bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of equivocal small cystic pancreatic lesions with spectral-detector computed tomography
Authors: Laukamp Kai Roman , Tirumani Sree Harsha , Lennartz Simon , Hokamp Nils Große , Gupta Amit , Pennig Lenhard , Persigehl Thorsten , Gilkeson Robert , Ramaiya Nikhil
Published: April 2020

Background

Evaluation of small cystic lesions of the pancreas remains a challenging task, as due to their size appearance can be rather hypodense than clearly fluid-filled.

Purpose

To evaluate whether additional information provided by novel dual-layer spectral-detector computed tomography (SDCT) imaging can improve assessment of these lesions.

Material and Methods

For this retrospective study, we reviewed reports of 1192 contrast-enhanced portal-venous phase SDCT scans of the abdomen conducted between May 2017 and January 2019. On basis of the radiological report 25 small (≤1.5 cm) cystic pancreatic lesions in 22 patients were identified, in which additional short-term follow-up imaging was recommended to confirm/clarify cystic nature. Conventional images (CI) and spectral images (SI) including virtual-monoenergetic images at 40 keV (VMI), iodine-density and iodine-overlay images were reconstructed. Two readers indicated lesion conspicuity and confidence for presence of cystic nature on three-point scales. First, solely CI were evaluated, while in a second reading after a four-week interval, the combination of CI and corresponding SI were reviewed. Quantitatively, ROI-based mean attenuation was measured in CI and VMI.

Results

In the subjective reading, SI significantly improved lesion conspicuity (CI 2 [1–2], SI 3 [2–3], P < 0.001) and confidence regarding presence of cystic nature (CI 2 [1–2], SI 3 [3–3], P < 0.001). Inter-observer agreement depicted by intraclass correlation coefficient improved considerably from 0.51 with only CI to 0.85 when the combination with SI was used. Further, VMI displayed significantly higher signal-to-noise (CI 1.2 ± 0.8, VMI 3.2 ± 1.8, P < 0.001) and contrast-to-noise ratios (CI 2.6 ± 0.8, VMI 4.7 ± 1.9).

Conclusion

Compared to CI alone, combination with SI significantly improves visualization and confidence in evaluation of small equivocal cystic pancreatic lesions.
Guaranteeing prescribed performance fast tracking control of air-breathing hypersonic vehicles
Authors: Cheng Zian , Chen Fuyang , Hu Kaiyu
Published: April 2020

This paper investigates a fast-tracking controller with prescribed performance for flexible air-breathing hypersonic vehicles subject to uncertain parameters, external disturbances, actuator faults and backlash non-linearity. For the velocity and altitude dynamics, a prescribed performance control scheme is respectively utilized to provide preselected bounds on the transient and steady characteristics of tracking errors, also it can effectively relieve the constraint of scramjet on the angle of attack. A sliding mode exact observer is introduced to estimate the lumped disturbance, meanwhile the analytic differential computation on virtual controllers is avoided in the back-stepping design for altitude tracking. Based on prescribed performance control and sliding mode exact observer, the non-singular fast terminal sliding mode technology is introduced to design a control law, which is capable of ensuring both velocity and altitude tracking errors converge into the prescribed sets in finite-time. Simulations on the high-fidelity air-breathing hypersonic vehicle mode are implemented to highlight the effectiveness of the developed controller.
Mechanical properties of hexagonal boron nitride monolayers: Finite element and analytical predictions
Authors: Georgantzinos SK , Kariotis K , Giannopoulos GI , Anifantis NK
Published: April 2020

The mechanical response of two-dimensional nanostructures may be significantly affected by their size. In this work, a molecular structural mechanics model is developed and is implemented in order to predict the nanomechanical behavior and calculate the corresponding elastic properties of hexagonal boron nitride sheets and describe their size-dependence. The finite element approach utilizes appropriate spring-like elements for the modeling of interactions between atoms within the hexagonal boron nitride structure, the stiffness constants of which are obtained by the molecular mechanics theory. Adopting conventional finite element techniques, the global stiffness matrix of the structure of a desired sheet size can be assembled. Applying appropriate boundary conditions, the governing equilibrium static equation can be solved and the elastic mechanical properties as Young’s modulus, shear modulus, and Poisson’s ratio of the structure can be calculated. Fitting the results of the mechanical properties calculated by the finite element analysis, analytical–empirical equations are proposed for their direct prediction for an hexagonal boron nitride sheet having the size parameters of the structure as independent variables.
Mathematical and simulation analysis of natural convection heat transfer for DC–DC converter
Authors: Kumar Vipan , Garg Harry , Singh Chetandeep , Kandoria Sucheta , Karar Vinod
Published: April 2020

Thermal management of electronic systems is the utmost concern to achieve optimum efficiency under space and weight constraints. For the optimal functioning of a system, the heat generated by the electronic components needs to be dissipated efficiently. The passive cooling technique is extensively used in electronic systems, wherein the more contact surface area of a heat source and the surroundings are utilized. This paper focuses on mathematical and simulation analysis for different types of heat sink designs for the 30 W multi-output DC–DC converter. Heat sink with inverted trapezoidal fins has resulted in efficient thermal management of the converter at its safe operating temperature of 398 K. Results show that the maximum temperature attained by the converter was 352 K which was in the safe operating zone of the converter. A comparative study of the effectiveness of heat dissipation with respect to maximum temperature attained has been discussed. Mathematical verification of Rayleigh number for different heat sink designs has also been carried out for its critical value.
Coupled tribo-dynamic modelling of linear guideways for high precision machining application
Authors: Soleimanian Parivash , Mohammadpour Mahdi , Ahmadian Hamid
Published: April 2020

