Computational evaluation of the thrombogenic potential of a hollow-fiber oxygenator with integrated heat exchanger during extracorporeal circulation

The onset of thromboembolic phenomena in blood oxygenators, even in the presence of adequate anticoagulant strategies, is a relevant concern during extracorporeal circulation (ECC). For this reason, the evaluation of the thrombogenic potential associated with extracorporeal membrane oxygenators should play a critical role into the preclinical design process of these devices. This study extends the use of computational fluid dynamics simulations to guide the hemodynamic design optimization of oxygenators and evaluate their thrombogenic potential during ECC. The computational analysis accounted for both macro- (i.e., vortex formation) and micro-scale (i.e., flow-induced platelet activation) phenomena affecting the performances of a hollow-fiber membrane oxygenator with integrated heat exchanger. A multiscale Lagrangian approach was adopted to infer the trajectory and loading history experienced by platelet-like particles in the entire device and in a repetitive subunit of the fiber bundles. The loading history was incorporated into a damage accumulation model in order to estimate the platelet activation state (PAS) associated with repeated passes of the blood within the device. Our results highlighted the presence of blood stagnation areas in the inlet section that significantly increased the platelet activation levels in particles remaining trapped in this region. The order of magnitude of PAS in the device was the same as the one calculated for the components of the ECC tubing system, chosen as a term of comparison for their extensive diffusion. Interpolating the mean PAS values with respect to the number of passes, we obtained a straightforward prediction of the thrombogenic potential as a function of the duration of ECC.     

A new approach to develop a biohybrid artificial liver using a tightly regulated human hepatocyte cell line

Currently patients with liver failure have been treated with a various liver support systems including a whole liver perfusion, a non-biological artificial liver, and a biohybrid artificial liver. In a hepatocyte-based bioreactor, porcine hepatocytes or transformed human liver tumor cells have been utilized because of the ease of preparation. According to the clinical data reported as of now, satisfactory results have not been obtained from the use of currently available liver support devices. One of the problems is limited availability of primary human liver cells for developing live support systems because of the shortage of human liver. To resolve this issue, human hepatocytes were immortalized with a retroviral vector SSR#69 which contained the genes of simian virus 40 large T antigen (SV40Tag) and herpes simplex virus-thymidine kinase (HSV-TK). One of the immortal cell lines, NKNT-3, showed the gene expression of differentiated liver functions, grew steadily in chemically defined serum-free CS-C medium, and doubled in number in about 48 hours. Essentially unlimited availability of NKNT-3 cells supports their clinical use for liver support devices. To realize the high density culture of NKNT-3 cells in a bioartificial liver device, we have developed cellulose microspheres (CMS) which contain cell adhesive GRGDS (Gly-Arg-Gly-Asp-Ser) peptides. Within 24 hours after starting a stirring suspension culture, GRGDS-CMS efficiently immobilized NKNT-3 cells. An electron microscopic examination demonstrated that NKNT-3 cells attached on GRGDS-CMS had well-developed mitochondria, rough reticulums, and villous extensions. In this article, we review the history of extracorporeal liver support systems and describe an attractive strategy for developing a novel extracorporeal liver assist device using NKNT-3 cells and GRGDS-coated cellulose microspheres.     

Improved preferential tumor hyperthermia with regional heating and systemic blood cooling: a balanced heat transfer method

Absorption of power in large body volumes can occur with some approaches used for hyperthermia treatment of cancer. A systemic heat absorption rate exceeding the heat dissipation rate can lead to systemic temperature elevation that limits the magnitude and duration of application of power and hence the degree of preferential tumor temperature rise. We describe a hyperthermia approach consisting of regional electromagnetic power absorption and extracorporeal blood cooling with regulation of both systemic heat absorption and dissipation rates ("balanced heat transfer"). A test of this approach in five dogs with nonperfused tumor models demonstrated intratumoral temperatures greater than 42 degrees C, while systemic temperature remained at 33 degrees C and visceral temperatures within the heated region equilibrated between 33 and 42 degrees C. Solutions of the bioheat transfer equation were obtained for a simplified model with a tumor perfusion rate lower than surrounding normal tissue perfusion rate. In this model, the use of arterial blood temperatures less than 37 degrees C allowed higher power densities to be used, for given normal tissue temperatures, than when arterial temperature was greater than or equal to 37 degrees C. As a result, higher intratumoral temperatures were predicted. Control of arterial blood temperature using extracorporeal cooling may thus (1) limit systemic temperature rise produced by regional heating devices and (2) offer a means of improving intratumoral temperature elevations.     

