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Purpose: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F-mutant cell lines. Patients and Methods: In a phase I dose-escalation and -expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor, umbralisib, in combination with ruxolitinib in patients with MF who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that MTD at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose-escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas. Results: Thirty-seven patients with MF (median age, 67 years) with prior exposure to ruxolitinib were enrolled. A total of 2 patients treated with 800 mg umbralisib experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved a durable complete response, and 12 patients (32%) met the International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria of clinical improvement. With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up. Conclusions: Adding umbralisib to ruxolitinib in patients was well tolerated and may resensitize patients with MF to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors. Randomized trials testing umbralisib in the treatment of MF should be pursued.

Supplemental Tables S1-S9 Supplemental Figures S1-S2

Purpose:Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F-mutant cell lines.Patients and Methods:In a phase I dose-escalation and -expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor, umbralisib, in combination with ruxolitinib in patients with MF who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that MTD at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose-escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas.Results:Thirty-seven patients with MF (median age, 67 years) with prior exposure to ruxolitinib were enrolled. A total of 2 patients treated with 800 mg umbralisib experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved a durable complete response, and 12 patients (32%) met the International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria of clinical improvement. With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up.Conclusions:Adding umbralisib to ruxolitinib in patients was well tolerated and may resensitize patients with MF to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors. Randomized trials testing umbralisib in the treatment of MF should be pursued.

On March 10th, 2020 the Public Health Agency of Sweden raised the risk level for the spread of the coronavirus in Sweden to "very high". The capital Stockholm quickly emerged as the center for the spread and hospitals in the Stockholm Region switched to crisis management. This is the story of how the libraries at Stockholm’s three major hospitals handled their coronavirus journey during spring 2020: what actions were taken to uphold services and what lessons were learned.

A single layer polymeric backsheet material has been evaluated for use in silicon PV modules and as a luminescent solar collector. Physical and optical properties of the backsheet have been examined after damp heat, thermal cycling, and UV exposure for two different polymeric grades and three different pigment options including white, transparent, and photo-luminescent. As the importance of developing a white backsheet that is cost-effective, recyclable, and reliable is evident, the increased availability and use of bifacial cells is bound to increase the demand for transparent backsheets as well. In today’s market, the cost of a clear backsheet is significantly higher than a white backsheet which is motivation for research and development of new material options in this field. Results from these extensive tests reveal the need for continued research in white pigments and positive results in transparent and luminescent backsheet options.

Best known for his landmark After Auschwitz, Richard Rubenstein work was known in the 1960s as Jewish Death of God theology. Since then his contributions have been wide ranging, especially in the field of holocaust studies, and his legacy has been disassociated with radical theology. In this chapter, however, Rubenstein’s life and works are presented as an ongoing work of radicalism.

The purpose of this study is to provide nationally representative estimates of children visiting hospital-based emergency departments (ED) for motor vechicle traffic accidents (MVTA) in the United States during the year of 2008. Nationwide Emergency Department Sample for 2008 was used. All pediatric (age ≤18 years) ED visits with external cause for injury ICD-9-diagnostic codes for MVTA were selected. Outcomes examined included discharge status following ED visit and presence of concomitant injuries. Descriptive statistics was used to summarize the estimates. Totally 604 027 hospital-based ED visits occurred in the United States among children (age ≤18 years) due to MVTA. Following an ED visit, 91% were discharged routinely, while 6% were admitted as inpatients into the same hospital. A total of 928 children died in the ED. A total of 34 004 ED visits required inpatient admission into the same hospital and 768 patients died during hospitalization. Mean charge per ED visit was $1887 and total ED charges across the United States were close to $970 million. Among those admitted into the same hospital following ED visit (n=34 004), the mean hospitalization charge was $53 726 and total hospitalization charge across the entire United States were $1.8 billion. Study findings illustrate the burden associated with pediatric ED visits due to MVTA. Close to $970 million of hospital charges were incurred by children who made an ED visit due to a MVTA during 2008 and about $1.8 billion was incurred among those hospitalized following an ED visit.