Linear guideways play a crucial role in determining precision of machine tools. Understanding their dynamic response is essential for objectively controlling their behavior and performance in operation. Due to highly loaded lubricated contacts, mixed-elastohydrodynamic regime is dominant. The mixed-elastohydrodynamic film maintains the coupling between horizontal degree of freedom (feed velocity) and vertical degree of freedom (loading direction). This paper presents a novel tribo-dynamic solution for linear guideways, taking in to account the lubricant effects and coupling between horizontal and vertical degrees of freedom. An analytical tribology model is used implicitly within the dynamic model. For in-depth tribological quantities including pressure and film thickness distribution, an explicit full numerical solution for mixed-elastohydrodynamic is utilized. Results show that the coupled solution of vertical and horizontal degrees of freedom taking in to account lubricated contacts is essential. It is shown that at moderate and light loads, the effect of this coupling and presence of lubricant is more pronounced.
The effectiveness of mHealth interventions on postpartum depression: A systematic review and meta-analysis
Authors: Zhou Chuqing , Hu Hua , Wang Chunyi , Zhu Ziyu , Feng Gengchen , Xue Jingping , Yang Ziyi
Published: April 2020

Introduction

Postpartum depression (PPD) is a common psychiatric condition during the postnatal period that negatively impacts the well-being of both the mother and her infant. This study describes a systematic review and preliminary meta-analysis to assess the efficacy of mobile health (mHealth) interventions, which is defined as the use of portable electronic devices to support public health and medical practice, in addressing depressive symptoms among postpartum women.

Methods

Databases including PubMed, PsycINFO, the Cochrane Library, Embase and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) assessing the effectiveness of mHealth interventions on PPD from database inception to December 2019.

Results

The initial search identified 754 studies, of which, 11 studies fulfilled the inclusion criteria. These studies evaluated four types of distinct mHealth interventions and involved 2424 participants across six countries. Pooled results demonstrated that compared to the controls, the Edinburgh Postnatal Depression Scale score decreased in the mHealth intervention group (mean difference: –1.09, 95% confidence interval: –1.39 to –0.79).

Discussion

Our study suggested that mHealth interventions may be a promising tool to complement routine clinical care in the prevention and treatment of PPD, but the clinical effectiveness of mHealth interventions needs to be better established. While most studies focused on telephone-based interventions, recent researches have also suggested the superiority and effectiveness of short messaging service (SMS) and smartphone applications, but the exact efficacy needs further evaluation. Therefore, more high-quality RCTs on app-based and SMS-based interventions are needed before the large-scale roll-out of these interventions in clinical practice.
Introduction Special Issue “Paradoxical orders: Parenting encounters, the welfare state, and difference in Europe”
Authors: de Koning Anouk , Johansen Mette-Louise , Marchesi Milena
Published: April 2020

This special issue examines welfare programs as sites where Europe’s increasingly diverse societies are being shaped and negotiated. It zooms in on parenting as a central governmental domain where concerns about, and hopes for, the future of society intersect with notions of citizenship, family care, welfare, and deservingness of public resources. In this introduction to the special issue, we draw out three paradoxical orders that shape the encounters between migrant parents and welfare actors we have studied. One is concerned with the tension between the universal and difference, the other with the re-articulation of the public and the private, and a third with irreconcilable social and institutional demands. This helps us understand how Europe’s diverse societies are being shaped on the ground, beyond the often strongly racialized, nationalist rhetoric that has come to dominate public debates.
Exploring mistakes and errors of professional judgement in social work in China and Italy: The impact of culture, organization and education
Authors: Sicora Alessandro , Lu Wei , Lei Jie
Published: April 2020

This article reports the results of an exploratory comparative study that investigated errors made by social work practitioners. Two groups of social workers, one in Italy and one in Mainland China, answered questions about the causes and effects of mistakes, professional errors and reactions to errors committed by their colleagues, and the influence of intuition on the decision-making process that generates mistakes and errors of professional judgement.

Findings

The most salient differences between the Italian and Chinese respondents related to their willingness to talk about their mistakes and their confidence in the training received. A longer social work tradition in Italy helps practitioners in that country to feel stronger and to engage in a reflective learning process rather than defensive actions. As members of a new and not yet fully recognized profession, social workers in Mainland China are more likely to blame external circumstances for negative outcomes. Both groups shared the same positive consideration of intuition and the risk of losing service users’ trust.

Applications

The purpose of the article is to foster better understanding of errors and mistakes in social work, as well as more open discussion and reflection on social work practice and how to prevent negative outcomes.
Radial club hand treated with soft-tissue distraction and subsequent pin stabilization: mid- to long-term results
Authors: Pfister Georges , Le Hanneur Malo , Bachy Manon , Fitoussi Franck
Published: April 2020

Radial club hand deformities are commonly treated with arthrolysis to allow centralization of the ulna. In this retrospective cohort study of 31 hands in 28 patients, we aimed to assess the outcomes of correction using progressive distraction and subsequent percutaneous pinning of the wrist with a corrective ulnar osteotomy. Mean follow-up time was 7 years (range 2 to 20). The angulation of the hand–forearm complex was decreased after each step of the procedure. Mean correction of the angulation was 64°, and the residual total forearm–hand angulation was 12° after completion of the surgery. At the time of bony maturity (four patients), all wrists had fused. Fifty-eight reoperations were required in 31 wrists because of pin migration or breakage, and in addition 18 secondary osteotomies of the ulna were performed. From this study we conclude that distraction and pinning provide satisfactory and stable realignment of the wrist to correct the deformity, but this treatment has drawbacks regarding the high number of reoperations and the loss of wrist mobility.

