De novo and salvage purine synthesis pathways across tissues and tumors.

Purine nucleotides are vital for RNA and DNA synthesis, signaling, metabolism, and energy homeostasis. To synthesize purines, cells use two principal routes: the de novo and salvage pathways. Traditionally, it is believed that proliferating cells predominantly rely on de novo synthesis, whereas differentiated tissues favor the salvage pathway. Unexpectedly, we find that adenine and inosine are the most effective circulating precursors for supplying purine nucleotides to tissues and tumors, while hypoxanthine is rapidly catabolized and poorly salvaged in vivo. Quantitative metabolic analysis demonstrates comparative contribution from de novo synthesis and salvage pathways in maintaining purine nucleotide pools in tumors. Notably, feeding mice nucleotides accelerates tumor growth, while inhibiting purine salvage slows down tumor progression, revealing a crucial role of the salvage pathway in tumor metabolism. These findings provide fundamental insights into how normal tissues and tumors maintain purine nucleotides and highlight the significance of purine salvage in cancer.

Involvement of the inhibition of mitochondrial apoptotic, p53, NF-κB pathways and the activation of Nrf2/HO-1 pathway in the protective effects of curcumin against copper sulfate-induced nephrotoxicity in mice.

Chronic copper exposure could cause potential nephrotoxicity and effective therapy strategies are limited. This study investigated the protective effects of curcumin on copper sulfate (CuSO4)-induced renal damage in a mouse model and the underlying molecular mechanisms. Mice were administrated orally with CuSO4 (100 mg/kg per day) in combination with or without curcumin (50, 100 or 200 mg/kg per day, orally) for 28 days. Results showed that curcumin supplementation significantly reduce the Cu accumulation in the kidney tissues of mice and improved CuSO4-induced renal dysfunction. Furthermore, curcumin supplantation also significantly ameliorated Cu exposure-induced oxidative stress and tubular necrosis in the kidneys of mice. Moreover, compared to the CuSO4 alone group, curcumin supplementation at 200 mg/kg per day significantly decreased CuSO4-induced the expression of p53, Bax, IL-1ß, IL-6, and TNF-α proteins, levels of NF-κB mRNA, levels of caspases-9 and - 3 activities, and cell apoptosis, and significantly increased the levels of Nrf2 and HO-1 mRNAs in the kidney tissues. In conclusion, for the first time, our results reveal that curcumin could trigger the inhibition of oxidative stress, mitochondrial apoptotic, p53, and NF-κB pathways and the activation of Nrf2/HO-1 pathway to ameliorate Cu overload-induced nephrotoxicity in a mouse model. Our study highlights that curcumin supplementation may be a promising treatment strategy for treating copper overload-caused nephrotoxicity.

Purine nucleotide depletion prompts cell migration by stimulating the serine synthesis pathway.

Purine nucleotides are necessary for various biological processes related to cell proliferation. Despite their importance in DNA and RNA synthesis, cellular signaling, and energy-dependent reactions, the impact of changes in cellular purine levels on cell physiology remains poorly understood. Here, we find that purine depletion stimulates cell migration, despite effective reduction in cell proliferation. Blocking purine synthesis triggers a shunt of glycolytic carbon into the serine synthesis pathway, which is required for the induction of cell migration upon purine depletion. The stimulation of cell migration upon a reduction in intracellular purines required one-carbon metabolism downstream of de novo serine synthesis. Decreased purine abundance and the subsequent increase in serine synthesis triggers an epithelial-mesenchymal transition (EMT) and, in cancer models, promotes metastatic colonization. Thus, reducing the available pool of intracellular purines re-routes metabolic flux from glycolysis into de novo serine synthesis, a metabolic change that stimulates a program of cell migration.

Efficacy evaluation of Chinese herbal medicine, VGH-BPH1, for patients with benign prostatic hyperplasia: A randomized, double-blind, placebo-controlled, and crossover study.

