Macromolecular condensation organizes nucleolar sub-phases to set up a pH gradient.

Nucleoli are multicomponent condensates defined by coexisting sub-phases. We identified distinct intrinsically disordered regions (IDRs), including acidic (D/E) tracts and K-blocks interspersed by E-rich regions, as defining features of nucleolar proteins. We show that the localization preferences of nucleolar proteins are determined by their IDRs and the types of RNA or DNA binding domains they encompass. In vitro reconstitutions and studies in cells showed how condensation, which combines binding and complex coacervation of nucleolar components, contributes to nucleolar organization. D/E tracts of nucleolar proteins contribute to lowering the pH of co-condensates formed with nucleolar RNAs in vitro. In cells, this sets up a pH gradient between nucleoli and the nucleoplasm. By contrast, juxta-nucleolar bodies, which have different macromolecular compositions, featuring protein IDRs with very different charge profiles, have pH values that are equivalent to or higher than the nucleoplasm. Our findings show that distinct compositional specificities generate distinct physicochemical properties for condensates.

Programmable synthetic biomolecular condensates for cellular control.

The formation of biomolecular condensates mediated by a coupling of associative and segregative phase transitions plays a critical role in controlling diverse cellular functions in nature. This has inspired the use of phase transitions to design synthetic systems. While design rules of phase transitions have been established for many synthetic intrinsically disordered proteins, most efforts have focused on investigating their phase behaviors in a test tube. Here, we present a rational engineering approach to program the formation and physical properties of synthetic condensates to achieve intended cellular functions. We demonstrate this approach through targeted plasmid sequestration and transcription regulation in bacteria and modulation of a protein circuit in mammalian cells. Our approach lays the foundation for engineering designer condensates for synthetic biology applications.

Phase Transitions of Associative Biomacromolecules.

Multivalent proteins and nucleic acids, collectively referred to as multivalent associative biomacromolecules, provide the driving forces for the formation and compositional regulation of biomolecular condensates. Here, we review the key concepts of phase transitions of aqueous solutions of associative biomacromolecules, specifically proteins that include folded domains and intrinsically disordered regions. The phase transitions of these systems come under the rubric of coupled associative and segregative transitions. The concepts underlying these processes are presented, and their relevance to biomolecular condensates is discussed.

Addition of PEG-interferon to long-term nucleos(t)ide analogue therapy enhances HBsAg decline and clearance in HBeAg-negative chronic hepatitis B: Multicentre Randomized Trial (PAS Study).

We studied whether 48 weeks of PEG-IFN alfa-2a add-on increases HBsAg-decline and clearance in HBeAg-negative patients on long-term nucleo(s)tide analogue (NA) therapy. In this investigator-initiated, randomized, controlled trial conducted in Europe and Canada, HBeAg-negative patients treated with NA > 12 months, with HBVDNA < 200 IU/mL, were enrolled. Patients were randomized 2:1 to 48 weeks of PEG-IFN alfa-2a add-on (180 µg per week) or continued NA-monotherapy with subsequent follow-up to Week 72. Endpoints were HBsAg decline (≥1 log10 IU/mL) and HBsAg clearance at Week 48. Of the 86 patients in the modified-intention-to-treat analysis, 58 patients received PEG-IFN add-on, and 28 continued NA monotherapy. At Week 48, 16(28%) patients achieved HBsAg decline ≥1 log10 in the add-on arm versus none on NA-monotherapy (p < .001), and HBsAg clearance was observed in 6 (10%) PEG-IFN add-on patients versus 0% NA-monotherapy (p = .01). HBVRNA was only detected in 2% after PEG-IFN treatment versus 19% in NA-monotherapy (p = .002) at Week 48. PEG-IFN add-on therapy was well tolerated in majority of patients. Low baseline HBsAg levels (<10 IU/mL) identified patients most likely to achieve HBsAg loss with PEG-IFN add-on, whereas an HBsAg level > 200 IU/mL at on-treatment Week 12 was highly predictive of non-response (NPV = 100%). Addition of PEG-IFN to long-term NA enhanced HBsAg decline and increased the chance of HBsAg clearance in HBeAg-negative patients on long-term NA. On-treatment HBsAg levels >200 IU/mL identify patients unlikely to benefit from PEG-IFN add-on and could be used as a potential stopping-rule for PEG-IFN therapy. Our findings support further exploration of immune modulation add-on to antiviral therapy, preferably using response-guided strategies, to increase functional cure rates in patients with CHB.