Level of evidence: IV
Impact of depressive disorders on primary total shoulder arthroplasties: a matched control analysis of 113,648 Medicare patients
Authors: Swiggett Samuel J , Vakharia Ajit M , Ehiorobo Joseph O , Vakharia Rushabh M , Roche Martin W , Mont Michael A , Choueka Jack
Published: April 2020

Introduction

The purpose of this study was to investigate whether patients with depressive disorders undergoing primary total shoulder arthroplasty have higher rates of (1) in-hospital lengths of stay, (2) readmission rates, (3) medical complications, and (4) implant-related complications.

Methods

A retrospective query was performed using a national claims database. Study group patients were matched to controls in a 1:5 ratio according to age, sex, and medical comorbidities. The query yielded 113,648 patients who were with (n = 18,953) and without (n = 94,695) depressive disorders. Pearson’s χ 2 analyses were used to compare patient demographics. Logistic regression analyses were used to calculate odds-ratios of complications and readmission rates. Welch’s t-tests were used to test for significance for in-hospital lengths of stay. A p-value less than 0.003 was considered statistically significant.

Results

Study group patients had significantly longer in-hospital lengths of stay (2.7 days versus 2.3 days; p < 0.0001). Patients who have depressive disorders had higher incidences and odds of readmissions (9.4 versus 6.15%; odds-ratio: 1.6, p < 0.0001), medical complications (2.7 versus 0.9%; odds-ratio: 3.0, p < 0.0001), and implant-related complications (6.1 versus 2.4%; odds-ratio: 2.59, p < 0.0001) compared to controls.

Conclusion

Depressive disorder patients have longer in-hospital lengths of stay and increased odds of readmissions and complications following primary total shoulder arthroplasty.
Preparing teachers for transition to an international Christian school
Authors: Barnes Roslyn
Published: April 2020

The study reported here sought to gain insight into the experience of transition into teaching in an international Christian school that could inform the development of a pre-field orientation (PFO) programme for Australian Christian teachers. The experiences of five American teachers who had participated in a pre-field orientation programme was compared with the experiences of six Australian teachers who did not have access to such a programme. Based on the insights from participants gained through semi-structured interviews, recommendations are made regarding the content and structure of a PFO programme that could be developed for Australian teachers.
Aging-induced IL27Ra signaling impairs hematopoietic stem cells
Authors: He Hanqing , Xu Panglian , Zhang Xiaofei , Liao Min , Dong Qiongye , Cong Tingting , Tang Baixue , Yang Xiuxiu , Ye Maoqing , Chang Yingjun , Liu Weihua , Wang Xiaowo , Ju Zhenyu , Wang Jianwei
Published: April 2020

Hematopoietic stem cell (HSC) aging correlates with an increasing risk of myeloproliferative disease and immunosenescence. In this study, we show that aging-related inflammation promotes HSC aging through tumor necrosis factor-α (TNF-α)→ERK→ETS1→interleukin27Ra (IL27Ra) pathway. TNF-α, a well-known biomarker of inflammation, increases during aging and induces the expression of IL27Ra on HSCs via ERK-ETS1 signaling. Deletion of IL27Ra rescues the functional decline and myeloid bias of HSCs and also reverses the inhibitory effect of TNF-α on HSCs. Aged IL27Ra−/− mice had a reduced proportion of myeloid-biased HSCs and did not display the biased myeloid differentiation that occurs in aged wild-type mice. IL27Ra+ HSCs exhibit impaired reconstitution capacity and myeloid-bias compared with IL27Ra− HSCs and serve as a myeloid-recovery pool upon inflammatory insult. Inflammation-related genes were enriched in IL27Ra+ HSCs and this enrichment increases with aging. Our study demonstrates that age-induced IL27Ra signaling impairs HSCs and raises the possibility that interfering with IL27Ra signaling can counter the physiologically deleterious effect of aging on hematopoietic capacity.
Tissue Factor (TF) Activity in Trauma Patients Is Suppressed on Cell-Derived Microparticles (MP).
Authors: Horstman Lawrence L. , Jy Wenche , Bidot Carlos J. , Jimenez Joaquin J. , Ahn Yeon S.
Published: April 2020

BACKGROUND & AIMS. Traumatic injury is expected to expose or release into circulation large amounts of procoagulant material, including TF from subendothelial tissues, yet thrombosis is rarely an immediate concern. To investigate the basis of this, we measured TF activity and TF antigen (TF:Ag) associated with MP (believed to be a main carrier of circulating TF) in trauma patients.

METHODS. With IRB approval, two tubes of citrated blood were obtained upon admission from each of 18 patients and were processed within 2hr. Four patients were followed up 5–7 days later. MP were isolated from 0.9mL platelet-poor plasma (PPP) by centrifuging at 16,000g for 15min, then resuspending in 0.45mL Tris-saline pH 8.0 with brief (5sec) ultrasonic probe. Then 10uL was added to reaction mix (0.2mL final vol) in 96-well plate on ice containing physiologic amounts of FX, FVII, FVa, prothrombin, phospholipid and chromogenic substrate for thrombin, S-2238, then calcium to start reaction. Plate was then warmed (t=0) on metal block in 37° oven with fan and absorbance (OD) read at intervals from 6 min to 20min at 405nm. Known standards of pure thrombin and TF enabled conversion from OD to units of thrombin per ug TF/min. Flow cytometry was used to measure TF:Ag in PPP by fluorescent mAb.

