A case for the reuse and adaptation of mechanistic computational models to study transplant immunology

Computational mechanistic models constitute powerful tools for summarizing our knowledge in quantitative terms, providing mechanistic understanding, and generating new hypotheses. The present review emphasizes the advantages of reusing publicly available computational models as a way to capitalize on existing knowledge, reduce the number of parameters that need to be adjusted to experimental data, and facilitate hypothesis generation. Finally, it includes a step‐by‐step example of the reuse and adaptation of an existing model of immune responses to tuberculosis, tumor growth, and blood pathogens, to study donor‐specific antibody (DSA) responses. This review aims to illustrate the benefit of leveraging the currently available computational models in immunology to accelerate the study of alloimmune responses, and to encourage modelers to share their models to further advance our understanding of transplant immunology.     

The impact of the SARS-CoV-2 pandemic on the management of chronic limb-threatening ischemia and wound care

In the wake of the coronavirus pandemic, the critical limb ischemia (CLI) Global Society aims to develop improved clinical guidance that will inform better care standards to reduce tissue loss and amputations during and following the new SARS-CoV-2 era. This will include developing standards of practice, improve gaps in care, and design improved research protocols to study new chronic limb-threatening ischemia treatment and diagnostic options. Following a round table discussion that identified hypotheses and suppositions the wound care community had during the SARS-CoV-2 pandemic, the CLI Global Society undertook a critical review of literature using PubMed to confirm or rebut these hypotheses, identify knowledge gaps, and analyse the findings in terms of what in wound care has changed due to the pandemic and what wound care providers need to do differently as a result of these changes. Evidence was graded using the Oxford Centre for Evidence-Based Medicine scheme. The majority of hypotheses and related suppositions were confirmed, but there is noticeable heterogeneity, so the experiences reported herein are not universal for wound care providers and centres. Moreover, the effects of the dynamic pandemic vary over time in geographic areas. Wound care will unlikely return to prepandemic practices. Importantly, Levels 2–5 evidence reveals a paradigm shift in wound care towards a hybrid telemedicine and home healthcare model to keep patients at home to minimize the number of in-person visits at clinics and hospitalizations, with the exception of severe cases such as chronic limb-threatening ischemia. The use of telemedicine and home care will likely continue and improve in the postpandemic era.     

Teamwork and patient safety in dynamic domains of healthcare: a review of the literature

Aims/Background: This review examines current research on teamwork in highly dynamic domains of healthcare such as operating rooms, intensive care, emergency medicine, or trauma and resuscitation teams with a focus on aspects relevant to the quality and safety of patient care.
Results: Evidence from three main areas of research supports the relationship between teamwork and patient safety: (1) Studies investigating the factors contributing to critical incidents and adverse events have shown that teamwork plays an important role in the causation and prevention of adverse events. (2) Research focusing on healthcare providers' perceptions of teamwork demonstrated that (a) staff's perceptions of teamwork and attitudes toward safety-relevant team behavior were related to the quality and safety of patient care and (b) perceptions of teamwork and leadership style are associated with staff well-being, which may impact clinician' ability to provide safe patient care. (3) Observational studies on teamwork behaviors related to high clinical performance have identified patterns of communication, coordination, and leadership that support effective teamwork.
Conclusion: In recent years, research using diverse methodological approaches has led to significant progress in team research in healthcare. The challenge for future research is to further develop and validate instruments for team performance assessment and to develop sound theoretical models of team performance in dynamic medical domains integrating evidence from all three areas of team research identified in this review. This will help to improve team training efforts and aid the design of clinical work systems supporting effective teamwork and safe patient care.     

Noninvasive technique for measuring in vivo three-dimensional carpal bone kinematics

Our present knowledge of the three-dimensional kinematic behavior of skeletal joints has been largely acquired with cadaveric models and use of invasive monitoring. In the wrist, the small size and complex motion of the carpal bones present a difficult challenge for implanted internal or external marker systems. This paper describes a technique for quantifying the three-dimensional kinematics of the wrist and carpal bones in vivo using noninvasive computed tomographic imaging. An error analysis employing a cadaveric specimen suggests that noninvasive carpal kinematics can be measured with an accuracy within 2° of rotation and 1 mm of translation along a helical axis of motion. The in vivo application of this technique is illustrated with a single normal individual. Potential applications include the quantification of normal wrist motion, analysis of pathomechanics, and evaluation of surgical intervention. The technique is also applicable to other joints and imaging modalities.     