BACKGROUND: Benign prostatic hyperplasia (BPH) can affect quality of life and cause various complications. Previous studies have suggested that Chinese herbal medicine can alleviate symptoms in patients with BPH. This study aimed to investigate whether the Chinese herbal medicine prescription VGH-BPH1 can alleviate BPH symptoms when used as an add-on treatment. METHODS: In this crossover, randomized, double-blind, placebo-controlled trial, patients with BPH were randomly segregated into two groups: group A received VGH-BPH1, and group B received a placebo for 8 weeks. Subsequently, after a 2-week wash-out period, the two groups were switched to the opposite treatment for another 8 weeks. The International Prostate Symptoms Score and Aging Male Symptoms Score were adopted as the primary outcomes to assess improvement in BPH and patient quality of life. The secondary outcomes were the International Index of Erectile Function, Constitution Chinese Medicine Questionnaire, uroflowmetry results, and postvoid residual urine volume. RESULTS: VGH-BPH1 treatment significantly decreased the International Prostate Symptoms Score total score (p = 0.027); however, no significant difference was observed between the treatment and placebo groups. The Aging Male Symptoms Score "joint pain and muscular ache" score in the VGH-BPH1 group was significantly lower than that of the placebo group (p = 0.022). The "physical exhaustion" score also exhibited a decreasing trend when both groups were compared (p = 0.057). CONCLUSION: Although VGH-BPH1 treatment did not outperform the placebo in terms of improving BPH symptoms, it resulted in improvement in several quality of life indicators when relative to the placebo. Future research using a larger sample size with appropriate amendments to the protocol should be conducted to further investigate the effects of VGH-BPH1.

Preoperative left ventricular end-systolic dimension predicts occurrence of aortic insufficiency following aortic valve preservation and repair surgery.

BACKGROUND: Preoperative left ventricular (LV) end-systolic dimension (LVESD) ≥5.0 cm is a class IIa indication for surgical intervention for aortic insufficiency (AI); however, the effect of LV dilatation on the longevity of the aortic valve (AV) has not yet been investigated. This study aimed to assess the impact of preoperative LV dimension on the long-term outcome of AV preservation surgery. METHODS: Between 2009 and 2019, 256 patients underwent AV preservation surgery at a single center. The median duration of follow-up was 5 years. The primary outcome was the development of >1+ AI at 6 years; secondary outcomes include long-term mortality, freedom from >2+ AI, and freedom from AV reoperation. Cox proportional hazard analysis was performed to identify predictors of AV deterioration. RESULTS: In-hospital mortality was 0.8%, and mean survival at 8 years was 85.5 ± 3.4%. Mean freedom from >1+ AI at 6 years was 71.1 ± 3.4%. Patients with preoperative indexed LVESD (LVESDi) ≥2.0 cm/m2 were at greater risk of developing >1+ AI at 6 years compared with patients with preoperative LVESDi of 1.5 to 1.9 cm/m2 and ≤1.4 cm/m2 (50.3 ± 0.1% vs 80.9 ± 0.1% vs 92.2 ± 0.1%, respectively; P < .01). On risk-adjusted multivariable analysis, preoperative LVESDi was an independent predictor for recurrence of >1+ AI (hazard ratio, 2.2; 95% confidence interval, 1.5-3.4). CONCLUSIONS: Preoperative LVESDi ≥2 cm/m2 is associated with increased risk of recurrent >1+ AI following AV preservation surgery. Further investigation of the appropriate operative threshold for AI may be warranted.

A Systematic Review and Meta-analysis Examining the Impact of Age on Perioperative Inflammatory Biomarkers.

BACKGROUND: Dysregulation of immune responses to surgical stress in older patients and those with frailty may manifest as differences in inflammatory biomarkers. We conducted a systematic review and meta-analysis to examine differences in perioperative inflammatory biomarkers between older and younger patients, and between patients with and without frailty. METHODS: MEDLINE, Embase, Cochrane, and CINAHL databases were searched (Inception to June 23, 2020). Observational or experimental studies reporting the perioperative level or activity of biomarkers in surgical patients stratified by age or frailty status were included. The primary outcome was inflammatory biomarkers (grouped by window of ascertainment: pre-op; post-op: <12 hours, 12-24 hours, 1-3 days, 3 days to 1 week, and >1 week). Quality assessment was conducted using the Newcastle-Ottawa Scale. Inverse-variance, random-effects meta-analysis was conducted. RESULTS: Forty-five studies (4263 patients) were included in the review, of which 36 were pooled for meta-analysis (28 noncardiac and 8 cardiac studies). Two studies investigated frailty as the exposure, while the remaining investigated age. In noncardiac studies, older patients had higher preoperative levels of interleukin (IL)-6 and C-reactive protein (CRP), lower preoperative levels of lymphocytes, and higher postoperative levels of IL-6 (<12 hours) and CRP (12-24 hours) than younger patients. In cardiac studies, older patients had higher preoperative levels of IL-6 and CRP and higher postoperative levels of IL-6 (<12 hours and >1 week). CONCLUSIONS: Our findings demonstrate a paucity of frailty-specific studies; however, the presence of age-associated differences in the perioperative inflammatory response is consistent with age-associated states of chronic systemic inflammation and immunosenescence. Additional studies assessing frailty-specific changes in the systemic biologic response to surgery may inform the development of targeted interventions.

