The impact of post-operative enteral nutrition on duodenal injury outcomes: A post hoc analysis of an EAST multicenter trial.

BACKGROUND: Leak following surgical repair of traumatic duodenal injuries results in prolonged hospitalization and oftentimes nil per os(NPO) treatment. Parenteral nutrition(PN) has known morbidity; however, duodenal leak(DL) patients often have complex injuries and hospital courses resulting in barriers to enteral nutrition(EN). We hypothesized EN alone would be associated with 1)shorter duration until leak closure and 2)less infectious complications and shorter hospital length of stay(HLOS) compared to PN. METHODS: This was a post-hoc analysis of a retrospective, multicenter study from 35 Level-1 trauma centers, including patients >14 years-old who underwent surgery for duodenal injuries(1/2010-12/2020) and endured post-operative DL. The study compared nutrition strategies: EN vs PN vs EN + PN using Chi-Square and Kruskal-Wallis tests; if significance was found pairwise comparison or Dunn's test were performed. RESULTS: There were 113 patients with DL: 43 EN, 22 PN, and 48 EN + PN. Patients were young(median age 28 years-old) males(83.2%) with penetrating injuries(81.4%). There was no difference in injury severity or critical illness among the groups, however there were more pancreatic injuries among PN groups. EN patients had less days NPO compared to both PN groups(12 days[IQR23] vs 40[54] vs 33[32],p = <0.001). Time until leak closure was less in EN patients when comparing the three groups(7 days[IQR14.5] vs 15[20.5] vs 25.5[55.8],p = 0.008). EN patients had less intra-abdominal abscesses, bacteremia, and days with drains than the PN groups(all p < 0.05). HLOS was shorter among EN patients vs both PN groups(27 days[24] vs 44[62] vs 45[31],p = 0.001). When controlling for predictors of leak, regression analysis demonstrated EN was associated with shorter HLOS(ß -24.9, 95%CI -39.0 to -10.7,p < 0.001). CONCLUSION: EN was associated with a shorter duration until leak closure, less infectious complications, and shorter length of stay. Contrary to some conventional thought, PN was not associated with decreased time until leak closure. We therefore suggest EN should be the preferred choice of nutrition in patients with duodenal leaks whenever feasible. LEVEL OF EVIDENCE: IV.

Outcomes among trauma patients with duodenal leak following primary versus complex repair of duodenal injuries: An Eastern Association for the Surgery of Trauma multicenter trial.

BACKGROUND: Duodenal leak is a feared complication of repair, and innovative complex repairs with adjunctive measures (CRAM) were developed to decrease both leak occurrence and severity when leaks occur. Data on the association of CRAM and duodenal leak are sparse, and its impact on duodenal leak outcomes is nonexistent. We hypothesized that primary repair alone (PRA) would be associated with decreased duodenal leak rates; however, CRAM would be associated with improved recovery and outcomes when leaks do occur. METHODS: A retrospective, multicenter analysis from 35 Level 1 trauma centers included patients older than 14 years with operative, traumatic duodenal injuries (January 2010 to December 2020). The study sample compared duodenal operative repair strategy: PRA versus CRAM (any repair plus pyloric exclusion, gastrojejunostomy, triple tube drainage, duodenectomy). RESULTS: The sample (N = 861) was primarily young (33 years) men (84%) with penetrating injuries (77%); 523 underwent PRA and 338 underwent CRAM. Complex repairs with adjunctive measures were more critically injured than PRA and had higher leak rates (CRAM 21% vs. PRA 8%, p < 0.001). Adverse outcomes were more common after CRAM with more interventional radiology drains, prolonged nothing by mouth and length of stay, greater mortality, and more readmissions than PRA (all p < 0.05). Importantly, CRAM had no positive impact on leak recovery; there was no difference in number of operations, drain duration, nothing by mouth duration, need for interventional radiology drainage, hospital length of stay, or mortality between PRA leak versus CRAM leak patients (all p > 0.05). Furthermore, CRAM leaks had longer antibiotic duration, more gastrointestinal complications, and longer duration until leak resolution (all p < 0.05). Primary repair alone was associated with 60% lower odds of leak, whereas injury grades II to IV, damage control, and body mass index had higher odds of leak (all p < 0.05). There were no leaks among patients with grades IV and V injuries repaired by PRA. CONCLUSION: Complex repairs with adjunctive measures did not prevent duodenal leaks and, moreover, did not reduce adverse sequelae when leaks did occur. Our results suggest that CRAM is not a protective operative duodenal repair strategy, and PRA should be pursued for all injury grades when feasible. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Examining the Definition of Ventilator-Associated Pneumonia in the Trauma Setting: A Single-Center Analysis.