FIREBALL: A tool to fit protein phase diagrams based on mean-field theories for polymer solutions.

Biomolecular condensates form via phase transitions of condensate-specific biomacromolecules. Intrinsically disordered regions featuring the appropriate sequence grammars can contribute via homotypic and heterotypic interactions to the driving forces for phase separation of multivalent proteins. Experiments and computations have matured to the point where the concentrations of coexisting dense and dilute phases can be measured or computed for individual intrinsically disordered regions in complex milieus. For a macromolecule such as a disordered protein in a solvent, the locus of points that connects concentrations of the two coexisting phases defines a phase boundary, or binodal. Often, only a few points along the binodal are accessible via measurements. In such cases, and for quantitative and comparative analysis of parameters that describe the driving forces for phase separation, it is useful to fit measured or computed binodals to mean-field free energies for polymer solutions. The nonlinearity of the underlying free energy functions makes it challenging to put mean-field theories into practice. Here, we present FIREBALL, a suite of computational tools designed to enable efficient construction, analysis, and fitting to experimental or computed data of binodals. We show that depending on the theory being used, one can also extract information regarding coil-to-globule transitions of individual macromolecules.

Crohn's Disease Features in Anastomotic Biopsies from Patients With and Without Crohn's Disease: Diagnostic and Prognostic Value.

Endoscopic evidence of disease activity is a critical predictor of clinical relapse in patients with Crohn's disease (CD), and histologic disease activity is evolving as a similarly important end point for patient management. However, classical morphologic features of CD may overlap with postoperative inflammatory changes, confounding the evaluation of anastomotic biopsies. There is a clear unmet need for better characterization of diagnostic and clinically significant histologic features of CD in these surgically altered sites. We evaluated ileocolonic and colocolonic/rectal anastomotic biopsies performed at 3 academic institutions in patients with and without CD. The biopsies were blindly assessed for CD histologic features and correlated to clinical and endoscopic characteristics. In CD patients, the presence of each feature was correlated with the subsequent clinical exacerbation or relapse. We obtained anastomotic biopsies from 208 patients, of which 109 were operated on for CD and 99 for another indication (neoplasia [80%], diverticular disease (11%), and other [9%]). Mean time since surgery was 10 years (0-59; 14 years for CD [1-59], 6 years for non-CD [0-33]). Endoscopic inflammation was noted in 52% of cases (68% for CD and 35% for non-CD). Microscopic inflammation was present in 74% of cases (82% for CD and 67% for non-CD). Only discontinuous lymphoplasmacytosis (P < .001) and pyloric gland metaplasia (P = .04) occurred significantly more often in CD patients. However, none of the histologic features predicted clinical disease progression. In subset analysis, the presence of histologic features of CD in nonanastomotic biopsies obtained concurrently in CD patients was significantly associated with relapse (P = .03). Due to extensive morphologic overlap between CD and postoperative changes and the lack of specific histologic features of relapse, biopsies from anastomotic sites are of no value in predicting clinical CD progression. Instead, CD activity in biopsies obtained away from anastomotic sites should be used for guiding endoscopic sampling and clinical management.

Hepatitis B Virus RNA as Early Predictor for Response to Pegylated Interferon Alpha in HBeAg-Negative Chronic Hepatitis B.

