A Treatment System for Implementing an Extracorporeal Liver Assist Device

Abstract: Biologically active devices are receiving increasing attention, especially in the management of endocrine pancreatic failure (diabetes) and acute liver failure. In both instances, mechanical devices have been unable to replace the function of the original organ, and consequences range from inconvenient (e.g., regular insulin shots, diabetic vasculopathy) to fatal (e.g., fulminant hepatic failure). In developing a cell-based liver assist device, we concluded that currently available extracorporeal blood treatment systems are not suited to the delivery of high molecular weight substances and that they do not adequately address the metabolic needs of the device. We therefore developed a system that provides safe, continuous perfusion of an extracorporeal organ. We detail the design and first clinical use of the system.     

Alginate-encapsulated human hepatoblastoma cells in an extracorporeal perfusion system improve some systemic parameters of liver failure in a xenogeneic model

Previous studies have demonstrated that alginate encapsulation of proliferating hepatocyte-derived cell lines (e.g., HepG2 cells) enhances the expression of differentiated hepatocyte function compared with conventional monolayer culture. Furthermore, such capsules have the advantage of cryopreservability, and can be readily manipulated, e.g., for the charging of extracorporeal devices. We utilize a rabbit model of acute liver failure caused by acetaminophen administration to rabbits pretreated to enhance cytochrome p450 enzyme activity, and demonstrate that encapsulated HepG2 cells, in an extracorporeal chamber, perfused by rabbit plasma separated on-line at a rate of 2-5 mL/min, and perfused over cells at 40-60 mL/min, improve systemic parameters of liver failure (diastolic blood pressure and transjugular venous oxygen saturation). Such encapsulated cells have the potential to be developed for extracorporeal liver support systems for acute liver failure.     

In vivo gene transfer: focus on the kidney

Renal gene transfer techniques are being developed as a novelexperimental approach to understand the pathogenesis of renaldisease and to potentially develop new therapeutic tools. Wereview the currently available technology to introduce foreigngenetic material into renal tissue, i.e., retroviral, adenoviral,and liposomal transfer systems with their respective advantagesand caveats. Today, the transfer efficiency of these methodsappears to be sufficiently high to study the effects of transducedgenes on renal function and morphology in rat kidney. This willallow (i) the elucidation of the function of genes on the courseof renal disease in experimental animal models and (ii) themodulation of local expression of endogenous genes which presumptivelycontribute to renal pathology in these models. One strategyto accomplish this aim is the use of recombinant DNA technologyto design antisense DNA constructs or oligonucleotides, whichinterfere with the renal expression of target genes. We willalso discuss some of the shortcomings of the currently usedtechniques with respect to potential therapeutic use of genetransfer systems and gene modulation.     

Medical applications of nanotechnology: polymeric micelles for drug delivery

Recently, medical applications of nanotechnology have received much attention. Among them, drug delivery systems (DDSs) are expected to be the leading technology in diagnostic and therapeutic medicine. An increasing number of DDSs have been approved for clinical use or are currently being studied in clinical trials. Polymeric micelles, self-assemblies of block copolymers, are one of the most refined and promising modalities of DDSs, since the critical parameters such as size, drug loading, and release can be controlled by engineering the constituent block copolymers. It has been demonstrated that polymeric micelles show unique disposition characteristics in the body suitable for drug targeting (e.g., prolonged blood circulation and significant tumor accumulation). Also, recent advances in polymer synthesis have allowed the development of polymeric micelles with integrated smart functions such as environmental sensitivity and targetability. Thus polymeric micelles might have great potential for nanotechnology-based DDSs for clinical use.     

