RNA Polymerase II Regulates Topoisomerase 1 Activity to Favor Efficient Transcription.

We report a mechanism through which the transcription machinery directly controls topoisomerase 1 (TOP1) activity to adjust DNA topology throughout the transcription cycle. By comparing TOP1 occupancy using chromatin immunoprecipitation sequencing (ChIP-seq) versus TOP1 activity using topoisomerase 1 sequencing (TOP1-seq), a method reported here to map catalytically engaged TOP1, TOP1 bound at promoters was discovered to become fully active only after pause-release. This transition coupled the phosphorylation of the carboxyl-terminal-domain (CTD) of RNA polymerase II (RNAPII) with stimulation of TOP1 above its basal rate, enhancing its processivity. TOP1 stimulation is strongly dependent on the kinase activity of BRD4, a protein that phosphorylates Ser2-CTD and regulates RNAPII pause-release. Thus the coordinated action of BRD4 and TOP1 overcame the torsional stress opposing transcription as RNAPII commenced elongation but preserved negative supercoiling that assists promoter melting at start sites. This nexus between transcription and DNA topology promises to elicit new strategies to intercept pathological gene expression.

MYC assembles and stimulates topoisomerases 1 and 2 in a "topoisome".

High-intensity transcription and replication supercoil DNA to levels that can impede or halt these processes. As a potent transcription amplifier and replication accelerator, the proto-oncogene MYC must manage this interfering torsional stress. By comparing gene expression with the recruitment of topoisomerases and MYC to promoters, we surmised a direct association of MYC with topoisomerase 1 (TOP1) and TOP2 that was confirmed in vitro and in cells. Beyond recruiting topoisomerases, MYC directly stimulates their activities. We identify a MYC-nucleated "topoisome" complex that unites TOP1 and TOP2 and increases their levels and activities at promoters, gene bodies, and enhancers. Whether TOP2A or TOP2B is included in the topoisome is dictated by the presence of MYC versus MYCN, respectively. Thus, in vitro and in cells, MYC assembles tools that simplify DNA topology and promote genome function under high output conditions.

Decolonization in Nursing Homes to Prevent Infection and Hospitalization.

BACKGROUND: Nursing home residents are at high risk for infection, hospitalization, and colonization with multidrug-resistant organisms. METHODS: We performed a cluster-randomized trial of universal decolonization as compared with routine-care bathing in nursing homes. The trial included an 18-month baseline period and an 18-month intervention period. Decolonization entailed the use of chlorhexidine for all routine bathing and showering and administration of nasal povidone-iodine twice daily for the first 5 days after admission and then twice daily for 5 days every other week. The primary outcome was transfer to a hospital due to infection. The secondary outcome was transfer to a hospital for any reason. An intention-to-treat (as-assigned) difference-in-differences analysis was performed for each outcome with the use of generalized linear mixed models to compare the intervention period with the baseline period across trial groups. RESULTS: Data were obtained from 28 nursing homes with a total of 28,956 residents. Among the transfers to a hospital in the routine-care group, 62.2% (the mean across facilities) were due to infection during the baseline period and 62.6% were due to infection during the intervention period (risk ratio, 1.00; 95% confidence interval [CI], 0.96 to 1.04). The corresponding values in the decolonization group were 62.9% and 52.2% (risk ratio, 0.83; 95% CI, 0.79 to 0.88), for a difference in risk ratio, as compared with routine care, of 16.6% (95% CI, 11.0 to 21.8; P<0.001). Among the discharges from the nursing home in the routine-care group, transfer to a hospital for any reason accounted for 36.6% during the baseline period and for 39.2% during the intervention period (risk ratio, 1.08; 95% CI, 1.04 to 1.12). The corresponding values in the decolonization group were 35.5% and 32.4% (risk ratio, 0.92; 95% CI, 0.88 to 0.96), for a difference in risk ratio, as compared with routine care, of 14.6% (95% CI, 9.7 to 19.2). The number needed to treat was 9.7 to prevent one infection-related hospitalization and 8.9 to prevent one hospitalization for any reason. CONCLUSIONS: In nursing homes, universal decolonization with chlorhexidine and nasal iodophor led to a significantly lower risk of transfer to a hospital due to infection than routine care. (Funded by the Agency for Healthcare Research and Quality; Protect ClinicalTrials.gov number, NCT03118232.).

