Deciphering the True Immunologic Risk in Renal Transplantation in Patients With HIV.

Since 1995, rates of end-stage renal disease have risen dramatically in patients living with HIV infection. However, given the concern for higher rates of acute rejection in this patient population, the immunologic threat posed by HIV infection is a specter clinicians must continually confront. Living donor transplantation may negate this risk; this study aims to assess the benefit of living donor transplantation in this population and to ascertain the immunologic risk faced by patients who are HIV-infected. The 2021 UNOS database was queried, and all HIV-infected kidney transplant recipients since 1987 were identified. Recipients were stratified based on deceased (DDKT) vs living (LDKT) donor status. Overall survival, allograft survival, acute rejection, panel reactive antibody (PRA) percentage, and crossmatch positivity were compared between groups. One thousand two hundred twenty-six patients underwent DDKT, and 304 patients underwent LDKT. Living donor kidney transplantation demonstrated greater overall survival (P = .045) and graft survival (P < .001). However, no difference in acute rejection was noted between the cohorts, and no difference in overall or graft survival was evident based on PRA percentage. Crossmatch positive status did not negatively affect graft survival. Patients with HIV undergoing LDKT fared better than those undergoing DDKT. Nevertheless, patients at higher immunologic risk-elevated PRA% and crossmatch positivity-did not experience graft loss at a higher rate than patients at lower immunologic risk. These results were valid in both DDKT and LDKT cohorts. These findings suggest that infection with HIV does not overtly increase patients' immunologic risk, and concerns surrounding transplantation in this population may be overestimated.

Increased-risk versus standard-risk donation in lung transplantation: A United Network of Organ Sharing analysis.

OBJECTIVES: Donors with characteristics that increase risk of hepatitis B virus, hepatitis C virus, and HIV transmission are deemed increased-risk donors (IRDs) per Public Health Service guidelines. Compared with organs from standard-risk donors (SRDs), IRD organs are more frequently declined. We sought to investigate the outcomes of IRD lung transplant recipients following the 2013 guideline change. METHODS: We retrospectively identified lung transplant recipients using the United Network of Organ Sharing registry (February 2014 to March 2020). Patients were divided into 2 cohorts, based on Centers for Disease Control and Prevention risk status of the donor: SRD or IRD. Demographics and clinical parameters were compared across groups. Survival was compared using Kaplan-Meier curves and log-rank tests. Cox proportional hazard model was performed to identify variables associated with survival outcome. RESULTS: We identified 13,205 lung transplant recipients, 9963 who received allografts from SRDs and 3242 who received allografts from IRDs. In both groups, most donors were White, male, and <30 years old. IRDs demonstrated greater rates of heavy alcohol, cigarette, and cocaine use. SRDs had greater rates of cancer, hypertension, previous myocardial infarction, and diabetes. Survival analysis demonstrated no significant difference in 90-day, 1-year, 3-year, or 5-year survival outcome between SRD and IRD recipients (P = .34, P = .67, P = .40, P = .52, respectively). Cox regression demonstrated that double-lung transplants were associated with 13% decreased mortality risk compared with single-lung (P = .0009). CONCLUSIONS: IRD and SRD recipients demonstrated equivalent survival outcomes. Our study suggests that IRDs offer a safe approach to expand the donor pool and increase availability of lungs for transplantation.

Refined Balloon Pulmonary Angioplasty in Chronic Thromboembolic Pulmonary Hypertension: Initial Results of U.S. Regional Program.