Background: Ventilator associated pneumonia (VAP) is defined by the American College of Surgeons Trauma Quality Improvement Program (ACS TQIP) using laboratory findings, pathophysiologic signs/symptoms, and imaging criteria. However, many critically ill trauma patients meet the non-specific laboratory and sign/symptom thresholds for VAP, so the TQIP designation of VAP depends heavily upon imaging evidence. We hypothesized that physician opinions widely vary regarding chest radiograph findings significant for VAP. Patients and Methods: The TQIP Spring 2021 Benchmark Report (BR) was used to identify 14 patients with VAP at an academic Level 1 Trauma Center. Critically ill trauma patients (n = 7) who spent at least four days intubated and met TQIP's laboratory and sign/symptom thresholds for VAP but did not appear as VAPs on the BR comprised the control group. For each deidentified patient, four successive chest radiographic images were compiled and arranged chronologically. Cases and controls were randomly arranged in digital format. Blinded physicians (n = 27) were asked to identify patients with VAP based solely on imaging evidence. Results: Radiographic evidence of VAP was highly subjective (Krippendorff α = 0.134). Among physicians of the same job description, inter-rater reliability remained low (α = 0.137 for trauma attending physicians; α = 0.141 for trauma fellows; α = 0.271 for radiologists). When majority judgment was compared to the TQIP BR, there was disagreement between the two tests (Cohen κ = -0.071; sensitivity, 64.3%; specificity, 28.6%). Conclusions: Current definitions of VAP rely on subjective imaging interpretation and ignore the reality that there are numerous explanations for opacities on CXR. The inconsistency of physicians' imaging interpretation and protean physiologic findings for VAP in trauma patients should preclude the current definition of VAP from being used as a quality improvement metric in TQIP.

FOXP1 and NDRG1 act differentially as downstream effectors of RAD9-mediated prostate cancer cell functions.

Metastatic progression is the key feature of prostate cancer primarily responsible for mortality caused by this disease. RAD9 is an oncogene for prostate cancer, and the encoded protein enhances metastasis-related phenotypes. RAD9 is a transcription factor with a limited set of regulated target genes, but the complete list of downstream genes critical for prostate carcinogenesis is unknown. We used microarray gene expression profiling and chromatin immunoprecipitation in parallel to identify genes transcriptionally controlled by RAD9 that contribute to this cancer. We found expression of 44 genes altered in human prostate cancer DU145 cells when RAD9 is knocked down by siRNA, and all of them bind RAD9 at their genomic location. FOXP1 and NDRG1 were down regulated when RAD9 expression was reduced, and we evaluated them further. We demonstrate that reduced RAD9, FOXP1 or NDGR1 expression decreases cell proliferation, rapid migration, anchorage-independent growth, anoikis resistance, and aerobic glycolysis. Ectopic expression of FOXP1 or NDRG1 partially restored aerobic glycolysis to prostate cancer cells with reduced RAD9 abundance, but only FOXP1 significantly complemented the other deficiencies. We thus show, for the first time, that RAD9 regulates FOXP1 and NDRG1 expression, and they function differently as downstream effectors for RAD9-mediated prostate cancer cell activities.

DNMT1 and DNMT3B regulate tumorigenicity of human prostate cancer cells by controlling RAD9 expression through targeted methylation.