The role of O-GlcNAcylation in RNA polymerase II transcription.

Eukaryotic RNA polymerase II (RNAPII) is responsible for the transcription of the protein-coding genes in the cell. Enormous progress has been made in discovering the protein activities that are required for transcription to occur, but the effects of post-translational modifications (PTMs) on RNAPII transcriptional regulation are much less understood. Most of our understanding relates to the cyclin-dependent kinases (CDKs), which appear to act relatively early in transcription. However, it is becoming apparent that other PTMs play a crucial role in the transcriptional cycle, and it is doubtful that any sort of complete understanding of this regulation is attainable without understanding the spectra of PTMs that occur on the transcriptional machinery. Among these is O-GlcNAcylation. Recent experiments have shown that the O-GlcNAc PTM likely has a prominent role in transcription. This review will cover the role of the O-GlcNAcylation in RNAPII transcription during initiation, pausing, and elongation, which will hopefully be of interest to both O-GlcNAc and RNAPII transcription researchers.

Does psychological distress predict risk of orthopaedic surgery and postoperative opioid prescribing in patients with hip pain? A retrospective study.

BACKGROUND: Clinicians and public health professionals have allocated resources to curb opioid over-prescription and address psychological needs among patients with musculoskeletal pain. However, associations between psychological distress, risk of surgery, and opioid prescribing among those with hip pathologies remain unclear. METHODS: Using a retrospective cohort study design, we identified patients that were evaluated for hip pain from January 13, 2020 to October 27, 2021. Patients' surgical histories and postoperative opioid prescriptions were extracted via chart review. Risk of hip surgery within one year of evaluation was analyzed using multivariable logistic regression. Multivariable linear regression was employed to predict average morphine milligram equivalents (MME) per day of opioid prescriptions within the first 30 days after surgery. Candidate predictors included age, gender, race, ethnicity, employment, insurance type, hip function and quality of life on the International Hip Outcome Tool (iHOT-12), and psychological distress phenotype using the OSPRO Yellow Flag (OSPRO-YF) Assessment Tool. RESULTS: Of the 672 patients, n = 350 (52.1%) underwent orthopaedic surgery for hip pain. In multivariable analysis, younger patients, those with TRICARE/other government insurance, and those with a high psychological distress phenotype had higher odds of surgery. After adding iHOT-12 scores, younger patients and lower iHOT-12 scores were associated with higher odds of surgery, while Black/African American patients had lower odds of surgery. In multivariable analysis of average MME, patients with periacetabular osteotomy (PAO) received opioid prescriptions with significantly higher average MME than those with other procedures, and surgery type was the only significant predictor. Post-hoc analysis excluding PAO found higher average MME for patients undergoing hip arthroscopy (compared to arthroplasty or other non-PAO procedures) and significantly lower average MME for patients with public insurance (Medicare/Medicaid) compared to those with private insurance. Among those only undergoing arthroscopy, older age and having public insurance were associated with opioid prescriptions with lower average MME. Neither iHOT-12 scores nor OSPRO-YF phenotype assignment were significant predictors of postoperative mean MME. CONCLUSIONS: Psychological distress characteristics are modifiable targets for rehabilitation programs, but their use as prognostic factors for risk of orthopaedic surgery and opioid prescribing in patients with hip pain appears limited when considered alongside other commonly collected clinical information such as age, insurance, type of surgery pursued, and iHOT-12 scores.

Comparison of circulating tumor DNA between African American and Caucasian patients with metastatic castrate-resistant prostate cancer post-abiraterone and/or enzalutamide.