Organisation of care for patients using direct oral anticoagulants

Direct oral anticoagulants (DOACs) are recommended by several scientific societies as first-line therapy for the prevention of stroke and systemic embolism in patients with atrial fibrillation. However, there is uncertainty regarding the organisation of anticoagulation care, with various caregivers being involved. Patients and caregivers are often confronted by uncertainty about the coordination of treatment. With the functional resonance analysis method we visualised the process of anticoagulation care in daily practice in the Maastricht region. This resulted in recommendations on how to improve the organisation of anticoagulation care for DOAC patients.

     

Haemocompatibility of extracorporeal circulation technique with autooxygenation: influence on platelet function and homologous blood requirement.

Forty male patients: group A-autooxygenation and group B-bubble oxygenator used in extracorporeal circulation (ECC) were studied to evaluate the haemocompatibility of 2 types of ECC. The Plt count dropped significantly in group B patients: -73% of initial value vs only -27% in group A, (p less than 0.001). In both groups a rise in BTG was shown, but higher in group B, p less than 0.001. At the end of CPB aggregation decreased only slightly in group A after epinephrine and 4-ADP, and decreased hardly in group B with the significant difference between two groups (p less than 0.02 and p less than 0.001, respectively). In group A the mean blood loss was 278 +/- 49 ml/m2 and 483 +/- 67 ml/m2 in group B, p less than 0.001. The mean blood transfusion in group A and B was 198 +/- 82 ml/m2 and 427 +/- 85 ml/m2, respectively (p less than 0.001). We are positive that the elimination of artificial oxygenator from the ECC diminished markedly the decline in Plt count and Plt activation during CPB.     

Existing and Emerging Technologies for Point-of-Care Testing

The volume of point-of-care testing (PoCT) has steadily increased over the 40 or so years since its widespread introduction. That growth is likely to continue, driven by changes in healthcare delivery which are aimed at delivering less costly care closer to the patient’s home. In the developing world there is the challenge of more effective care for infectious diseases and PoCT may play a much greater role here in the future. PoCT technologies can be split into two categories, but in both, testing is generally performed by technologies first devised more than two decades ago. These technologies have undoubtedly been refined and improved to deliver easier-to-use devices with incremental improvements in analytical performance. Of the two major categories the first is small handheld devices, providing qualitative or quantitative determination of an increasing range of analytes. The dominant technologies here are glucose biosensor strips and lateral flow strips using immobilised antibodies to determine a range of parameters including cardiac markers and infectious pathogens. The second category of devices are larger, often bench-top devices which are essentially laboratory instruments which have been reduced in both size and complexity. These include critical care analysers and, more recently, small haematology and immunology analysers. New emerging devices include those that are utilising molecular techniques such as PCR to provide infectious disease testing in a sufficiently small device to be used at the point of care. This area is likely to grow with many devices being developed and likely to reach the commercial market in the next few years.     

Oscillatory Threshold Logic

In the 1940s, the first generation of modern computers used vacuum tube oscillators as their principle components, however, with the development of the transistor, such oscillator based computers quickly became obsolete. As the demand for faster and lower power computers continues, transistors are themselves approaching their theoretical limit and emerging technologies must eventually supersede them. With the development of optical oscillators and Josephson junction technology, we are again presented with the possibility of using oscillators as the basic components of computers, and it is possible that the next generation of computers will be composed almost entirely of oscillatory devices. Here, we demonstrate how coupled threshold oscillators may be used to perform binary logic in a manner entirely consistent with modern computer architectures. We describe a variety of computational circuitry and demonstrate working oscillator models of both computation and memory.     