A statistical analysis of information-processing properties of lamina-specific cortical microcircuit models

A major challenge for computational neuroscience is to understand the computational function of lamina-specific synaptic connection patterns in stereotypical cortical microcircuits. Previous work on this problem had focused on hypothesized specific computational roles of individual layers and connections between layers and had tested these hypotheses through simulations of abstract neural network models. We approach this problem by studying instead the dynamical system defined by more realistic cortical microcircuit models as a whole and by investigating the influence that its laminar structure has on the transmission and fusion of information within this dynamical system. The circuit models that we examine consist of Hodgkin-Huxley neurons with dynamic synapses, based on detailed data from Thomson and others (2002), Markram and others (1998), and Gupta and others (2000). We investigate to what extent this cortical microcircuit template supports the accumulation and fusion of information contained in generic spike inputs into layer 4 and layers 2/3 and how well it makes this information accessible to projection neurons in layers 2/3 and layer 5. We exhibit specific computational advantages of such data-based lamina-specific cortical microcircuit model by comparing its performance with various types of control models that have the same components and the same global statistics of neurons and synaptic connections but are missing the lamina-specific structure of real cortical microcircuits. We conclude that computer simulations of detailed lamina-specific cortical microcircuit models provide new insight into computational consequences of anatomical and physiological data.     

Fibroproliferative scars

Fibroproliferative scars remain an ongoing clinical challenge. Both hypertrophic scars and keloids require multimodal therapy toachieve partally successful treatment. At the present time incomplete understanding about the pathogenesis of fibroproliferative scars makes targeted, mechanistic treatment impossible. As understanding of these abnormal wound problems increases, more effective treatments will likely be available. Until that time, clinicians must utilize existing knowledge to treat patients while continuing to experiment with new approaches.     

COVID-19 outbreak and surgical practice: The rationale for suspending non-urgent surgeries and role of testing modalities

One-hundred years after the 1918-19 H1N1 flu pandemic and 10 years after the2009 H1N1 flu pandemic, another respiratory virus has now inserted itself into the human population. Severe acute respiratory syndrome coronavirus has become a critical challenge to global health with immense economic and social disruption. In this article we review salient aspects of the coronavirus disease2019(COVID-19) outbreak that are relevant to surgical practice. The emphasis is on considerations during the pre-operative and post-operative periods as well as the utility and limitations of COVID-19 testing. The focus of the media during this pandemic is centered on predictive epidemiologic curves and models. While epidemiologists and infectious disease physicians are at the forefront in the fight against COVID-19, this pandemic is also a "stress test" to evaluate the capacity and resilience of our surgical community in dealing with the challenges imposed to our health system and society. As recently pointed out by Dr. Anthony Fauci,the virus decides the timelines in the models. However, the models can also change based on our decisions and behavior. It is our role as surgeons, to make every effort to bend the curves against the virus' will.     

Translating research findings of chronic kidney disease management to clinical practice: Challenges and opportunities

Chronic Kidney disease (CKD) has been identified as a public health epidemic, fueled in part by improved outcomes of both diabetic and cardiac patient populations, as well as by the increasing recognition that it is possible to identify CKD at earlier stages. The estimated 8 to 10 million Americans that have CKD, with its concomitant morbidity and mortality, have the potential to overwhelm the current system of specialty practice medicine and health care resources. How can clinicians, clinician scientists, and health care administrators translate research findings into clinical practice in an effective manner to improve the care of this burgeoning patient group? The challenge of translating research into clinical care requires identification of that which we do and do not know, communication of knowledge between those who do and do not know, and efficient collection of information for systematic evaluation. This article will describe the challenges of translating current research findings into clinical practice. There is a need to identify the complexity of CKD disease processes and issues associated with delivery of care and to describe the difficulties in the dissemination of new knowledge to physicians. Because of the propensity of CKD to affect identifiable groups of patients, we will discuss the potential challenges of these strategies given the racial, ethnic, and cultural diversity in North America. A potential solution to these challenges is a new paradigm of "process-based medicine" that integrates clinical and basic science research findings with multidisciplinary and shared care models of health care delivery. In this context, attention to advances in information technology, the cognitive processes that underlie physician learning, and the findings of outcome research may ensure true integration of clinical research and clinical practice.     