Prophylaxis for patients at Risk to Eliminate Post-operative Atrial Fibrillation (PREP-AF trial): a protocol for a feasibility randomized controlled study.

BACKGROUND: Postoperative atrial fibrillation (POAF) is a frequent adverse event after thoracic surgery with associated morbidity, mortality, and healthcare costs. It has been shown to be preventable with prophylactic amiodarone, which is only recommended in high-risk individuals due to the potential associated side effects. Risk factors for POAF have been identified and incorporated into a prediction model to identify high-risk patients. Further evaluation in the form of a multicenter clinical trial is required to assess the effectiveness of prophylaxis specifically in this high-risk population. The feasibility of such a trial first needs to be assessed. METHODS: The PREP-AF trial is a double-blind randomized controlled feasibility trial. Individuals undergoing major thoracic surgery who are identified to be high-risk by the POAF prediction model will be randomized 1:1 to receive a short course of amiodarone vs. placebo in the immediate postoperative period. The primary outcome is feasibility, which will be measured by the number of eligible patients identified, consented, and randomized; intervention adherence; and measurement of future outcomes of a full trial. DISCUSSION: This study will determine the feasibility of a randomized controlled trial to assess the effectiveness of prophylactic amiodarone, in high-risk patients undergoing major thoracic surgery. This will inform the development of a multi-center trial to establish if prophylactic amiodarone is safe and effective at reducing the incidence of POAF. Preventing this adverse event will not only improve outcomes for patients but also reduce the associated health resource utilization and costs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04392921 . Registered on 19 May 2020.

Mitochondrial NADP+ is essential for proline biosynthesis during cell growth.

Nicotinamide adenine dinucleotide phosphate (NADP+) is vital to produce NADPH, a principal supplier of reducing power for biosynthesis of macromolecules and protection against oxidative stress. NADPH exists in separate pools, in both the cytosol and mitochondria; however, the cellular functions of mitochondrial NADPH are incompletely described. Here, we find that decreasing mitochondrial NADP(H) levels through depletion of NAD kinase 2 (NADK2), an enzyme responsible for production of mitochondrial NADP+, renders cells uniquely proline auxotrophic. Cells with NADK2 deletion fail to synthesize proline, due to mitochondrial NADPH deficiency. We uncover the requirement of mitochondrial NADPH and NADK2 activity for the generation of the pyrroline-5-carboxylate metabolite intermediate as the bottleneck step in the proline biosynthesis pathway. Notably, after NADK2 deletion, proline is required to support nucleotide and protein synthesis, making proline essential for the growth and proliferation of NADK2-deficient cells. Thus, we highlight proline auxotrophy in mammalian cells and discover that mitochondrial NADPH is essential to enable proline biosynthesis.

Moderate to Severe Acute Kidney Injury Leads to Worse Outcomes in Complex Thoracic Aortic Surgery.