Objectives: We sought to evaluate the efficacy and safety of refined balloon pulmonary angioplasty (BPA) in the treatment of patients with chronic thromboembolic pulmonary hypertension (CTEPH). Background: BPA is rapidly evolving therapeutic option for patients with nonsurgical CTEPH. There are few US studies that have reported on the outcomes of this novel therapeutic option. Methods: This is a retrospective study of CTEPH patients that underwent BPA at Temple University Hospital. The primary efficacy endpoint was the change in pulmonary vascular resistance (PVR) after BPA as compared to baseline and the primary safety endpoint was the rate of hemoptysis within 24 hours. Secondary endpoints included death, WHO functional class, and 6-minute walk distance (6MWD). We used logistic regression to evaluate factors associated with a hemodynamic and functional response. Results: A total of 211 BPA sessions were performed on 77 patients (average 2.7 ± 1.7 sessions/patient). After BPA the mean PVR improved by 26% (P<0.001) while the mean 6MWD improved by 71.7 meters (P <0.001) and WHO functional class improved by one functional class (P <0.001). Ten sessions (4.7%) were complicated by hemoptysis. The independent factors associated with a improved functional and hemodynamic response included the pre-procedural use of riociguat, reduce baseline PA compliance and > 3 BPA sessions per patient. Conclusion: This single center study from the US showed that BPA with refined techniques in patients with CTEPH was safe and was associated with significant improvements in pulmonary hemodynamics and functional capacity.

Incidence and predictors of acute limb ischemia in acute myocardial infarction complicated by cardiogenic shock.

OBJECTIVE: To describe the incidence and predictors of acute limb ischemia (ALI) in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS). METHODS: Patients with index hospitalizations for AMI complicated by cardiogenic shock from 2016 to 2019 in the US National Readmission Database were identified. We evaluated the incidence of ALI and its associated mortality, length of stay, and cost of hospitalization. We used multivariable logistic regression to determine independent predictors of ALI in this population. RESULTS: A total of 84,615 patients had AMI complicated by cardiogenic shock and 1302 (1.54%) developed ALI. The rates of ALI increased from 1.29% in 2016 to 1.66% in 2019 (P ≤ .002). The use of microaxial mechanical circulatory support increased from 2.25% in 2016 to 13.36% in 2019 (P = .0001). The major predictors of ALI included peripheral arterial disease (odds ratio [OR], 7.34; 95% confidence interval [CI], 6.12-8.81), venoarterial extracorporeal membrane oxygenation (OR, 4.40; 95% CI, 3.19-6.07), and microaxial mechanical circulatory support (OR, 3.12; 95% CI, 2.74-3.55). ALI in patients with cardiogenic shock was associated higher mortality (39.20% vs 33.53%; P ≤ .0001). CONCLUSIONS: This nationwide observational study shows that ALI is an important complication of AMI with cardiogenic shock. This complication is associated with higher mortality. In addition to peripheral artery disease, the use of mechanical circulatory devices was associated with significantly higher rates of ALI.

DNA polymerase θ protects leukemia cells from metabolically induced DNA damage.

Leukemia cells accumulate DNA damage, but altered DNA repair mechanisms protect them from apoptosis. We showed here that formaldehyde generated by serine/1-carbon cycle metabolism contributed to the accumulation of toxic DNA-protein crosslinks (DPCs) in leukemia cells, especially in driver clones harboring oncogenic tyrosine kinases (OTKs: FLT3(internal tandem duplication [ITD]), JAK2(V617F), BCR-ABL1). To counteract this effect, OTKs enhanced the expression of DNA polymerase theta (POLθ) via ERK1/2 serine/threonine kinase-dependent inhibition of c-CBL E3 ligase-mediated ubiquitination of POLθ and its proteasomal degradation. Overexpression of POLθ in OTK-positive cells resulted in the efficient repair of DPC-containing DNA double-strand breaks by POLθ-mediated end-joining. The transforming activities of OTKs and other leukemia-inducing oncogenes, especially of those causing the inhibition of BRCA1/2-mediated homologous recombination with and without concomitant inhibition of DNA-PK-dependent nonhomologous end-joining, was abrogated in Polq-/- murine bone marrow cells. Genetic and pharmacological targeting of POLθ polymerase and helicase activities revealed that both activities are promising targets in leukemia cells. Moreover, OTK inhibitors or DPC-inducing drug etoposide enhanced the antileukemia effect of POLθ inhibitor in vitro and in vivo. In conclusion, we demonstrated that POLθ plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde, and it can be targeted to achieve a therapeutic effect.

Lung Transplantation in Systemic Sclerosis: a Practice Survey of United States Lung Transplant Centers.

