Predictors and Outcomes of Postcontrast Acute Kidney Injury after Endovascular Renal Artery Intervention

Purpose

To determine incidence, predictors, and clinical outcomes of postcontrast acute kidney injury (PC-AKI) following renal artery stent placement for atherosclerotic renal artery stenosis.

Enhanced recovery pathway in adult patients undergoing thoracolumbar deformity surgery

BACKGROUND CONTEXTEnhanced recovery (ERAS) pathways can help hospitals maximize the incentives of bundled payment models while maintaining high-quality patient care. A key component of an enhanced recovery pathway is the ability to predictably reduce inpatient length of stay, as this is a critical component of the cost equation.PURPOSETo determine the efficacy of an enhanced recovery pathway on reducing length of stay after thoracolumbar adult deformity surgery.STUDY DESIGNSingle surgeon retrospective review of prospectively-collected data.PATIENT SAMPLEForty adult deformity patients who underwent ≥5 levels of fusion to the pelvis (two to L5) with a single surgeon before and after implementation of an ERAS pathway.METHODSThe pathway involved participation by anesthesiology, hospital medicine, and physical therapy, and was designed to achieve goals previously associated with decreased LOS (eg, EBL<1200 mL, procedure time <4.5 hours, avoidance of ICU postoperatively, and mobilization POD0-1). Patients were propensity-score matched 1:1 to a historical cohort (enhanced recovery [ER] and historical [H] cohorts), based on demographics, medical comorbidities, radiographic alignment parameters, and surgical factors. Outcomes were compared to determine the effect of the enhanced recovery pathway. Primary outcomes included LOS and 90-day complications and readmissions.RESULTSAfter matching, gender, BMI, ASA class, preoperative opioid dependence, day of surgery, sagittal alignment parameters, rate of revision surgery, three-column osteotomies, and interbody fusions were comparable between the cohorts (p>.05). In the ER cohort, there was reduced EBL (920±640 vs. 1437±555, p=.004) and no ER patient went to the ICU immediately following surgery, compared with 30% of H patients (p=.022). The ER cohort also had a greater number of patients ambulating by POD1 compared to the H cohort (100% vs. 55%, p=.010). ER patients had a shorter LOS (4.5±1.3 vs. 7.3±4.4 days, p=.010). A 90-day readmission and complications were comparable between the cohorts (p>.05).CONCLUSIONSThe creation of an ERAS pathway for patients undergoing thoracolumbar adult deformity surgery reduced length of stay without negatively affecting short-term morbidity and complications. Given the specificity of this pathway to a single surgeon and hospital, the resources and staffing changes that were instrumental in creating the pathway may not be generalizable to other centers.     

Inhibition of the phosphatidylinositol 3’-kinase signaling pathway increases the responsiveness of pancreatic carcinoma cells to sulindac

Nonsteroidal anti-inflammatory drugs (NSAIDs) may be effective treatment for pancreatic cancer. We have previously demonstrated that NSAIDs suppress pancreatic cell growth in vitro by inhibiting cell cycle progression but have little effect on apoptosis. In fact, we have shown that NSAIDs, in some instances, increase Akt phosphorylation in human pancreatic carcinoma cells suggesting activation of the phosphatidy linositol 3’-kinase (PI3K)-Akt survival (antiapoptotic) pathway. We subsequently examined the effects of treating the human pancreatic cancer cell lines BxPC-3 and PaCa-2 with a specific inhibitor of the PI3K/Akt pathway, LY294002, in the presence or absence of the NSAID sulindac. The growth effects of sulindac (250 to 500 ώmol/L) and/or LY2 94002 (1 to 100 ώmol/L) were determined by a colorimetric proliferation assay and cell counts. The combination of low-dose LY294002 (10 ώmol/L) and sulindac enhanced the growth inhibitory effects of sulindac in BxPC-3 and PaCa-2 cells. Treatment of both cell lines with the LY294002/sulindac combination altered the cell cycle distribution as determined by flow cytometry and also lowered the apoptotic threshold as measured with an enzyme-linked immunosorbent asssay to detect DNA fragmentation. These effects were associated with changes in the expression and/or phosphorylation level of proteins and kinases that regulate cell cycle progression and apoptosis. Taken together, our results suggest that inhibition of the PI3K/Akt signaling pathway may sensitize pancreatic tumor cells to therapy with NSAIDs such as sulindac. Presented at the Forty-Third Annual Meeting of The Society for Surgery of the Alimentary Tract, San Francisco, California, May 19–22, 2002 (poster presentation). Supported by institutional research grant IRG-84-002-18 from the American Cancer Society.     

The Impact of Bariatric Surgery on Menstrual Patterns

Background: Obesity and anovulation are common medical problems in the United States. Anovulation in obese patients primarily manifests with irregular, sporadic or absent menstrual bleeding. Weight loss of at least 5% has been shown to reverse obesity-related anovulation. The aim of this study was to assess the impact of bariatric surgery on infertility in morbidly obese women and to identify factors associated with return of normal menses following bariatric surgery. Methods: A survey of patients was collected from the bariatric surgery data-base at the Hospital of the University of Pennsylvania. 410 women under the age of 40 were sent questionnaires. 195 patients completed the questionnaire, and 29 patients had incorrect addresses without a forwarding address, resulting in a 51.2% response rate. Patients who reported menstrual cycle lengths >35 days were considered abnormal. 92 of the 195 responders were considered anovulatory preoperatively, based on menstrual history. Results: There was no significant difference in postoperative BMI, BMI decrease or age at surgery between the survey responders and non-responders. There was a significant difference between these 2 groups in time since surgery (P=.01). Both groups had a decrease in BMI of >18 kg/m². The mean menstrual cycle length preoperatively among those categorized as ovulatory and anovulatory was 27.3 and 127.5 days, respectively. Of the 98 patients who were anovulatory preoperatively, 70 patients (71.4%) regained normal menstrual cycles after surgery. Those patients who regained ovulation had greater weight loss than those who remained anovulatory (61.4 kg vs 49.9 kg, P=0.02). Conclusions: Anovulation resulting in abnormal menses is a common problem in morbidly obese premenopausal women. The menstrual cycle disorders may completely resolve after bariatric surgery. Thus, infertility due to anovulation among morbidly obese women could potentially be viewed as an additional indication for bariatric surgery.     