Macroscopic model for biological fixation and its uncover-ing idea in Chinese Mongolian traditional osteopathy

Splintage external fixation in Chinese Mongolian oste-opathy is a biological macroscopic model. In this model, the ideas of self-life "unity of mind and body" and vital natural "correspondence of nature and human" combine the physi-ological and psychological self-fixation with supplementary external fixation of fracture using small splints. This model implies macroscopic ideas of uncovering fixation and healing: structural stability integrating geometrical "dy-namic" stability with mechanical "dynamic" equilibrium and the stability of state integrating statics with dynamics, and osteoblasts with osteoclasts, and psychological stability in-tegrating closed and open systems of human and nature. These ideas indicate a trend of development in modem osteopathy.     

The application of computational modeling for risk prediction in type B aortic dissection

ObjectiveNew tools are urgently needed to help with surgical decision-making in type B aortic dissection (TBAD) that is uncomplicated at the time of initial presentation. This narrative review aims to answer the clinical question, Can computational modeling be used to predict risk in acute and chronic Stanford TBAD?MethodsThe review (PROSPERO 2018 CRD42018104472) focused on risk prediction in TBAD. A comprehensive search of the Ovid MEDLINE database, using terms related to computational modeling and aortic dissection, was conducted to find studies of any form published between 1998 and 2018. Cohort studies, case series, and case reports of adults (older than 18 years) with computed tomography or magnetic resonance imaging diagnosis of TBAD were included. Computational modeling was applied in all selected studies.ResultsThere were 37 studies about computational modeling of TBAD identified from the search, and the findings were synthesized into a narrative review. Computational modeling can produce numerically calculated values of stresses, pressures, and flow velocities that are difficult to measure in vivo. Hemodynamic parameters—high or low wall shear stress, high pressure gradient between lumens during the cardiac cycle, and high false lumen flow rate—have been linked to the pathogenesis of branch malperfusion and aneurysm formation by numerous studies. Considering the major outcomes of end-organ failure, aortic rupture, and stabilization and remodeling, hypotheses have been generated about inter-relationships of measurable parameters in computational models with observable anatomic and pathologic changes, resulting in specific clinical outcomes.ConclusionsThere is consistency in study findings about computational modeling in TBAD, although a limited number of patients have been analyzed using various techniques. The mechanistic patterns of association found in this narrative review should be investigated in larger cohort prospective studies to further refine our understanding. It highlights the importance of patient-specific computational hemodynamic parameters in clinical decision-making algorithms. The current challenge is to develop and to test a risk assessment method that can be used by clinicians for TBAD.     

Mouse models for genes involved in impaired spermatogenesis

Since the introduction of molecular biology and gene ablation technologies there have been substantial advances in our understanding of how sperm are made and fertilization occurs. There have been at least 150 different models of specifically altered gene function produced that have resulted in male infertility spanning virtually all aspects of the spermatogenic, sperm maturation and fertilization processes. While each has, or potentially will reveal, novel aspects of these processes, there is still much of which we have little knowledge. The current review is by no means a comprehensive list of these mouse models, rather it gives an overview of the potential for such models which up to this point have generally been 'knockouts'; it presents alternative strategies for the production of new models and emphasizes the importance of thorough phenotypic analysis in order to extract a maximum amount of information from each model.     

Conceptualizing a resilience research framework at The National Institutes of Health

The National Institutes of Health (NIH) have recently gathered internal and external input towards a shared understanding of resilience in the wide context of human health and the biomedical sciences that would help accelerate advances in human health and its maintenance. This shared view is that resilience refers in general to a system's capacity to recover, grow, adapt, or resist perturbation from a challenge or stressor. Over time, a system's response to a challenge might show varied degrees of reactions that likely fluctuate in response to the type of challenge (internal and/or external), severity of the challenge, the length of time exposed to the challenge, other external factors and/or biological factors (innate and/or external). We have embarked on this special issue as an opportunity to explore commonalities amongst viewpoints on the science of resilience covered by the various NIH Institutes, Centers, and Offices (ICOs) with respect to the characterization of various systems, stressors, outcomes measures and metrics, and interventions and/or protective factors that are shared within each domain and across multiple domains. Here, resilience is characterized broadly by four areas of scientific study: molecular/cellular, physiologic, psychosocial and spiritual, and environmental/community resilience. Each area or domain provides general frameworks for designing studies that may help advance the science of resilience within the context of health maintenance. This special issue will also acknowledge the remaining gaps that impede advancement of the science of resilience and offer considerations for potential next steps towards addressing the research gaps.     