BACKGROUND: The impact of acute kidney injury (AKI) in thoracic aortic surgery is not well defined. This study aimed to examine the impact of varying severity of AKI on in-hospital and long-term outcome in these patients. METHODS: From 2004 to 2018, 1142 patients underwent thoracic aortic surgery at a single institution (University of Ottawa Heart Institute, Ottawa, Canada) and were stratified into 4 groups on the basis of the severity of postoperative AKI: no AKI (n = 705), Acute Kidney Injury Network (AKIN) stage 1 (n = 261), AKIN stage 2 (n = 72), and AKIN stage 3 (n = 104). Outcomes include in-hospital mortality, morbidity, and long-term survival. Multivariable logistic regression was used to identify independent predictors of AKI. Propensity score matching was performed to identify pairs of patients without postoperative AKI or with AKIN stage 1 AKI, as well as pairs of patients without postoperative AKI and those with AKIN stage 2 or higher AKI. Kaplan-Meier curves were plotted for late survival. RESULTS: In the propensity-matched cohort, patients with postoperative AKIN stage I AKI had worse in-hospital mortality but comparable long-term survival when compared with patients without postoperative AKI. Patients with AKIN stage 2 or higher AKI experienced significantly higher in-hospital mortality compared with patients without postoperative AKI (15.9% vs 4.6%; P < .01) and worse 8-year survival (65.9% ± 34.1% vs 80.1% ± 20.0%; P < .01). CONCLUSIONS: Moderate to severe AKI is a serious complication and is associated with significantly worse short- and long-term outcomes; targeting mild AKI with therapeutic intervention is an important step in improving patient outcomes.

Treatment of Multi-Focal Epilepsy With Resective Surgery Plus Responsive Neurostimulation (RNS): One Institution's Experience.

Objective: Patients with medically refractory focal epilepsy can be difficult to treat surgically, especially if invasive monitoring reveals multiple ictal onset zones. Possible therapeutic options may include resection, neurostimulation, laser ablation, or a combination of these surgical modalities. To date, no study has examined outcomes associated with resection plus responsive neurostimulation (RNS, Neuropace, Inc., Mountain View, CA) implantation and we describe our initial experience in patients with multifocal epilepsy undergoing this combination therapy. Methods: A total of 43 responsive neurostimulation (RNS) devices were implanted at UCI from 2015 to 2019. We retrospectively reviewed charts of patients from the same time period who underwent both resection and RNS implantation. Patients were required to have independent or multifocal onset, undergo resection and RNS implantation, and have a minimum of six-months for follow-up to be included in the study. Demographics, location of ictal onset, location of surgery, complications, and seizure outcome were collected. Results: Ten patients met inclusion criteria for the study, and seven underwent both procedures in the same setting. The average age was 36. All patients had multifocal ictal onset on video electroencephalogram or invasive EEG with four patients undergoing subdural grid placement and four patients undergoing bilateral sEEG prior to the definitive surgery. Five patients underwent resection plus ipsilateral RNS placement and the remainder underwent resection with contralateral RNS placement. Two minor complications were encountered in this group. At six months follow up, there was an average of 81% ± 9 reduction in seizures, while four patients experienced complete seizure freedom at 1 year. Conclusion: Patients with multifocal epilepsy can be treated with partial resection plus RNS. The complication rates are low with potential for worthwhile seizure reduction.

Optimal Configuration for Bypass of the Left Anterior Descending Artery During Bilateral Internal Thoracic Artery Grafting.

BACKGROUND: The left internal thoracic artery (LITA) to left anterior descending (LAD) artery bypass remains the reference standard for coronary artery bypass graft surgery. With the advent of bilateral internal thoracic artery (BITA) grafting, optimal bypass configuration to the LAD is unclear. The objective of this study was to compare clinical outcomes between LITA-LAD and right internal thoracic artery (RITA)-LAD configurations in BITA grafting. METHODS: The primary outcome was the need for percutaneous or surgical reintervention of the LAD. Secondary outcomes included all-cause mortality and cardiac mortality. Cox proportional hazard and competing risk models were used with entropy weighting. RESULTS: Among BITA patients, 1527 had LITA-LAD grafts, and 523 RITA-LAD. Before entropy weighting, RITA-LAD patients were older with more diabetes, peripheral vascular disease, and left ventricular dysfunction, more urgent status (P < .05), and more frequently performed off-pump (P < .001). Need for repeat revascularization of the LAD territory at 10 years was 2.8% in the LITA-LAD group and 1.8% in the RITA-LAD group (subhazard ratio = 0.686; 95% confidence interval [CI], 0.296-1.589; P = .38). Adjusted survival at 10 years was 97.2% in the LITA-LAD group and 98.2% in the RITA-LAD group (hazard ratio = 1.056; 95% CI, 0.677-1.647; P = .81). There was no difference in cardiac mortality (subhazard ratio = 1.063; 95% CI, 0.502-2.251; P = .87). CONCLUSIONS: Use of either LITA or RITA for LAD grafting during BITA revascularization has no effect on long-term all-cause or cardiac mortality or need for repeat revascularization of the LAD. Cardiac surgeons should be confident in using a RITA-LAD bypass during BITA grafting.