Alterations in plasma angiogenic growth factor concentrations after coronary artery bypass graft surgery: relationships with post-operative complications

To determine whether angiogenic growth factor levels are altered during and after cardiac surgery, plasma concentrations of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and transforming growth factor beta1 (TGFbeta1) were measured in 32 patients undergoing coronary artery bypass graft (CABG) surgery with extracorporeal circulation (ECC). EGF levels significantly decreased during ECC and remained low until the 24th post-operative hour with no difference between complicated and uncomplicated patients. TGFbeta1 and bFGF concentrations significantly increased at the end of ECC and after cross-clamp release, and returned to pre-operative values at the 6th post-operative hour suggesting that the source of these elevations are the lungs and heart. After cross-clamp release bFGF levels but not TGFbeta1 ones were higher in patients with respiratory impairments. VEGF values increased significantly at the 6th and 24th post-operative hours. At the 24th post-operative hour plasma VEGF levels were higher in patients with cardiovascular and hematological impairments. In conclusion, these results highlight that the angiogenic network is profoundly altered in patients undergoing cardiopulmonary bypass as previously demonstrated for lipidic, cytokine and haematopoietic growth factor ones and identify an association between specific post-CABG complications and systemic release of bFGF and VEGF.     

蛋白质即时检测新技术

蛋白质是细胞各类代谢和调控等生命功能的执行者,也是致病因子、药物等对机体作用的重要靶分子.研究蛋白质表达是理解生命现象、疾病进程和药物作用的基础.临床上常规检测方法需要大型仪器支持,但随着医学事业的发展,即时检测(POCT,也称现场检测、床旁检测)成为重要的发展趋势.POCT可以改善患者和医生之间的互动方式,建立一种积...     

综述与专论：蛋白质即时检测新技术

蛋白质是细胞各类代谢和调控等生命功能的执行者,也是致病因子、药物等对机体作用的重要靶分子。研究蛋白质表达是理解生命现象、疾病进程和药物作用的基础。临床上常规检测方法需要大型仪器支持,但随着医学事业的发展,即时检测(POCT,也称现场检测、床旁检测)成为重要的发展趋势。POCT可以改善患者和医生之间的互动方式,建立一种积极的医疗模式。除诊断、治疗疾病外,对从事应急工作的人员来说,POCT在现场和远程检测方面都有优势,因此研发既准确灵敏又简便快捷的蛋白质即时检测方法至关重要。     

Plasma macrophage colony-stimulating factor levels during cardiopulmonary bypass with extracorporeal circulation

Leukocytosis and thrombocytopenia occur during cardiopulmonary bypass (CPB) with extracorporeal circulation (ECC). Elevated circulating concentrations of macrophage colony-stimulating factor (M-CSF) are reported during thrombocytopenia and leukopenia of different origins. We have assessed M-CSF concentrations in 40 patients undergoing CPB with ECC. Plasma M-CSF concentrations were stable during ECC and increased at the 6th (7.3 +/- 0.7 IU/mug protein) and 24th (8.6 +/- 0.8 IU/mug protein) postoperative hour compared with pre-ECC values (4.9 +/- 0.5 IU/mug protein). A deep thrombocytopenia was found during ECC and until the 24th postoperative hour. A drop of leukocyte counts was found during ECC followed by an increase after ECC weaning. While no correlation was found between M-CSF concentrations and the leukocyte counts, M-CSF values were positively correlated with platelet counts only before and during ECC. Thus, M-CSF is not implicated in the thrombocytopenia and the leukopenia generated during CPB with ECC. However the elevated levels of M-CSFa few hours after the end of ECC might play a role in the inflammatory process often observed after CPB.     

Data warehousing methods and processing infrastructure for brain recovery research

In order to accelerate translational neuroscience with the goal of improving clinical care it has become important to support rapid accumulation and analysis of large, heterogeneous neuroimaging samples and their metadata from both normal control and patient groups. We propose a multi-centre, multinational approach to accelerate the data mining of large samples and facilitate data-led clinical translation of neuroimaging results in stroke. Such data-driven approaches are likely to have an early impact on clinically relevant brain recovery while we simultaneously pursue the much more challenging model-based approaches that depend on a deep understanding of the complex neural circuitry and physiological processes that support brain function and recovery. We present a brief overview of three (potentially converging) approaches to neuroimaging data warehousing and processing that aim to support these diverse methods for facilitating prediction of cognitive and behavioral recovery after stroke, or other types of brain injury or disease.     