Prostate cancer is the second most common type of cancer and the second leading cause of cancer death in American men. RAD9 stabilizes the genome, but prostate cancer cells and tumors often have high quantities of the protein. Reduction of RAD9 level within prostate cancer cells decreases tumorigenicity of nude mouse xenographs and metastasis phenotypes in culture, indicating that RAD9 overproduction is essential for the disease. In prostate cancer DU145 cells, CpG hypermethylation in a transcription suppressor site of RAD9 intron 2 causes high-level gene expression. Herein, we demonstrate that DNA methyltransferases DNMT1 and DNMT3B are highly abundant in prostate cancer cells DU145, CWR22, LNCaP and PC-3; yet, these DNMTs bind primarily to the transcription suppressor in DU145, the only cells where methylation is critical for RAD9 regulation. For DU145 cells, DNMT1 or DNMT3B shRNA reduced RAD9 level and tumorigenicity, and RAD9 ectopic expression restored this latter activity in the DNMT knockdown cells. High levels of RAD9, DNMT1, DNMT3B and RAD9 transcription suppressor hypermethylation were significantly correlated in prostate tumors, and not in normal prostate tissues. Based on these results, we propose a novel model where RAD9 is regulated epigenetically by DNMT1 and DNMT3B, via targeted hypermethylation, and that consequent RAD9 overproduction promotes prostate tumorigenesis.

Acute Kidney Injury Risk in Patients Treated with Vancomycin Combined with Meropenem or Cefepime.

Background: No previous studies have determined the incidence of acute kidney injury (AKI) in trauma patients treated with vancomycin + meropenem (VM) versus vancomycin + cefepime (VC). The purpose of this study was to fill this gap. Methods: A series of 99 patients admitted to an American College of Surgeons-verified level 1 trauma center over a two-year period who received VC or VM for >48 hours were reviewed retrospectively. Exclusion criteria were existing renal dysfunction or on renal replacement therapy. The primary outcome was AKI as defined by a rise in serum creatinine (SCr) to 1.5 times baseline. Multi-variable analysis was performed to control for factors associated with AKI (age, obesity, gender, length of stay [LOS], nephrotoxic agent(s), and baseline SCr), with significance defined as p < 0.05. Results: The study population was 50 ± 19 years old, 76% male, with a median LOS of 21 [range 15-39] days, and baseline SCr of 0.9 ± 0.2 mg/dL. Antibiotics, diabetes mellitus, and Injury Severity Score were independent predictors of AKI (odds ratio [OR] 4.4; 95% confidence interval [CI] 1.4-12; OR 9.3; 95% CI 1-27; OR 1.2; 95% CI 1.023-1.985, respectively). The incidence of AKI was higher with VM than VC (10/26 [38%] versus 14/73 [19.1%]; p = 0.049). Conclusions: The renal toxicity of vancomycin is potentiated by meropenem relative to cefepime in trauma patients. We recommend caution when initiating vancomycin combination therapy, particularly with meropenem.

Colonic perforation due to inadvertent intraperitoneal LVAD driveline placement.

BACKGROUND: Left ventricular assist devices (LVAD) are placed for patients with advanced heart failure or cardiogenic shock as destination therapy or as a bridge to cardiac transplantation. Significant complications associated with LVAD placement include bleeding, infection, pump thrombosis, right heart failure, device malfunction and stroke. The case below illustrates inadvertent intraperitoneal driveline placement causing colonic perforation and the subsequent management. CASE PRESENTATION: A 54 year old male with a history of Wolff-Parkinson-White syndrome resulting in multiple readmissions for heart failure, ultimately required placement of a left ventricular assist device (LVAD). Several weeks later, he was found to have stool draining from the driveline site. The patient was taken to the operating room for limited exploration by the Cardiothoracic Surgery team and a bowel injury was identified and repaired. Three days after this repair, stool was once again leaking from the driveline site, requiring re-exploration by the Acute Care Surgery team. Intraoperatively, the prior repair was found to be leaking and multiple intra-abdominal abscesses were discovered. The transverse colon was resected and left in discontinuity. On a planned second look operation, the LVAD driveline was relocated to be extra-peritoneal and a colostomy was formed. DISCUSSION AND CONCLUSION: This case demonstrates the importance of early recognition and involvement of an Acute Care Surgeon in the management of this complex problem. Appropriate treatment involves a complete exploration, source control, driveline relocation and possible fecal diversion. Although the incidence of this complication is low, it must be considered in the differential in a septic LVAD patient.