Integration of TGF‐β‐ and EGFR‐based signaling pathways using an agent‐based model of epithelial restitution

Damage to an epithelial surface disrupts its mechanical and immunologic barrier function and exposes underlying tissues to a potentially hostile external environment. Epithelial restitution occurs quickly to reestablish the barrier and comprises a major part of the immediate host response to injured tissue. Pathways involving transforming growth factor beta and activation of epidermal growth factor receptor are both of critical importance, although cross‐pathway interactions have been poorly characterized. Agent‐based modeling has been showed to be useful in integrating disparate bodies of knowledge and showing the dynamic consequences of pathway structures and cellular population behavior and is used herein to create an in silico analog of an in vitro scratch assay. The In Vitro Scratch Agent‐Based Model consists of agents representing individual epithelial cells in a simulated extracellular matrix. Agents sense signals from the damaged environment and produce effector molecules, leading to their healing behavior. The In Vitro Scratch Agent‐Based Model qualitatively matched wound healing dynamics when compared against data from traditional experiments. Putative cross‐talk mechanisms were then instantiated into the In Vitro Scratch Agent‐Based Model and their relative plausibility examined, suggesting interaction at the receptor tyrosine kinase level. This highlights the utility of dynamic knowledge representation in the integration of pathways previously studied in separate contexts.     

Bone substitutes for lumbar fusion:present and future

Recent advances in our knowledge regarding the spinal fusion process, as well as the potential for biological manipulation of bone formation, make it timely to review the use of bone grafts, graft adjuncts, and bone graft substitutes in the lumbar spinal fusion process. Despite technical advances such as rigid segmental internal fixation, the success of a spine fusion depends largely on the effective use of bone graft materials and the application of sound bone grafting techniques. In this article, the properties and use of various graft materials are reviewed. In addition, results from studies using animal models to study graft materials and data from limited clinical studies are briefly presented. Lastly, gaps in our existing knowledge are highlighted and areas of future research discussed. An understanding of the biology and properties of bone graft materials, including adjuncts and substitutes, will enable the surgeon to apply sound principles in minimizing the current problems associated with achieving a successful spinal fusion.     

Regenerative orthopaedics: in vitro,in vivo … in silico

In silico, defined in analogy to in vitro and in vivo as those studies that are performed on a computer, is an essential step in problem-solving and product development in classical engineering fields. The use of in silico models is now slowly easing its way into medicine. In silico models are already used in orthopaedics for the planning of complicated surgeries, personalised implant design and the analysis of gait measurements. However, these in silico models often lack the simulation of the response of the biological system over time. In silico models focusing on the response of the biological systems are in full development. This review starts with an introduction into in silico models of orthopaedic processes. Special attention is paid to the classification of models according to their spatiotemporal scale (gene/protein to population) and the information they were built on (data vs hypotheses). Subsequently, the review focuses on the in silico models used in regenerative orthopaedics research. Contributions of in silico models to an enhanced understanding and optimisation of four key elements—cells, carriers, culture and clinics—are illustrated. Finally, a number of challenges are identified, related to the computational aspects but also to the integration of in silico tools into clinical practice.     

Biological and Mechanical Predictors of Meniscus Function: Basic Science to Clinical Translation

Progressive knee joint degeneration occurs following removal of a torn meniscus. However, there is significant variability in the rate of development of post-meniscectomy osteoarthritis (OA). While there is no current consensus on the risk factors for development of knee OA in patients with meniscus tears, it is likely that both biological and biomechanical factors play critical roles. In this perspective paper, we review the mechanical and the biological predictors of the response of the knee to partial meniscectomy. We review the role of patient-based studies, in vivo animal models, cadaveric models, bioreactor systems, and statistically augmented computational models for the study of meniscus function and post-meniscectomy OA, providing insight into the important interplay between biomechanical and biologic factors. We then discuss the clinical translation of these concepts for “biologic augmentation” of meniscus healing and meniscus replacement. Ultimately, collaborative studies between engineers, biologists, and clinicians is the optimal way to improve our understanding of meniscus pathology and response to injury and/or disease, and to facilitate effective translation of laboratory findings to improved treatments for our patients. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:937-945, 2020     

Mechanical Stimuli in the Local In Vivo Environment in Bone: Computational Approaches Linking Organ-Scale Loads to Cellular Signals

Purpose of Review

Connecting organ-scale loads to cellular signals in their local in vivo environment is a current challenge in the field of bone (re)modelling. Understanding this critical missing link would greatly improve our ability to anticipate mechanotransduction during different modes of stimuli and the resultant cellular responses. This review characterises computational approaches that could enable coupling links across the multiple scales of bone.