Lung transplantation in patients with systemic sclerosis (SSc) can be complicated by extrapulmonary manifestations of the disease, leading to concerns regarding posttransplant complications and outcomes. METHODS: We conducted a web-based survey of adult lung transplant programs in the United States regarding their practices in patients with SSc. RESULTS: Sixty percent (37/62) of the eligible centers responded to the survey, majority of the respondents were medical directors (81%). Most centers would consider transplanting patients with mild or moderate esophageal disease (92% or 75%, respectively) or gastroparesis (59%). A minority would consider patients with severe esophageal dysmotility (37%), digital ulcers (21%), or low body mass index (19%). Most centers conducted extensive pretransplant gastrointestinal evaluation and use a conservative feeding approach with prolonged nothing by mouth (83%) and postpyloric feeding (89%). Antireflux surgery is commonly considered (40%) with partial fundoplication being the procedure of choice (67%). Most respondents expected similar outcomes of acute or chronic rejection (81% and 51%, respectively), respiratory infections (76%), and 1-year survival (70%). CONCLUSIONS: Most US lung transplant centers do not universally exclude SSc from lung transplant listing, but most support extensive pretransplant gastrointestinal testing and a conservative approach to feeding in the early posttransplant period.

Relationship Between α1-Antitrypsin Deficiency and Ascending Aortic Distention.

OBJECTIVE: To investigate the relationship between α1-antitrypsin deficiency (AATD), a disorder resulting in protease activity imbalances, and the risk of ascending aortic aneurysm. METHODS: In this single-center study, from August 1, 2018, to February 25, 2019, demographic data were retrospectively collated for patients with AATD-associated emphysema (AATD group) or non-AATD-associated emphysema (control group) with available high-resolution computed tomography scans. Mean ascending aortic diameter was compared between the groups, and the correlation of diameter with age was analyzed. RESULTS: Patients with AATD (n=51; mean AAT level, 20.3 mg/dL [to convert to µmol/L, multiply by 0.184]) were approximately 10 years younger than those in the control group (n=93; mean AAT level, 172.0 mg/dL), with a mean age of 55 vs 65 years. Overall and grouped by sex, the mean ascending aortic diameter in patients with AATD was not different from that in the control group (overall, 3.34 vs 3.37 cm; P=.68); however, ascending aortic diameter was significantly associated with age for patients in the AATD group (r=0.43; P=.0016), whereas no correlation was observed between age and aortic diameter in the control group (r=0.16; P=.11). CONCLUSION: Results of this study suggest that there is a pathologic association between AATD and aortic distention and that AATD may increase the risk of ascending aortic aneurysm. These data provide a basis for the regular assessment of aortic diameter in patients with AATD as well as for the testing of patients with aortic distention or aneurysm for AATD.

Venoarterial Extracorporeal Membrane Oxygenation in Massive Pulmonary Embolism-Related Cardiac Arrest: A Systematic Review.

OBJECTIVE: Management of patients experiencing massive pulmonary embolism-related cardiac arrest is controversial. Venoarterial extracorporeal membranous oxygenation has emerged as a potential therapeutic option for these patients. We performed a systematic review assessing survival and predictors of mortality in patients with massive PE-related cardiac arrest with venoarterial extracorporeal membranous oxygenation use. DATA SOURCES: A literature search was started on February 16, 2020, and completed on March 16, 2020, using PubMed, Embase, Cochrane Central, Cinahl, and Web of Science. STUDY SELECTION: We included all available literature that reported survival to discharge in patients managed with venoarterial extracorporeal membranous oxygenation for massive PE-related cardiac arrest. DATA EXTRACTION: We extracted patient characteristics, treatment details, and outcomes. DATA SYNTHESIS: About 301 patients were included in our systemic review from 77 selected articles (total screened, n = 1,115). About 183 out of 301 patients (61%) survived to discharge. Patients (n = 51) who received systemic thrombolysis prior to cannulation had similar survival compared with patients who did not (67% vs 61%, respectively; p = 0.48). There was no significant difference in risk of death if PE was the primary reason for admission or not (odds ratio, 1.62; p = 0.35) and if extracorporeal membranous oxygenation cannulation occurred in the emergency department versus other hospital locations (odds ratio, 2.52; p = 0.16). About 53 of 60 patients (88%) were neurologically intact at discharge or follow-up. Multivariate analysis demonstrated three-fold increase in the risk of death for patients greater than 65 years old (adjusted odds ratio, 3.08; p = 0.03) and six-fold increase if cannulation occurred during cardiopulmonary resuscitation (adjusted odds ratio, 5.67; p = 0.03). CONCLUSIONS: Venoarterial extracorporeal membranous oxygenation has an emerging role in the management of massive PE-related cardiac arrest with 61% survival. Systemic thrombolysis preceding venoarterial extracorporeal membranous oxygenation did not confer a statistically significant increase in risk of death, yet age greater than 65 and cannulation during cardiopulmonary resuscitation were associated with a three- and six-fold risks of death, respectively.