Targeting MEK5 impairs nonhomologous end-joining repair and sensitizes prostate cancer to DNA damaging agents.

Radiotherapy is commonly used to treat a variety of solid human tumors, including localized prostate cancer. However, treatment failure often ensues due to tumor intrinsic or acquired radioresistance. Here we find that the MEK5/ERK5 signaling pathway is associated with resistance to genotoxic stress in aggressive prostate cancer cells. MEK5 knockdown by RNA interference sensitizes prostate cancer cells to ionizing radiation (IR) and etoposide treatment, as assessed by clonogenic survival and short-term proliferation assays. Mechanistically, MEK5 downregulation impairs phosphorylation of the catalytic subunit of DNA-PK at serine 2056 in response to IR or etoposide treatment. Although MEK5 knockdown does not influence the initial appearance of radiation- and etoposide-induced γH2AX and 53BP1 foci, it markedly delays their resolution, indicating a DNA repair defect. A cell-based assay shows that nonhomologous end joining (NHEJ) is compromised in cells with ablated MEK5 protein expression. Finally, MEK5 silencing combined with focal irradiation causes strong inhibition of tumor growth in mouse xenografts, compared with MEK5 depletion or radiation alone. These findings reveal a convergence between MEK5 signaling and DNA repair by NHEJ in conferring resistance to genotoxic stress in advanced prostate cancer and suggest targeting MEK5 as an effective therapeutic intervention in the management of this disease.

Ballistic and Penetrating Injuries of the Chest.

Ballistic injuries are a major cause of morbidity and mortality in the United States. Unstable patients have high mortality, and only a small subset arrive at the hospital alive. Many patients undergo emergent surgery upon arrival, but a small subset undergo imaging with plain film, computed tomography, and echocardiography. We present a pictorial essay of ballistic and penetrating injuries and their complications with a focus on lung, cardiac, and vascular injury.

Pexy of intraperitoneal LVAD driveline to relieve small bowel obstruction.

BACKGROUND: Left ventricular assist device (LVAD) implantation is a lifesaving intervention in advanced heart failure. However, LVAD is not without complication. In this case, an inadvertent intraperitoneal driveline caused small bowel obstruction, subsequently requiring pexy of the driveline to the abdominal wall to avoid future complications. CASE PRESENTATION: A 37-year-old male with worsening, nonischemic, dilated cardiomyopathy underwent LVAD implantation. Postoperative day (POD) 15 he developed small bowel obstruction, and abdominal exploration showed transition point at an inadvertently placed intraperitoneal LVAD driveline. The patient was LVAD-dependent precluding removal, so the driveline was secured to the anterior abdominal wall. He subsequently improved and was discharged. CONCLUSIONS: While LVAD is increasingly common for heart failure patients, the tunneled driveline may inadvertently enter the peritoneal cavity where it can cause significant morbidity. In this case, we propose securing the driveline to the abdominal wall to prevent complications when LVAD removal is not an option.

A survey of the practice and attitudes of surgeons regarding the treatment of appendicitis.