BACKGROUND: Sports-related injuries in adolescents incur a significant amount of hospital resources. Sports-related injuries are not an uncommon cause of ED visit; however, national estimates of such injuries in teenagers are unknown. OBJECTIVES: The aim of this study was to identify and characterize emergency department (ED) visits that result from sports-related injuries among teenagers across the United States. This study describes the outcomes associated with sports-related injuries necessitating ED visits among teenagers at a national level. STUDY DESIGN: This is a descriptive epidemiology study. METHODS: The 2008 Nationwide Emergency Department Sample data set, the largest all-payer health care database in the United States, was used to identify ED visits with external cause of injury related to sports occurring in patients aged 13 through 19 years. Outcomes examined included discharge status after the ED visit and presence of concomitant injuries. Descriptive statistics was used to summarize the estimates. Nationwide representative estimates were computed using the discharge weight variable. RESULTS: There were 432,609 ED visits by those between the ages of 13 and 19 years who experienced sports-related injuries, with total charges close to $447.4 million, with a mean total per-visit charge of $1205. The male patients accounted for 76.8% of the total ED visits. The most frequently occurring injuries were superficial injury or contusion (n = 118,250 ED visits); sprains and strains (n = 105,476); fracture of the upper limb (n = 63,151); open wounds of the head, the neck, and the trunk (n = 46,176); as well as intracranial injury (n = 30,726). Close to 29% of all ED visits occurred among those residing in geographical areas with median household income levels of greater than $64,000. After the ED visit, 1.6% were admitted to the same hospital, with a mean length of stay of 2.4 days and a mean hospital charge for ED visit and inpatient services of $22,703. The male patients composed 87.5% of the hospitalizations. The total of hospitalization charges across the entire United States was $154.8 million. CONCLUSIONS: Sports injuries account for a substantial number of 2008 teenage ED visits in the United States. Patient- and hospital-level characteristics were analyzed and highlighted. Language: en

INTRODUCTION: Skeletal myoblasts have been shown to survive transfer into myocardial scar tissue. The purpose of this study was to investigate differentiation after intramyocardial transplantation. Additionally, we evaluated an intravital fluorescence dye. MATERIALS AND METHODS: Skeletal myoblasts were harvested from 8 male inbred Lewis rats and expanded in culture. For each transplantation planned, 10(6) cells were trypsinized and incubated for three minutes with 2 ml of buffered PKH-26 solution (Sigma, St. Louis). This dye was integrated into the cell membrane. After washing three times, the cells were plated again for two more days. The cells were then transplanted into the hearts of 60 female Lewis-rats, mean weight 380 g (260 - 450 g). At implantation, 10(6) cells suspended in 100 microliters were injected into the apex region of the left ventricle. 12 animals served as the control group with only cell medium injected. Animals were sacrificed after 1, 2, 6, 8, 12, and 16 weeks (n = 10 each). The hearts were explanted and serial frozen sections of the hearts were prepared for detecting labeled cells. Sections with labeled cells were stained immunohistochemically for Myo D1 (myogenic origin), n-cam (early myotubes), desmin (muscular filament), myosin light chain (muscular contractile protein), and connexin 43 (tight junction). RESULTS: Cell labeling was successful in all cases. After two days, the myoblasts had recovered from the staining procedure. The fluorescing dye, however, was only rarely transmitted by cell division. Marked cells were found in the intercellular spaces between the cardiac myofibers in at least 8 animals from each group. No fibrotic reaction or inflammation was seen surrounding the transplanted cells. Up to 6 weeks after implantation, the cells stained positive for n-cam and Myo D1, and particularly for desmin. More n-cam positive cells were found than labeled cells, indicating cell division after the cell transfer. Two animals suffered sudden death after a follow-up time of 8 and 10 weeks, which was possibly due to cardiac arrhythmia. After 8 weeks, the cells formed conglomerates and stained positive for desmin, myosin light chain, and connexin 43. The cells were not structurally integrated into the recipient myocardial tissue, however. CONCLUSIONS: Myoblasts divided further after transplantation into rat myocardium. Positive staining for desmin demonstrated the development of myofibers. Starting at 8 weeks after transplantation, the cells started differentiation without reaching structural integration during follow-up. Labeling the cells with PKH-26 proved to be a reliable method to detect the cells.

