An Exploratory Study Using Next-Generation Sequencing to Identify Prothrombotic Variants in Patients with Cerebral Vein Thrombosis.

Prothrombotic hereditary risk factors for cerebral vein thrombosis (CVT) are of clinical interest to better understand the underlying pathophysiology and stratify patients for the risk of recurrence. This study explores prothrombotic risk factors in CVT patients. An initial screening in patients of the outpatient clinic of the Department of Transfusion Medicine and Hemostaseology of the University Hospital Erlangen, Germany, revealed 183 patients with a history of CVT. An initial screening identified a number of common prothrombic risk factors, including Factor V Leiden (rs6025) and Prothrombin G20210A (rs1799963). All patients without relevant findings (58 individuals) were invited to participate in a subsequent genetic analysis of 55 relevant genes using next-generation sequencing (NGS). Three intron variants (ADAMTS13: rs28446901, FN1: rs56380797, rs35343655) were identified to occur with a significantly higher frequency in the CVT patient cohort compared to the general European population. Furthermore, the combined prevalence of at least two of four potentially prothrombic variants (FGA (rs6050), F13A1 (rs5985), ITGB3 (rs5918), and PROCR (rs867186)) was significantly higher in the CVT subjects. The possible impact of the identified variants on CVT is discussed.

Coupled Interactions at the Ionic Graphene-Water Interface.

We compute ionic free energy adsorption profiles at an aqueous graphene interface by developing a self-consistent approach. To do so, we design a microscopic model for water and put the liquid on an equal footing with the graphene described by its electronic band structure. By evaluating progressively the electronic and dipolar coupled electrostatic interactions, we show that the coupling level including mutual graphene and water screening permits one to recover remarkably the precision of extensive quantum simulations. We further derive the potential of mean force evolution of several alkali cations.

SALARECON connects the Atlantic salmon genome to growth and feed efficiency.

Atlantic salmon (Salmo salar) is the most valuable farmed fish globally and there is much interest in optimizing its genetics and rearing conditions for growth and feed efficiency. Marine feed ingredients must be replaced to meet global demand, with challenges for fish health and sustainability. Metabolic models can address this by connecting genomes to metabolism, which converts nutrients in the feed to energy and biomass, but such models are currently not available for major aquaculture species such as salmon. We present SALARECON, a model focusing on energy, amino acid, and nucleotide metabolism that links the Atlantic salmon genome to metabolic fluxes and growth. It performs well in standardized tests and captures expected metabolic (in)capabilities. We show that it can explain observed hypoxic growth in terms of metabolic fluxes and apply it to aquaculture by simulating growth with commercial feed ingredients. Predicted limiting amino acids and feed efficiencies agree with data, and the model suggests that marine feed efficiency can be achieved by supplementing a few amino acids to plant- and insect-based feeds. SALARECON is a high-quality model that makes it possible to simulate Atlantic salmon metabolism and growth. It can be used to explain Atlantic salmon physiology and address key challenges in aquaculture such as development of sustainable feeds.

Repair of common arterial trunk: palliation and delayed correction as a viable alternative strategy in selected patients.

OBJECTIVES: Primary repair of common arterial trunk (CAT) is burdened by high mortality rates, especially in the presence of multiple risk factors. Timing, possible palliative methods, optimal management of associated cardiac lesions and handling of a poor preoperative state are still under discussion. METHODS: We retrospectively analysed all patients who underwent surgery for CAT in our institution between 2008 and November 2020. We included 22 patients, 11 of whom received primary correction (PC) and 11 of whom underwent initial palliation by partial repair, leaving the ventricular septal defect open and connecting the right ventricle to the pulmonary arteries with a small valveless right ventricle-to-pulmonary artery conduit. A delayed correction (DC) was performed after 11.5 ± 3.6 months. RESULTS: The overall operative mortality was 4.5%; 1 patient (affected by severe truncal valve stenosis and presenting in a poor state preoperatively) in the DC group died after palliation. The incidence of postoperative pulmonary hypertensive crisis was significantly higher in the PC group (P = 0.027). No patient from either group required postoperative extracorporeal support. Survival rates after 6 years differed slightly (PC group, 90%; DC group, 70%; log-rank = 0.270). CONCLUSIONS: PC of CAT remains an optimal surgical approach for patients with an expected low mortality. However, our data support palliation and DC as a suitable alternative strategy, especially in the presence of significant risk factors like interrupted aortic arch, poor preoperative condition or complex surgical anatomy.