BACKGROUND: We surveyed surgeons to document their attitudes, practice, and risk tolerance regarding the treatment of appendicitis. METHODS: A web-based survey was sent to the EAST membership. The primary composite endpoint was defined as 1-year incidence of perioperative complications, antibiotic failure, infections, ED visits, and readmissions. RESULTS: A total of 563 of 1645 surveys were completed (34% response). Mean age was 47 ±â€¯10 years and 98% were from the United States. Most (72%) were employed at academic teaching hospitals and 66% practiced in an urban setting. There were significant differences in treatment recommendations for different presentations of appendicitis. Regarding the primary composite endpoint, surgeons would tolerate a median 17% [10%-25%] excess morbidity in order to avoid an operation (i.e. non-inferiority) and would require a median 24% [10%-50% lower morbidity for the surgical approach in order to declare it a superior treatment (i.e. superiority). CONCLUSIONS: To be considered non-inferior, antibiotic therapy of appendicitis cannot have >17% excess morbidity and appendectomy must have at least 24% lower morbidity to be considered superior.

RAD9A promotes metastatic phenotypes through transcriptional regulation of anterior gradient 2 (AGR2).

RAD9A plays an important role in prostate tumorigenesis and metastasis-related phenotypes. The protein classically functions as part of the RAD9A-HUS1-RAD1 complex but can also act independently. RAD9A can selectively transactivate multiple genes, including CDKN1A and NEIL1 by binding p53-consensus sequences in or near promoters. RAD9A is overexpressed in human prostate cancer specimens and cell lines; its expression correlates with tumor progression. Silencing RAD9A in prostate cancer cells impairs their ability to form tumors in vivo and migrate as well as grow anchorage independently in vitro. We demonstrate herein that RAD9A transcriptionally controls AGR2, a gene aberrantly overexpressed in patients with metastatic prostate cancer. Transient or stable knockdown of RAD9A in PC-3 cells caused downregulation of AGR2 protein abundance. Reduced AGR2 protein levels were due to lower abundance of AGR2 mRNA. The AGR2 genomic region upstream of the coding initiation site contains several p53 consensus sequences. RAD9A bound specifically to the 5'-untranslated region of AGR2 in PC-3 cells at a partial p53 consensus sequence at position +3136 downstream from the transcription start site, determined by chromatin immunoprecipitation, followed by PCR amplification. Binding of RAD9A to the p53 consensus sequence was sufficient to drive AGR2 gene transcription, shown by a luciferase reporter assay. In contrast, when the RAD9A-binding sequence on the AGR2 was mutated, no luciferase activity was detected. Knockdown of RAD9A in PC-3 cells impaired cell migration and anchorage-independent growth. However, ectopically expressed AGR2 in RAD9A-depleted PC-3 cells restored these phenotypes. Our results suggest RAD9A drives metastasis by controlling AGR2 abundance.

Prostate cancer: unmet clinical needs and RAD9 as a candidate biomarker for patient management.

Prostate cancer is a complex disease, with multiple subtypes and clinical presentations. Much progress has been made in recent years to understand the underlying genetic basis that drives prostate cancer. Such mechanistic information is useful for development of novel therapeutic targets, to identify biomarkers for early detection or to distinguish between aggressive and indolent disease, and to predict treatment outcome. Multiple tests have become available in recent years to address these clinical needs for prostate cancer. We describe several of these assays, summarizing test details, performance characteristics, and acknowledging their limitations. There is a pressing unmet need for novel biomarkers that can demonstrate improvement in these areas. We introduce one such candidate biomarker, RAD9, describe its functions in the DNA damage response, and detail why it can potentially fill this void. RAD9 has multiple roles in prostate carcinogenesis, making it potentially useful as a clinical tool for men with prostate cancer. RAD9 was originally identified as a radioresistance gene, and subsequent investigations revealed several key functions in the response of cells to DNA damage, including involvement in cell cycle checkpoint control, at least five DNA repair pathways, and apoptosis. Further studies indicated aberrant overexpression in approximately 45% of prostate tumors, with a strong correlation between RAD9 abundance and cancer stage. A causal relationship between RAD9 and prostate cancer was first demonstrated using a mouse model, where tumorigenicity of human prostate cancer cells after subcutaneous injection into nude mice was diminished when RNA interference was used to reduce the normally high levels of the protein. In addition to activity needed for the initial development of tumors, cell culture studies indicated roles for RAD9 in promoting prostate cancer progression by controlling cell migration and invasion through regulation of ITGB1 protein levels, and anoikis resistance by modulating AKT activation. Furthermore, RAD9 enhances the resistance of human prostate cancer cells to radiation in part by regulating ITGB1 protein abundance. RAD9 binds androgen receptor and inhibits androgen-induced androgen receptor's activity as a transcription factor. Moreover, RAD9 also acts as a gene-specific transcription factor, through binding p53 consensus sequences at target gene promoters, and this likely contributes to its oncogenic activity. Given these diverse and extensive activities, RAD9 plays important roles in the initiation and progression of prostate cancer and can potentially serve as a valuable biomarker useful in the management of patients with this disease.