RESULTS. (i) The apparent TF activity of patient MP was significantly or markedly reduced in 16 of 18 trauma patients, to as little as 10% of controls (mean of the 16 was 45.4%, median 47.7%). This was not seen in any other group of clinical patients. (ii) However, comparing rates of thrombin production by plotting log OD vs. time (giving straight line, R>0.97, as expected since thrombin accumulates in this method) revealed that final rates were often similar to controls. This was explained by prolonged lag phase in patients. Extrapolation back to OD=0.01 showed origin delayed by 2–8min in trauma patients relative to controls. (iii) Neither MP numbers or TF antigen differed significantly or consistently from controls; TF-positive MP in plasma were 529 ±196 vs. 581 ±279 per mL for patients and controls respectively.

CONCLUSIONS. Trauma patients do not exhibit elevated circulating TF activity on MP. The prolonged lag phase might be explained by presence of increased protective TFPI or cryptic state in patients, requiring more time for expression of full activity in assay medium, supported by other experiments showing that anti-TFPI restored normal or above-normal activity in trauma patients.
Treatment of B-CLL Cells with Bortezomib and Rituximab Reduces Cell Viability In Vitro..
Authors: Lewintre Eloisa Jantus , Sarsotti Elena , Terol Maria Jose , Benet Isabel , Martinez-Climent Jose A. , Garcia-Conde Javier
Published: April 2020

Introduction: In B-CLL, somatic mutation of IgVH genes defines a group of patients with favorable prognosis, whereas the absence of IgVH mutations is correlated with a worse outcome. Our previous data suggested that BCL-6 mutations identify a subgroup of patients with high risk of progression despite the presence of mutated IgVH gene, but the clinical significance of this molecular alteration remains uncertain. New approaches are now being tested for the treatment of B-CLL. Proteasome inhibitor, Bortezomib (Btz), and monoclonal antibodies specific for surface antigens, Rituximab (Rtx), represent potential therapeutic strategy.

Objetives: To study the effects of Btz and Rtx on viability of CLL cells in culture, and to correlate the responses to the mutational status of the samples.

Material and Methods: PBMC from 29 B-CLL patients (Binet stage A) were isolated by Ficoll-Hypaque gradient centrifugation. Samples were culture in RPMI supplemented with 20% FCS. Complement rabbit serum was added to the cultures in Rtx treated cells. Cells were exposed to various concentrations of Btz (0.1, 1 and 10 uM), Rtx (10 ug/ml) or both together during 24 hours. Then, cells were stained with Propidium Iodide and subjected to flow cytometry analysis.

Results: Btz and Rtx reduce viability of B-CLL cells in a dose and time dependent manner. The kinetic of both drugs were different, whereas Rtx reaches its maximun effect within 3 hours after treatment, Btz do the same after 48 hours. Combined treatment (Btz + Rtx) increases the effect of each one separately. All differences between treatments with increased doses of Btz + Rtx vs Btz alone were statistically significant. In the group of IgVH mutated patients, there were a significant difference in the response to Btz and Rtx in BCL-6 mutated (mut) and unmutated (unmut) groups (n= 10 and 8 respectively), whereas no significant differences were observed in the number of lymphocytes, lymphocyte doubling time, CD38 expression and cytogenetic alterations.

Effects of Btz and Rtx on IgVH mutated samples: correlation with BCL-6 mutations

BCL-6 Mean viability (%) SD p * * U. Mann Whitney test Control unmut 82.13 8.70 0.42 mut 86.36 6.01 Btz 0.1 uM unmut 49.05 10.39 0.006 mut 64.28 12.16 Btz 1 uM unmut 39.86 7.19 0.040 mut 53.27 13.35 Btz 10 uM unmut 30.21 7.41 0.041 mut 43.99 14.73 Rtx 10 ug/ml unmut 48.31 14.51 0.050 mut 34.62 12.51 Btz 0.1 uM + Rtx unmut 32.96 14.15 0.153 mut 24.50 10.01 Btz 1 uM + Rtx unmut 25.99 10.88 0.315 mut 19.89 7.53 Btz 10 uM + Rtx unmut 19.27 9.04 0.491 mut 16.31 7.52

Conclusion: Our data show that Btz and Rtx have in vitro activity on B-CLL cells, being used alone or in combination. Interesting, in IgVH mutated cells, Btz and Rtx have statistically significant differences in their in vitro activity on B-CLL cells according to their BCL-6 mutational status, but the biological significance of this differential responses remains unclear
Thrombophylic Profile of Fabry Patients in Argentina.
Authors: Aggio Mario C. , Martinez Pablo A.
Published: April 2020

Anderson-Fabry disease (AFD), described independently in the 1890s by William Anderson and Johann Fabry, is the second most frequent lysosomal storage disorder (after Gaucher disease). AFD is a pan-ethnic disorder due to a deficiency of the lysosomal enzime alpha-galactosidase A (alpha-GAL), with an estimated frequency of 1 in 117,000 male births, although recent studies suggest that the incidence may be underestimated, as certain patients with residual alpha-GAL activity (5 to 35% of normal levels) have disease too. Increased incidence of thrombotic events has been demonstrated in AFD. We evaluated the prevalence of prothrombotic risk factors in Argentine patients. Patients/methods: 36 patients (15 hemizygous and 21 heterozygous from 3 families) were studied for: protein C pathway (PCSys), antithrombin (AT), protein C (PC), protein S (PS), activated protein C resistance (APCR), lupus anticoagulant (LA), total plasma homocysteine (tHcy), anticardiolipin antibodies (ACA), and antiphosphatidylserine antibodies (APA). Results: The evaluation of PCSys, APCR, plasmatic levels of PC, PS, AT and APA were normal in all patients. Elevated levels of tHcy were found in 19.4% (n=7). Positive for LA were 38.9% (n=14) and for ACA 8.3% (n=3). Conclusions: 1) Our results confirm data from the literature reporting elevated homocysteinemia in AFD patients. Nutritional deficiencies, renal failure and metabolic disturbances are probable etiologic factors. 2) Thrombophilia was more frequent in hemizygous (13 patients, 86.7%) than in heterozygous (8 patients, 38.1%). Four hemizygous patients showed coexistence of two risk factors. 3) We found an unexpected high incidence of procoagulant autoantibodies. This association has also been reported and might contribute to thrombophilia in AFD: as in Gaucher disease, the accumulation of immunogenic glucocerebrosides might induce chronic immunostimulation.
Appliance of the DNA-Micro Array Technique for the Identification of Patients with Thrombophilic Diathesis. I-Comparison to the Classic PCR Analysis.
Authors: Tsaousidou Maria M.K.T. , Girtovitis Fotis F.I.G. , Boutou Afroditi A.K. , Pithara Elefteria E.P. , Makris Pantelis M.E.P.
Published: April 2020