First clinical realization of continuous monitoring of liver microcirculation after transplantation by thermodiffusion

Abstract  To date, no method is available for the continuous long-term monitoring of liver microcirculation in patients. Experimentally, thermodiffusion has been validated in the quantification of hepatic per-fusion. In an attempt to investigate the practicability of thermodiffusion technology in patients after liver transplantation thermodiffusion probes were inserted into the graft in seven patients during liver transplantation. Continous monitoring started intraoperatively and was performed until day 7, when the probes were extracted transcutane-ously. No probe-related complications (i. e., hemorrhage, infection) were observed. In four patients with normal graft function, liver perfu-sion recovered within 12 h from the intraoperative reduction to a range between 85 and 93 ml/100 g per min. In contrast, primary graft failure ( n = 1) was characterized by a constant decrease of hepatic perfusion (< 50 ml/100 g per min). In prolonged reperfusion injury ( n = 1), a second peak of transaminases was paralled by an impairment of liver microcirculation. In one patient, rejection on day 7 was preceded by a drop in hepatic perfusion 48 h earlier. Thus, thermodiffusion is a safe and reliable method for the continuous quantification of liver micro-circulation after transplantation in patients. Measurements are reproducible for at least 7 days. Changes in hepatic perfusion during postoperative complications can be detected. The characteristics of micro-circulatory disorders will have to be defined in a larger number of patients.     

Changing allocations of operating room time from a system based on historical utilization to one where the aim is to schedule as many surgical cases as possible

Many facilities allocate operating room (OR) time based on historical utilization of OR time. This assumes that there is a fixed amount of regularly scheduled OR time, called "block time". This "Fixed Hours" system does not apply to many surgical suites in the US. Most facilities make OR time available for all its surgeons' patients, even if cases are expected to finish after the end of block time. In this setting, OR time should be allocated to maximize OR efficiency, not historical utilization. Then, cases are scheduled either on "Any Workday" (i.e., date chosen by patient and surgeon) or within a reasonable time (e.g., "Four Weeks"). In this study, we used anesthesia billing data from two facilities to study statistical challenges in converting from a Fixed Hours to an Any Workday or Four Weeks patient scheduling system. We report relationships among the number of staffed ORs (i.e., first case of the day starts), length of the regularly scheduled OR workday, OR efficiency, OR staffing cost, and changes in services' OR allocations. These relationships determine the expected changes in each service's OR allocation, when a facility using Fixed Hours considers converting to the Any Workday or Four Weeks systems. IMPLICATIONS: We investigated the complex relationships among the number of surgical services, number of staffed operating rooms (ORs), length of the regularly scheduled OR workday, efficiency of use of OR time, OR staffing cost, and changes in each services' allocated OR time.     

The molecular adsorbents recycling system as a liver support system based on albumin dialysis: a summary of preclinical investigations, prospective, randomized, controlled clinical trial, and clinical experience from 19 centers

Artificial liver support aims to prolong survival time of patients with liver failure by detoxification. Albumin as a molecular adsorbent in dialysis solution is capable of attracting even tightly albumin-bound toxins from blood into the dialysate if a specific dialysis membrane is used and if the albumin's binding sites are on-line-purified by a sorbent/dialysis-based recycling system (i.e., molecular adsorbents recycling system, or MARS). The MARS technology has been shown to remove water-soluble and albumin-bound toxins and to provide renal support in case of renal failure. Fourteen centers have reported that MARS treatment improved mental status of patients with liver failure and hepatic encephalopathy. In treating liver failure and cholestasis, MARS was associated with hemodynamic stabilization, improvement of hepatic and kidney function, and disappearance of pruritus. In hepatic failure and hepatorenal syndrome, a prospective, randomized, controlled trial of MARS treatment was able to prolong survival time significantly. MARS has been used in 26 patients with acute liver failure or primary graft dysfunction. Nineteen centers reporting on 103 patients have shown that MARS treatment is safe, easy to handle, feasible, and effective.     