BACKGROUND: Hepatitis B virus RNA (HBV-RNA) is a novel serum biomarker that correlates with transcription of intrahepatic covalently closed circular (cccDNA), which is an important target for pegylated interferon (PEG-IFN) and novel therapies for functional cure. We studied HBV-RNA kinetics following PEG-IFN treatment and its potential role as a predictor to response in HBeAg-negative chronic hepatitis B (CHB) patients. METHODS: HBV-RNA levels were measured in 133 HBeAg-negative CHB patients treated in an international randomized controlled trial (PARC study). Patients received PEG-IFN α-2a for 48 weeks. HBV-RNA was measured from baseline through week 144. Response was defined as HBV-DNA <2000 IU/mL and ALT normalization at week 72. Kinetics of HBV-RNA were compared with HBV-DNA, HBsAg, and HBcrAg. RESULTS: Mean HBV-RNA at baseline was 4.4 (standard deviation [SD] 1.2) log10 c/mL. At week 12, HBV-RNA declined by -1.6 (1.1) log10 c/mL. HBV-RNA showed a greater decline in responders compared to nonresponders early at week 12 (-2.0 [1.2] vs -1.5 [1.1] log10 c/mL, P = .04). HBV-RNA level above 1700 c/mL (3.2 log10 c/mL) had a negative predictive value of 91% at week 12 and 93% at week 24 (P = .01) for response. Overall, HBV-RNA showed a stronger correlation with HBV-DNA and HBcrAg (.82 and .80, P < .001) and a weak correlation with HBsAg (.25). At week 12, HBV-RNA was significantly lower among patients with lower HBsAg (<100 IU/mL) or HBsAg loss at week 144. CONCLUSIONS: During PEG-IFN treatment for HBeAg-negative CHB, HBV-RNA showed a fast and significant decline that correlates with treatment response and HBsAg loss at long-term follow-up. CLINICAL TRIALS REGISTRATION: NCT00114361.

Effects of on-treatment ALT flares on serum HBsAg and HBV RNA in patients with chronic HBV infection.

As pegylated interferon alpha (PEG-IFN-α) is increasingly used in combination regimens of novel drugs, we aimed to characterize ALT flares and their relationship with serum HBsAg and HBV RNA kinetics in a large combined cohort of chronic hepatitis B (CHB) patients on PEG-IFN-α-based therapy. In this post hoc analysis of four international randomized trials, 269/130/124/128 patients on PEG-IFN-α monotherapy, PEG-IFN-α plus nucleos(t)ide analogue (NA) de novo combination, PEG-IFN-α add-on to NA or NA monotherapy were included, respectively. A flare was defined as an episode of ALT ≥5 × ULN. The association between flares and HBsAg and HBV RNA changes were examined. On-treatment flares occurred in 83/651 (13%) patients (median timing/magnitude: week 8 [IQR 4-12], 7.6 × ULN [IQR 6.2-10.5]). Flare patients were more often Caucasians with genotype A/D and had higher baseline ALT, HBV DNA, HBV RNA and HBsAg levels than the no-flare group. More flares were observed on PEG-IFN-α monotherapy (18%) and PEG-IFN+NA de novo combination (24%) vs. PEG-IFN-α add-on (2%) or NA monotherapy (1%) (p < .001). On-treatment flares were significantly and independently associated with HBsAg and HBV RNA decline ≥1 log10 at the final visit declines started shortly before the flare, progressing towards 24 weeks thereafter. On-treatment flares were seen in 16/22 (73%) patients who achieved HBsAg loss. In conclusion, ALT flares during PEG-IFN-α treatment are associated with subsequent HBsAg and HBV RNA decline and predict subsequent HBsAg loss. Flares rarely occurred during PEG-IFN-α add-on therapy and associated with low HBsAg loss rates. Combination regimens targeting the window of heightened response could be promising.

Effectiveness and Renal Safety of Tenofovir Alafenamide Fumarate among Chronic Hepatitis B Patients: Real-World Study.