Recent Findings

Current approaches using strain and fluid shear stress concepts have begun to link organ-scale loads to cellular signals; however, these approaches fail to capture localised micro-structural heterogeneities. Furthermore, models that incorporate downstream communication from osteocytes to osteoclasts, bone-lining cells and osteoblasts, will help improve the understanding of (re)modelling activities. Incorporating this potentially key information in the local in vivo environment will aid in developing multiscale models of mechanotransduction that can predict or help describe resultant biological events related to bone (re)modelling.

Summary

Progress towards multiscale determination of the cell mechanical environment from organ-scale loads remains elusive. Construction of organ-, tissue- and cell-scale computational models that include localised environmental variation, strain amplification and intercellular communication mechanisms will ultimately help couple the hierarchal levels of bone.

     

社区COPD患者家庭疾病管理现状调查

目的了解上海市社区慢性阻塞性肺疾病家庭（患者及照顾者）的疾病管理相关知识和行为的现状,为针对性干预提供参考。方法采用自行设计的患者及照顾者疾病管理相关知识、行为调查表,对上海市COPD患者及其照顾者各84例进行问卷调查。结果COPD疾病管理一般知识和氧疗知识得分率：患者分别为51.09%、19.34%,照顾者分别为38.99%、10.42%;疾病管理行为得分率：患者为39.93%,照顾者为38.51%。患者及照顾者疾病管理知识与其行为的相关系数r为0.575、0.523,均P〈0.01。结论社区COPD家庭疾病管理知识及管理行为处于中低水平,管理知识水平较高者管理行为较好。社区医护人员应寻求有效的干预策略提高COPD家庭疾病管理相关知识和行为,以控制COPD患者疾病进展,提高其生活质量。     

Cross-cultural adaptation and validation of the Questionnaire for Pruritus Assessment for use in the French Canadian burn survivor population

BACKGROUND: Severe pruritus after burn continues to be a clinical challenge. To address this challenge, thorough documentation of burn survivors' itch experience is required. A "Questionnaire for Pruritus Assessment" has been developed to capture the sensory and affective experiences associated with itch as well as its functional and quality of life implications, but to evaluate the Quebec burn survivor population, a Canadian French version is required. Thus, the purpose of this study was to generate a Canadian French cross-cultural adaptation of the questionnaire suitable for the burn survivor population. METHODS: Cross-cultural adaptation followed six steps: forward translation into Canadian French, back translations into English, resolution between the two versions, synthesis of the Canadian French versions, revision by a committee of experts, and testing of the pre-final version. RESULTS: The adaptation process resolved issues surrounding translation, content validity, burn survivor-specific modifications, and format, resulting in a Canadian French pre-final version that was pilot-tested among 32 burn survivors. Content validity of the Canadian French version was assessed by a committee of experts and the participants. The results showed good item completion and adequate distribution of scores without a ceiling or floor effect. CONCLUSIONS: This study resulted in a Canadian French version of the "Questionnaire for Pruritus Assessment" that can confidently be compared to other investigations utilizing the same tool. The adapted questionnaire also provides a valuable data collection means, enabling more thorough documentation of the burn survivor itch experience.     

Agent-based model of epithelial host–pathogen interactions in anastomotic leak

Background

There is a growing recognition of the significance of host–pathogen interactions (HPIs) in gut biology leading to a reassessment of the role of bacteria in intestinal anastomotic leak. Understanding the complexities of the early postsurgical gut HPI requires integrating knowledge of both epithelial and bacterial behaviors to generate hypotheses of potential mechanisms of interaction. Agent-based modeling is a computational method well suited to achieve this goal, and we use an agent-based model (ABM) to examine alterations in the HPI affecting reestablishment of the epithelial barrier that may subsequently lead to anastomotic leak.

Methods

Computational agents representing Pseudomonas aeruginosa were added to a previously validated ABM of epithelial restitution. Simulated experiments were performed examining the effect of radiation on bacterial binding to epithelial cells, plausibility of putative binding targets, and potential mechanisms of epithelial cell killing by virulent bacteria.

Results

Simulation experiments incorporating radiation effects on epithelial monolayers produced binding patterns akin to those seen in vitro and suggested that promotility integrin–laminin associations represent potential sites for bacterial binding and disruption of restitution. Simulations of potential mechanisms of epithelial cell killing suggested that an injected cytotoxin was the means by which virulent bacteria produced the tissue destruction needed to generate an anastomotic leak, a mechanism subsequently confirmed with genotyping of the virulent P aeruginosa strain.

Conclusions

This study emphasizes the utility of ABM as an adjunct to traditional research methods and provides insights into the potentially critical role of HPI in the pathogenesis of anastomotic leak.