Online-Kurs Notfallmedizin Kurrikulare Integration von Computer-based Training

Emergency medicine is characterized by rapid decision making to help patients in life-threatening situations. Teaching these skills requires a high level of interaction between medical students and the lecturer. We designed, implemented, and evaluated a generic computer-based training (CBT) system to provide a more active way of learning emergency medicine. The content of the training program is adapted to the knowledge of third year medical students and is focused on basic skills and real-world problems. The teacher presents the case with authentic video sequences and slides. The cases are classified into four groups: heart (e.g., myocardial infarction), respiration (e.g., asthma bronchiale), trauma (e.g., car accident), and loss of consciousness (e.g., coma). Within a realistic time frame, the students have to answer free text and multiple choice questions on a work-station. All answers given by the students are processed anonymously by the CBT system via a central server and displayed on a large video screen, thus enabling a detailed discussion without intimidation of individual students. This interactive technique allows for immediate feedback from the lecturer based on the specific knowledge of his group and his own experience. The IT concept, which is scalable to many subjects, is based on state of the art internet technology and therefore suitable for teleteaching. A major design objective for the program was a self-explaining and robust user interface. The system has been in routine use since 1998. We designed an evaluation form consisting of 21 items focused on subjective rating of learning success, acceptance of CBT, and technical feasibility. We analyzed forms from 138 students and found high scores for acceptance and learning success (median 5 on a 6-point scale). user problems with the program were denied (median 1 on a 6-point scale). Computer-based training with Internet technology can provide a successful method for interactive teaching of emergency medicine and is well accepted by students.     

Evolution of Gas Permeable Membranes for Extracorporeal Membrane Oxygenation

Gas permeable membranes are a vital component of extracorporeal membrane oxygenation systems. Over more than half a century, membrane fabrication and packaging technology have progressed to enable safer and longer duration use of respiratory life support. Current research efforts seek to improve membrane efficiency and hemocompatibility, with the aim of producing smaller and more robust systems for ambulatory use. This review explores past and present innovations in oxygenator technology, suggesting possible applications of state‐of‐the‐art membrane fabrication methods to address shortcomings of earlier concepts.     

Technological advances in transurethral resection of the prostate: bipolar versus monopolar TURP

One of the most significant recent advancements in transurethral resection of the prostate (TURP) is the incorporation of bipolar technology. Bipolar circuitry allows TURP to be performed in a normal saline environment, which addresses a fundamental concern of conventional monopolar TURP (i.e., the use of hypo-osmolar irrigation). As a result, the risks of dilutional hyponatremia and transurethral resection (TUR) syndrome are eliminated, allowing for longer and safer resection. This review discusses the principles and applications of electrosurgery in conventional monopolar as well as new bipolar saline-based TURP systems. This review also addresses the positive impact on patient safety and resident training.     

Statistical grand rounds: Importance of appropriately modeling procedure and duration in logistic regression studies of perioperative morbidity and mortality

Multiple logistic regression studies frequently are performed with duration (e.g., operative time) included as an independent variable. We use narrative review of the statistical literature to highlight that when the association between duration and outcome is presumptively significant, the procedure itself (e.g., video-assisted thoracoscopic lobectomy or thoracotomy lobectomy) needs to be tested for inclusion in the logistic regression. If the procedure is a true covariate but excluded in lieu of category of procedure (e.g., lung resection), estimates of the odds ratios for other independent variables are biased. In addition, actual durations are sometimes used as the independent variable, rather than scheduled (forecasted) durations. Only the scheduled duration is known when a patient would be randomized in a trial of preoperative or intraoperative intervention and/or meets with the surgeon and anesthesiologist preoperatively. By reviewing the literature about logistic regression and about predicting case duration, we show that the use of actual instead of scheduled duration can result in biased logistic regression results.     

Technology assessment of anaesthesia monitors: problems and future directions

Specific factors have limited the interpretation of studies regarding the efficacy, effectiveness and efficiency of technology in anaesthesia. Some of these problems are reviewed, including the lack of specific outcomes necessitating the use of intermediate measures (e.g., hypoxaemia, myocardial ischaemia), which are not necessarily related to ultimate patient outcomes. This emphasizes the need for anaesthesia investigators to define fundamental issues specifically and design studies accordingly. With respect to anaesthesia monitors, the “lead time” or early warning provided by a monitor relative to that required to alter therapy effectively needs to be defined better and compared with the “lead time” without the monitor. After defining the benefit of a monitor, investigators should analyze the cost relative to alternatives (cost-benefit and cost-effectiveness). A hierarchical model to guide technology assessment is presented that addresses in order, the scientific basis of the technology, and the influence on the patient followed by societal issues. Anaesthetists have relied on traditional methods of technology assessment adopted from other disciplines. These methodologies do not address specific issues related to anaesthesia practice (such as “lead time”). In defining problems specific to the specialty of anaesthesia, new outcome measures that focus on the human factors related to decision-making in the operating room need to be developed. Future evaluations of anaesthesia technology require innovative approaches that address specific anaesthesia-related problems. One such approach is the use of simulation-based studies of response patterns to critical incidents.     

