bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interactome of Aiolos/Ikaros Reveals Combination Rationale of Cereblon Modulators with HDAC Inhibitors in DLBCL
Authors: Hagner Patrick R. , Chiu Hsiling , Chopra Vivek S. , Colombo Martino , Patel Nisha , Estevez Maria Ortiz , Waldman Michelle F. , Loos Remco , Towfic Fadi , Gandhi Anita K. 
Published: May 2022

Abstract

Purpose:
Cereblon (CRBN), a substrate receptor of the E3 ubiquitin ligase complex CRL4CRBN, is the target of the small molecules lenalidomide and avadomide. Upon binding of the drugs, Aiolos and Ikaros are recruited to the E3 ligase, ubiquitylated, and subsequently degraded. In diffuse large B-cell lymphoma (DLBCL) cells, Aiolos and Ikaros are direct transcriptional repressors of interferon-stimulated genes (ISG) and degradation of these substrates results in increased ISG protein levels resulting in decreased proliferation and apoptosis. Herein, we aimed to uncover the mechanism(s) Aiolos and Ikaros use to repress ISG transcription and provide a mechanistic rationale for a combination strategy to enhance cell autonomous activities of CRBN modulators (CELMoD).

Experimental Design:
We conducted paired RNA sequencing with histone modification and Aiolos/Ikaros chromatin immunoprecipitation sequencing to identify genes regulated by these transcription factors and to elucidate correlations to drug sensitivity. We confirmed Aiolos/Ikaros mediated transcriptional complex formation in DLBCL patient samples including those treated with avadomide.

Results:
In DLBCL, the repression of ISG transcription is accomplished in part through recruitment of large transcriptional complexes such as the nucleosome remodeling and deacetylase, which modify the chromatin landscape of these promoters. A rational combination approach of avadomide with a specific histone deacetylase inhibitor leads to a significant increase in ISG transcription compared with either single agent, and synergistic antiproliferative activity in DLBCL cell lines.

Conclusions:
Our results provide a novel role for lineage factors Aiolos and Ikaros in DLBCL as well as further insight into the mechanism(s) of Aiolos and Ikaros–mediated transcriptional repression and unique therapeutic combination strategies.
Multiphoton Phosphorescence Quenching Microscopy Reveals Kinetics of Tumor Oxygenation during Antiangiogenesis and Angiotensin Signaling Inhibition
Authors: Martin John D. , Lanning Ryan M. , Chauhan Vikash P. , Martin Margaret R. , Mousa Ahmed S. , Kamoun Walid S. , Han Hee-Sun , Lee Hang , Stylianopoulos Triantafyllos , Bawendi Moungi G. , Duda Dan G. , Brown Edward B. , Padera Timothy P. , Fukumura Dai , Jain Rakesh K. 
Published: May 2022

Abstract

Purpose:
The abnormal function of tumor blood vessels causes tissue hypoxia, promoting disease progression and treatment resistance. Although tumor microenvironment normalization strategies can alleviate hypoxia globally, how local oxygen levels change is not known because of the inability to longitudinally assess vascular and interstitial oxygen in tumors with sufficient resolution. Understanding the spatial and temporal heterogeneity should help improve the outcome of various normalization strategies.

Experimental Design:
We developed a multiphoton phosphorescence quenching microscopy system using a low-molecular-weight palladium porphyrin probe to measure perfused vessels, oxygen tension, and their spatial correlations in vivo in mouse skin, bone marrow, and four different tumor models. Further, we measured the temporal and spatial changes in oxygen and vessel perfusion in tumors in response to an anti-VEGFR2 antibody (DC101) and an angiotensin-receptor blocker (losartan).

Results:
We found that vessel function was highly dependent on tumor type. Although some tumors had vessels with greater oxygen-carrying ability than those of normal skin, most tumors had inefficient vessels. Further, intervessel heterogeneity in tumors is associated with heterogeneous response to DC101 and losartan. Using both vascular and stromal normalizing agents, we show that spatial heterogeneity in oxygen levels persists, even with reductions in mean extravascular hypoxia.