Tenofovir alafenamide fumarate (TAF) has high plasma stability resulting in fewer renal adverse events compared to tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients. We aimed to study the effectiveness and renal safety of TAF in a real-world setting, in patients with or without compromised kidney function. CHB patients (Nucleos(t)ide Analogue [NA]-naïve or experienced) who received TAF >1 year from 11 academic institutions as part of the Canadian Hepatitis B Network (CanHepB) were included. Kidney function was measured by estimated glomerular filtration rate (eGFR) as per Cockcroft-Gault. Patients were followed for up to 160 weeks. Of 176 patients receiving TAF, 143 switched from NA (88% TDF), and 33(19%) were NA naïve. Majority of NA-naïve patients (75%) achieved undetectable HBV DNA after one year of TAF treatment. Majority of patients with eGFR <60 mL/min who had renal deterioration during TDF (76%) reversed to eGFR increase after one year of TAF (p=0.009). Among patients with stage 2 chronic kidney disease (CKD) (eGFR 60-89), the estimated eGFR decline during TDF was halted after switching to TAF (p=0.09). NA-experienced patients with abnormal ALT before TAF showed a significant decline after switching to TAF: -0.005 [-0.006 - -0.004] log10 ULN U/L/month, p<0.001). In CHB patients, TAF was safe, well-tolerated and effective in this real-world cohort. Switching to TAF led to improved kidney function, particularly in those with stage 2 CKD, which suggests that the indication for TAF in the guidelines could be extended to patients with an eGFR higher than 60 mL/min.

Integrated Molecular Analysis of Papillary Renal Cell Carcinoma and Precursor Lesions Unfolds Evolutionary Process from Kidney Progenitor-Like Cells.

Papillary renal cell carcinoma (PRCC) is the most common type of RCC in end-stage kidney disease (ESKD). Papillary adenoma (PA) is a small benign lesion morphologically similar to PRCC and is suggested to be its precursor. PA is also prevalent in ESKD. The evolution of PAs to PRCCs and their relationship to ESKD are poorly understood. A total of 140 PAs, normal kidneys, ESKDs, and PRCCs were analyzed. Previously described markers of renal tubular progenitor cells were analyzed using immunohistochemistry and quantified with digital analysis. Progenitor cells were significantly increased in ESKD (P < 0.0001) and PAs (P = 0.02) in comparison with the normal kidney. Pathway analysis using global miRNA and chromosomal copy number variations revealed a common developmental theme between PA and the PRCCs. Whole exome sequencing showed a KMT2C-specific pathogenic mutation among all PAs and PRCCs. KMT2C is a chromosome 7 epigenetic regulator implicated in development and oncogenesis. Collectively, results show possible connection of PRCCs to PA and the progenitor-like cell population, which are increased in response to renal tubular injury. In addition, each PRCC histologic subtype had its own set of mutational changes, indicating divergence from a common precursor. The study reports previously unknown biological aspects of PRCC development and could influence current surveillance criteria and early detection strategies of PRCC tumors.

Sunitinib induces early histomolecular changes in a subset of renal cancer cells that contribute to resistance.

Sunitinib is the standard-of-care, first-line treatment for advanced renal cell carcinoma (RCC). Characteristics of treatment-resistant RCC have been described; however, complex tumor adaptation mechanisms obstruct the identification of significant operators in resistance. We hypothesized that resistance is a late manifestation of early, treatment-induced histomolecular alterations; therefore, studying early drug response may identify drivers of resistance. We describe an epithelioid RCC growth pattern in RCC xenografts, which emerges in sunitinib-sensitive tumors and is augmented during resistance. This growth modality is molecularly and morphologically related to the RCC spheroids that advance during in vitro treatment. Based on time-lapse microscopy, mRNA and microRNA screening, and tumor behavior-related characteristics, we propose that the spheroid and adherent RCC growth patterns differentially respond to sunitinib. Gene expression analysis indicated that sunitinib promoted spheroid formation, which provided a selective survival advantage under treatment. Functional studies confirm that E-cadherin is a key contributor to the survival of RCC cells under sunitinib treatment. In summary, we suggest that sunitinib-resistant RCC cells exist in treatment-sensitive tumors and are histologically identifiable.-Lichner, Z., Saleeb, R., Butz, H., Ding, Q., Nofech-Mozes, R., Riad, S., Farag, M., Varkouhi, A. K., dos Santos, C. C., Kapus, A., Yousef, G. M. Sunitinib induces early histomolecular changes in a subset of renal cancer cells that contribute to resistance.