Perioperative and Long-Term Morbidity and Mortality for Elderly Patients Undergoing Thoracic Aortic Surgery.

The impact of age on outcome in elective thoracic aortic surgery is not well characterized. We aim to evaluate age-related differences in short- and long-term outcomes in elderly patients undergoing elective thoracic aortic surgery. From 2004 to 2018, 786 patients underwent elective thoracic aortic surgery at a single center and were divided into 2 groups; <75 years old (n = 651) and ≥75 years old (n = 135). Outcomes include in-hospital mortality, morbidity, and long-term survival. Median follow-up was 4.8 years. Multivariable logistic regression was used to identify independent predictors of mortality and morbidity; Kaplan-Meier curves were plotted for late survival. Similar analysis was performed to the propensity-matched cohort. The elderly cohort had higher in-hospital mortality (8.2% vs 1.7%; P < 0.01), stroke (11.9 vs 2.8%; P< 0.01) and prolonged ventilation (17.3% vs 8.3%; P < 0.01), and intensive care unit stay (5.6 ± 10.9 vs 2.9 ± 6.0 days; P < 0.01). After adjusting for baseline differences and surgical complexity, age ≥75 years remained a significant predictor of hospital mortality (odds ratio [95% confidence interval]: 3.7 [1.3-10.3]). Eight-year survival was 75.4 ± 7.7% in the older group compared to 93.3 ± 1.9% in the younger group (hazard ratio [95% confidence interval]: 4.2 [1.7-11.0]). Propensity score-matched analysis also confirmed worse early- and long-term outcomes in the elderly group. Elderly patients experience higher in-hospital mortality and morbidity following elective thoracic aortic surgery compared to their younger counterparts and have a higher burden of mortality over long-term follow-up.

A Novel Robotic-Assisted Technique to Implant the Responsive Neurostimulation System.

BACKGROUND: The responsive neurostimulation system (RNS) (NeuroPace Inc, Mountain View, California) was approved as an adjunctive therapy for medically refractory focal epilepsy. RNS detects epileptiform patterns and delivers electrical stimulation to abort seizures. OBJECTIVE: To describe a novel technique of RNS lead implantation using robotic-assisted targeting of ictal-onset zones based on stereoelectroencephalography (sEEG) localization. Secondary objectives are to report the accuracy of robotic-assisted lead implantation using the ROSA robot as well as to report the clinical outcome achieved after RNS implantation by this method. METHODS: A total of 16 patients with medically refractory focal epilepsy underwent sEEG implantation for ictal-onset localization followed by robotic RNS implantation. The electrode most correlative with ictal onset on sEEG was chosen as the target for the RNS electrode. Seizure control was measured at 6-mo and 1-yr follow-up. Ictal-onset electrocorticography (ECoG) data from RNS were compared with ictal onset from sEEG leads based on calculations of lead target to actual lead location from the ROSA robot. RESULTS: At 6-mo follow-up, the average percent seizure reduction was 82% based upon self-reported seizure diaries. At 1-yr follow-up, 8 patients had an average of 90% seizure reduction. The location of seizure onset from ECoG data show similar onset from sEEG leads within 0.165-mm discrepancy. CONCLUSION: The ROSA robot provides an ideal method for targeting subcortical ictal-onset zones. This method of RNS lead implantation achieves high accuracy and is associated with favorable clinical outcomes.

Cardioinformatics: the nexus of bioinformatics and precision cardiology.

Cardiovascular disease (CVD) is the leading cause of death worldwide, causing over 17 million deaths per year, which outpaces global cancer mortality rates. Despite these sobering statistics, most bioinformatics and computational biology research and funding to date has been concentrated predominantly on cancer research, with a relatively modest footprint in CVD. In this paper, we review the existing literary landscape and critically assess the unmet need to further develop an emerging field at the multidisciplinary interface of bioinformatics and precision cardiovascular medicine, which we refer to as 'cardioinformatics'.