Borophenes made easy.

To date, the scalable synthesis of elemental two-dimensional materials beyond graphene still remains elusive. Here, we introduce a versatile chemical vapor deposition (CVD) method to grow borophenes, as well as borophene heterostructures, by selectively using diborane originating from traceable byproducts of borazine. Specifically, metallic borophene polymorphs were successfully synthesized on Ir(111) and Cu(111) single-crystal substrates and conjointly with insulating hexagonal boron nitride (hBN) to form atomically precise lateral borophene-hBN interfaces or vertical van der Waals heterostructures. Thereby, borophene is protected from immediate oxidation by a single hBN overlayer. The ability to synthesize high-quality borophenes with large single-crystalline domains in the micrometer scale by a straight-forward CVD approach opens up opportunities for the study of their fundamental properties and for device incorporation.

Spontaneous liquid water dissociation on hybridised boron nitride and graphene atomic layers from ab initio molecular dynamics simulations.

Two-dimensional materials such as graphene (G) and hexagonal boron nitride (BN) have demonstrated potential applications in membrane science and in particular for the harvesting of blue energy. Although pure G and BN atomic layers are known to remain inert towards neutral water, one may wonder about the aqueous reactivity of hybridized monolayers formed by joining BN and G sheets in a planar fashion. Here, we perform ab initio molecular dynamics calculations of liquid water in contact with all possible planar heterostructures. Remarkably, we could observe the spontaneous chemisorption and dissociation of the interfacial water molecule into its self-ions at one specific and non-standard one-dimensional border. Our simulations predict that this type of heterostructure is prone to ionize liquid water in the absence of any electrical gating.

On-Surface Synthesis of Nonmetal Porphyrins.

We report the on-surface synthesis of a nonmetal porphyrin, namely, silicon tetraphenylporphyrin (Si-TPP), by the deposition of atomic silicon onto a free-base TPP layer on a Ag(100) surface under ultrahigh vacuum (UHV) conditions. Scanning tunneling microscopy provides insights into the self-assembly of the TPP molecules before and after Si insertion. Silicon coordinates with all four nitrogen atoms of the TPP macrocycle and interacts with a silver atom of the substrate as confirmed by scanning tunneling spectroscopy, X-ray photoelectron spectroscopy, and complementary density functional theory calculations. The Si-TPP complex presents a saddle-shaped conformation that is stable under STM manipulation. Our study shows how protocols established for the on-surface metalation of tetrapyrroles can be adopted to achieve nonmetal porphyrins. Complementary experiments yielding Si-TPP and Ge-TPP on Ag(111) highlight the applicability to different main group elements and supports. The success of our nonmetal porphyrin synthesis procedure is further corroborated by a temperature-programmed desorption experiment, revealing the desorption of Ge-TPP. This extension of interfacial complex formation beyond metal elements opens promising prospects for new tetrapyrrole architectures with distinct properties and functionalities.

Pressure correction for solvation theories.

Liquid state theories such as integral equations and classical density functional theory often overestimate the bulk pressure of fluids because they require closure relations or truncations of functionals. Consequently, the cost to create a molecular cavity in the fluid is no longer negligible, and those theories predict incorrect solvation free energies. We show how to correct them simply by computing an optimized Van der Walls volume of the solute and removing the undue free energy to create such volume in the fluid. Given this versatile correction, we demonstrate that state-of-the-art solvation theories can predict, within seconds, hydration free energies of a benchmark of small neutral drug-like molecules with the same accuracy as day-long molecular simulations.

Reduction of exposure to plasticizers in stored red blood cell units.

