controlled and blinded superiority trial of 45 patients. Baseline and perioperative variables were collected to evaluate immune function, clinical outcomes and feasibility outcomes. The primary outcome is a reduction in natural killer cell killing as measured on postoperative day 1 compared with baseline between the control and experimental cohorts. ETHICS AND DISSEMINATION: This trial has been approved by the research ethics boards at participating sites and Health Canada (parent control number: 223646). Results will be distributed widely through local and international meetings, presentation, publication and ClinicalTrials.gov (identifier: NCT04549662). Any modifications to the protocol will be communicated via publications and ClinicalTrials.gov. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT04549662.

Disparities in postoperative complications and perioperative events based on insurance status following elective spine surgery: A systematic review and meta-analysis.

Background: Increasing evidence demonstrates disparities among patients with differing insurance statuses in the field of spine surgery. However, no pooled analyses have performed a robust review characterizing differences in postoperative outcomes among patients with varying insurance types. Methods: A comprehensive literature search of the PUBMED, MEDLINE(R), ERIC, and EMBASE was performed for studies comparing postoperative outcomes in patients with private insurance versus government insurance. Pooled incidence rates and odds ratios were calculated for each outcome and meta-analyses were conducted for 3 perioperative events and 2 types of complications. In addition to pooled analysis, sub-analyses were performed for each outcome in specific government payer statuses. Results: Thirty-eight studies (5,018,165 total patients) were included. Compared with patients with private insurance, patients with government insurance experienced greater risk of 90-day re-admission (OR 1.84, p<.0001), non-routine discharge (OR 4.40, p<.0001), extended LOS (OR 1.82, p<.0001), any postoperative complication (OR 1.61, p<.0001), and any medical complication (OR 1.93, p<.0001). These differences persisted across outcomes in sub-analyses comparing Medicare or Medicaid to private insurance. Similarly, across all examined outcomes, Medicare patients had a higher risk of experiencing an adverse event compared with non-Medicare patients. Compared with Medicaid patients, Medicare patients were only more likely to experience non-routine discharge (OR 2.68, p=.0007). Conclusions: Patients with government insurance experience greater likelihood of morbidity across several perioperative outcomes. Additionally, Medicare patients fare worse than non-Medicare patients across outcomes, potentially due to age-based discrimination. Based on these results, it is clear that directed measures should be taken to ensure that underinsured patients receive equal access to resources and quality care.

Problem-solving processes for central venous catheter occlusion within pediatric cancer care: A qualitative study.

PURPOSE: Central venous access devices play a crucial role in healthcare settings. However, there is concern regarding the high incidence of blockages occurring before the completion of treatments and existing guidelines for occlusion management are not consistently followed. To explore the decision-making and problem-solving process of occlusion management and identify enablers and barriers to implementing evidence for occlusion management in pediatric cancer care. METHODS: A qualitative design with individual semi-structured interviews. Participants were selected by purposeful sampling from a tertiary-referral pediatric facility, and semi-structured interviews were conducted. RESULTS: A total of 13 clinicians and 5 parents were interviewed. The thematic analysis revealed four main decision-making/problem-solving themes: 1) clinical reasoning and judgement for central venous access devices occlusion, 2) capability in central venous access devices occlusion management, 3) colleague collaboration in the escalation process and 4) lack of adequate support to manage the occlusion. This study identified positive and negative influences on the problem-solving process, including clinicians' psychological capabilities, social and physical resources, and beliefs about consequences. CONCLUSION: This study found that clinicians in pediatric cancer care were able to manage central venous access device occlusions using clinical reasoning and judgment skills, which may conflict with evidence-based practices. The study confirmed the importance of a team approach and prior experience in managing central venous access devices in pediatric oncology settings and identified potential conflicts between clinician decisions based on the patient's current and anticipated conditions and implementation of evidence-based practice. Improving documentation and providing visual aids could benefit clinicians' problem-solving processes.

An mHealth application for chronic vascular access: Consumer led co-creation.

PURPOSE: Children with chronic and complex health conditions frequently need intravenous devices. The current approach to intravenous device selection, insertion, and monitoring is inconsistent, and healthcare consumers are often negatively affected by siloed health information, and poor future planning. Despite child- and family-centred care being recognised as a pillar of paediatric nursing care, limited implementation for vascular access device planning and management is evident. DESIGN AND METHODS: To address this, we conducted a multi-phased approach to co-create, then evaluate, a mobile health (mHealth) application: IV Passport. Co-creation involved a prioritisation survey, followed by a Passport advisory panel consensus meeting. Following confirmation of the required content and features of the Passport, the mHealth application was designed and content validation achieved via survey. RESULTS: The prioritisation survey yielded recommendations for seven features (e.g., graphical presentations of current/past devices). Content for nine device types (e.g., totally implanted ports) was suggested, each with 10 related items (e.g., insertion site). Content items for device-associated complications, future vascular access plans, and educational resources were also suggested. Following design, the application was released through Apple and Android platforms; and adapted to a paper version. Content validation was established; 100% strongly agreed the application was easy to use; 80% agreed/strongly agreed that they would recommend the Passport to others. CONCLUSION: IV Passport embodies effective child- and family-centred care through consumer co-creation to empower patients and families manage vascular access devices. PRACTICE IMPLICATIONS: IV Passport remains active; and can be utilised across many healthcare settings and patient populations.