Predictors of intracranial hemorrhage in patients treated with catheter-directed thrombolysis for deep vein thrombosis.

BACKGROUND: Although acute intracranial hemorrhage (ICH) is a rare complication of catheter-directed thrombolysis (CDT), it remains a major concern associated with the use of CDT. The incidence and clinical predictors of developing ICH in the setting of CDT are not known. METHODS: The National Inpatient Sample database was used to identify all patients with proximal lower extremity or caval deep vein thrombosis (DVT) from January 2005 to December 2013 in the United States. Multivariate logistic regression was performed to identify the clinical predictors of ICH between patients with DVT who had received anticoagulation therapy alone and those who had been treated with CDT plus anticoagulation therapy. RESULTS: Of 138,049 patients with proximal lower extremity or caval DVT, 7119 (5.2%) had received anticoagulation therapy and CDT. Of the patients treated with anticoagulation alone, ICH had occurred in 0.2% compared with 0.7% for those treated with CDT (P < .01). The independent predictors of ICH in the CDT cohort were a history of stroke (odds ratio [OR], 19.4; 95% confidence interval [CI], 8.8-42.8; P < .01), chronic kidney disease (OR, 2.2; 95% CI, 1.1-4.7; P = .03), age >74 years (OR, 2.2; 95% CI, 1.2-4.3; P = .02), male sex (OR, 1.8; 95% CI, 1.01-3.3; P = .048). Of those patients treated with anticoagulation alone, the risk factors for the development of ICH were a history of stroke, hospital teaching status, and age >74 years. CONCLUSIONS: The results from the present nationwide observational study showed that of patients with DVT treated with CDT, the independent predictors for developing ICH were a history of stroke, chronic kidney disease, male sex, and age >74 years.

Contemporary nationwide trends and in-hospital outcomes of adjunctive stenting in patients undergoing catheter-directed thrombolysis for proximal deep venous thrombosis.

OBJECTIVE: Outflow venous stenting as an adjunct to catheter-directed thrombolysis (CDT) is performed to prevent recurrent thrombosis and to reduce the risk of post-thrombotic syndrome. Historical data show that stenting improves outcomes of surgical thrombectomy in patients with iliofemoral deep venous thrombosis (DVT), and recent observational data suggest that stenting improves long-term outcomes of CDT. However, the impact of stenting during CDT on acute safety outcomes is unknown. We sought to investigate the contemporary trends, safety outcomes, and resource utilization of adjunctive stent placement in patients undergoing CDT. METHODS: Patients with proximal lower extremity and caval DVT were identified within the National Inpatient Sample from January 2005 to December 2013. From this data set, we stratified our patients into three groups: patients who received CDT alone, patients who received CDT plus angioplasty, and patients who received CDT plus angioplasty with stenting. We used an inverse probability treatment weighting algorithm to create three weighted cohorts. Cochran-Armitage test was used to evaluate the trends of stent placement among patients treated with CDT. The primary outcome was a composite end point of all-cause mortality, gastrointestinal bleed, or intracranial hemorrhage. RESULTS: A total of 138,049 patients were discharged with a principal diagnosis of proximal and caval DVT; 7097 of these patients received CDT (5.1%). From this group, 2854 (40.2%) were treated with CDT alone, 2311 (32.6%) received adjunctive angioplasty alone, and 1932 (27.2%) received adjunctive angioplasty and stent. Adjunctive stenting had a significantly lower rate of primary composite outcome compared with CDT alone (2.7% vs 3.8%; P = .04). Stent placement was associated with a similar length of stay compared with angioplasty and CDT alone groups (6.8 vs 6.9 vs 7.1 days, respectively; P = .94) and higher in-hospital charges ($115,164.01 ± $76,985.31 vs $98,089.82 ± $72,921.94 vs $80,441.63 ± $74,024.98; P < .001). CONCLUSIONS: This nationwide study suggests that one in four patients undergoing CDT is treated with adjunctive stent placement in the United States. This observational study showed that adjunctive stenting does not adversely affect the acute safety outcomes of CDT; however, it was associated with increased hospital charges.