Robotic Orthogonal Implantation of Responsive Neurostimulation (RNS) Depth Electrodes in the Mesial Temporal Lobe: Case Series.

BACKGROUND: Responsive neurostimulation (RNS) is a closed-loop neurostimulation modality for treating intractable epilepsy in patients who are not candidates for resection. In the past, implantation of depth electrodes was done through a transoccipital approach that transverses the hippocampus. There have been no descriptions of orthogonal approaches to RNS electrode placement. OBJECTIVE: To describe our initial experience with placing RNS depth electrodes using an orthogonal approach to target the short axis of the mesial temporal lobe. METHODS: Presurgical work-up included magnetic resonance imaging, video electroencephalography, and neuropsychological testing. During the procedure, patients were placed with their heads in a neutral position. Electrodes were placed via stereotactic robotic assistance using a unilateral orthogonal approach targeting the amygdala or hippocampus. Patients who underwent RNS electrode implantation via orthogonal approach were identified. Multiple variables were collected, including age, disease onset, complications, follow-up, semiology, and seizure reduction. RESULTS: There were 8 patients who underwent RNS electrode placement with orthogonal approach. The mean age and follow-up were 44.8 and 1.2 yr, respectively. There were 4 patients with at least 1-yr follow-up. Of them, 1 was seizure free and 2 experienced over 50% reduction in seizures. There were no complications associated with electrode implantation. CONCLUSION: The initial experience using an orthogonal approach for depth electrode placement for RNS implantation was described. The potential advantages may include better safety, accuracy, and positioning in comparison to a transoccipital approach.

Geospatial mapping and resource utilization tool in support of a national smoke-free public housing rule.

OBJECTIVE: To advance public health support for the U.S. Department of Housing and Urban Development's smoke-free rule, the Centers for Disease Control and Prevention collaborated with the Georgia Institute of Technology to develop a geospatial mapping tool. The objective was to create a tool state and local public health agencies could use to tailor smoke-free educational materials and cessation interventions for specific public housing development resident populations. RESULTS: The resulting "Extinguish Tool" includes an interactive map of U.S. public housing developments (PHDs) and healthcare facilities that provides detailed information on individual PHDs, their proximity to existing healthcare facilities, and the demographic characteristics of residents. The tool also estimates the number of PHD residents who smoke cigarettes and calculates crude estimates of the potential economic benefits of providing cessation interventions to these residents. The geospatial mapping tool project serves as an example of a collaborative and innovative public health approach to protecting the health and well-being of the nation's two million public housing residents, including 760,000 children, from the harms of tobacco smoking and secondhand smoke exposure in the places where they live, play, and gather.

Effect of Fibrinogen Concentrate vs Cryoprecipitate on Blood Component Transfusion After Cardiac Surgery: The FIBRES Randomized Clinical Trial.

IMPORTANCE: Excessive bleeding is a common complication of cardiac surgery. An important cause of bleeding is acquired hypofibrinogenemia (fibrinogen level <1.5-2.0 g/L), for which guidelines recommend fibrinogen replacement with cryoprecipitate or fibrinogen concentrate. The 2 products have important differences, but comparative clinical data are lacking. OBJECTIVE: To determine if fibrinogen concentrate is noninferior to cryoprecipitate for treatment of bleeding related to hypofibrinogenemia after cardiac surgery. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial at 11 Canadian hospitals enrolling adult patients experiencing clinically significant bleeding and hypofibrinogenemia after cardiac surgery (from February 10, 2017, to November 1, 2018). Final 28-day follow-up visit was completed on November 28, 2018. INTERVENTIONS: Fibrinogen concentrate (4 g; n = 415) or cryoprecipitate (10 units; n = 412) for each ordered dose within 24 hours after cardiopulmonary bypass. MAIN OUTCOMES AND MEASURES: Primary outcome was blood components (red blood cells, platelets, plasma) administered during 24 hours post bypass. A 2-sample, 1-sided test for the ratio of the mean number of units was conducted to evaluate noninferiority (threshold for noninferiority ratio, <1.2). RESULTS: Of 827 randomized patients, 735 (372 fibrinogen concentrate, 363 cryoprecipitate) were treated and included in the primary analysis (median age, 64 [interquartile range, 53-72] years; 30% women; 72% underwent complex operations; 95% moderate to severe bleeding; and pretreatment fibrinogen level, 1.6 [interquartile range, 1.3-1.9] g/L). The trial met the a priori stopping criterion for noninferiority at the interim analysis after 827 of planned 1200 patients were randomized. Mean 24-hour postbypass allogeneic transfusions were 16.3 (95% CI, 14.9 to 17.8) units in the fibrinogen concentrate group and 17.0 (95% CI, 15.6 to 18.6) units in the cryoprecipitate group (ratio, 0.96 [1-sided 97.5% CI, -∞ to 1.09; P < .001 for noninferiority] [2-sided 95% CI, 0.84 to 1.09; P = .50 for superiority]). Thromboembolic events occurred in 26 patients (7.0%) in the fibrinogen concentrate group and 35 patients (9.6%) in the cryoprecipitate group. CONCLUSIONS AND RELEVANCE: In patients undergoing cardiac surgery who develop clinically significant bleeding and hypofibrinogenemia after cardiopulmonary bypass, fibrinogen concentrate is noninferior to cryoprecipitate with regard to number of blood components transfused in a 24-hour period post bypass. Use of fibrinogen concentrate may be considered for management of bleeding in patients with acquired hypofibrinogenemia in cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03037424.