BACKGROUND: African American men are much more likely than Caucasian men to be diagnosed with and to die of prostate cancer. Genetic differences likely play a role. The cBioPortal database reveals that African American men with prostate cancer have higher rates of CDK12 somatic mutations compared to Caucasian men. However, this does not account for prior prostate cancer treatments, which are particularly important in the castrate-resistant setting. We aimed to compare somatic mutations based on circulating tumor DNA (ctDNA) in metastatic castration-resistant prostate cancer (mCRPC) between African American and Caucasian men after exposure to abiraterone and/or enzalutamide. METHODS: This single-institution retrospective study characterizes the somatic mutations detected on ctDNA for African American and Caucasian men with mCRPC who had progressed after abiraterone and/or enzalutamide from 2015 through 2022. We evaluated the gene mutations and types of mutations in this mCRPC cohort. RESULTS: There were 50 African American and 200 Caucasian men with CRPC with available ctDNA data. African American men were younger at the time of diagnosis (p = 0.008) and development of castration resistance (p = 0.006). African American men were more likely than Caucasian men to have pathogenic/likely pathogenic (P/LP) mutations in CDK12 (12% vs. 1.5%; p = 0.003) and copy number amplifications and P/LP mutations in KIT (8.0% vs. 1.5%; p = 0.031). African American men were also significantly more likely to have frameshift mutations (28% vs. 14%; p = 0.035). CONCLUSIONS: Compared to Caucasian men, African American men with mCRPC after exposure to abiraterone and/or enzalutamide had a higher incidence of somatic CDK12 P/LP mutations and KIT amplifications and P/LP mutations based on ctDNA. African American men also had more frameshift mutations. We hypothesize that these findings have potential implications for tumor immunogenicity.

Clinical and molecular determinants of PSA response to bipolar androgen therapy in prostate cancer.

BACKGROUND: Bipolar androgen therapy (BAT) is a novel therapy known to be effective in a subset of men with metastatic castrate resistant prostate cancer (mCRPC). A better understanding of responders and nonresponders to BAT would be useful to clinicians considering BAT therapy for patients. Herein we analyze clinical and genetic factors in responders/nonresponders to better refine our understanding regarding which patients benefit from this innovative therapy. METHODS: mCRPC patients were assessed for response or no response to BAT. Patients with PSA declines of greater than 50% from baseline after 2 or more doses of testosterone were considered to be responders. Whereas, nonresponders had no PSA decline after 2 doses of testosterone and subsequently manifest a PSA increase of >50%. Differences between these two groups of patients were analyzed using clinical and laboratory parameters. All patients underwent genomic testing using circulating tumor DNA (ctDNA) and germline testing pre-BAT. RESULTS: Twenty five patients were nonresponders and 16 were responders. Baseline characteristics between nonresponders and responders varied. Responders were more likely to have had a radical prostatectomy as definitive therapy and were more likely to have been treated with an androgen receptor (AR) antagonist (enzalutamide or apalutamide) immediately before BAT (compared to abiraterone). Duration of prior enzalutamide therapy was longer in responders. Nonresponders were more likely to have bone-only metastases and responders were more likely to have nodal metastases. Assays detected ctDNA AR amplifications more often in responding patients. Responders trended toward having the presence of more TP53 mutations at baseline. CONCLUSIONS: BAT responders are distinct from nonresponders in several ways however each of these distinctions are imperfect. Patterns of metastatic disease, prior therapies, duration of prior therapies, and genomics each contribute to an understanding of patients that will or will not respond. Additional studies are needed to refine the parameters that clinicians can utilize before choosing among the numerous treatment alternatives available for CRPC patients.

Black Patients with Metastatic Castrate-Resistant Prostate Cancer Have a Shorter Time Interval Between PSA and Clinical Progression on Novel Hormonal Therapies plus Avelumab.