Cardiac surgery in the heart transplant recipient: Outcome analysis and long-term results.

BACKGROUND: Survival rates following cardiac transplantation continue to improve. Due to the scarcity of available organs, extended donor criteria have become more prevalent in clinical practice. In this context, the risk of developing cardiac pathology requiring surgical correction is increasing. METHODS: Between January 1991 and October 2010, a total of 479 patients received cardiac transplantations at the University Hospital Heidelberg. Of those, 18 (3.8%) patients required subsequent cardiac surgery until 2018. Short- and long-term analyses were performed. RESULTS: Indications for cardiac surgery included valvular disease (n = 16) with the majority of cases affecting the tricuspid valve (n = 10), while 6 patients received mitral valve surgery, of whom 3 patients underwent concomitant valve surgery. Other indications included CABG (n = 1) and re-transplantation (n = 1) for allograft dysfunction. Mean follow-up time was 6.5 years, while mean interval to surgery was 6.0 years. Early mortality was 11.1% (n = 2), while overall survival at 1, 5, and 10 years were, 88.1%, 81.4%, and 52.2%, respectively. Compared to an overall survival of that transplant cohort at 1, 5, and 10 years of 76.7%, 66.7%, and 52.4% percent, respectively (P = .271). CONCLUSION: According to our data, redo cardiac surgery can be performed with acceptable mortality and morbidity. Atrioventricular valve pathology plays a chief role in these patients.

Heads Up, Phones Down: A Pedestrian Safety Intervention on Distracted Crosswalk Behavior.

Cell phone use has been implicated in driver distraction and motor vehicle crashes, and more recently has been associated with distracted pedestrians. There are limited data on interventions aimed at this important public health issue. We hypothesized that the use of a visual intervention near street crossings would decrease the frequency of distracted behaviors of pedestrians. We performed a prospective observational cohort study examining painted sidewalk stencils reading, "Heads Up, Phones Down" as an intervention to decrease cell phone distractions amongst pedestrians. These stenciled messages were placed at a children's hospital, middle school, and high school in Los Angeles County. Anonymous observations of pedestrian distractions (texting, talking on a phone, headphone use, and other) were conducted before, 1 week after, and 4 months after the intervention. Distractions were compared before and after intervention using Chi square tests. A total of 11,533 pedestrians were observed, with 71% children and 29% adults. Total distractions decreased from 23% pre-intervention to 17% 1 week after stencil placement (p < 0.01), but this was not sustained at 4 months (23%, p = 0.4). A sustained decrease was observed only for texting at 4 months post-intervention (8.5% vs. 6.8%, p < 0.01). A simple visual intervention reduced distracted cell phone usage in pedestrians crossing the street, but this was most effective early after the intervention. Future studies are warranted to determine how to sustain this effect over time and how to minimize other types of distractions.

Repair or Replacement for Isolated Tricuspid Valve Pathology? Insights from a Surgical Analysis on Long-Term Survival.