INTRODUCTION: Plastic can be toxic and hazardous to an organism's health, but it is being widely used in our daily lives. Di-2-ethylhexyl-phthalate is the most common plasticizer in medical devices made of polyvinylchloride and is commonly found in soft bags storing red blood cell units. Di-2-ethylhexyl-phthalate and its degradation product mono-2-ethylhexyl-phthalate can migrate into human body fluids, for example, blood and tissues. The aim of the study was to assess the concentration of plasticizers in red blood cell units according to storage time and after mechanical rinsing using a cell salvage device. METHODS: Levels of di-2-ethylhexyl-phthalate and mono-2-ethylhexyl-phthalate were analysed in 50 unwashed red blood cell units using liquid chromatography coupled with tandem mass spectrometry. In addition, phthalate concentrations were measured before and after mechanical rinsing in six more washed red blood cell units with storage times ranging between 36 and 56 days. A linear regression model was determined by the daily increase of di-2-ethylhexyl-phthalate and mono-2-ethylhexyl-phthalate in the stored red blood cell units subject to their storage time (range = 4-38 days), and the effect of mechanical rinsing on their phthalate concentration was calculated. RESULTS: A linear correlation was found between storage time of unwashed red blood cell units and the concentration of di-2-ethylhexyl-phthalate (p < 0.001) or mono-2-ethylhexyl-phthalate (p < 0.001). Stored red blood cell units older than 14 days had significantly higher concentrations of both contaminants than red blood cell units of shorter storage time (p < 0.001). Mechanical rinsing in washed red blood cell units attained a reduction in the di-2-ethylhexyl-phthalate and mono-2-ethylhexyl-phthalate concentration by a median of 53% (range = 18-68%; p = 0.031) and 87% (range = 68-96%; p = 0.031), respectively. CONCLUSION: Leaching of di-2-ethylhexyl-phthalate and mono-2-ethylhexyl-phthalate into red blood cell units depends on the duration of storage time. Plasticizers can be significantly reduced by mechanical rinsing using cell salvage devices, and thus, red blood cell units can be regenerated with respect to chemical contamination.

Pain response in a population-based study of radium-223 (Ra223) for metastatic castration-resistant prostate cancer.

INTRODUCTION: Clinical trials have shown that radium-223 (Ra223) can prolong survival and improve quality of life in patients with metastatic castration-resistant prostate cancer (mCRPC). The objectives of this study were to evaluate pain responses with Ra223 at a population-based level and to determine if there is an association between pain response and alkaline phosphatase (ALP) response. METHODS: All patients from the Vancouver and Kelowna Cancer Centers (CC) in British Columbia who were treated with Ra223 between June 2015 and December 2016 were identified. Patients completed the Brief Pain Inventory (BPI) just prior to each Ra223 injection. Pain response was defined as a two or more point improvement in worst pain relative to baseline, without an increase in pain medication level. ALP was determined at each visit, with a response threshold defined as a 30% decrease from baseline, consistent with the definition of response used in the ALSYMPCA trial. RESULTS: A total of 65 patients in Vancouver and Kelowna CC received Ra223 during the study period and 56 patients had at least one BPI record, of which 44 (79%) patients were assessable for change in worst pain. Of the assessable patients, 23 (52%, 95% confidence interval [CI] 38-67) had a pain response, although the use of concurrent external beam radiotherapy was a confounder in four cases. Of the 44 patients assessable for change in worst pain, 59% had ALP responses greater than 30%. An ALP response was seen in 56% of pain-responders vs. 43% of non-pain-responders. There was no association between pain response and ALP response (Phi =-0.05; p=0.77). CONCLUSIONS: Ra223 administration was associated with a meaningful pain response rate in this cohort. There was no correlation between pain response and ALP response.

Deep hypothermic circulatory arrest or tepid regional cerebral perfusion: impact on haemodynamics and myocardial integrity in a randomized experimental trial.

OBJECTIVES: Organ protective management during aortic arch surgery comprises deep hypothermic (18°C) circulatory arrest (DHCA), or moderate hypothermia (28°C/ 'tepid') with regional cerebral perfusion (TRCP). The aim of this experimental study was to evaluate the effect of distinct organ protective management on hemodynamic performance and myocardial integrity. METHODS: Ten male piglets were randomized to group DHCA (n = 5) or TRCP (n = 5) group and operated on cardiopulmonary bypass (CPB) with 60 min of aortic cross-clamping. Blood gas analysis was performed throughout the experiment. Haemodynamic assessment was performed using a thermodilution technique before and after CPB. Myocardial biopsies were taken 2 h after CPB and evaluated using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling assay and western blot analysis. RESULTS: At reperfusion, levels of central venous saturation were significantly higher (P = 0.016) and levels of lactate significantly lower (P = 0.029) in the DHCA group. After CPB, thermodilution measurements revealed higher stroke volume and lower peripheral resistance in the TRCP group (P = 0.012 and 0.037). At the end of the experiment, no significant differences regarding laboratory and haemodynamic parameters were evident. All specimens showed enrichment of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling-positive cells exclusively at the left ventricular subendocardium with no difference between groups and equal concentrations of cyclo-oxygenase-2. CONCLUSIONS: TRCP is associated with decreased peripheral resistance and higher stroke volume immediately after CPB. However, this beneficial effect is contrasted by signs of lower body hypoperfusion, which is expressed by lower central venous saturations and higher lactate levels. Distinct strategies of organ protection did not seem to affect apoptotic/necrotic and inflammatory changes in the left ventricular myocardium.

