Alternate Approach to Concomitant Carotid and Coronary Disease: Perioperative IABP Use during Carotid Endarterectomy.

BACKGROUND: Demographics are shifting toward an increasingly older population in the United States; thus, it is imperative that patients with a complex cardiovascular history are approached in a systematic fashion. Currently, there is no clear protocol on how best to manage elderly patients who present with both severe coronary artery disease and symptomatic carotid stenosis. For cardiac patients with severe, asymptomatic, high-grade carotid artery stenosis, there may be even more of a conundrum. Although most centers would tend to manage the asymptomatic carotid stenosis expectantly, it is well known that patients with severe, uncorrected internal carotid artery disease are at an increased risk of experiencing a cerebrovascular accident during coronary artery bypass grafting (CABG). One approach that has been recognized in other settings as a cost-effective strategy to stabilize high-risk elderly patients preoperatively is the use of an intra-aortic balloon pump (IABP). To better understand the best approach to take in these patients with concomitant disease, we analyzed the outcomes of 4 patients who underwent placement of an IABP before carotid endarterectomy (CEA) as a bridge to CABG. METHODS: Between 2017 and 2019, 4 patients presented with multivessel symptomatic coronary artery disease and greater than 90% stenosis of at least one internal carotid artery and underwent either staged or simultaneous CEA and CABG. There was placement of an IABP in all patients before the CEA. Time to CABG ranged from a simultaneous procedure to 23 days after CEA. RESULTS: The only death within 30-day postoperation involved the patient who had CEA and CABG performed simultaneously. None of the surviving patients experienced a myocardial infarction. Two of the 4 patients experienced acute kidney injury after surgery, and one patient developed atrial fibrillation postoperatively. None of the patients experienced a postoperative neurological complication. In addition, there were no access site complications associated with IABP placement. CONCLUSIONS: A staged procedure with placement of an IABP can be successfully used in carefully selected patients presenting with concomitant severe carotid and coronary artery disease who will undergo surgical management of their disease. The stabilization provided by IABP was potentially protective against adverse postoperative events and appeared to allow for flexibility in the time between CEA to CABG for patients. Additional studies are necessary to further understand the impact of such an approach.

DDX39B interacts with the pattern recognition receptor pathway to inhibit NF-κB and sensitize to alkylating chemotherapy.

BACKGROUND: Nuclear factor-κB (NF-κB) plays a prominent role in promoting inflammation and resistance to DNA damaging therapy. We searched for proteins that modulate the NF-κB response as a prerequisite to identifying novel factors that affect sensitivity to DNA damaging chemotherapy. RESULTS: Using streptavidin-agarose pull-down, we identified the DExD/H-box RNA helicase, DDX39B, as a factor that differentially interacts with κB DNA probes. Subsequently, using both RNA interference and CRISPR/Cas9 technology, we demonstrated that DDX39B inhibits NF-κB activity by a general mechanism involving inhibition of p65 phosphorylation. Mechanistically, DDX39B mediates this effect by interacting with the pattern recognition receptor (PRR), LGP2, a pathway that required the cellular response to cytoplasmic double-stranded RNA (dsRNA). From a functional standpoint, loss of DDX39B promoted resistance to alkylating chemotherapy in glioblastoma cells. Further examination of DDX39B demonstrated that its protein abundance was regulated by site-specific sumoylation that promoted its poly-ubiquitination and degradation. These post-translational modifications required the presence of the SUMO E3 ligase, PIASx-ß. Finally, genome-wide analysis demonstrated that despite the link to the PRR system, DDX39B did not generally inhibit interferon-stimulated gene expression, but rather acted to attenuate expression of factors associated with the extracellular matrix, cellular migration, and angiogenesis. CONCLUSIONS: These results identify DDX39B, a factor with known functions in mRNA splicing and nuclear export, as an RNA-binding protein that blocks a subset of the inflammatory response. While these findings identify a pathway by which DDX39B promotes sensitization to DNA damaging therapy, the data also reveal a mechanism by which this helicase may act to mitigate autoimmune disease.

Women working in violence intervention and outreach: providing space for emotional vulnerability and empathy.