GDF11 Decreases Pressure Overload-Induced Hypertrophy, but Can Cause Severe Cachexia and Premature Death.

RATIONALE: Possible beneficial effects of GDF11 (growth differentiation factor 11) on the normal, diseased, and aging heart have been reported, including reversing aging-induced hypertrophy. These effects have not been well validated. High levels of GDF11 have also been shown to cause cardiac and skeletal muscle wasting. These controversies could be resolved if dose-dependent effects of GDF11 were defined in normal and aged animals as well as in pressure overload-induced pathological hypertrophy. OBJECTIVE: To determine dose-dependent effects of GDF11 on normal hearts and those with pressure overload-induced cardiac hypertrophy. METHODS AND RESULTS: Twelve- to 13-week-old C57BL/6 mice underwent transverse aortic constriction (TAC) surgery. One-week post-TAC, these mice received rGDF11 (recombinant GDF11) at 1 of 3 doses: 0.5, 1.0, or 5.0 mg/kg for up to 14 days. Treatment with GDF11 increased plasma concentrations of GDF11 and p-SMAD2 in the heart. There were no significant differences in the peak pressure gradients across the aortic constriction between treatment groups at 1 week post-TAC. Two weeks of GDF11 treatment caused dose-dependent decreases in cardiac hypertrophy as measured by heart weight/tibia length ratio, myocyte cross-sectional area, and left ventricular mass. GDF11 improved cardiac pump function while preventing TAC-induced ventricular dilation and caused a dose-dependent decrease in interstitial fibrosis (in vivo), despite increasing markers of fibroblast activation and myofibroblast transdifferentiation (in vitro). Treatment with the highest dose (5.0 mg/kg) of GDF11 caused severe body weight loss, with significant decreases in both muscle and organ weights and death in both sham and TAC mice. CONCLUSIONS: Although GDF11 treatment can reduce pathological cardiac hypertrophy and associated fibrosis while improving cardiac pump function in pressure overload, high doses of GDF11 cause severe cachexia and death. Use of GDF11 as a therapy could have potentially devastating actions on the heart and other tissues.

Tyrosine kinase inhibitor-induced defects in DNA repair sensitize FLT3(ITD)-positive leukemia cells to PARP1 inhibitors.