Accuracy of Prehospital Triage in Selecting Severely Injured Trauma Patients.

Importance: A major component of trauma care is adequate prehospital triage. To optimize the prehospital triage system, it is essential to gain insight in the quality of prehospital triage of the entire trauma system. Objective: To prospectively evaluate the quality of the field triage system to identify severely injured adult trauma patients. Design, Setting, and Participants: Prehospital and hospital data of all adult trauma patients during 2012 to 2014 transported with the highest priority by emergency medical services professionals to 10 hospitals in Central Netherlands were prospectively collected. Prehospital data collected by the emergency medical services professionals were matched to hospital data collected in the trauma registry. An Injury Severity Score of 16 or more was used to determine severe injury. Main Outcomes and Measures: The quality and diagnostic accuracy of the field triage protocol and compliance of emergency medical services professionals to the protocol. Results: A total of 4950 trauma patients were evaluated of which 436 (8.8%) patients were severely injured. The undertriage rate based on actual destination facility was 21.6% (95% CI, 18.0-25.7) with an overtriage rate of 30.6% (95% CI, 29.3-32.0). Analysis of the protocol itself, regardless of destination facility, resulted in an undertriage of 63.8% (95% CI, 59.2-68.1) and overtriage of 7.4% (95% CI, 6.7-8.2). The compliance to the field triage trauma protocol was 73% for patients with a level 1 indication. Conclusions and Relevance: More than 20% of the patients with severe injuries were not transported to a level I trauma center. These patients are at risk for preventable morbidity and mortality. This finding indicates the need for improvement of the prehospital triage protocol.

Comparable Cerebral Blood Flow in Both Hemispheres During Regional Cerebral Perfusion in Infant Aortic Arch Surgery.

BACKGROUND: Cerebral protection during aortic arch repair can be provided by regional cerebral perfusion (RCP) through the innominate artery. This study addresses the question of an adequate bilateral blood flow in both hemispheres during RCP. METHODS: Fourteen infants (median age 11 days [range, 3 to 108]; median weight, 3.6 kg [range, 2.8 to 6.0 kg]) undergoing RCP (flow rate 54 to 60 mL · kg-1 · min-1) were prospectively included. Using combined transfontanellar/transtemporal two- and three-dimensional power/color Doppler sonography, cerebral blood flow intensity in the main cerebral vessels was displayed. Mean time average velocities were measured with combined pulse-wave Doppler in the basilar artery, and both sides of the internal carotid, anterior, and medial cerebral arteries. In addition, bifrontal regional cerebral oximetry (rSO2) was assessed. Comparing both hemispheres, measurements were performed at target temperature (28°C) during full-flow total body perfusion (TBP) and RCP. RESULTS: A regular circle of Willis with near-symmetric blood flow intensity to both hemispheres was visualized in all infants during both RCP and TBP. In the left internal carotid artery, blood flow direction was mixed (retrograde, n = 5; antegrade, n = 8) during TBP and retrograde during RCP. Comparison between sides showed comparable cerebral time average velocities and rSO2, except for higher time average velocities in the right internal carotid artery (TBP p = 0.019, RCP p = 0.09). Unilateral comparison between perfusion methods revealed significantly higher rSO2 in the right hemisphere during TBP (82% ± 9%) compared with RCP (74% ± 11%, p = 0.036). CONCLUSIONS: Bilateral assessment of cerebral rSO2 and time average velocity in the main great cerebral vessels suggests that RCP is associated with near-symmetric blood flow intensity to both hemispheres. Further neurodevelopmental studies are necessary to verify RCP for neuroprotection during aortic arch repair.

Goal-directed-perfusion in neonatal aortic arch surgery.