Introduction: There is a growing presence of violence intervention workers who identify as women, yet their unique strengths and challenges have not been described previously. The purpose of this study was to characterize the intersections of gender and violence intervention work. Methods: We conducted a qualitative study of women working in violence intervention via focus groups. Perceived strengths and risks were explored using a semistructured interviewing technique. Focus groups were transcribed and coded by two separate evaluators. Grounded theory methodology was used for thematic analysis. Results: 17 violence intervention and outreach specialists who identify as women were included in three focus groups. Common challenges include a sense of powerlessness when faced with inequitable structural limitations and vicarious trauma. When discussing the role of their gender identity in the work, the women reported that men seem more willing to be emotionally vulnerable with women, including disclosures of a history of sexual abuse. Women also experience a lack of respect personally and professionally in their role related to gender. The women revealed a need for leadership opportunities to leverage their strengths and for enhanced training, especially for male colleagues who may benefit from the insights of colleagues who are women. Conclusions: Women bring unique strengths to roles as violence intervention specialists to deal with trauma and prevent future violence. These findings suggest a need for specific curricula to support women working in violence intervention and further studies that explore the intersectional role of race as well as gender in violence intervention work. Level of Evidence: 6.

Effect of Race and Insurance Type on Access to, and Outcomes of, Epilepsy Surgery: A Literature Review.

BACKGROUND: Despite higher rates of seizure freedom, a large proportion of patients with medically refractory seizures who could benefit from epilepsy surgery do not receive surgical treatment. This literature review describes the association of race and insurance status with epilepsy surgery access and outcomes. METHODS: Searches in Scopus and PubMed databases related to disparities in epilepsy surgery were conducted. The inclusion criteria consisted of data that could be used to compare epilepsy surgery patient access and outcomes by insurance or race in the United States. Two independent reviewers determined article eligibility. RESULTS: Of the 289 studies reviewed, 26 were included. Most of the studies were retrospective cohort studies (23 of 26) and national admissions database studies (13 of 26). Of the 17 studies that evaluated epilepsy surgery patient demographics, 11 showed that Black patients were less likely to receive surgery than were White patients or had an increased time to surgery from seizure onset. Nine studies showed that patients with private insurance were more likely to undergo epilepsy surgery and have shorter time to surgery compared with patients with public insurance. No significant association was found between the seizure recurrence rate after surgery with insurance or race. CONCLUSIONS: Black patients and patients with public insurance are receiving epilepsy surgery at lower rates after a prolonged waiting period compared with other patients with medically refractory epilepsy. These results are consistent across the current reported literature. Future efforts should focus on additional characterization and potential causes of these disparities to develop successful interventions.

Supervised weight loss requirements disproportionately affect Black patients seeking weight loss surgery.

BACKGROUND: We use our high-volume institutional experience with a majority Black population to examine the role of supervised weight loss (SWL) requirements perpetuating disparities in bariatric surgery. OBJECTIVE: To determine if there are racial disparities in the required amount of supervised weight loss prior to approval for bariatric surgery. SETTING: University hospital. METHODS: A retrospective review was conducted of all patients seen at our institution's bariatric surgery clinic in 2018. Odds of undergoing surgery within 1 year and mean number of SWL requirements were determined using descriptive statistics for Black patients as compared with non-Hispanic White patients. Finally, a logistic model was constructed to examine likelihood of undergoing an operation within 1 year for patients of varying SWL requirements. RESULTS: A total of 335 patients were included (75% Black, 25% White). Within 1 year, 37% of Black patients compared with 53% of White patients had undergone an operation (relative risk .7, P = .01). Mean insurance-mandated SWL sessions were significantly higher for Black patients (3.6 ± 2.8) versus non-Hispanic White patients (2.2 ± 2.7) (P < .01). Mean program-mandated SWL sessions were also significantly higher for Black patients (2.5 ± 2.6) versus non-Hispanic White patients (.8 ± 1.8) (P < .01). Increasing SWL requirements significantly reduced the odds of undergoing surgery at 1 year within the entire cohort (odds ratio .86, P < .01). CONCLUSIONS: Black patients are disproportionally affected by SWL requirements, which strongly correlate with decreased likelihood of undergoing a bariatric operation as compared with their White counterparts. Even after overcoming barriers to see a bariatric surgery provider, Black patients still face disproportionally more barriers to surgery. Bariatric centers must be sensitive to the effect of SWL requirements, as it is negatively associated with the likelihood of a patient receiving a bariatric operation.