BACKGROUND Long-term follow-up data concerning isolated tricuspid valve pathology after replacement or reconstruction is limited. Current American Heart Association guidelines equally recommend repair and replacement when surgical intervention is indicated. Our aim was to investigate and compare operative mortality and long-term survival in patients undergoing isolated tricuspid valve repair surgery versus replacement. MATERIAL AND METHODS Between 1995 and 2011, 109 consecutive patients underwent surgical correction of tricuspid valve pathology at our institution for varying structural pathologies. A total of 41 (37.6%) patients underwent tricuspid annuloplasty/repair (TAP) with or without ring implantation, while 68 (62.3%) patients received tricuspid valve replacement (TVR) of whom 36 (53%) were mechanical and 32 (47%) were biological prostheses. RESULTS Early survival at 30 days after surgery was 97.6% in the TAP group and 91.1% in the TVR group. After 6 months, 89.1% in the TAP group and 87.8% in the TVR group were alive. In terms of long-term survival, there was no further mortality observed after one year post surgery in both groups (Log Rank p=0.919, Breslow p=0.834, Tarone-Ware p=0.880) in the Kaplan-Meier Survival analysis. The 1-, 5-, and 8-year survival rates were 85.8% for TAP and 87.8% for TVR group. CONCLUSIONS Surgical repair of the tricuspid valve does not show survival benefit when compared to replacement. Hence valve replacement should be considered generously in patients with reasonable suspicion that regurgitation after repair will reoccur.

Surgery for Infective Endocarditis: Outcomes and Predictors of Mortality in 360 Consecutive Patients.

BACKGROUND A retrospective analysis was conducted of the early and long-term outcomes after surgery for infective endocarditis (IE). MATERIAL AND METHODS We included 360 patients with IE operated upon between 1993 and 2012. The primary endpoint was overall cumulative postoperative survival at 30 days. Secondary endpoints were early postoperative outcomes and complication rates. Factors associated with 30-day mortality were analyzed. RESULTS Mean age was 58.7±14.7 years and 26.9% (n=97) were female. The mean follow-up was 4.41±4.53 years. Postoperative survival was 81.7% at 30 days, 69.4% at 1 year, 63.3% at 5 years, and 63.3% at 10 years. Non-survivors were significantly older (p=0.014), with higher NYHA Class (p=0.002), had higher rates of preoperative diabetes mellitus (p=0.005), renal failure (p=0.001), and hepatic disease (p=0.002). Furthermore, non-survivors had higher baseline alanine aminotransferase (ALT, p=0.048), aspartate transaminase (AST, p=0.027), bilirubin (p=0.013), white cell count (WCC, p=0.034), and CRP (p=0.049). Factors associated with 30-day mortality were longer duration of surgery, CPB, and aortic cross-clamping times (p<0.001, p<0.001, and p=0.003, respectively), as well as higher RBC, FFP, and platelet transfusion requirements (p<0.001, p=0.005, and p<0.001, respectively). Multivariate logistic regression analysis revealed liver cirrhosis (OR 4.583, 95-CI: 1.096-19.170, p=0.037) and longer CPB time (OR 1.025, 95-CI 1.008-1.042, p=0.004) as independent predictors of 30-day mortality. CONCLUSIONS Surgical treatment of IE shows satisfactory early, midterm, and long-term results. Multivariate logistic regression analysis revealed cirrhosis and longer CPB time as independent predictors of 30-day mortality.

Comparison of Two Miniaturized Cardiopulmonary Bypass Systems Regarding Inflammatory Response.

Cardiopulmonary bypass (CPB) is a known mediator of systemic inflammatory response. Extracorporeal circulations are undergoing continuous modifications and optimizations to achieve better results. Hence we aim to compare the inflammatory response associated with two recent miniature extracorporeal circulation systems during normothermic CPB. We measured plasma levels of cytokines including interleukin (IL)-1ß, IL-6, IL-10, tumor necrosis factor-α, migration inhibitory factor (MIF), receptor for advanced glycation endproduct, and cluster of differentiation 40 ligand in 60 consecutive patients during the first 24 h after CPB. The patients were prospectively randomized to one of three trial groups: patients in group A were operated with the minimal extracorporeal circulation circuit (MECC, Maquet, Rastatt, Germany), group B operated with the extracorporeal circulation circuit optimized (ECC.O, Sorin, Italy), and group C operated with a conventional extracorporeal circuit (CECC, Maquet). Arterial blood samples were collected at intervals before, 30 min after initiation, and after termination of CPB. Further samples were collected 6 and 24 h after CPB. IL-10 levels were significantly raised in the CECC group as compared with either of the mini ECC-circuits with a peak concentration at 6 h postoperatively. Human MIF concentrations were significantly higher in the CECC group starting 30 min after CPB and peaking at the end of CPB. The overall reduction in cytokine concentrations in the mini-ECC groups correlated with a lower need for blood transfusion in MECC and a shorter mechanical ventilation time for ECC.O. Normothermic CPB using minimally invasive extracorporeal circulation circuits can reduce the inflammatory response as measured by cytokine levels, which may be beneficial for perioperative preservation of pulmonary function and hemostasis in low risk patients.