Objective: This study represents the development of a treatment and seeding procedure to improve endothelial cellular adhesion on glutaraldehyde-fixed valves. Methods: Porcine aortic valves were fixed with 0.2% glutaraldehyde. Wall pieces of these valves had either no additional treatment (n = 4), incubation in M199 Earle (1×), with sodium carbonate at 2.2 g/L without l-glutamine for 24 hours (n = 4), or additional pretreatment with 5%, 10%, or 15% citric acid (three groups, n=4 each). Thereafter the pieces were washed and buffered to a physiologic pH. This was followed by seeding of human endothelial cells (5 × 10 6 cells). On the basis of the results of these pilot tests, complete glutaraldehyde-fixed aortic roots treated with 10% citric acid were subjected to cell seeding. The valves were seeded with endothelial cells (4.3 × 10 6 cells) either alone (n = 4) or in combination with preseeding of autologous fibroblasts (2.4 × 10 7 cells, n=4). After each seeding procedure specimens of the free wall of the grafts were taken. In addition, one leaflet was taken for histologic examination after endothelial cell seeding, after 7 days, and after 21 days. Finally, two commercially available stentless aortic valve prostheses (Freestyle; Medtronic, Inc, Minneapolis, Minn) were treated with 10% citric acid and seeded with human fibroblasts and endothelial cells. Specimen were taken according to the glutaraldehyde-fixed aortic roots. Specimen of all experiments were examined with scanning electron microscopy. Frozen sections were stained immunohistochemically for collagen IV, factor VIII, and CD31. Results: On untreated glutaraldehyde-fixed aortic wall pieces, only poor adhesion (24%) was seen. No viable cells were found after 1 week. Cellular adhesion was best on aortic wall pieces pretreated with 10% citric acid. After 7 days, the cells formed a confluent layer. Endothelial cell seeding on citric acid-treated complete aortic valves showed 45% adhesion, but no confluent layer was found after 1 week. Preseeding of these valves with autologous fibroblasts resulted in an endothelial cellular adhesion of 76% and a confluent endothelial cell layer after 7 days. The layer remained stable for at least 21 days. Results of staining for collagen IV, factor VIII, and CD31 were positive on the luminal side of these valves, indicating the synthesis of matrix proteins and viability of the cells. Pretreatment of commercially available porcine valves with 10% citric acid and preseeding with autologous fibroblasts followed by endothelial cell seeding resulted in an adhesion of 78%. The cells formed a confluent cell layer after 7 days. Conclusions: Pretreatment of glutaraldehyde-fixed porcine aortic valves with citric acid established a surface more suitable for cellular attachment. Preseeding these valves with autologous fibroblasts resulted in a confluent endothelial cell layer on the luminal surface. Flow tests and animal experiments are necessary for further assessment of durability and shear stress resistance. J Thorac Cardiovasc Surg 2003;125:592-601

OBJECTIVE: The aim of this study was to provide nationally representative hospital-based emergency department (ED) estimate visits in children (aged ≤ 18 y) attributed to poisoning in the United States in 2008. METHODS: Nationwide Emergency Department Sample for the year 2008 was used. All ED visits among children (aged ≤ 18 y) with an external cause of injury for "poisoning" were selected for analysis. Demographic characteristics of the ED visits and outcomes examined included ED charges (EDCs), hospitalization charges (HCs), length of stay in hospital, and disposition after ED visit. RESULTS: During the year 2008, a total of 191,197 ED visits were attributed to poisoning with close to 56% of all ED visits occurring among those aged younger than 4 years. Boys comprised approximately 54% of all ED visits. After an ED visit, 87% were routinely discharged, and 7.3% were admitted into the same hospital. Forty-eight children died in the ED. The frequently reported poisonings included accidental poisoning by other drugs (44,219 ED visits); accidental poisoning by other gases and vapors (27,035 ED visits); and accidental poisoning by analgesics, antipyretics, and antirheumatics (22,334 ED visits). The mean EDC per visit was $1077. The total EDC across the entire United States was $171.8 million. Mean length of stay was 1.9 days. Among those who were hospitalized, the mean HC was $11,792. The total HC across the entire United States was $162.3 million. CONCLUSIONS: The current study provides nationally representative estimates of ED visits attributed to poisoning among children in the United States. High-risk groups and economics associated with treating these injuries are estimated. Language: en