Reduction of gaseous microembolism during aortic valve replacement using a dynamic bubble trap

Serious postoperative psycho-neurological dysfunction is at least partially attributed to the occurrence of gaseous microbubbles in the arterial line of extracorporeal circulation (ECC). Therefore, we investigated in a prospective randomized double blind study whether the usage of dynamic bubble trap (DBT) will reduce microbubble load of patients undergoing aortic valve replacement. Patients (n = 41) were divided into group I (GI, n = 22) with DBT introduced into the arterial line of ECC and group II (GII, n = 19) with placebo-DBT instead. Doppler ultrasonography was used for detection of microbubbles before and after DBT, and for detection of high intensity transient signals (HITS) within the middle cerebral artery. The recording time during ECC was divided into period 1 (P1, until aortic clamp removal) and period 2 (P2, clamp removal until the end of ECC). A significant reduction of microbubble load was found in GI only (p < 0.0001 for ECC; p < 0.0001 for P1; p < 0.0025 for P2). A significant difference in number of HITS between the groups was observed in P1 only (p < 0.002 left middle cerebral artery, p < 0.005 right middle cerebral artery), since in P2 the trapped air in left chamber can go to the supraaortal vessels without passing ECC. In conclusion the use of DBT cannot substitute careful venting after aortic declamping. Nevertheless, reduction of HITS in the cross-clamped period of ECC justifies the use of DBT in patients undergoing open chamber surgery.     

组学时代下机器学习方法在临床决策支持中的应用

随着组学技术的不断发展,对于不同层次和类型的生物数据的获取方法日益成熟。在疾病诊治过程中会产生大量数据,通过机器学习等人工智能方法解析复杂、多维、多尺度的疾病大数据,构建临床决策支持工具,辅助医生寻找快速且有效的疾病诊疗方案是非常必要的。在此过程中,机器学习等人工智能方法的选择显得尤为重要。基于此,本文首先从类型和算法角度对临床决策支持领域中常用的机器学习等方法进行简要综述,分别介绍了支持向量机、逻辑回归、聚类算法、Bagging、随机森林和深度学习,对机器学习等方法在临床决策支持中的应用做了相应总结和分类,并对它们的优势和不足分别进行讨论和阐述,为临床决策支持中机器学习等人工智能方法的选择提供有效参考。     

Meeting Community Health Worker Needs for Maternal Health Care Service Delivery Using Appropriate Mobile Technologies in Ethiopia

Background

Mobile health applications are complex interventions that essentially require changes to the behavior of health care professionals who will use them and changes to systems or processes in delivery of care. Our aim has been to meet the technical needs of Health Extension Workers (HEWs) and midwives for maternal health using appropriate mobile technologies tools.

Methods

We have developed and evaluated a set of appropriate smartphone health applications using open source components, including a local language adapted data collection tool, health worker and manager user-friendly dashboard analytics and maternal-newborn protocols. This is an eighteen month follow-up of an ongoing observational research study in the northern of Ethiopia involving two districts, twenty HEWs, and twelve midwives.

Results

Most health workers rapidly learned how to use and became comfortable with the touch screen devices so only limited technical support was needed. Unrestricted use of smartphones generated a strong sense of ownership and empowerment among the health workers. Ownership of the phones was a strong motivator for the health workers, who recognised the value and usefulness of the devices, so took care to look after them. A low level of smartphones breakage (8.3%,3 from 36) and loss (2.7%) were reported. Each health worker made an average of 160 mins of voice calls and downloaded 27Mb of data per month, however, we found very low usage of short message service (less than 3 per month).

Conclusions

Although it is too early to show a direct link between mobile technologies and health outcomes, mobile technologies allow health managers to more quickly and reliably have access to data which can help identify where there issues in the service delivery. Achieving a strong sense of ownership and empowerment among health workers is a prerequisite for a successful introduction of any mobile health program.     

Rewarming from severe accidental hypothermia with circulatory arrest

This case report demonstrates successful cardiopulmonary and cerebral resuscitation (CPCR) of a young male explored 15 hours following a suicide attempt (carbamazepine intoxication) in deep hypothermia (19 degrees C) with circulatory arrest. An extracorporeal circuit was used to rewarm the patient's blood. Weaning from extracorporeal circulation (ECC) was successful and without complications as was recovery from multiorgan dysfunction, severe rhabdomyolysis and carbamazepine intoxication. An excellent outcome was achieved without any neurological deficit at the time of discharge from the hospital.     