BACKGROUND: Black men are at higher risk for prostate cancer death. Previous studies showed a benefit of different therapies, including immune-based therapy, for Black men with metastatic prostate cancer. We sought to explore the efficacy of the PD-L1 inhibitor avelumab in Black men with metastatic castrate-resistant prostate cancer (mCRPC) progressing after abiraterone or enzalutamide. METHODS: This pilot phase II study enrolled self-identified Black patients who developed mCRPC on next-generation hormonal therapies (NHTs) abiraterone acetate or enzalutamide (NCT03770455). Enrolled patients received avelumab 10mg/kg IV every 2 weeks while remaining on the same NHTs. The primary endpoint of our study was ≥ 50% reduction in prostate specific antigen (PSA) at ≥8 weeks. RESULTS: A total of eight patients were enrolled. The median duration on NHTs prior to enrollment was 364 days (95% CI, 260.9-467.1). The median time to initiate avelumab was 8 days (3-14). With a median follow-up of 196 days, no patients achieved the primary endpoint. The median time to PSA progression was 35 days (95 CI%, 0-94.8) and the median time to radiographic and/or clinical progression was 44 days (95 CI%, 0-118.5). The study was closed prematurely due to safety concerns related to the rapid clinical progression observed in the patients enrolled on study. CONCLUSION: In conclusion, the addition of avelumab to NHT did not demonstrate clinical activity in Black men with new mCRPC. The unexpected short interval between PSA and radiographic and/or clinical progression observed in this study has potential clinical implications.ClinicalTrials.gov Identifier: NCT03770455 (IND number 139559).

Development and Evaluation of an Enhanced Recovery Protocol to Reduce Length of Stay following Elective Endovascular Aneurysm Repair.

BACKGROUND: Elective endovascular abdominal aortic aneurysm repair (EVAR) can be performed safely with a short postoperative length of stay (LOS). We aimed to develop and assess the impact of an enhanced recovery protocol (ERP) on LOS after elective EVAR. METHODS: Pre-ERP development single center retrospective review of elective EVAR procedures from January 2012 to December 2019. ERP was developed by targeting factors associated with prolonged LOS (>2 days) elucidated from semistructured interviews and Bayesian additive regression tree analysis. Post-ERP development, a subsequent retrospective review of elective EVAR performed from January 2018 to June 2021 was performed to evaluate LOS before and after ERP. Primary outcome was LOS. RESULTS: Two hundred sixteen patients underwent elective infrarenal EVAR from 2012 to 2019. Periprocedural factors identified as associated with LOS >2 days included noncommercial insurance (43.6% vs. 26.5%; P = 0.01), preoperative anemia (hemoglobin 12.56 g/dL vs. 13.57 g/dL; P = 0.001), worse renal function (creatinine 1.31 mg/dL vs. 1.01/dL; P = 0.004), open femoral access (74.4% vs. 26.5%; P < 0.001), intensive care unit (ICU) stay (2.7 days vs. 0.9 days; P < 0.001), postoperative anemia (9.8 g/dL vs. 11.9 g/dL; P < 0.001), postoperative creatinine (1.55 mg/dL vs. 0.97 mg/dL; P < 0.001), and beta blocker need on discharge (45.5% vs. 25%; P = 0.003) as significant between patients with short and prolonged LOS groups. Semistructured interviews revealed postoperative day 1 complete blood count/chemistry, postoperative physical therapy evaluation, ICU admission, urinary retention, patient expectations, and unavailability of transportation home as modifiable factors that delayed early discharge. A 14-component ERP was created to target the factors identified from combined qualitative and quantitative results. Post-ERP development, 74 elective EVAR patients were reviewed from 2018 to 2021 (37 pre-ERP and 37 post-ERP). Following ERP development, the mean LOS was reduced from 2.6 (standard deviation: 1.9) to 1.3 days (standard deviation: 1.3); P < 0.01. There were no significant differences in 30-day readmission, postoperative complications, emergency room visits, or 90-day mortality before and after the ERP was used. CONCLUSIONS: Practice and procedural factors can be modified through an informed and safe process to reduce LOS after elective EVAR. LOS following elective EVAR was safely reduced following the use of a systematically developed ERP.