To evaluate the accuracy of a tool developed to predict timing of death following withdrawal of life support in children.Pertinent variables for all pediatric deaths (age ≤ 21 years) from 1/2009 to 6/2014 in our pediatric intensive care unit (PICU) were extracted through a detailed review of the medical records. As originally described, a recently developed tool that predicts timing of death in children following withdrawal of life support (dallas predictor tool [DPT]) was used to calculate individual scores for each patient. Individual scores were calculated for prediction of death within 30 min (DPT30) and within 60 min (DPT60). For various resulting DPT30 and DPT60 scores, sensitivity, specificity and area under the receiver operating characteristic curve were calculated.There were 8829 PICU admissions resulting in 132 (1.5%) deaths. Death followed withdrawal of life support in 70 patients (53%). After excluding subjects with insufficient data to calculate DPT scores, 62 subjects were analyzed. Average age of patients was 5.3 years (SD: 6.9), median time to death after withdrawal of life support was 25 min (range; 7 min to 16 h 54 min). Respiratory failure, shock and sepsis were the most common diagnoses. Thirty-seven patients (59.6%) died within 30 min of withdrawal of life support and 52 (83.8%) died within 60 min. DPT30 scores ranged from -17 to 16. A DPT30 score ≥ -3 was most predictive of death within that time period, with sensitivity = 0.76, specificity = 0.52, AUC = 0.69 and an overall classification accuracy = 66.1%. DPT60 scores ranged from -21 to 28. A DPT60 score ≥ -9 was most predictive of death within that time period, with sensitivity = 0.75, specificity = 0.80, AUC = 0.85 and an overall classification accuracy = 75.8%.In this external cohort, the DPT is clinically relevant in predicting time from withdrawal of life support to death. In our patients, the DPT is more useful in predicting death within 60 min of withdrawal of life support than within 30 min. Furthermore, our analysis suggests optimal cut-off scores. Additional calibration and modifications of this important tool could help guide the intensive care team and families considering DCD.

Background The current study was designed to determine the relation between preoperative cerebral oxygen saturation (Sco2), variables of cardiopulmonary function, mortality, and morbidity in a heterogeneous cohort of cardiac surgery patients. Methods In this study, 1,178 consecutive patients scheduled for on-pump surgery were prospectively studied. Preoperative Sco2, demographics, N-terminal pro-B-type natriuretic peptide, high-sensitive troponin T, clinical outcomes, and 30-day and 1-yr mortality were recorded. Results Median additive EuroSCORE was 5 (range: 0-19). Thirty-day and 1-yr mortality and major morbidity (at least two major complications and/or a high-dependency unit stay of at least 10 days) were 3.5%, 7.7%, and 13.3%, respectively. Median minimal preoperative oxygen supplemented Sco2 (Sco2min-ox) was 64% (range: 15-92%). Sco2min-ox was correlated (all: P value 10), Sco2min-ox, and duration of cardiopulmonary bypass showed that a Sco2min-ox equal or less than 50% is an independent risk factor for 30-day and 1-yr mortality. Conclusions Preoperative Sco2 levels are reflective of the severity of cardiopulmonary dysfunction, associated with short- and long-term mortality and morbidity, and may add to preoperative risk stratification in patients undergoing cardiac surgery.

ObjectivesThrombogenity of small-diameter vascular prostheses might be reduced by complete coverage of the luminal surface with vascular cells. We investigated cell seeding on polyurethane vascular prostheses.MethodsThirty polyurethane vascular prostheses were divided into 3 groups of 10 each: group A, diameter of 20 mm and γ-sterilized; group B, diameter of 4 mm and γ-sterilized; and group C, diameter of 4 mm and ethylene oxide sterilized. Human smooth muscle cells, fibroblasts, and endothelial cells were isolated from saphenous vein segments and expanded in culture. Five polyurethane vascular prostheses of each group were seeded with endothelial cells alone (mean, 4.8 ± 1.2 × 106 cells), and the remaining 5 polyurethane vascular prostheses were preseeded with a mixed culture of fibroblasts and smooth muscle cells (mean, 7.7 ± 2.3 × 106 cells), followed by endothelial cell seeding (mean, 4.4 ± 0.9 × 106 cells). Seven days after cell seeding, the polyurethane vascular prostheses were perfused under a pulsatile flow (80 pulses/min, 140/80 mm Hg, and 120 mL/min) for 2 hours. Specimens were taken after each seeding procedure both before and after perfusion and then examined both with a scanning electron microscope and immunohistochemically.ResultsIsolated endothelial cell seeding revealed better initial adhesion in groups A and B than in group C (63% vs 33%). After 7 days, the cells had covered approximately 80% of the luminal surface in groups A and B, whereas group C cells rounded up and lost adhesion. After perfusion testing of group A and B prostheses, only 10% of the surface was still covered with endothelial cells. Preseeding with the mixed culture again revealed a better initial adhesion in groups A and B compared with that in group C (76% vs 41%). In groups A and B endothelial cell seeding (adhesion, 72%) resulted in a confluent endothelial cell layer. The results of immunohistochemical staining were positive for collagen IV, laminin, CD31, and Factor VIII. In group C only isolated cells were found after each seeding procedure, which rounded up and vanished during the next days. Perfusion testing of group A and B prostheses revealed that the confluent cell layer remained stable, with only small defects (