Conclusions:
High-resolution spatial and temporal responses of tumor vessels to two agents known to improve vascular perfusion globally reveal spatially heterogeneous changes in vessel structure and function. These dynamic vascular changes should be considered in optimizing the dose and schedule of vascular and stromal normalizing strategies to improve the therapeutic outcome.
Impact of Venous Thromboembolism on Readmissions and Resource Use Following Emergency General Surgery
Authors: Dobaria BS Vishal , Hadaya Joseph , Ebrihiminan Shayan , Verma Arjun , Sanaiha Yas , Benharash Peyman 
Published: May 2022

Background Acute deep vein thrombosis and pulmonary embolism collectively known as venous thromboembolism (VTE), are associated with increased risk of poor clinical sequelae during inpatient hospitalizations. We examined the association of VTE with mortality, readmissions, and costs among patients undergoing emergency general surgery (EGS) operations using a national cohort. Methods Adult hospitalizations for EGS (laparotomy, small bowel resection, large bowel resection, appendectomy, lysis of adhesions, cholecystectomy, and repair of perforated ulcer) within two days of admission were identified in the 2016-18 Nationwide Readmissions Database. Hospitalizations were stratified based on diagnosis of VTE and others (n-VTE). Results Of an estimated 860,747 EGS patients 7,513, (.87%) developed VTE during the index hospitalization. Patients in the VTE group were on average older (65.5 ± 15.3 vs 54.8 ± 18.6 years, P < .001) and more commonly male (46.7 vs 39.3%, P < .001). Venous thromboembolism was independently associated with greater odds of mortality (AOR:1.7 95% CI 1.6-1.9), increased costs (+27,700 95% CI 23, 100-28,300) and greater odds of 30-day readmissions (AOR 1.3 95% CI 1.2-1.4). Discussion Despite national efforts to reduce its incidence, VTE affects nearly 1/100 EGS patients and is associated with increased odds of mortality as well as costs, and readmissions. Tailored approaches are warranted to reduce the impact of this pernicious complication.
Why Trauma Care is Not Expensive: Detailed Analysis of Actual Costs and Cost Differences of Patient Cohorts
Authors: Checchi Kyle D. , Goljan Christopher , Rooney Alexandra S. , Calvo Richard Y. , Benham Derek A. , Prieto James M. , Badiee Jayraan , Krzyzaniak Andrea , Sise Michael J. , Martin Matthew J. , Bansal Vishal 
Published: May 2022

Background Trauma patients are resource intensive, requiring a variety of medical and procedural interventions during hospitalization. These expenses often label trauma care as “high cost” based on gross hospital charges. We hypothesized that a financial metric built on actual costs and clinically relevant trauma patient cohorts would demonstrate a lower true cost of trauma care than the standardly reported gross hospital charges. Methods We examined all trauma patients (≥16 yr) treated in 2017 from a single institution and matched them to the institution’s detailed financial accounting data. The organization’s Financial Operations Division is uniquely able to allocate total operating costs across patient encounters to include medications, procedures, and salaries/fees from medical professionals and administrators. Patient subgroups were identified by Trauma Quality Improvement Program (TQIP) criteria for cost comparisons. Results Overall median cost per patient was $6,544 [IQR $4,975-14,532] for 2,548 patients. The median cost per patient increased with Injury Severity Score (ISS) ranging from $5,457(ISS ≤ 7) to $34,898(ISS ≥ 21), each accompanied by an average 548% increase in gross charges. Costs also varied widely from $13,498 [IQR $8,247–26,254] to $45,759 [IQR $22,186-113,993] across TQIP patient cohorts. Of the total cost, 91% was attributed to personnel alone. Discussion Measuring the true cost of trauma care is feasible. As hypothesized, the true cost of trauma care is lower than charges. True cost increased with injury severity with variable cost across subgroups. Non-physician staff and administration are the largest component of the cost of trauma care.
Stop the Bleed: A Prospective Evaluation and Comparison of Tourniquet Application in Security Personnel Versus Civilian Population
Authors: Petrone Patrizio , Baltazar Gerard , Jacquez Ricardo A. , Akerman Meredith , Brathwaite Collin E. M. , Joseph D’Andrea K. 
Published: May 2022