Reduction of mortality and morbidity in congenital cardiac surgery has always been and remains a major target for the complete team involved. As operative techniques are more and more standardized and refined, surgical risk and associated complication rates have constantly been reduced to an acceptable level but are both still present. Aortic arch surgery in neonates seems to be of particular interest, because perfusion techniques differ widely among institutions and an ideal form of a so called "total body perfusion (TBP)" is somewhat difficult to achieve. Thus concepts of deep hypothermic circulatory arrest (DHCA), regional cerebral perfusion (RCP/with cardioplegic cardiac arrest or on the perfused beating heart) and TBP exist in parallel and all carry an individual risk for organ damage related to perfusion management, chosen core temperature and time on bypass. Patient safety relies more and more on adequate end organ perfusion on cardiopulmonary bypass, especially sensitive organs like the brain, heart, kidney, liver and the gut, whereby on adequate tissue protection, temperature management and oxygen delivery should be visualized and monitored.

Comparison of patient-reported outcomes with single versus multiple fraction palliative radiotherapy for bone metastasis in a population-based cohort.

BACKGROUND: Despite randomized control trials showing equivalent efficacy between single-fraction (SF) and multiple-fraction (MF) radiation therapy (RT) for bone metastases (BoM), considerable variation in fractionation exists. We compared patient-reported outcomes (PROs) following SF versus MF RT in a population-based cohort. METHODS: PROs were chosen to assess patients' perception of pain, function, and symptom frustration. Total score was the sum of the 3 questions. RESULTS: 968 patients completed pre and post-RT PROs, 35% (335) had complicated BoM. Overall, there were no differences in total score improvement (79% vs. 83%; p=0.13), nor for complicated BoM (77% vs. 84%; p=0.12), SFRT and MFRT respectively. On multivariate analysis no differences in improvement in total score were observed between SFRT and MFRT overall (OR=0.71; 95% CI 0.49-1.02; p=0.06), nor for complicated BoM (OR=0.74; 95% CI 0.39-1.39; p=0.35). In the complicated BoM subset, pain complete response (CR) (19% vs. 33%; p=0.01) and functional improvement occurred more commonly in the MFRT group (69% vs. 81%; p=0.04). CONCLUSION: Improvements in PROs for pain, function and symptom frustration were similar between SFRT and MFRT supporting the use of hypofractionated regimens. Using a simple, 3-question, telephone-based questionnaire to assess response to palliative RT is a feasible strategy to collect PROs.

Myocardial Protection During Aortic Arch Repair in a Piglet Model: Beating Heart Technique Compared With Crystalloid Cardioplegia.

BACKGROUND: Selective myocardial perfusion enables repair of congenital aortic arch obstruction without cardiac arrest. This study was inspired by the lack of prospective controlled studies of the beating heart (BH) technique compared with cold crystalloid cardioplegia (CC) regarding effects on myocardial performance, ischemic damage, and serum electrolyte levels. METHODS: In a prospective study, 20 male piglets weighing 11.1 ± 1.3 kg were operated on using cardiopulmonary bypass (CPB) and underwent 60 minutes of aortic cross-clamping. According to prospective randomization, myocardial protection included either a BH modification with selective myocardial perfusion using an individual roller pump or CC. Hemodynamic performance was evaluated by a conductance catheter technique before and after CPB and calculated in relation to baseline levels. Laboratory analysis included blood levels of troponin T and serum electrolytes. RESULTS: Eighteen piglets entered analysis. There were significantly higher slopes of end-systolic pressure-volume relations (168% ± 92% versus 89% ± 16%; p = 0.046) and preload-recruitable stroke work (PRSW) (139% ± 37% versus 103% ± 31%; p = 0.040) in BH piglets compared with those who underwent CC. Laboratory analysis during reperfusion revealed higher levels of troponin T (1.31 ± 0.28 ng/mL versus 0.49 ± 0.17 ng/mL; p < 0.01) and sodium (131 ± 4 mmol/L versus 120 ± 8 mmol/L; p = 0.003) and lower levels of potassium (4.8 ± 0.4 mmol/L versus 6.4 ± 1.0 mmol/L; p = 0.001) with BH compared with CC, whereas no significant differences were calculated at the end of the experiment. CONCLUSIONS: The BH technique is associated with improved contractility compared with standard CC. There is comparable ischemic damage in both groups, with an earlier rise in blood levels of troponin T after BH and more fluctuation of serum electrolytes with CC. Evidence of ischemic changes should dissuade one from using the BH technique imprudently.