Introduction: DNA Micro array have the ability to test a large number of samples for a large number of mutations on the same time, something practically impossible with the traditional hybridization methods. The goal of this study is to compare the ability of DNA micro array application to recognize genetic predisposition to thrombosis, with the one of RLF-PCR.

Material: DNA samples from 37 subjects (24 male with mean age 41.9 and 13 female with mean age 38.8) were studied both with micro arrays and PCR analysis. All of these subjects had a history of either recurrent thrombosis or thrombosis at unusual sites (e.g. retina’s central vein thrombosis).

Method: The thrombo-check microarray contains the following mutations and polymorphisms: Factor V Leiden (FV G1691A), FII G20210A (prothrombin mutation), FV Cambridge (FV G1091C), MTHFR C677T, MTHFR A1298C, CBS 844ins68, Plasminogen Activator Inhibitor (PAI 1 4G/5G). The thrombo-check microarray can distinguish between the normal sequence, as well as heterozygosity and homozygosity for the mutated sequence. To ensure the result is correct specific probes are included on the microarray to control for the RLF-PCR reaction, the hybridization reaction and the silver staining procedure. In addition, the correct functioning of the entire reaction can be checked using an external control DNA.

Results: As long as FVL and FII are concerned, in 35 out of 37 patients (pts) both methods gave similar results. However, the results of DNA analysis were different for the other two patients. The first one was found to be, using the micro array DNA method, a double heterozygous carrier of both FVL and FII mutations, while RLF-PCR did not relieve any such genetic defects. The other patient was found to be, using the RLF-PCR a homozygous carrier for the prothrombin mutation, while micro array also revealed heterozygous mutation of FV Leiden. Moreover, the micro array method detected totally 1 patient with FVC, 4 pts homozygous for MTHFR1, 6 pts homozygous for PAI and 4 pts homozygous for MTHFR2 mutation. Further more, micro array detected the co-existence of FVL and homozygocity in a) FII mutation (2 pts), b) PAI mutation (1patient) and c) MTHFR2 (2pts). Finally, 1 patient with FII was found to be also homozygous for MTHFR1 mutation.
Incorporation of a Comprehensive Pediatric Thrombosis Program into the Multidisciplinary Care Team for Children with Congenital Heart Disease: A Prospective Cohort Study.
Authors: Massicotte Mary Patricia , Rebeyka Ivan M. , Bauman Mary , Mitchell Lesley G. , Conradi Alf
Published: April 2020

BACKGROUND: Over the last 10 years, children with congenital heart disease (CHD) have been experiencing increased survival due to diagnostic and surgical techniques. However, associated with this is a requirement for prolonged central venous access which has serious associated sequelae, of which thrombosis is one of the most important. In a busy comprehensive cardiovascular program, the diagnosis, treatment and management of children with or at risk for thrombosis is extremely demanding and constantly changing based on current evidence based recommendations. The Stollery Children’s Hospital, a member of the Western Canadian Children’s Heart Network (WCCHN), is the cardiovascular surgical centre for children with CHD from British Columbia, Manitoba, Alberta, and Saskatchewan An expert Pediatric Thrombosis Team has been incorporated into the multi disciplinary management of children with CHD. This team is dedicated entirely to the diagnosis, management and long term followup of children requiring anticoagulation.

MATERIALS/METHODS: A standard approach to the diagnosis, management and long term followup of children with CHD with or at risk for thrombosis was initiated. The Pendragon data base was custom designed to prospectively collect the following data on all children: demographics, treatment and long term outcome.

RESULTS: Since the inception of the Thrombosis service (Oct 2003) there have been 325 children who required cardiac surgery with 40% (n=129) of these children requiring Thrombosis consultation. The 4 most common causes for Thrombosis referral have been primary prophylaxis post CHD surgery including mechanical valves, Blalock Taussig shunts, and Fontan procedures, 51% (n=66), suspected CVL related thrombosis 26% (n=33), arterial catheter related thrombosis (catheterization or monitoring) 16% (n=19), and extracorporeal membranous oxygenation 9% (n=11). By Oct 2004, it is anticipated that 300 children will have been consulted on.