Introduction Stop the Bleed (STB) is a national training program aiming to decrease the mortality associated with life-threatening bleeding due to injury. The purpose of this study was to evaluate the efficacy and confidence level of security personnel placing a tourniquet (TQ) compared to civilians. Methods Pre and post questionnaires were shared with security personnel (Group 1) and civilians (Group 2). Both groups were assessed to determine comfort level with TQ placement. Time and success rate for placement was recorded pre- and post-STB training. A generalized linear mixed model or generalized estimating equations was used to compare pre and post measurements. Results There were 234 subjects enrolled. There was a statistically significant improvement between the pre- and post-training responses in both groups with respect to comfort level in placing a TQ. Participants also demonstrated increased familiarity with the anatomy and bleeding control after STB training. A higher successful TQ placement was obtained in both groups after STB training (Pre-training: Group 1 [17.4%], Group 2 [12.8%]; Post-training: Group 1 [94.8%], Group 2 [92.3%]). Both groups demonstrated improved time to TA placement with a longer mean time improvement achieved in Group 1. Although the time to TQ placement pre-and post-training was statistically significant, we found that the post-training times between Groups 1 and 2 were similar (P = .983). Conclusions Participants improved their confidence level with the use of hemorrhage control techniques and dramatically increased the rate and time to successful placement of a TQ. While civilians had the greatest increase in comfort level, the security personnel group saw the most significant reduction in the time to successful TQ placement. These findings highlight the critical role of STB in educating and empowering both civilians and security personnel in bleeding control techniques.
Laparoscopic-Assisted Pancreatic Necrosectomy: Technique and Initial Outcomes
Authors: Eng Nina L. , Fitzgerald Caitlin A. , Fisher Jeremy G. , Small William C. , Willingham Field F. , Galloway John R. , Kooby David A. , Haack Carla I. 
Published: May 2022

Background Necrotizing pancreatitis (NP) may result de novo or following procedures such as ERCP or partial pancreatectomy (post-procedural), and may require surgical debridement. Video-assisted retroperitoneal debridement (VARD) is a standard approach for NP that employs a 5 cm incision with varying degrees of blind and open debridement. We describe our technique and outcomes of a modified VARD called laparoscopic-assisted pancreatic necrosectomy (LAPN) performed through a single 12 mm incision that uses direct laparoscopic visualization during debridement. Methods At one medical center, all LAPN patients (2012-2020) were assessed for demographics, disease factors, and outcomes. Bivariate logistic regression analyses were performed to identify factors independently associated with recovery after LAPN for patients with de novo vs post-procedural necrosum. Results Over 9 years, 60 patients underwent LAPN for NP. Median age was 57 years (IQR: 47-66) and 43 (69%) were men. Pancreas necrosum was de novo in 39 (63%) patients and post-procedural in 23 (37%). NP resolved with a median of 1 LAPN procedure and median hospitalization was 33 days. The LAPN major morbidity rate and in-hospital mortality rate were 47% and 5%. No significant differences were seen between NP etiology cohorts, although post-procedure NP patients trended towards a faster clinical recovery to baseline compared to de novo patients (193 vs 394 days; p-value = .07). Conclusions LAPN offers a smaller incision with excellent visualization and non-inferior outcomes, regardless of etiology, with likely faster recovery for patients with post-procedural vs de novo necrotizing pancreatitis.
Which Pelvic Fractures Are Associated With Extravasation on Angiography?
Authors: Fierro Nicole M. , Dhillon Navpreet K. , Siletz Anaar E. , Muníz Tobias , Barmparas Galinos , Ley Eric J. , Hashim Yassar M. 
Published: May 2022

Background Bleeding from pelvic fractures can result in a high mortality rate unless quickly triaged by the trauma surgeon. Upon presentation, pelvic radiography may identify fractures that require angiography with possible embolization. We sought to address which fracture patterns seen on initial x-ray are associated with extravasation on angiography. Methods Data from a single institution retrospective review were collected on trauma patients admitted from 2011 to 2018 with pelvic fractures that required angiography. These fractures were identified by initial pelvic x-ray in the trauma bay and include anteroposterior compression (APC), lateral compression (LC), vertical shear (VS), and combined mechanism (CM) fractures, which are graded by severity. Fracture patterns high risk for bleeding, defined as APC II, APC III, LC III, VS, and CM, were compared to low-risk fracture patterns. Results Of the patients reviewed, 28 underwent pelvic angiography, 16 (57%) of which had extravasation. The difference in the incidence of extravasation between high and low-risk fracture patterns did not reach significance (36% vs 79%, P = .05). When comparing patients with acetabular fractures to those without, there was a significantly higher rate of extravasation associated with acetabular fractures (89% vs 42%, P value = .04), which were more likely to occur with LC I fractures (56% vs 11%, P = .02). Conclusion Our data suggest that traditional pelvic fracture patterns may overestimate the presence of extravasation. Acetabular fractures had a high rate of extravasation, suggesting that these fractures should be considered for early angiography with possible embolization when clinically warranted.
Detection of Ischemic Colitis on Routine Lower Endoscopy and Its Implications After Repair of Ruptured Abdominal Aortic Aneurysm
Authors: Kim Woihwan , Slipak Sasha H. , Webber Alexis , Ata Ashar , Canete Jonathan J. , Chismark A. David , Valerian Brian T. , Darling Ralph C. , Lee Edward C. 
Published: May 2022