Toxicokinetics of metformin overdose treated with CVVHDF.

A 53-year-old man died following a reported ingestion of 80 g of his metformin tablets resulting in severe, refractory shock and metformin-associated lactic acidosis. His peak serum metformin concentration was 53 µg/mL (therapeutic range 1-2 µg/mL), peak lactic acid concentration was 49.7 mmol/L, and arterial pH nadir was 7.06. He died despite vasopressors and renal replacement therapy [RRT; both intermittent hemodialysis (IHD) and continuous venovenous hemodiafiltration (CVVHDF)]. Serial metformin concentrations during CVVHDF suggested a half-life of 33-h. Similar to previous reports of RRT for metformin toxicity, CVVHDF appears to provide first-order elimination of metformin.

A novel image-based method for simultaneous counting of Lactobacillus and Saccharomyces in mixed culture fermentation.

Mixed microorganism cultures are prevalent in the food industry. A variety of microbiological mixtures have been used in these unique fermenting processes to create distinctive flavor profiles and potential health benefits. Mixed cultures are typically not well characterized, which may be due to the lack of simple measurement tools. Image-based cytometry systems have been employed to automatically count bacteria or yeast cells. In this work, we aim to develop a novel image cytometry method to distinguish and enumerate mixed cultures of yeast and bacteria in beer products. Cellometer X2 from Nexcelom was used to count of Lactobacillus plantarum and Saccharomyces cerevisiae in mixed cultures using fluorescent dyes and size exclusion image analysis algorithm. Three experiments were performed for validation. (1) Yeast and bacteria monoculture titration, (2) mixed culture with various ratios, and (3) monitoring a Berliner Weisse mixed culture fermentation. All experiments were validated by comparing to manual counting of yeast and bacteria colony formation. They were highly comparable with ANOVA analysis showing p-value > 0.05. Overall, the novel image cytometry method was able to distinguish and count mixed cultures consistently and accurately, which may provide better characterization of mixed culture brewing applications and produce higher quality products.

Social Vulnerability and Rurality Associated With Higher Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection-Induced Seroprevalence: A Nationwide Blood Donor Study-United States, July 2020-June 2021.

BACKGROUND: Most studies on health disparities during the coronavirus disease 2019 (COVID-19) pandemic focused on reported cases and deaths, which are influenced by testing availability and access to care. This study aimed to examine severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody seroprevalence in the United States and its associations with race/ethnicity, rurality, and social vulnerability over time. METHODS: This repeated cross-sectional study used data from blood donations in 50 states and Washington, DC, from July 2020 through June 2021. Donor zip codes were matched to counties and linked with Social Vulnerability Index (SVI) and urban-rural classification. SARS-CoV-2 antibody seroprevalences induced by infection and infection-vaccination combined were estimated. Association of infection-induced seropositivity with demographics, rurality, SVI, and its 4 themes were quantified using multivariate regression models. RESULTS: Weighted seroprevalence differed significantly by race/ethnicity and rurality, and increased with increasing social vulnerability. During the study period, infection-induced seroprevalence increased from 1.6% to 27.2% and 3.7% to 20.0% in rural and urban counties, respectively, while rural counties had lower combined infection- and vaccination-induced seroprevalence (80.0% vs 88.1%) in June 2021. Infection-induced seropositivity was associated with being Hispanic, non-Hispanic Black, and living in rural or more socially vulnerable counties, after adjusting for demographic and geographic covariates. CONCLUSIONS: The findings demonstrated increasing SARS-CoV-2 seroprevalence in the United States across all geographic, demographic, and social sectors. The study illustrated disparities by race-ethnicity, rurality, and social vulnerability. The findings identified areas for targeted vaccination strategies and can inform efforts to reduce inequities and prepare for future outbreaks.