Bowel obstruction due to retained intraperitoneal left ventricular assist device (LVAD) driveline.

BACKGROUND: Left ventricular assist devices (LVAD) provide a lifesaving bridge to cardiac transplant. Utilization of these devices is increasing in the United States. When a patient undergoes cardiac transplant, the left ventricular device is surgically removed and the driveline is extracted or left tunneled in the subcutaneous tissue. Our group encountered a rare and previously unreported complication of this device: intraperitoneal infiltration of a retained driveline after cardiac transplant causing a small bowel obstruction. CASE PRESENTATION: A 62 year old male with a past medical history of non-ischemic cardiomyopathy induced heart failure, status post bridging left ventricular assist device and orthotopic heart transplant presented with abdominal distention, tenderness, and leukocytosis six days post-transplant. CT abdomen and pelvis revealed dilated loops of bowel, air-fluid levels and a transition point in the proximal small bowel. The patient was diagnosed with small bowel obstruction and taken for exploratory laparotomy. He was found to have a retained intraabdominal LVAD driveline strangulating a loop of small bowel in the left upper quadrant. The driveline was removed and the section of bowel released with return of perfusion. CONCLUSIONS: We had encountered a rare complication of retained left ventricular assist device driveline after cardiac transplant: inadvertent penetration into the peritoneal cavity resulting in strangulation of small bowel. This complication, though uncommon, provides substantial risk to patients previously treated with left ventricular assist devices. Meticulous care must be taken to ensure proper device insertion and extraction, as well as consideration of this etiology when patients present with bowel obstruction after cardiac transplant.

Same-Hospital Re-Admission Rate Is Not Reliable for Measuring Post-Operative Infection-Related Re-Admission.

BACKGROUND: Post-operative infections cause morbidity, consume resources, and are an important quality measure in assessing and comparing hospitals. Commonly used metrics do not account for re-admission to a different hospital. The Nationwide Readmissions Database (NRD) tracks re-admissions across United States (US) hospitals. Infection-related re-admission across US hospitals has not been studied previously. PATIENTS AND METHODS: The 2013 NRD was queried for admissions with a primary International Classification of Diseases and Related Health Problems, 9th revision, Clinical Modification code for the most frequently performed operations. Non-elective all-cause, infection-related, and different hospital 30-day re-admission rates were calculated, using All Patient Refined Diagnosis Related Groups codes. Multi-variable logistic regression identified risk factors for re-admission. RESULTS: Of 826,836 surviving to discharge, 39,281 (4.8%) had an unplanned re-admission within 30 days, occurring at a different hospital 20.5% of the time. The most common reason for re-admission was infection (25.1%). Orthopedic and spinal procedures were at highest risk for all-cause and infection-related different hospital re-admission. Infection-related different hospital re-admission risk factors included: Length of stay >30 days (odds ratio [OR] 2.28 [1.62-3.21], p < 0.01), age ≥65 years (OR 1.56 [1.38-1.76], p < 0.01), and Charlson Comorbidity Index >1 (OR 1.14 [1.01-1.28], p < 0.01) and differed from predictors of same-hospital infectious re-admission. Non-elective surgical procedure (OR 0.79 [0.72-0.87], p < 0.01) and initial hospitalization at a large hospital (OR 0.66 [0.59-0.74], p < 0.01) were protective. CONCLUSION: A substantial proportion of post-operative re-admissions are missed by same-hospital re-admission data. All-cause and infection-related post-operative re-admissions to a different hospital are affected by unique patient and institution-specific factors. Re-admission reduction programs, quality metrics, and policy based on same hospital re-admission data should be updated to incorporate different hospital re-admission.