Partial Surface Modification of Low Generation Polyamidoamine Dendrimers: Gaining Insight into their Potential for Improved Carboplatin Delivery.

Carboplatin (CAR) is a second generation platinum-based compound emerging as one of the most widely used anticancer drugs to treat a variety of tumors. In an attempt to address its dose-limiting toxicity and fast renal clearance, several delivery systems (DDSs) have been developed for CAR. However, unsuitable size range and low loading capacity may limit their potential applications. In this study, PAMAM G3.0 dendrimer was prepared and partially surface modified with methoxypolyethylene glycol (mPEG) for the delivery of CAR. The CAR/PAMAM G3.0@mPEG was successfully obtained with a desirable size range and high entrapment efficiency, improving the limitations of previous CAR-loaded DDSs. Cytocompatibility of PAMAM G3.0@mPEG was also examined, indicating that the system could be safely used. Notably, an in vitro release test and cell viability assays against HeLa, A549, and MCF7 cell lines indicated that CAR/PAMAM G3.0@mPEG could provide a sustained release of CAR while fully retaining its bioactivity to suppress the proliferation of cancer cells. These obtained results provide insights into the potential of PAMAM G3.0@mPEG dendrimer as an efficient delivery system for the delivery of a drug that has strong side effects and fast renal clearance like CAR, which could be a promising approach for cancer treatment.

External Validation and Updating of the Cardiac Surgery Score for Prediction of Mortality in a Cardiac Surgery Intensive Care Unit.

OBJECTIVE: To externally validate the predictive performance of the logistic and additive Cardiac Surgery Score (CASUS), a postoperative severity of illness score designed specifically for prediction of mortality in the cardiac surgery intensive care unit. DESIGN: A retrospective analysis of prospectively collected data between July 1, 2012, and September 30, 2015. SETTING: Single university cardiac surgery intensive care unit in Canada. PARTICIPANTS: Consecutive adult patients (n = 4,519) admitted to the intensive care unit after cardiac surgery. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The mortality predicted by logistic CASUS was calculated for each patient on admission day 0 and postoperative days 2, 4, 7, and 10 using the original model equation. The mortality predicted by additive CASUS was determined on each day with separate logistic regression models, using the total score as a single variable. The observed mortality was 1.8%. Logistic CASUS overestimated mortality by 78%, 59%, 51%, 52%, and 29% on days 0, 2, 4, 7, and 10, respectively. After model updating with logistic calibration, logistic CASUS consistently provided estimates of death comparable with the observed mortality, as determined with the Hosmer-Lemeshow goodness-of-fit test. The stability of those estimates was confirmed by bootstrapping. Similar calibration results were obtained with additive CASUS. Logistic and additive CASUS had good discrimination with areas under the receiver operating characteristic curve greater than 0.7 on each study day. CONCLUSIONS: Recalibrated logistic CASUS reliably predicts mortality in the intensive care unit after cardiac surgery. Logistic regression models derived from additive CASUS perform as well as logistic CASUS.