CONCLUSIONS: The 1st year results of the data collected on this prospective cohort will be presented including demographics, reason for anticoagulation, diagnosis, and long term outcome.
Low Molecular Weight Heparin during Surgery in Parients on Long Term Oral Anticoagulant Treatment (OAT): A Prospective Observational Study.
Authors: Baudo Francesco , Mostarda Gianni , Ghirarduzzi Angelo , Molinatti Maurizio , Pengo Vittorio , Poli Daniela , Tosetto Alberto , Tiraferri Eros , Morra Enrica
Published: April 2020

The perioperative management of patients on long term OAT is an open issue. The problem is the prevention of both the thromboembolic (TE) and the hemorrhagic complications. The therapeutic options are: 1) discontinuation of OAT with an INR target <2.0 at the scheduled time and its resumption after surgery, 2) substitution of OAT with low molecular weight heparin (LMWH) in the perioperative period. We report on 477 consecutive patients who underwent elective surgery in 7 FCSA centers (November 2001 to August 2003). Major and minor surgery and other minor procedures were carried out in 68, 206 and 203 patients respectively; median age 72 years (25–97); 279 males, 198 females. The aim of the study was to evaluate the complications occurring during and within 2 months after surgery with the different modalities of prophylaxis. Indications for OAT./bold]Low and intermediate TE risk patients:secondary prophylaxis of venous thrombosis (VT) 75; non valvular atrial fibrillation (AF) 225; aortic mechanical or biological valves 58, dilatative myocardiopathy 8, valvulopathy 10; myocardial infarction 3; coronary artery by-pass graft 4; stroke 4.High TE risk patients: mitral mechanical valve, mechanical valves + AF or previous TE 53, AF + ≥2 other risk factors (arterial hypertension, dilatative myocardiopathy, previous TE, biological heart valve) 6; intracardiac thrombosis 1.

Results: LMWH therapy: Nadroparin (Seleparina®) and enoxaparin (Clexane®) in 394 and 28 patients respectively. Comments . One patients with high thromboembolic risk died because of sudden cardiac arrest 13 days after a procedure. TE events (0.6%) occurred in 2 patients with mechanical aortic valve and valvulopathy respectively and treated with s.i.d dose. Incidence of major bleeding is higher in patients treated with LMWH b.i.d but it is in accordance with the data reported in the literature.

Table I

Therapy no OAT LMWH (s.i.d.) LMWH (b.i.d.) s.i.d.=single in die; b.i.d.= bis in die Dose (U/kg) 60.6 (±12.8) 65.9 (±17.4) Patients-number 55 329 93 Complications TE n (%) 0 2 (0.6) 0     arterial 0 2 (0.6) 0     venous 0 0 0 Bleeding n (%) 0 9 (2.7) 7 (7.5)     major 0 4 (1.2) 3 (3.2)     minor 0 5 (1.5) 4 (4.3)
Anti-Xa Levels in Critically Ill Patients Receiving Dalteparin for Thromboprophylaxis.
Authors: McDonald Ellen , Dale Craig , Pleasance Susan , McNeill Andrea , Harvey Johanne , Wynne Christine , Duffett Mark , Provost Louise , Rioux Anik , LaRouche Genevieve , Davidson Carson , Watpool Irene , McCardle Tracy , Foxall Julia , Bouwers Kim , Jo Mary , Zytaruk Nicole , Griffith Lauren , Crowther Mark , Cook Deborah ,   for the PROTECT Investigatorsand the Canadian Critical Care Trials Group
Published: April 2020

Rationale: Despite the efficacy and safety of low molecular weight heparin (LWMH) compared to unfractionated (UFH) in many patients, LMWH may bioaccumulate in patients with renal insufficiency which could cause an increased risk of bleeding. If LMWH thromboprophylaxis is safe in ICU patients with renal insufficiency, this could reduce the risk of DVT and HIT. Since the extent to which LMWH bioaccumulates in critically ill patients in prophylactic rather than therapeutic doses is unclear, our objective was to measure peak and trough anti-Xa levels during a multicenter randomized pilot trial of LMWH vs UFH for thromboprophylaxis in the medical-surgical ICU setting.

Methods: We included 128 patients ≥18 years with an expected ICU stay ≥72h. We excluded patients with trauma, orthopedic, cardiac, or neurosurgery, severe hypertension, DVT, PE or hemorrhage within 3 mos, INR >2ULN, PTT >2ULN, platelets <100 x109/L, and if creatinine clearance was <30 ml/min on ICU admission. Trough anti-Xa levels were drawn when patients developed creatinine clearance <30ml/min, trough and peak anti-Xa levels were drawn on Tuesdays and Thursdays regardless of serum creatinine, and random anti-Xa levels were drawn if patients had a bleeding event.

Results: No differences were found in the 2 groups (median anti-Xa levels) as shown below.

Conclusions: We did not observe LWMH or UFH bioaccumulation when administered in prophylactic doses in these critically ill patients with a range of renal dysfunction.

Anti-Xa Levels

Allocation Cr Cl <30 (trough) Tues & Thurs (trough) Tues & Thurs (peak) Bleeding (random) Group A 8 tests in 2 pts 17 tests in 9 pts 17 tests in 9 pts 7 tests in 4 pts Group A 0.1 IU/mL 0.09 IU/mL 0.11 IU/mL 0.1 IU/mL Group B 23 tests in 5 pts 46 tests in 12 pts 46 tests in 12 pts 10 tests in 8 pts Group B 0.1 IU/mL 0.09 IU/mL 0.11 IU/mL 0.1 IU/mL
Safety and Efficacy of Venous Thromboembolism Prophylaxis with Low Molecular Weight Heparin in Hospitalised Patients with Acute Medical Illness and Renal Failure.
Authors: Tincani Enrico , Mannucci Caterina , Casolari Barbara , Turrini Fabrizio , Crowther Mark A. , Ferrari Patrizia , Cenci Anna Maria , Bondi Marco
Published: April 2020

Objectives: To study the incidence of bleeding complications during thromboprophylaxis with dalteparin in patients with acute medical illness and renal failure.

Design: Prospective, cohort study.

Setting: Community Hospital.

Main outcome: The primary safety outcome was the incidence of major and minor bleeding, while the primary efficacy outcomes were objectively verified symptomatic DVT, pulmonary embolism, and objectively verified asymptomatic DVT detected on routine compression ultrasonography. Secondary outcomes included anti-Xa heparin levels.