A Single Center 8 Year Experience of Segmental Arterial Mediolysis Management.

OBJECTIVE: Segmental Arterial Mediolysis (SAM) is a rare, poorly understood vasculopathy that involves vacuolization of the arterial wall, most commonly of the visceral arteries. There are no established therapeutic or monitoring guidelines for SAM, and intervention typically depends on patient presentation. The purpose of this study is to review the management and outcomes of patients with this rare vascular disease METHODS: Single center retrospective review of patients diagnosed with SAM between 2011 and 2019. Included were patients with radiological diagnosis of SAM. Demographic factors, past medical history, presenting symptoms, affected vessels, management, and lesion characteristics over time were collected. Demographic and periprocedural factors, and medical management strategies were compared for those who required operative intervention versus those managed non-operatively. RESULTS: Thirty patients were included, 21 (70%) were male, mean age was 53.5 years (range: 35.7-72.2). Twenty-seven patients were managed non-operatively, 3 patients required surgical intervention. Patients who underwent operative intervention were more likely to present with pain >30 days (P < 0.05), and hemorrhage (P < 0.01). Abdominal pain was the most common presenting symptom (n = 24, 80%). Arterial dissection was the most common radiological finding at time of presentation (n = 20, 67%). The celiac artery and its branches were most often involved (n=22, 73%) followed by the superior mesenteric artery and its branches (n = 15, 50%). Non-operative management most often consisted of anti-hypertensive therapy (n = 13, 43%), antiplatelet agents (n = 17, 57%%), and lipid-lowering agents (n = 13, 43%), with 7 patients receiving all three. Six patients demonstrated confirmed resolution of lesions during surveillance imaging, with average time to resolution of 325.5 days. CONCLUSIONS: Patients who underwent intervention for SAM presented with either mesenteric ischemia or pseudoaneurysm rupture. In patients that present without those conditions, medical management consisting of anti-hypertensives, antiplatelet agents, and lipid-lowering therapy was effective. Non operative management resulted in symptom resolution in all patients and surveillance imaging showed resolution of radiographic abnormalities in 6 patients out of 27 at less than one year.

Differentiating Live Versus Dead Gram-Positive and Gram-Negative Bacteria With and Without Oxidative Stress Using Buoyant Mass Measurements.

Expeditious and accurate determination of pathogenic bacteria cell viability is of great importance to public health for numerous areas including medical diagnostics, food safety, and environmental monitoring. In this work a cell buoyant mass classifier approach is presented to assess bacteria cell viability in real time. Buoyant mass measurements for live and dead Gram-positive and Gram-negative bacteria populations were acquired with a commercial suspended microchannel resonator, Archimedes, to generate receiver operating characteristic (ROC) curves. To quantitatively assess the difference in buoyant mass for live and dead bacteria populations, ROC curves were generated to demonstrate cell viability determination. The results are presented as a binary classifier with a decision boundary, above which cells are considered live and below which cells are considered dead. A decision threshold value is evaluated with consideration that a certain true positive rate (correct classification of a live cell) is maintained with an acceptable false positive rate. The potential for this approach to monitor cell viability in real time is significant, especially when considering multiple classifier dimensions such as buoyant mass and density. This classifier approach represents a next generation technique for rapid and label-free diagnostics based on cell feature measurements.

Axillary pullout syndrome: A novel approach to managing a devastating complication.