Mutations in FMS-like tyrosine kinase 3 (FLT3), such as internal tandem duplications (ITDs), can be found in up to 23% of patients with acute myeloid leukemia (AML) and confer a poor prognosis. Current treatment options for FLT3(ITD)-positive AMLs include genotoxic therapy and FLT3 inhibitors (FLT3i's), which are rarely curative. PARP1 inhibitors (PARP1i's) have been successfully applied to induce synthetic lethality in tumors harboring BRCA1/2 mutations and displaying homologous recombination (HR) deficiency. We show here that inhibition of FLT3(ITD) activity by the FLT3i AC220 caused downregulation of DNA repair proteins BRCA1, BRCA2, PALB2, RAD51, and LIG4, resulting in inhibition of 2 major DNA double-strand break (DSB) repair pathways, HR, and nonhomologous end-joining. PARP1i, olaparib, and BMN673 caused accumulation of lethal DSBs and cell death in AC220-treated FLT3(ITD)-positive leukemia cells, thus mimicking synthetic lethality. Moreover, the combination of FLT3i and PARP1i eliminated FLT3(ITD)-positive quiescent and proliferating leukemia stem cells, as well as leukemic progenitors, from human and mouse leukemia samples. Notably, the combination of AC220 and BMN673 significantly delayed disease onset and effectively reduced leukemia-initiating cells in an FLT3(ITD)-positive primary AML xenograft mouse model. In conclusion, we postulate that FLT3i-induced deficiencies in DSB repair pathways sensitize FLT3(ITD)-positive AML cells to synthetic lethality triggered by PARP1i's. Therefore, FLT3(ITD) could be used as a precision medicine marker for identifying AML patients that may benefit from a therapeutic regimen combining FLT3 and PARP1i's.

Initial Right Ventricular Dysfunction Severity Identifies Severe Peripartum Cardiomyopathy Phenotype With Worse Early and Overall Outcomes: A 24-Year Cohort Study.

BACKGROUND: Outcomes in peripartum cardiomyopathy (PPCM) vary. We sought to determine whether severity of left or right ventricular dysfunction (RVD) at PPCM diagnosis differentially associates with adverse outcomes. METHODS AND RESULTS: We conducted a single-center retrospective cohort study of 53 patients with PPCM. The primary outcome was a composite of left ventricular assist device implantation, cardiac transplantation, or death. We used Kaplan-Meier curves to examine event-free survival and Cox proportional hazards models to examine associations of left ventricular (LV) ejection fraction <30%, LV end-diastolic diameter ≥60 mm, and moderate-to-severe RVD at PPCM diagnosis with the primary outcome. Median (interquartile range) follow-up time was 3.6 (1.4-7.3) years. Seventeen patients (32%) experienced the primary outcome, of whom 11 had moderate-to-severe RVD at time of PPCM diagnosis. Overall event-free survival differed by initial RVD severity and LV ejection fraction <30%, but not by LV end-diastolic diameter ≥60 mm. In univariable analyses, LV ejection fraction <30% and moderate-to-severe RVD were associated with the outcome (hazard ratios [95% confidence intervals] of 4.85 [1.11-21.3] and 4.26 [1.47-11.6], respectively). In a multivariable model with LV ejection fraction <30%, LV end-diastolic diameter ≥60 mm, and moderate-to-severe RVD, only moderate-to-severe RVD was independently associated with the outcome (hazard ratio [95% confidence interval], 3.21 [1.13-9.10]). Although most outcomes occurred within the first year, nearly a third occurred years after PPCM diagnosis. CONCLUSIONS: Initial moderate-to-severe RVD is associated with a more advanced cardiomyopathy phenotype and increased risk of adverse outcomes in PPCM, within and beyond the first year of diagnosis. By identifying a worse PPCM phenotype, initial moderate-to-severe RVD may prompt earlier consideration of advanced heart replacement therapies.

Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs) often carry JAK2(V617F), MPL(W515L), or CALR(del52) mutations. Current treatment options for MPNs include cytoreduction by hydroxyurea and JAK1/2 inhibition by ruxolitinib, both of which are not curative. We show here that cell lines expressing JAK2(V617F), MPL(W515L), or CALR(del52) accumulated reactive oxygen species-induced DNA double-strand breaks (DSBs) and were modestly sensitive to poly-ADP-ribose polymerase (PARP) inhibitors olaparib and BMN673. At the same time, primary MPN cell samples from individual patients displayed a high degree of variability in sensitivity to these drugs. Ruxolitinib inhibited 2 major DSB repair mechanisms, BRCA-mediated homologous recombination and DNA-dependent protein kinase-mediated nonhomologous end-joining, and, when combined with olaparib, caused abundant accumulation of toxic DSBs resulting in enhanced elimination of MPN primary cells, including the disease-initiating cells from the majority of patients. Moreover, the combination of BMN673, ruxolitinib, and hydroxyurea was highly effective in vivo against JAK2(V617F)+ murine MPN-like disease and also against JAK2(V617F)+, CALR(del52)+, and MPL(W515L)+ primary MPN xenografts. In conclusion, we postulate that ruxolitinib-induced deficiencies in DSB repair pathways sensitized MPN cells to synthetic lethality triggered by PARP inhibitors.