Evaluation of a Device Combining an Inferior Vena Cava Filter and a Central Venous Catheter for Preventing Pulmonary Embolism Among Critically Ill Trauma Patients.

PURPOSE: To evaluate efficacy and safety of a novel device that combines an inferior vena cava (IVC) filter and central venous catheter (CVC) for prevention of pulmonary embolism (PE) in critically ill patients. MATERIALS AND METHODS: In a multicenter, prospective, single-arm clinical trial, the device was inserted at the bedside without fluoroscopy and subsequently retrieved before transfer from the intensive care unit (ICU). The primary efficacy endpoint was freedom from clinically significant PE or fatal PE 72 hours after device removal or discharge, whichever occurred first. Secondary endpoints were incidence of acute proximal deep venous thrombosis (DVT), catheter-related thrombosis, catheter-related bloodstream infections, major bleeding events, and clinically significant thrombus (occupying > 25% of volume of filter) detected by cavography before retrieval. RESULTS: The device was placed in 163 critically ill patients with contraindications to anticoagulation; 151 (93%) were critically ill trauma patients, 129 (85%) had head or spine trauma, and 102 (79%) had intracranial bleeding. The primary efficacy endpoint was achieved for all 163 (100%) patients (95% confidence interval [CI], 97.8%-100%, P < .01). Diagnosis of new or worsening acute proximal DVT was time dependent with 11 (7%) occurring during the first 7 days. There were no (0%) catheter-related bloodstream infections. There were 5 (3.1%) major bleeding events. Significant thrombus in the IVC filter occurred in 14 (8.6%) patients. Prophylactic anticoagulation was not initiated for a mean of 5.5 days ± 4.3 after ICU admission. CONCLUSIONS: This novel device prevented clinically significant and fatal PE among critically ill trauma patients with low risk of complications.

p53 and RAD9, the DNA Damage Response, and Regulation of Transcription Networks.

The way cells respond to DNA damage is important since inefficient repair or misrepair of lesions can have deleterious consequences, including mutation, genomic instability, neurodegenerative disorders, premature aging, cancer or death. Whether damage occurs spontaneously as a byproduct of normal metabolic processes, or after exposure to exogenous agents, cells muster a coordinated, complex DNA damage response (DDR) to mitigate potential harmful effects. A variety of activities are involved to promote cell survival, and include DNA repair, DNA damage tolerance, as well as transient cell cycle arrest to provide time for repair before entry into critical cell cycle phases, an event that could be lethal if traversal occurs while damage is present. When such damage is prolonged or not repairable, senescence, apoptosis or autophagy is induced. One major level of DDR regulation occurs via the orchestrated transcriptional control of select sets of genes encoding proteins that mediate the response. p53 is a transcription factor that transactivates specific DDR downstream genes through binding DNA consensus sequences usually in or near target gene promoter regions. The profile of p53-regulated genes activated at any given time varies, and is dependent upon type of DNA damage or stress experienced, exact composition of the consensus DNA binding sequence, presence of other DNA binding proteins, as well as cell context. RAD9 is another protein critical for the response of cells to DNA damage, and can also selectively regulate gene transcription. The limited studies addressing the role of RAD9 in transcription regulation indicate that the protein transactivates at least one of its target genes, p21/waf1/cip1, by binding to DNA sequences demonstrated to be a p53 response element. NEIL1 is also regulated by RAD9 through a similar DNA sequence, though not yet directly verified as a bonafide p53 response element. These findings suggest a novel pathway whereby p53 and RAD9 control the DDR through a shared mechanism involving an overlapping network of downstream target genes. Details and unresolved questions about how these proteins coordinate or compete to execute the DDR through transcriptional reprogramming, as well as biological implications, are discussed.