Gender disparities in postoperative outcomes following elective spine surgery: a systematic review and meta-analysis.

OBJECTIVE: Several studies have described disparities between male and female patients following spine surgery, but no pooled analyses have performed a robust review characterizing differences in postoperative outcomes based on gender. The purpose of this study was to broadly assess the effects of gender on postoperative outcomes following elective spine surgery. METHODS: Between November 2022 and March 2023, PubMed, MEDLINE, ERIC, and Embase were queried using artificial intelligence-assisted software for relevant cohort studies. Cohort studies with a minimum sample of 100 patients conducted in the United States since 2010 were eligible. Studies related to trauma, tumors, infections, and spinal cord pathology were excluded. Independent extraction by multiple reviewers was performed using Nested Knowledge software. A fixed- or random-effects model was used if heterogeneity among included studies in a meta-analysis was < 50% or ≥ 50%, respectively. Risk of bias was assessed independently by multiple reviewers using the Newcastle-Ottawa Scale. Pooled effect sizes were calculated for readmission, nonroutine discharge (NRD), length of stay (LOS), extended LOS, reoperation, mortality, all medical complications (individual analyses for cardiovascular, deep venous thrombosis/pulmonary embolism, genitourinary, neurological, respiratory, and systemic infection complications), and wound-related complications. For each outcome, two subanalyses were performed with studies that used either center-based (single- or multi-institution) or high-volume (national or state-wide) databases. RESULTS: Across 124 included studies, male patients had an increased incidence of mortality (OR 0.54, p < 0.0001) and all medical complications (OR 0.80, p = 0.0114), specifically cardiovascular (OR 0.68, p < 0.0001) and respiratory (OR 0.76, p = 0.0008) complications. Female patients were more likely to experience a wound-related surgical complication (OR 1.16, p = 0.0183). These findings persisted in the high-volume database subanalyses. Only center-based subanalyses showed that female patients were at greater odds of experiencing an NRD (OR 1.18, p = 0.0476), longer LOS (SMD 0.23, p = 0.0036), and extended LOS (OR 1.28, p < 0.0001). CONCLUSIONS: Males are more likely to experience death and medical complications, whereas females were more likely to face wound-related surgical complications. At the institution level, females more often experience NRD and longer hospital stays. These findings may better inform preoperative expectation management and provide more detailed postoperative risk assessments based on the patient's gender.

Optimized expression and purification of a human adenosine deaminase in E. coli and characterization of its Asp8Asn variant.

Homo sapiens adenosine deaminase isoform 1 (HsADA1) hydrolyzes adenosine and 2-deoxyadenosine as a key step in the purine nucleoside salvage pathway. Some HsADA1 mutations have severe deleterious effects, as is the case in a severe combined immunodeficiency resulting from loss of enzyme activity (ADA-SCID). Other mutations that reduce enzyme activity, for instance the Asp8Asn (D8N) variant, do not cause ADA-SCID but are correlated with other consequences to health. To ease further study of HsADA1 and its variants, we optimized an inexpensive, recombinant expression process in an Escherichia coli host through multiplexed parameter testing enabled by a lysate-based microtiter plate assay. We demonstrate the importance of gene codon usage, induction time and temperature, and alcohol supplementation towards improving enzyme yield to a final titer of 5 mg per liter of culture. We further show that use of a double-histidine-tag (his-tag) system greatly improves purity. We then utilize our expression and purification framework to produce the HsADA1 D8N variant, which had previously not been purified to homogeneity. We confirm that the D8N variant is ∼30% less active than the wildtype HsADA1 and show that it better retains its activity in human serum. Additionally, we show that both HsADA1 and the D8N variant have heightened activity in serum, driven in part by a previously undescribed phenomenon involving albumin. Therefore, this work presents a valuable process to produce HsADA1 that allows for insights into it and its variants' behavior. We also confirm the utility of lysate-based activity assays towards finding optimal E. coli expression conditions for enzymes and show how fusing his-tags in tandem can enhance product purity.

Iron Pathophysiology in Stroke.

Ischemic and hemorrhagic stroke are the common types of stroke that lead to brain injury neurological deficits and mortality. All forms of stroke remain a serious health issue, and there is little successful development of drugs for treating stroke. Incomplete understanding of stroke pathophysiology is considered the main barrier that limits this research progress. Besides mitochondria and free radical-producing enzymes, labile iron is an important contributor to oxidative stress. Although iron regulation and metabolism in cerebral stroke are not fully understood, much progress has been achieved in recent years. For example, hepcidin has recently been recognized as the principal regulator of systemic iron homeostasis and a bridge between inflammation and iron regulation. This review discusses recent research progress in iron pathophysiology following cerebral stroke, focusing molecular regulation of iron metabolism and potential treatment targets.