Optimizing Radiation Dose in Computed Tomography of Articular Fractures.

OBJECTIVES: To determine whether a substantially lowered radiation protocol would provide satisfactory information for the surgeon, using the distal tibia as a model. METHODS: Eleven adult cadaveric distal tibia specimens were used to create Orthopaedic Trauma Association (OTA/AO) 43C distal tibia fractures with varying displacements in 2 planes. Each specimen was scanned at 3 modified protocols, which were then subsequently read by both qualified attending orthopaedists and midlevel residents. Observer reliability was evaluated, as well as confidence levels of identifying fracture pattern and treatment protocols. RESULTS: On average, there was less than a millimeter of variability in the measured gap to true gap as a whole (mean = 0.74 mm, P < 0.0001). With regard to measurements in gap, pattern, and treatment plans, no significant difference was found between CT images acquired with standard (110 mAs) compared with medium (60 mAs; mean 0.0 mm, P = 1.0; k = 0.14, P = 0.56; k = 0.38, P = 0.13, respectively) and low protocols (45 mAs; mean 0.01 mm, P = 0.95; k = 0.24, P = 0.32; k = 0.31, P = 0.13, respectively). Furthermore, no significant difference was found in measuring step-off across standard, medium, and low radiation dose (0.21 mm, P = 0.46; 0.28 mm, P = 0.39; -0.16 mm, P = 0.48, respectively). CONCLUSION: The results of this study show no significant difference when evaluating current standard and low-dose CT scans using less than one-half the amount of exposure. This suggests that in complex extremity fractures, a new CT protocol may potentially be used. Our initial data show promise that we may retain satisfactory imaging to formulate a treatment plan while also reducing the collective radiation burden to the population.

MLL-AF9 leukemias are sensitive to PARP1 inhibitors combined with cytotoxic drugs.

PARP1 is required for the maintenance of MLL-AF9 leukemias.PARP1 inhibitors enhance the therapeutic effect of cytotoxic drugs against MLL-AF9 leukemias.

Comparative outcomes of catheter-directed thrombolysis plus anticoagulation versus anticoagulation alone in the treatment of inferior vena caval thrombosis.

BACKGROUND: The contemporary practice patterns and role of catheter-directed thrombolysis (CDT) in the treatment of inferior vena cava thrombosis is unknown. METHODS AND RESULTS: The Nationwide Inpatient Sample database was used to identify patients with a principal discharge diagnosis of inferior vena cava thrombosis (International Classification of Diseases-Ninth Revision-Clinical Modification, 453.2) from 2005 to 2011. We compared patients treated with CDT plus anticoagulation with patients treated with anticoagulation alone. We used propensity scores to construct 2 matched groups of 563 patients for comparative outcomes analysis. Among 2674 patients admitted with inferior vena cava thrombosis, 718 (26.9%) underwent CDT. The national CDT utilization rates increased from 16.0% in 2005 to 34.7% in 2011 (P<0.001). Based on the propensity-matched comparison, the inhospital mortality was not significantly different between the CDT and the anticoagulation groups (2.0% versus 1.4%; P=0.49). The rates of pulmonary embolism (12.1% versus 7.8%; P=0.02), intracranial hemorrhage (1.6% versus 0.2%; P=0.03), and acute renal failure (13.9% versus 9.4%; P=0.02) were significantly higher in the CDT group. The CDT group had longer length of stay and higher hospital charges compared with the anticoagulation group. CONCLUSIONS: There has been a steady increase in the use of CDT in the treatment of patients with inferior vena cava thrombosis in the United States. This observational study showed no significant difference in mortality between CDT versus anticoagulation alone; however, the bleeding events and resource utilization were higher in the CDT group. Adequately powered randomized controlled trials are needed in this area.