Background Ischemic colitis (IC) is a known significant complication after repair of a ruptured abdominal aortic aneurysm (rAAA). Lower endoscopy (colonoscopy or flexible sigmoidoscopy) is a helpful adjunct to aid decision making for surgical exploration. We believe routine use of lower endoscopy after rAAA repair provides better patient care through expeditious diagnosis and surgical care. Methods We performed a retrospective chart review of rAAA repairs from 2008 to 2019. All patients undergo screening lower endoscopy after rAAA repair at our institution. The incidence of IC, mortality, and diagnostic characteristics of routine lower endoscopy was analyzed. Results Of these, 182 patients underwent rAAA repair, among which 139 (76%) underwent routine lower endoscopy. Ischemic colitis of any grade was diagnosed in 25% of patients. The 30-day mortality was 11% compared to 19% in those without lower endoscopy. The presence of IC portended a 4-fold increase in mortality rate compared to those without (26% vs 6%, P = .005). Surgical exploration rate was 8% after routine lower endoscopy. Grade III ischemia on lower endoscopy had a sensitivity of 50% (95% CI 12-88) and specificity of 99% (95% CI 94-100) for transmural necrosis. Discussion We found increased incidence of IC and reliable diagnostic characteristics of routine lower endoscopy in predicting the presence of transmural colonic ischemia. There was decreased mortality with use of routine lower endoscopy but this was not statistically significant.
Effects of Early Chemoprophylaxis in Traumatic Brain Injury and Risk of Venous Thromboembolism
Authors: Shulkosky Megan M. , Han Emily J. , Wahl Wendy L. , Hecht Jason P. 
Published: May 2022

Background The optimal timing to initiate venous thromboembolism (VTE) prophylaxis in patients with a traumatic brain injury (TBI) is still unknown. We designed a study to determine the effect that timing of initiation of VTE prophylaxis has on VTE rates in TBI patients. Methods Patient records were obtained from 32 level 1 and 2 trauma centers in the Michigan Trauma Quality Improvement Program from 2008 to 2018. Overall, 5589 patients with a TBI were included and split into cohorts based on VTE prophylaxis initiation time. Outcomes included rate of VTE, mortality, and serious in-hospital complications. Results There were nine patients (1.3%) in the <24 hour group with a VTE as compared to 36 (2.6%) in the 24-48 hour group, 51 (4.1%) in the 48-72 hour group, and 181 (8.1%) in the >72 hour group ( P < .001). The adjusted odds of VTE were significantly greater in patients initiated within 48-72 hours (AOR 2.861, 95% CI 1.271-6.439) and >72 hours (AOR 3.963, 95% CI 1.824-8.612) compared to <24 hours. Patients that received VTE prophylaxis within 24 hours had similar rates of serious in-hospital complication as patients initiated within 24-48 hours (AOR .956, 95% CI .637-1.434) and 48-72 hour (AOR 1.132, 95% CI .757-1.692) but less than the >72 hour group (AOR 1.662, 95% CI 1.154-2.393) groups. Discussion Patients initiated on VTE prophylaxis within 48 hours of presentation had lower incidence of VTE without a significant increase in serious complications.
Health and Well-Being Needs Among Head and Neck Cancer Caregivers – A Systematic Review
Authors: Benyo Sarah , Phan Chandat , Goyal Neerav 
Published: May 2022