Central Extracorporeal Life Support With Left Ventricular Decompression to Berlin Heart Excor: A Reliable "Bridge to Bridge" Strategy in Crash and Burn Patients.

The aim of this study was to compare patients with severe biventricular heart failure who underwent Berlin Heart Excor implantation with (cardiogenic shock [CS] status) or without the need for preoperative extracorporeal life support (ECLS) as a bridge to long-term device. A total of 40 consecutive patients with severe biventricular heart failure underwent Berlin Heart Excor implantation with (CS status, n = 20, 50%) or without (control, n = 20, 50%) the need for preoperative ECLS as a bridge to long-term device from March 2007 to May 2015 at our institution. Demographics and preoperative baseline characteristics as well as early and long-term outcomes including mortality and complication rates were retrospectively compared between the two groups. There were no statistically significant differences in terms of demographics and most preoperative clinical characteristics. The mean age in the ECLS (CS group) and control group was 43.5 ± 19.4 and 41.3 ± 16.4 (P = 0.705), whereas 20 and 25% of patients were females (P = 1.000). However, patients from the ECLS group had preoperatively higher lactate (P = 0.037), aspartate aminotransferase (P < 0.001), and alanine aminotransferase (P < 0.001) levels, all of them significantly decreased after surgery (P  = 0.004, P = 0.017, and P = 0.001, respectively) and did not show any statistical differences to the corresponding values from the control group (P = 0.597, P = 0.491, and P = 0.339, respectively). Postoperatively, patients from the control and ECLS groups had statistically similar incidences of liver failure (30 vs. 35%, P = 0.736), renal failure (45 vs. 70%, P = 0.110), need for reopening (35 vs. 60%, P = 0.113), major cerebrovascular events (35 vs. 30%, P = 0.736), sepsis (10 vs. 25%, P = 0.407), wound infection (20 vs. 30%, P = 0.716), abdominal ischemia requiring surgery (28.6 vs. 36.8%, P = 0.719), and acute respiratory distress syndrome (25 vs. 35.3%, P = 1.000). The proportion of patients who were bridged to transplantation was statistically similar between the ECLS and the control groups (40 vs. 52.6%, P = 0.429). Furthermore, there were no statistically significant differences in terms of early (Breslow [generalized Wilcoxon] P = 0.907) and long-term (log-rank [Mantel-Cox] P = 0.787) overall cumulative survival accounting for 30-day survival of 75 versus 75%, 6-month survival of 60 versus 55%, 1-year survival of 54 versus 40%, and 7-year survial of 47 versus 40% in the control and ECLS groups, respectively. ECLS in critical CS as a bridge to implantation of the Berlin Heart Excor ventricular assist device is safe and is associated with improvement in end-organ function leading to similar excellent early and long-term survival and incidences of major complications as in patients without the need for preoperative ECLS support.

Extracorporeal life support and digoxin-specific Fab fragments for successful management of Taxus baccata intoxication with low output and ventricular arrhythmia.