Validation of a small molecule inhibitor of PDE6D-RAS interaction with favorable anti-leukemic effects

RAS mutations prevalent in high-risk leukemia have been linked to relapse and chemotherapy resistance. Efforts to directly target RAS proteins have been largely unsuccessful. However, since RAS-mediated transformation is dependent on signaling through the RAS-related C3 botulinum toxin substrate (RAC) small GTPase, we hypothesized that targeting RAC may be an effective therapeutic approach in RAS mutated tumors. Here we describe multiple small molecules capable of inhibiting RAC activation in acute lymphoblastic leukemia cell lines. One of these, DW0254, also demonstrates promising anti-leukemic activity in RAS-mutated cells. Using chemical proteomics and biophysical methods, we identified the hydrophobic pocket of phosphodiester 6 subunit delta (PDE6D), a known RAS chaperone, as a target for this compound. Inhibition of RAS localization to the plasma membrane upon DW0254 treatment is associated with RAC inhibition through a phosphatidylinositol-3-kinase/AKT-dependent mechanism. Our findings provide new insights into the importance of PDE6D-mediated transport for RAS-dependent RAC activation and leukemic cell survival.Subject terms: Acute lymphocytic leukaemia, Acute myeloid leukaemia, Drug development, Targeted therapies     

Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors

New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1–positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.     

Differential Peripheral Blood Glycoprotein Profiles in Symptomatic and Asymptomatic COVID-19

Glycosylation is the most common form of post-translational modification of proteins, critically affecting their structure and function. Using liquid chromatography and mass spectrometry for high-resolution site-specific quantification of glycopeptides coupled with high-throughput artificial intelligence-powered data processing, we analyzed differential protein glycoisoform distributions of 597 abundant serum glycopeptides and nonglycosylated peptides in 50 individuals who had been seriously ill with COVID-19 and in 22 individuals who had recovered after an asymptomatic course of COVID-19. As additional comparison reference phenotypes, we included 12 individuals with a history of infection with a common cold coronavirus, 16 patients with bacterial sepsis, and 15 healthy subjects without history of coronavirus exposure. We found statistically significant differences, at FDR < 0.05, for normalized abundances of 374 of the 597 peptides and glycopeptides interrogated between symptomatic and asymptomatic COVID-19 patients. Similar statistically significant differences were seen when comparing symptomatic COVID-19 patients to healthy controls (350 differentially abundant peptides and glycopeptides) and common cold coronavirus seropositive subjects (353 differentially abundant peptides and glycopeptides). Among healthy controls and sepsis patients, 326 peptides and glycopeptides were found to be differentially abundant, of which 277 overlapped with biomarkers that showed differential expression between symptomatic COVID-19 cases and healthy controls. Among symptomatic COVID-19 cases and sepsis patients, 101 glycopeptide and peptide biomarkers were found to be statistically significantly abundant. Using both supervised and unsupervised machine learning techniques, we found specific glycoprotein profiles to be strongly predictive of symptomatic COVID-19 infection. LASSO-regularized multivariable logistic regression and K-means clustering yielded accuracies of 100% in an independent test set and of 96% overall, respectively. Our findings are consistent with the interpretation that a majority of glycoprotein modifications observed which are shared among symptomatic COVID-19 and sepsis patients likely represent a generic consequence of a severe systemic immune and inflammatory state. However, there are glycoisoform changes that are specific and particular to severe COVID-19 infection. These may be representative of either COVID-19-specific consequences or susceptibility to or predisposition for a severe course of the disease. Our findings support the potential value of glycoproteomic biomarkers in the biomedical understanding and, potentially, the clinical management of serious acute infectious conditions.     

Optimism Reduces Suicidal Ideation and Weakens the Effect of Hopelessness Among Military Personnel

Suicide risk is an issue of increasing concern among military personnel. To date, most studies have focused on identifying risk factors for suicide in military personnel, but have by and large overlooked possible protective factors that reduce suicide risk, such as optimism. In a clinical sample of 97 treatment-seeking active duty Air Force personnel, the protective effects of optimism on suicidal ideation was investigated by considering the direct effect of optimism on suicidal ideation as well as the possible moderating effects of optimism on several suicide risk factors: depression, posttraumatic stress, and hopelessness. When adjusting for demographic and clinical covariates, results of multiple regression indicated that optimism was significantly associated with less severe depression, hopelessness, and suicidal ideation, but not posttraumatic stress symptoms. The interaction of optimism with hopelessness was also significant, and indicated that severe hopelessness contributed to more severe suicidal ideation only among participants with low levels of optimism. Results suggest that optimism is associated with less severe suicidal ideation, and buffer the effects of hopelessness among military patients.