Objective: This review provides a summary of the current understanding of the health and well-being of the head and neck cancer (HNC) caregiver. Our goal is to understand the healthcare needs required by the caregivers of our oncologic patients, which may ultimately influence quality of care and support that cancer patients require during treatment and recovery. Methods: Independent database searches were conducted to identify articles describing HNC caregiver health and healthcare utilization. Search terms included key synonyms for head and neck cancer, caregiver, psychological stress, anxiety, depression, mental health service, and delivery of healthcare in the title/abstract. Results: After following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Protocol, a total of 21 studies were included. Among the 21 studies in the review, a total of 1745 caregivers were included. The average age was 57 years, the majority were female (58%-100%), and spouses/partners of the patients (77%). The literature demonstrates significant anxiety, depression, post-traumatic stress disorder (PTSD), and physical health decline in addition to multifaceted unmet physical and mental health needs among HNC caregivers. Conclusion: There is no standard for examining HNC caregiver healthcare needs, while there is evidence of increased healthcare utilization. The literature is limited regarding medical burdens faced by caregivers. Future research is needed to assess the physical health and comorbidities of HNC caregivers and their engagement with the healthcare system to guide further implementation of support models to address the needs of this population.
Serum human epididymis secretory protein 4 correlates with sepsis-associated acute respiratory distress syndrome and 28-day mortality in critically ill patients
Authors: Luo Jinmei , Liang Jingjing , Wang Shaofang , Huang Shaoqiong , Zhou Laizhi , Shi Yunfeng , Zhang Jingcong , Wang Yanhong , Wu Ben-Quan , Li Laisheng 
Published: May 2022

Background Acute respiratory distress syndrome (ARDS) is a severe disease with high mortality, and its primary cause is sepsis. The aim of this study was to detect and evaluate the role of Human epididymis protein 4 (HE4) in sepsis-related ARDS. Methods One hundred and twenty-three critically ill sepsis patients with/without ARDS and 102 healthy controls were enrolled in this study. Blood samples were collected upon admission for quantitative testing of HE4 by chemiluminescent microparticle immunoassay (CMIA). ROC curve analysis and Spearman’s correlation analysis were conducted to determine the diagnostic and prognostic value of HE4. Results Compared with controls, the serum HE4 concentrations of sepsis patients were elevated, and levels in sepsis patients with ARDS were significantly higher (all p < 0.0001). Moreover, HE4 concentrations were strongly correlated with the clinical severity characteristics of sepsis patients, and ROC curve suggested that the AUC of HE4 applied to discriminate sepsis-ARDS patients from sepsis patients was 0.903. HE4 was also found to be a prognostic biomarker of clinical severity and 28-day mortality among critically ill sepsis patients. Logistic regression analysis showed that HE4 was an independent factor for diagnosis of ARDS. Meanwhile, ROC curve analysis showed that the cut-off value of serum HE4 to discriminate 28-day mortality from sepsis patients (AUC: 0.782) was 646.5 pmol/L. Conclusions The concentration of serum HE4 in patients with sepsis-related ARDS was markedly increased and was significantly correlated with mortality, which suggests that serum HE4 could be a promising diagnostic and prognostic biomarker for ARDS in sepsis patients.
Mental health service utilisation and reoffending in offenders with a diagnosis of psychosis receiving non-custodial sentences: A 14-year follow-up study
Authors: Adily Armita , Albalawi Olayan , Sara Grant , Kariminia Azar , Wand Handan , Allnutt Stephen , Schofield Peter , Greenberg David , Grant Luke , Butler Tony 
Published: May 2022

Objective: While psychosis is considered a risk factor for offending, little is reported about mental health service utilisation in offenders with psychosis and its relationship with reoffending. We examined the association between contact with mental health services and reoffending in those diagnosed with psychosis. Methods: We linked health and offending records in New South Wales (Australia) and identified all individuals with a diagnosis of psychosis and a subsequent offence resulting in a non-custodial sentence between 2001 and 2012. We examined the incidence and risk factors for reoffending, and time to reoffending between 2001 and 2015 using Cox regression and Kaplan–Meier survival methods. We specifically examined the association between clinical contact with community mental health services following the index offence and reoffending. Results: Of the 7393 offenders with psychosis, 70% had clinical contact and 49% reoffended. There was a linear relationship between an increased number of clinical contacts and reduced risk of reoffending: those with no clinical contact had more than a fivefold risk of reoffending compared to those with the highest number of contacts (adjusted hazard ratio = 5.78, 95% confidence interval = [5.04, 6.62]). Offenders with substance-related psychosis and those convicted of non-violent offences had fewer clinical contacts and higher rates of reoffending when compared with controls (adjusted hazard ratio = 1.29, 95% confidence interval = [1.13, 1.47] and adjusted hazard ratio = 1.26, 95% confidence interval = [1.18, 1.35], respectively). Conclusion: This study supports an association between more frequent mental health service use and reduced risk of reoffending. Efforts to enhance mental health service utilisation in those with psychosis who are at a higher risk of reoffending should be promoted.