Pathogenesis of rheumatoid arthritis

Rheumatoid arthritis (RA) is initiated by an unknown antigen(s) in the genetically programmed host. HLA-DR4 is associated with RA. The antigen could be exogenous (e.g., Epstein-Barr virus, bacterial cell wall products) or endogenous (e.g., collagen or immunoglobulin). Within the synovium, where the immune response begins, monocytes and lymphocytes are activated. Polyclonal B-cell proliferation results, as well as production of monokines and lymphokines. The antibodies form immune complexes with other antibody molecules or antigens. Phagocytosis of immune complexes results in production of many autacoids and activation of other soluble mediator systems, e.g., the coagulation, kinin, complement, and fibrinolytic systems in synovial fluid. Chemotactic factors draw polymorphonuclear leukocytes into the joint space. Monokines stimulate synovial cell proliferation; these cells, in turn, synthesize proteinases and products of arachidonate metabolism capable of destroying normal articular structures.     

Carbon fiber-reinforced plastics as implant materials

Carbon fiber-reinforced plastics have been used clinically as an implant material for different applications for over 20 years.A review of technical basics of the composite materials (carbon fibers and matrix systems), fields of application,advantages (e.g., postoperative visualization without distortion in computed and magnetic resonance tomography), and disadvantages with use as an implant material is given. The question of the biocompatibility of carbon fiber-reinforced plastics is discussed on the basis of experimental and clinical studies. Selected implant systems made of carbon composite materials for treatments in orthopedic surgery such as joint replacement, tumor surgery, and spinal operations are presented and assessed. Present applications for carbon fiber reinforced plastics are seen in the field of spinal surgery, both as cages for interbody fusion and vertebral body replacement.     

Enforcing Imprecise Constraints on Generative Adversarial Networks for Emulating Physical Systems

Generative adversarial networks (GANs) were initially proposed to generate images by learning from a large number of samples. Recently, GANs have been used to emulate complex physical systems such as turbulent flows. However, a critical question must be answered before GANs can be considered trusted emulators for physical systems: do GANs-generated samples conform to the various physical constraints? These include both deterministic constraints (e.g., conservation laws) and statistical constraints (e.g., energy spectrum of turbulent flows). The latter have been studied in a companion paper (Wu et al., Enforcing statistical constraints in generative adversarial networks for modeling chaotic dynamical systems. Journal of Computational Physics. 406, 109209, 2020). In the present work, we enforce deterministic yet imprecise constraints on GANs by incorporating them into the loss function of the generator. We evaluate the performance of physics-constrained GANs on two representative tasks with geometrical constraints (generating points on circles) and differential constraints (generating divergence-free flow velocity fields), respectively. In both cases, the constrained GANs produced samples that conform to the underlying constraints rather accurately, even though the constraints are only enforced up to a specified interval. More importantly, the imposed constraints significantly accelerate the convergence and improve the robustness in the training, indicating that they serve as a physics-based regularization. These improvements are noteworthy, as the convergence and robustness are two well-known obstacles in the training of GANs.     