Patients: 56 consecutives patients (29 males, age 77.86±10.27 y, 27 females, age 84.60±6,78 y) admitted with acute medical illness were considered for the study. Eligible patients were 18 years or older and had none of the following: hepatic failure (prothrombin time <50%), platelet count <100.000/ml, chronic use of warfarin, or an ongoing requirement for anticoagulation. Two doses of dalteparin were prescribed as dictated by a venous thromboembolism risk score. 44 patients judged to be at high risk (age >75 y, 44 of 56, 78%, active cancer, 5 of 56, 8.9%, previous venous thromboembolism, 1 of 56, 1.8%) received a dose of 5.000 IU daily; the other 12 received 2.500 IU daily. Dalteparin was given at 8 am for 6 days. The timing of anti-Xa activity determination and of compression ultrasound examination of leg veins is shown in table 1.

Methods

Results: there was 1 case (1 of 56, 1.8%) of nose bleeding at the third day of treatment in a patient with moderate renal failure. The bled was easily stopped. None of the following variables: dose of dalteparin, age, sex, creatinine clearance, and anti-Xa activity when entered in a regression model were able to predict the hemorrhagic complication. There were no cases of venous thromboembolism. Though, peak anti-Xa activity was higher in patients with marked renal impairment, it never reached therapeutic levels (>0.5 IU/mL).

anti-Xa activity at day 6

Conclusions: The modest (and not significant) increase in anti-Xa activity in patients with reduced creatinine clearance was not associated with a clinically apparent risk of bleeding. Thromboprophylaxis with dalteparin appears safe even in acutely ill medical patients with renal failure.

day 0 Creatinine Clearance anti-Xa activity before Dalteparin CUS day 6 Creatinine Clearance anti-Xa activity 4 h after Dalteparin CUS CrCl >90 ml/min CrCl >89–60 ml/min CrCl >59–30 ml/min CrCl <29 ml/min p=0.45 Patients 5 12 26 13 anti-Xa activity IU/mL 0.012±0.02 0.016±0.054 0.066±0.12 0.20±0.66
The Influence of Prior Oral Anticoagulation Therapy on the Anticoagulant Effect of Low Molecular Weight Heparin.
Authors: Rouby Soumaya El , Patel Urvashi , Patsh Marsha , Cohen Marc , Zucker Marcia L. , Pan Chi-Miau , LaDuca Frank M.
Published: April 2020

Low Molecular Weight Heparins (LMWHs) have been suggested by the ACCP as an alternative to UFH for the anticoagulation of patients on chronic oral anticoagulation therapy (OAT) with warfarin. However, the optimal way to manage these patients remains to be established particularly for high-risk patients who require any type of general surgery or urgent invasive PCI procedures.

The purpose of this study is to evaluate the LMWH point-of-care (POC) HEMONOXTM assay (Edison, NJ) in patients on chronic OAT. This clot-based test uses rTF reagents and the Hemochron Jr. Signature+ system. The Hemonox clotting time (CT) was analyzed at baseline and at peak response post enoxaparin treatment.

Following IRB approval, blood samples from patients on chronic OAT (5 to 20 years, n=13) were evaluated with the Hemonox assay within 12– 18 hours of their last warfarin dose, patients were evaluated weekly for 4 –12 consecutive weeks. In vitro enoxaparin dose response was evaluated by adding 1 U/ml to blood samples obtained from the OAT patients. In supplemental clinical evaluation, 2 PCI cases on OAT were performed at Newark Beth Israel Medical Center, Newark, NJ. Patients were anticoagulated during their PCI procedure with enoxaparin at a final IV dose of 0.5 mg/kg

Hemonox CT baseline response was patient specific and the same response profile was obtained for each patient on OAT who underwent consecutive weekly testing. The majority of patients on OAT (9/13; 69%) exhibited elevated Hemonox baseline CT (150–350 secs) when compared to the previously reported range for PCI patients without prior OAT (baseline CT < 100 secs in 100% of cases, Mean = 71.2 ± 9.0, n= 39). Three patients on OAT (23%) showed CT≤150 secs, and only one patient (8%) yielded a baseline < 100 secs. When the blood of the patient with baseline < 100 sec (baseline value = 70 secs) was spiked in vitro with 1 U/ml enoxaparin, the Hemonox CT was 339 secs which was comparable with the peak response (386 and 308 secs; anti-Xa activity = 0.70 ± 0.01 U/ml; concentration of enoxaparin in the circulation = 0.77± 0.13) observed in the PCI patients receiving enoxaparin (0.5 mg/kg IV) and with a prior OAT who showed similar baseline values. Spiked samples from clinic patients with Hemonox baseline > 150 secs were > 700 secs.

Our results demonstrate that prior to administration of LMWH, baseline monitoring may be helpful in patients on OAT to alert clinicians to appropriate alterations of enoxaparin dosing and target anticoagulation times due to the influence of warfarin.
Gene Therapy for X-Linked Chronic Granulomatous Disease.
Authors: Ott Marion G. , Stein Stefan , Koehl Ulrike , Schilz Andrea , Kuhlcke Klaus , Schmidt Manfred , von Kalle Christof , Hassan Moustapha , Siler Ulrich , Hoelzer Dieter , Seger Reinhard , Grez Manuel
Published: April 2020