OBJECTIVES: Axillary pullout syndrome is a complex, potentially fatal complication following axillary-femoral bypass graft creation. The re-operative nature, in addition to ongoing hemorrhage, makes for a complicated and potentially morbid repair. METHODS: We present the case of a 57-year-old man with history of a previous left axillary-femoral-femoral bypass who presented with acute limb-threatening ischemia as a result of bypass thrombosis managed with a right axillary-femoral bypass for limb salvage. His postoperative course was complicated by an axillary anastomotic dehiscence while recovering in inpatient rehabilitation resulting in acute, life-threatening hemorrhage. He was managed utilizing a novel hybrid approach in which a retrograde stent graft was initially placed across the anastomotic dehiscence for control of hemorrhage. He then underwent exploration, decompression, and interposition graft repair utilizing the newly placed stent graft to reinforce the redo axillary anastomosis. RESULTS AND CONCLUSION: Compared with a traditional operative approach, the hybrid endovascular and open approach limited ongoing hemorrhage while providing a more stable platform for repair and graft revascularization. A hybrid approach to the management of axillary pullout syndrome provides a safe, effective means to the management of axillary anastomotic dehiscence while minimizing the morbidity of ongoing hemorrhage.

Post-Related Complications in Hip Arthroscopy Are Reported Significantly Greater in Prospective Versus Retrospective Literature: A Systematic Review.

PURPOSE: To determine whether there are differences in (1) the incidence of post-related complications following hip arthroscopy between prospective and retrospective publications; and (2) between post-assisted and postless techniques. METHODS: A systematic review was performed using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines to characterize post-related complications following hip arthroscopy for central or peripheral compartment hip pathology, including femoroacetabular impingement syndrome and chondrolabral injury. Inclusion criteria were prospective and retrospective Level I-IV evidence investigations that reported results of hip arthroscopy performed in the supine position. Exclusion criteria included open or extra-articular endoscopic hip surgery. Post-related complications included pudendal nerve injury (sexual dysfunction, dyspareunia, perineal pain or numbness) or perineum/external genitalia soft-tissue injury. RESULTS: Ninety-four studies (12,212 hips; 49% male, 51% female; 52% Level IV evidence) were analyzed. Prospective studies (3,032 hips) report a greater incidence of post-related complications compared with retrospective (8,116 hips) studies (7.1% vs 1.4%, P < .001). Three studies (1,064 hips) used a postless technique and all reported a 0% incidence of pudendal neurapraxia or perineal soft tissue injury. Most pudendal nerve complications were transient, resolving by 3 months, but permanent nerve injury was reported in 4 cases. Only 19%, 22%, 7%, and 4% of studies reported a total surgery time, traction time, traction force, and bed Trendelenburg angle for their study samples, respectively. CONCLUSIONS: The incidence of post-related complications is 5 times greater in prospective (versus retrospective) hip arthroscopy literature. Postless distraction resulted in a 0% incidence of post-related injuries. LEVEL OF EVIDENCE: IV, systematic review of Level I-IV evidence.

Family history and pathogenic/likely pathogenic germline variants in prostate cancer patients.

BACKGROUND: Recent literature highlights the importance of germline genetic testing in prostate cancer (PCa) patients. Surprisingly, a literature review indicates that family history (FH) records are incomplete in the major published studies from prostate cancer patients. METHODS: Prospective family history data were gathered from 496 men in a single institution with a personal history of PCa who underwent germline genetic testing using a panel of at least 79 genes. Comprehensive first degree FH were obtained in all PCa of patients and analysis of prevalent FH was assessed at the time of sample collection. RESULTS: Pathogenic/likely pathogenic variants (PV/LPVs) were not associated with age at diagnosis, race, or presence of metastasis. One or more first degree relatives (FDR) with any cancer was not predictive for germline PV/LPVs for men with PCa (p = .96). Separate analysis of patients with one or more FDR with breast, prostate, ovarian, or pancreatic cancer revealed that only FDR with breast or ovarian cancer was predictive for PV/LPVs (p = .028, p = .015 respectively). Patients with a FDR with breast cancer had 1.8 increased risk of PV/LPVs, and patients with a FDR with ovarian cancer had 2.9 increased risk of PV/LPV. CONCLUSION: In men with a personal history of PCa, germline PV/LPVs were associated with a FDR with breast or ovarian cancer. Notably having FDRs with PCa does not predict for PV/LPVs. These data emphasize the contribution of FH in a data set with complete ascertainment of FH.

Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer.

BACKGROUND: The goal of this study is to evaluate germline genetic variants in African American men with metastatic prostate cancer as compared to those in Caucasian men with metastatic prostate cancer in an effort to understand the role of genetic factors in these populations. METHODS: African American and Caucasian men with metastatic prostate cancer who had germline testing using multigene panels were used to generate comparisons. Germline genetic results, clinical parameters, and family histories between the two populations were analyzed. RESULTS: A total of 867 patients were included in this retrospective study, including 188 African American and 669 Caucasian patients. There was no significant difference in the likelihood of a pathogenic or likely-pathogenic variants (PV/LPVs) between African American and Caucasian patients (p = .09). African American patients were more likely to have a variant of unknown significance than Caucasians (odds ratio [OR] = 1.95; p < .0001). BRCA1 PV/LPVs were higher in African Americans (OR = 4.86; p = .04). African American patients were less likely to have a PV/LPV in non-BRCA DNA repair genes (OR = 0.30; p = .008). Family history of breast (OR = 2.09; p = .002) or ovarian cancer (OR = 2.33; p = .04) predicted PV/LPVs in Caucasians but not African-Americans. This underscores the limitations of family history in AA men and the importance of personal history to guide germline testing in AA men. CONCLUSIONS: In metastatic prostate cancer patients, PV/LPVs of tested genes did not vary by race, BRCA1 PV/LPVs were more common in the African American subset. However, PV/LPVs in non-BRCA DNA repair genes were less likely to be encountered in African Americans. Family history associated with genetic testing results in Caucasians only.

TRIB2 acts downstream of Wnt/TCF in liver cancer cells to regulate YAP and C/EBPα function.

Dysregulation of Wnt signaling is closely associated with human liver tumorigenesis. However, liver cancer-specific Wnt transcriptional programs and downstream effectors remain poorly understood. Here, we identify tribbles homolog 2 (TRIB2) as a direct target of Wnt/TCF in liver cancer and demonstrate that transcription of Wnt target genes, including TRIB2, is coordinated by the TCF and FoxA transcription factors in liver cancer cells. We show that Wnt-TRIB2 activation is critical for cancer cell survival and transformation. Mechanistically, TRIB2 promotes protein stabilization of the YAP transcription coactivator through interaction with the ßTrCP ubiquitin ligase. Furthermore, we find that TRIB2 relieves the liver tumor suppressor protein C/EBPα-mediated inhibition of YAP/TEAD transcriptional activation in liver cancer cells. Altogether, our study uncovers a regulatory mechanism underlying liver cancer-specific Wnt transcriptional output, and suggests that TRIB2 functions as a signaling nexus to integrate the Wnt/ß-catenin, Hippo/YAP, and C/EBPα pathways in cancer cells.

Primary Aortoduodenal Fistula: A Case Report and Current Literature Review.

Primary aortoduodenal fistula is a rare, life-threatening pathology that is difficult to diagnose and manage. We present the case of a 64-year-old male with a primary aortoduodenal fistula. Our patient initially underwent an endovascular aneurysm repair at an outside institution before being transferred to our tertiary care center, where he ultimately had definitive management with an extra-anatomic bypass, aortic ligation, duodenal resection with primary anastomosis, and gastrojejunostomy tube placement. His surgical cultures grew Candida albicans, and he was discharged with a 6-week course of intravenous antibiotics with subsequent antibiotic suppression for 1 year. He died 14 months postoperatively from tongue squamous cell carcinoma. We also review the current literature regarding epidemiology, pathology, diagnostics, management, and case reports from 2015 to present. Overall, timely diagnosis and treatment is imperative for reducing mortality from primary aortoduodenal fistula, and although formal consensus is lacking regarding most clinical aspects, an increasing number of case reports has helped describe options for management.