"We're playing on the same team": Communication (dis)connections between trauma patients and surgical residents.

BACKGROUND: Patient-physician communication is key to better clinical outcomes and patient well-being. Communication between trauma patients and their physicians remains relatively unexplored. We aimed to identify and characterize the range of strengths and challenges in patient-physician communication in the setting of trauma care. METHODS: A qualitative, grounded theory approach was used to explore communication strengths and challenges for patients and residents. Patients previously admitted to the trauma service for violent injuries were recruited and interviewed in-person during their trauma clinic appointments. Surgical residents were recruited via email and interviewed virtually via Zoom. Anonymous, semistructured interviews were conducted until thematic saturation was reached. RESULTS: Twenty-nine interviews with patients and 14 interviews with residents were conducted. Patients reported feeling ignored and misunderstood and having inadequate communication with physicians. Residents cited lack of time, patients' lack of health literacy, differences in background, and emotional responses to trauma as barriers to effective communication with patients. Patients and residents reported an understanding of each other's stressors, similar emotional experiences regarding traumatic stress, and a desire to communicate with each other in greater depth both inside and outside of the hospital. CONCLUSION: Trauma patients and residents can feel disconnected due to the lack of time for thorough communication and differences in background; however, they understand each other's stressors and share similar emotional responses regarding trauma and a desire for increased communication, connection, and solidarity. Leveraging these shared values to guide interventions, such as a resident curriculum, may help bridge disconnects and improve their communication. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Vitamin D Clinical Pharmacology: Relevance to COVID-19 Pathogenesis.

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CDK1 is up-regulated by temozolomide in an NF-κB dependent manner in glioblastoma.

The alkylating agent, temozolomide (TMZ), is the most commonly used chemotherapeutic for the treatment of glioblastoma (GBM). The anti-glioma effect of TMZ involves a complex response that includes G2-M cell cycle arrest and cyclin-dependent kinase 1 (CDK1) activation. While CDK1 phosphorylation is a well-described consequence of TMZ treatment, we find that TMZ also robustly induces CDK1 expression. Analysis of this pathway demonstrates that CDK1 is regulated by NF-κB via a putative κB-site in its proximal promoter. CDK1 was induced in a manner dependent on mature p50 and the atypical inhibitor κB protein, BCL-3. Treatment with TMZ induced binding of NF-κB to the κB-site as assessed by gel shift analysis and chromatin immunoprecipitation. Examination of a CDK1 promoter-reporter demonstrated the functional relevance of the κB-site and underlined the requirement of p50 and BCL-3 for activation. Targeted knockdown of CDK1 or chemical inhibition with the selective CDK1 inhibitor, RO-3306, potentiated the cytotoxic effect of TMZ. These results identify CDK1 as an NF-κB target gene regulated by p50 and BCL-3 and suggest that targeting CDK1 may be a strategy to improve the efficacy of TMZ against GBM.

p50 mono-ubiquitination and interaction with BARD1 regulates cell cycle progression and maintains genome stability.

p50, the mature product of NFKB1, is constitutively produced from its precursor, p105. Here, we identify BARD1 as a p50-interacting factor. p50 directly associates with the BARD1 BRCT domains via a C-terminal phospho-serine motif. This interaction is induced by ATR and results in mono-ubiquitination of p50 by the BARD1/BRCA1 complex. During the cell cycle, p50 is mono-ubiquitinated in S phase and loss of this post-translational modification increases S phase progression and chromosomal breakage. Genome-wide studies reveal a substantial decrease in p50 chromatin enrichment in S phase and Cycln E is identified as a factor regulated by p50 during the G1 to S transition. Functionally, interaction with BARD1 promotes p50 protein stability and consistent with this, in human cancer specimens, low nuclear BARD1 protein strongly correlates with low nuclear p50. These data indicate that p50 mono-ubiquitination by BARD1/BRCA1 during the cell cycle regulates S phase progression to maintain genome integrity.