Chronic Granulomatous Disease (CGD) is a primary immunodeficiency in which phagocytic cells of affected patients have impaired antimicrobial activity due to a defect in the production of reactive oxygen species (ROS). CGD is caused by mutations in any one of four genes encoding for the subunits of the NADPH oxidase complex. CGD is an ideal target for a gene replacement therapy, since females carriers of CGD with as low as 5-10% NADPH oxidase activity are healthy. Based on our preclinical work, we initiated a Phase I/II trial in January 2004. Two X-CGD patients, 26 and 25 years old, were recruited based on their long history of recurrent and life-threatening bacterial and fungal infections. G-CSF mobilized CD34+ cells were transduced with a monocistronic gp91phox retroviral vector. The transduction efficiency was 45% for Pat.1 and 40% for Pat. 2. The number of CD34+ cells reinfused was 1.2x10e7 per kg for Pat.1 and 0.9x10e7 per kg for Pat. 2. Before reinfusion, the patients were conditioned with liposomal busulphan given i.v. at a dose of 4 mg/kg at two consecutive days, starting at day -3. The treatment was well tolerated and no adverse effects have been observed. Neutrophil counts declined to less than 100 cells per μl at day 15 post reinfusion in both patients and recovered to more than 500 cells per μl at day 30 for Pat. 1 and day 20 for Pat. 2. A significant fraction of gene marked cells has been detected in peripheral blood of both patients since day +21. Similarly, therapeutically relevant levels of ROS production have been observed. In conclusion, the protocol we have used allows for stable engraftment of gene transduced hematopoietic cells under conditions in which gene corrected cells lack a selective advantage over non-corrected cells.
Freeze-Drying Human Red Blood Cells: Effect of Hematocrit and Composition of the Freeze-Drying Medium on Red Cell Survival.
Authors: Satpathy Gyana R. , Torok Zsolt , Banerjee Mitali , Bali Rachna , Little Erika , Crowe John H. , Tsvetkova Nelly M. , Tablin Fern
Published: April 2020

A wide variety of medical procedures require transfusion of red blood cells (RBCs). RBCs are currently preserved either at 4°C, at a higher hematocrit (70%) for up to 7–12 weeks or in a frozen state in the presence of glycerol at −80°C for several years. However, each procedure has its demerits. Storage in the dry state offers a possibility for storing the cells for long periods of time under conditions that are far easier to maintain (i.e. room temperature), making the transport to sites of immediate need feasible. We developed a method for freeze-drying RBCs using 15% hematocrit, resulting in a survival of 40% after rehydration, as assessed by the percent hemolysis. In this work, we report the effect of cell hematocrit, concentration of trehalose, salts and overall osmolality of the freeze-drying medium on the survival after freeze-drying and rehydration. Decreasing the percent hematocrit and trehalose in the freeze-drying buffer resulted in about 20% improvement in the post-rehydration survival. Freeze-dried and rehydrated RBCs showed high levels of ATP, 2,3-DPG and low percent methemoglobin. These data are discussed in terms of the glass transition properties of the freeze-drying buffer. This work provides an important step in formulating a freeze drying medium that will provide optimum RBC survival after freeze drying and rehydration.
Ex Vivo Gene Therapy of a Preadolescent with X-Linked Severe Combined Immunodeficiency.
Authors: Chinen Javier , Puck Jennifer M. , Davis Joie , Linton Gilda F. , Whiting-Theobald Narda L. , Woltz Patricia C. , Buckley Rebecca H. , Malech Harry L.
Published: April 2020

X-linked severe combined immunodeficiency (XSCID) results from mutations in IL2RG, which encodes the common gamma chain (γc) shared by receptors for IL-2, 4, 7, 9, 15 and 21. XSCID is best treated with bone marrow transplantation (BMT) from an HLA-matched sibling. Patients lacking a matched sibling can benefit from a T-cell depleted haploidentical BMT, but some do not achieve adequate immune reconstitution. Ex vivo autologous hematopoietic stem cell (HSC) gene therapy may be an alternative to haploidentical BMT. In a French trial, 9 of 10 XSCID infants had immune reconstitution following ex vivo transduction of autologous HSC with a retroviral vector encoding γc. Selective development and expansion of T, NK and B cells from progenitors expressing γc was important to the success of this therapy. However, the 2 youngest patients, treated at 1 and 3 months of age, later developed T cell leukemias associated with retrovirus insertions that activated the LMO2 transcription factor. Young age at treatment might have had a role in the development of these adverse events. We have developed an XSCID gene transfer protocol as salvage treatment for older patients who have failed haploidentical BMT. An 11 year-old XSCID patient with no detectable engraftment from prior haploidentical BMTs had lymphocytopenia, growth failure, infections, chronic diarrhea and skin rashes. After G-CSF mobilization and harvest by apheresis, his purified autologous peripheral blood CD34+ cells were transduced daily for 4 days with GALV-MFGS-γc retrovirus in the presence of growth factors and Retronectin®. Eighty million cells/kg (80% CD34+; 40% γc transgene positive) were reinfused. At 1, 2 and 3 months after treatment, provirus marking by PCR of unseparated blood leukocytes was 1.4%, 2.3% and <0.01%, respectively. At 4.5 months, marking reappeared in lineages dependent on IL2RG expression: 0.5% in T cells, 0.1% in NK cells and 0.05% in B cells. This lineage-specific marking persisted at the same level at 6 months. LAM PCR showed polyclonal marking. T-lymphocytes have not yet increased above 300/μl. However, from 2 months after gene therapy the patient experienced a sustained improvement in well-being with resolution of lifelong diarrhea and rashes. No infections have occurred except one episode of otitis externa 3 months post therapy that resolved promptly to oral antibiotics. At six months submandibular lymph nodes were palpable for the first time in his life. Thymus size on chest CT images increased from 1.8 cm3 to 3.2 cm3. Additional follow up is necessary to know if gene marking and clinical improvement persist and if significant expansion of corrected lymphocytes occurs. Our preliminary results suggest that ex vivo retrovirus-mediated gene therapy, targeting CD34+ cells from peripheral blood, may benefit older children with XSCID who have failed haploidentical BMT.