Device thrombogenicity emulation: a novel method for optimizing mechanical circulatory support device thromboresistance

Mechanical circulatory support (MCS) devices provide both short and long term hemodynamic support for advanced heart failure patients. Unfortunately these devices remain plagued by thromboembolic complications associated with chronic platelet activation--mandating complex, lifelong anticoagulation therapy. To address the unmet need for enhancing the thromboresistance of these devices to extend their long term use, we developed a universal predictive methodology entitled Device Thrombogenicity Emulation (DTE) that facilitates optimizing the thrombogenic performance of any MCS device--ideally to a level that may obviate the need for mandatory anticoagulation. DTE combines in silico numerical simulations with in vitro measurements by correlating device hemodynamics with platelet activity coagulation markers--before and after iterative design modifications aimed at achieving optimized thrombogenic performance. DTE proof-of-concept is demonstrated by comparing two rotary Left Ventricular Assist Devices (LVADs) (DeBakey vs HeartAssist 5, Micromed Houston, TX), the latter a version of the former following optimization of geometrical features implicated in device thrombogenicity. Cumulative stresses that may drive platelets beyond their activation threshold were calculated along multiple flow trajectories and collapsed into probability density functions (PDFs) representing the device 'thrombogenic footprint', indicating significantly reduced thrombogenicity for the optimized design. Platelet activity measurements performed in the actual pump prototypes operating under clinical conditions in circulation flow loops--before and after the optimization with the DTE methodology, show an order of magnitude lower platelet activity rate for the optimized device. The robust capability of this predictive technology--demonstrated here for attaining safe and cost-effective pre-clinical MCS thrombo-optimization--indicates its potential for reducing device thrombogenicity to a level that may significantly limit the extent of concomitant antithrombotic pharmacotherapy needed for safe clinical device use.     

Anticoagulation for the Acute Management of Ischemic Stroke

Few prospective studies support the use of anticoagulation during the acute phase of ischemic stroke, though observational data suggest a role in certain populations. Depending on the mechanism of stroke, systemic anticoagulation may prevent recurrent cerebral infarction, but concomitantly carries a risk of hemorrhagic transformation. In this article, we describe a case where anticoagulation shows promise for ischemic stroke and review the evidence that has discredited its use in some circumstances while showing its potential in others.     

A Roadmap to an Equitable Digital Diabetes Ecosystem

ObjectivesDiabetes management presents a substantial burden to individuals living with the condition and their families, health care professionals, and health care systems. Although an increasing number of digital tools are available to assist with tasks such as blood glucose monitoring and insulin dose calculation, multiple persistent barriers continue to prevent their optimal use.MethodsAs a guide to creating an equitable connected digital diabetes ecosystem, we propose a roadmap with key milestones that need to be achieved along the way.ResultsDuring the Coronavirus 2019 pandemic, there was an increased use of digital tools to support diabetes care, but at the same time, the pandemic also highlighted problems of inequities in access to and use of these same technologies. Based on these observations, a connected diabetes ecosystem should incorporate and optimize the use of existing treatments and technologies, integrate tasks such as glucose monitoring, data analysis, and insulin dose calculations, and lead to improved and equitable health outcomes.ConclusionsDevelopment of this ecosystem will require overcoming multiple obstacles, including interoperability and data security concerns. However, an integrated system would optimize existing devices, technologies, and treatments to improve outcomes.     

Development and application of biological technologies in fish genetic breeding

Fish genetic breeding is a process that remolds heritable traits to obtain neotype and improved varieties.For the purpose of genetic improvement,researchers can select for desirable genetic traits,integrate a suite of traits from different donors,or alter the innate genetic traits of a species.These improved varieties have,in many cases,facilitated the development of the aquaculture industry by lowering costs and increasing both quality and yield.In this review,we present the pertinent literatures and summarize the biological bases and application of selection breeding technologies(containing traditional selective breeding,molecular marker-assisted breeding,genome-wide selective breeding and breeding by controlling single-sex groups),integration breeding technologies(containing cross breeding,nuclear transplantation,germline stem cells and germ cells transplantation,artificial gynogenesis,artificial androgenesis and polyploid breeding)and modification breeding technologies(represented by transgenic breeding)in fish genetic breeding.Additionally,we discuss the progress our laboratory has made in the field of chromosomal ploidy breeding of fish,including distant hybridization,gynogenesis,and androgenesis.Finally,we systematically summarize the research status and known problems associated with each technology.