INTRODUCTION The main advantages of mitral homografts are preservation of the subvalvular apparatus and avoidance of life-long anticoagulation. In this communication, we will present our five-year experience using mitral homografts in mitral valve surgery. PATIENTS AND METHODS Since 1996, 14 patients (mean age 46 +/- 8 years, range 27 - 65 years have had mitral homografts implanted. Thirteen patients had mitral valve replacement; the septal leaflet of the tricuspid valve was replaced in one case. The indications were mitral (n = 6) or tricuspid endocarditis (n = 1), mitral valve stenosis (n = 3), and combined mitral valve disease (n = 4). Complete mitral homografts were implanted in eight patients; partial homografts were used in six cases. Preoperatively, the dimensions of the left ventricle and the mitral valve were measured by transoesophageal echocardiography (TOE). The mean left ventricular ejection fraction was 56 +/- 9%, the mean end-diastolic diameter 58 +/- 6 mm. The technique described by Acar/Carpentier was adapted for implantation; a Carpentier ring was implanted in all cases for annular stabilization. The patients had anticoagulative therapy which was discontinued when stable sinus rhythm was present after three months postoperatively. Follow-up included clinical examination, ECG, and echocardiography, and was initiated six months postoperatively and continued on a yearly basis. The following parameters were determined by echocardiography--left atrial size, left ventricular end-diastolic and end-systolic diameter, pressure gradient across the mitral valve (c/w Doppler, Bernoulli's equation), and mitral regurgitation. RESULTS All patients survived surgery; the mean operation-time was 281 +/- 37 minutes. Intraoperative TOE revealed a first degree insufficiency in 7 patients. Follow-up was completed in all patients, with a mean period of 30 months (6 - 60 months). Two patients had an acute endocarditis two years postoperatively, requiring repeat valve replacement with a mechanical prosthesis. An additional patient had to be reoperated due to chordal rupture three years postoperatively. All three patients had mitral valve stenosis as the initial indication for surgery and had received a complete homograft. In the remaining eleven patients, the morphological and functional state of the implanted grafts remained unchanged during follow-up. The freedom from valve-related events was 93% after one year, 86% after two years, and 79% after three years. At six-month follow-up, ECG and echocardiography revealed sinus rhythm and sufficient atrial contractions in 13 cases. At the last follow-up, the pressure gradients were 3.4 +/- 0.6 mmHg for complete homografts and 2.8 +/- 0.6 mmHg for partial homografts. In five cases, a mild insufficiency was documented, while six patients presented with competent grafts. CONCLUSIONS Mitral homografts can be used with acceptable mid-term results in selected cases with good left ventricular function and only slightly dilated left ventricles. Partial mitral homografts represent an additional technique, especially for mitral valve repair in patients with acute endocarditis. The susceptibility to bacterial infections of a homograft makes strict prophylaxis against endocarditis mandatory.

Pyrimethamine isethionate administered in 6% DMAA to rats on Days 10, 10 and 11, and 10, 11, and 12 of pregnancy at levels of 52.5 and 75 mg per kilogram rat caused fetal resorptions and malformations. A single dose on Day 10 was most destructive of pregnancy, while two injections on Days 10 and 11 seemed the least destructive treatment. This tendency was even more evident in the data for fetal size, where the quadratic response was highly significant for both CRL and weight. The incidence and severity of the abnormalities reflect the same effects of timing of the dose. By contrast, a single experiment with 45 mg per kilogram rat of pyrimethamine isethionate in 6% DMAA, 6% DMSO, or 95% ethanol showed that the effect of the antagonist was cumulative when administered in either DMSO or ethanol, but after administration in DMAA, the response-dose relation followed a parabolic curve. Statistical analysis of the size data reveals a significant dose-solvent interaction, and it appears that the effect of the teratogenic agent is confounded with solvent effects. Two attempts to reverse the effects of pyrimethamine isethionate by injections of folic acid 1 hour prior to the injections of the antagonist were without apparent effect.