Thermodynamic considerations in solid adsorption of bound solutes for patient support in liver failure

Abstract:  New detoxification modes of treatment for liver failure that use solid adsorbents to remove toxins bound to albumin in the patient bloodstream are entering clinical evaluations, frequently in head-to-head competition. While generally effective in reducing toxin concentration beyond that obtainable by conventional dialysis procedures, the solid adsorbent processes are largely the result of heuristic development. Understanding the principles and limitations inherent in competitive toxin binding, albumin versus solid adsorbent, will enhance the design process and, possibly, improve detoxification performance. An equilibrium thermodynamic analysis is presented for both the molecular adsorbent recirculating system (MARS) and fractionated plasma separation, adsorption, and dialysis system (Prometheus), two advanced systems with distinctly different operating modes but with similar equilibrium limitations. The Prometheus analysis also applies to two newer approaches: sorbent suspension reactor and microsphere-based detoxification system. Primary results from the thermodynamic analysis are that: (i) the solute–albumin binding constant is of minor importance to equilibrium once it exceeds about 10⁵ L/mol; (ii) the Prometheus approach requires larger solid adsorbent columns than calculated by adsorbent solute capacity alone; and (iii) the albumin-containing recycle stream in the MARS approach is a major reservoir of removed toxin. A survey of published results indicates that MARS is operating under mass transfer control dictated by solute–albumin equilibrium in the recycle stream, and Prometheus is approaching equilibrium limits under current clinical protocols.     

肝癌术前肝脏储备功能评估方法的应用与研究进展

肝癌是全球第六高发的恶性肿瘤,也是全球癌症死亡的第三大原因。尽管目前肝切除术仍然是根治肝癌的首选治疗方法,具有较高的治疗效果,但仍有部分患者的预后并不理想。其中,肝切除术后肝功能衰竭（PHLF）是围手术期主要的死亡原因。PHLF的发生与肝切除术后残余肝脏的体积和功能不足密切相关,因此,术前肝脏储备功能的准确评估显得至关重要。然而,慢性肝病的进展会引起肝功能储备的变化,肝脏不同区域功能存在差异,给术前准确评估带来巨大挑战。目前,常见的肝脏储备功能评估方法主要包括综合评分系统、实验室血清学检查、吲哚菁绿（ICG）清除试验、影像学以及核医学肝胆闪烁显像（HBS）等。其中血清学检查和临床评分系统是常用的肝功能不全筛查工具,成本低、易获取,广泛应用于临床。目前,ICG清除试验已纳入国内各规范指南及专家共识,但评估的仍是整体肝功能。钆塞酸二钠（Gd-EOB-DTPA）是肝胆特异性MRI对比剂,其不仅能够提供肝脏解剖信息,还能够对局部肝功能进行定量评估。与ICG清除试验相比,Gd-EOB-DTPA增强MRI在预测PHLF方面具有更高的预测价值。然而,由于高昂的成本、长时间的检查过程以及复杂的扫描序列...     

Associations Among Exposure to Potentially Morally Injurious Experiences,Spiritual Injury,and Alcohol Use Among Combat Veterans

Potentially morally injurious experiences (PMIEs) are events that may violate deeply held values or belief systems. Combat engagement places service members at a heightened risk for PMIE exposure. Exposure to PMIEs may elicit internal conflict between moral beliefs and experiences and, if unresolved, conflict may manifest as feelings of guilt, shame, and spiritual or existential crisis. Further, distress caused by these experiences may promote harmful behaviors (e.g., excessive alcohol use), which may serve as attempts to cope with PMIEs veterans have witnessed or participated in. The present study examined a sequential mediation model in which combat exposure was associated with alcohol use (i.e., alcohol consumption, dependence symptoms, and alcohol‐related problems) via PMIE exposure and spiritual injury (e.g., alienation from and/or anger towards respective higher power) in a community sample of 380 recent‐era combat veterans. Multiple‐group sequential mediation was then used to examine whether the model fit similarly across men and women. Exposure to PMIEs and spiritual injury sequentially mediated the association between combat and alcohol; higher levels of PMIE exposure and spiritual injury were associated with increased alcohol use, R² = .17, f² = 0.07. The multiple‐group model showed that these associations significantly varied between genders such that the mediation was only significant among men. The results indicated that PMIEs and spiritual injury were associated with increased alcohol use, but these associations differed as a function of gender. Future research is needed to refine our understanding of moral and spiritual injury and explore possible risk and protective factors.