Link between Brugada phenocopy and myocardial ischemia: Results from the International Registry on Brugada Phenocopy.

BACKGROUND: Brugada phenocopies clinical entities that have indistinguishable electrocardiographic (ECG) patterns from true congenital Brugada syndrome. However, they are induced by other clinical circumstances such as myocardial ischemia. The purpose of our study was to examine the clinical features and pathogenesis of ischemia-induced Brugada phenocopy (BrP). METHODS: Data from 17 cases of ischemia-induced BrP were collected from the International Registry (www.brugadaphenocopy.com). Data were extracted from these publications and authors were contacted to provide further insight into each case. RESULTS: Of the patients included in this study, 71% were male. Mean age was 59 ± 11 years (range: 38-76). Type-1 Brugada ECG pattern occurred in 15/17 (88%) of the cases, while a type-2 Brugada ECG pattern was observed in the other 2/17 (12%). In all cases, the Brugada ECG pattern resolved upon correction of the ischemia, indicating ischemia as the inducing circumstance. No arrhythmic events have been detected acutely or during the follow-up. Reported time to resolution ranged from 2 minutes to 5 hours. Provocative challenges using sodium channel blocking agents were performed in 7/17 cases (41%), and all failed to induce a Brugada ECG pattern (BrP Class A). The remaining 10/17 cases (59%) did not undergo provocative testing due to various clinical reasons. CONCLUSIONS: Myocardial ischemia is a commonly reported etiology of BrP. Importantly, this study found no association between BrP induced by myocardial ischemia and sudden cardiac death or malignant ventricular arrhythmias.

Expression of Hypoxia Inducible Factor 1alpha Is Protein Kinase A-dependent in Primary Cortical Astrocytes Exposed to Severe Hypoxia.

The hypoxia inducible factor 1 (HIF-1) and the cyclic AMP-responsive element binding protein (CREB) are two transcription factors that have been studied in the context of neuronal survival and neurodegeneration. HIF-1 upregulation and CREB activation have been observed not only in neurons but also in astrocytes under conditions of hypoxia. We hypothesized that activation of CREB regulate HIF-1α expression in the nucleus of cortical astrocytes under in vitro ischemic condition. To test the hypothesis, we determined the effects of inhibiting the CREB activation pathway on the expression of HIF-1α protein in astrocytes exposed to CoCl2 and severe hypoxia (near anoxia, 0.1% O2). The results demonstrated that inhibition of CaMKII and CaMKIV had no effect on both HIF-1α and pCREB expression in cortical astrocytes exposed to CoCl2 and anoxia. In contrast, PKA inhibition lowered the expression of HIF-1α and pCREB expression. Furthermore, the inhibition of PKA but not CaMKII or CaMKIV increased cell death of astrocytes exposed to near anoxia. The results suggest that PKA plays an important role in the cell survival signaling pathways in astrocytes.

Relation of the Brugada Phenocopy to Hyperkalemia (from the International Registry on Brugada Phenocopy).

Brugada phenocopies (BrPs) are clinical entities that differ in etiology from true congenital Brugada syndrome but have identical electrocardiographic (ECG) patterns. Hyperkalemia is known to be one of the causes of BrP. The aim of this study was to determine the clinical characteristics and evolution of hyperkalemia-induced BrP. Data from 27 cases of hyperkalemia-induced BrP were collected from the International Registry at www.brugadaphenocopy.com. Data were extracted from publications. Of the 27 patients included in the analysis, 18 (67%) were male; mean age was 53 ± 15 years (range 31 to 89). Mean serum potassium concentration was 7.45 ± 0.89 mmol/L. Type-1 Brugada ECG pattern was observed in 21 cases (78%), whereas 6 cases (22%) showed a type-2 Brugada ECG pattern. The Brugada ECG pattern resolved once the hyperkalemia was corrected, with no arrhythmic events. Estimated time to resolution was 7 ± 3 hours. In 4 cases (16%), a concurrent metabolic abnormality was detected: 3 (11%) presented with acidosis, 2 (7%) with hyponatremia, 1 (4%) with hypocalcaemia, 1 (4%) with hyperphosphatemia, and 1 (4%) with hyperglycemia. In 7 cases (26%), provocative testing using sodium channel blockers was performed, and all failed to reproduce a BrS ECG pattern (BrP class A). Additionally, no sudden cardiac death or malignant ventricular arrhythmias were detected. Hyperkalemia was found a common cause of BrP in our International Registry. The Brugada ECG pattern appears to occur at high serum potassium concentrations (>6.5 mmol/L). The ECG normalizes within hours of correcting the electrolyte imbalance. Importantly, hyperkalemia-induced BrP has not been associated with sudden cardiac death or ventricular arrhythmia.