INTRODUCTION: Yew plants are evergreen shrubs which are widely spread throughout the northern hemisphere. Taxane alkaloid derivatives, mainly taxine B, represent the main toxins of Taxus baccata and are highly cardiotoxic. Due to the lack of randomized clinical trials, case reports on accidental or suicidal yew intoxications build the only source of knowledge of clinical treatment options. CASE REPORT: We report the case of a suicidal yew ingestion admitted to our hospital under prolonged cardiopulmonary resuscitation due to pulseless electrical activity. Extra-corporeal life support (ECLS) was established to maintain adequate organ perfusion. Repeated administration of digoxin-specific Fab antibody fragments, which cross-react with taxine, was associated with an immediate conversion from asystole to broad-complex bradycardia and a gradual normalization of the electrocardiogram (ECG). This was paralleled by a recovery of the cardiac function and weaning from the ECLS. The taxine metabolite 3,5-dimethoxyphenol could be detected by mass spectrometry before but not after the first Fab-fragment treatment. In contrast, the total amount of taxine (including the neutralized, Fab fragment-bound fraction) was increased after each Fab fragment administration, suggesting an accumulation of neutralized, since antibody-bound taxine in the blood by anti-digoxin Fab fragments. DISCUSSION: In conclusion, the successful clinical course of this case suggests a benefit of an early anti-digoxin Fab-fragment administration for the treatment of yew intoxication.

Patients with systemic lupus erythematosus and antiphospholipid syndrome undergoing cardiac valve surgery.

BACKGROUND AND AIM OF THE STUDY: Systemic lupus erythematosus (SLE) and primary/secondary antiphospholipid syndrome (APLS) may cause early degenerative changes in cardiac valves, such as Libman-Sacks endocarditis, though few reports exist of this condition. Herein are presented the early and late clinical outcomes after cardiac valve surgery in patients diagnosed with SLE and APLS in a single-center experience. METHODS: A prospective analysis was conducted of the perioperative and follow up data acquired from patients with diagnosed SLE, and primary and secondary APLS, who underwent either single or combined valve surgery at the authors' department between 2002 and 2014. RESULTS: Fifteen patients (14 females, one male; mean age 53 ± 16 years; range: 16-77 years) were identified. The mean follow up time was 49 ± 32 months (range: 12.5-119 months). Thirteen patients (11 females, two males) were diagnosed with SLE; one of these patients had tricuspid Libman-Sacks endocarditis, while two female patients had primary APLS and four had secondary APLS. Besides bioprosthetic and mechanical valve replacements, mitral and tricuspid valve reconstruction were performed. The mean cross-clamp time was 112 ± 73 min (range: 55-294 min). Early major cardiovascular events occurred in two patients, and late non-fatal events in four patients, including one thromboembolic event. The 30-day and in-hospital mortalities were both 0%. Currently, 12 patients (80%) are alive at the end of follow up. Actuarial survival was 92 ± 7.4% at one year, 74 ± 18% at four years, and 49 ± 23% at ten years. CONCLUSION: Despite general concerns, the present results confirmed that patients with SLE and APLS can be operated on for cardiac valve disease, with favorable early results and acceptable long-term outcome.

A School-Hospital Partnership Increases Knowledge of Pedestrian and Motor Vehicle Safety.

Pedestrian and motor vehicle-related injuries are leading causes of morbidity and mortality in children. Trauma centers have specialized resources to conduct interventions that improve the safety of whole communities. In the present study, we evaluated the effectiveness of a school-hospital partnership in increasing knowledge of pedestrian and motor vehicle safety among students and parents in a large, urban community. Staff from a Level I pediatric trauma center conducted educational interventions in an urban public school district. Elementary school students participated in a pedestrian safety program, middle school students completed a community safety program, and high school students learned about the dangers of drunk and distracted driving. Students completed pre- and post-tests. Parents in the neighboring community received child passenger safety education at two child restraint (CR) inspection events. A total of 2203 students participated at a total of nine schools. Post-test scores were significantly higher than pre-test scores for students in all three age groups and within each grade level. At CR inspection events, 67 CRs were inspected, 49 (73 %) of which were replaced with new age- and weight- appropriate CRs. The most common instance of improper CR use was loose CR fit in vehicle seat (33 %). All 120 observed instances of misuse were corrected by a certified Child Passenger Safety Technician. Educational interventions effectively increased knowledge of pedestrian and motor vehicle safety among students and parents. We have demonstrated the utility of a school-hospital partnership for furthering knowledge of safety in an urban community.