Reparative inflammation takes charge of tissue regeneration.

Inflammation underlies many chronic and degenerative diseases, but it also mitigates infections, clears damaged cells and initiates tissue repair. Many of the mechanisms that link inflammation to damage repair and regeneration in mammals are conserved in lower organisms, indicating that it is an evolutionarily important process. Recent insights have shed light on the cellular and molecular processes through which conventional inflammatory cytokines and Wnt factors control mammalian tissue repair and regeneration. This is particularly important for regeneration in the gastrointestinal system, especially for intestine and liver tissues in which aberrant and deregulated repair results in severe pathologies.

Questioning Established Theories and Treatment Methods Related to Iron and Other Metal Metabolic Changes, Affecting All Major Diseases and Billions of Patients.

The medical and scientific literature is dominated by highly cited historical theories and findings [...].

Serum levels of TARC, MDC, IL-10, and soluble CD163 in Hodgkin lymphoma: a SWOG S0816 correlative study.

Serum soluble chemokines/cytokines produced by Hodgkin cells and the tumor microenvironment might be of value as biomarkers in classic Hodgkin lymphoma (cHL). We assessed serum thymus and activation-related chemokine (TARC), macrophage-derived chemokine (MDC), interleukin-10 (IL-10), and soluble CD163 (sCD163) levels at baseline, time of interim fluorodeoxyglucose positron emission tomography (PET), and after therapy in cHL patients treated on S0816, an intergroup phase 2 response-adapted study evaluating escalated therapy for interim PET (PET2)-positive patients (www.clinicaltrials.gov #NCT00822120). Epstein-Barr virus (EBV) status was assessed, and 559 serum samples were evaluated for TARC, MDC, IL-10, and sCD163 by immunoassay. EBV positivity correlated with higher sCD163 and IL-10 levels but lower TARC levels. While baseline biomarker levels were not associated with outcome, sCD163 levels at the time of PET2 were associated with favorable progression-free survival (PFS), adjusting for PET2 status. After therapy TARC, MDC, and IL-10 correlated with PFS and overall survival (OS) on univariable analysis, which remained significant adjusting for international prognostic score. When also adjusting for end-of-therapy PET results, TARC and IL-10 remained significantly associated with shorter PFS and OS. Exploratory analysis in PET2-negative patients showed that elevated posttherapy TARC and IL-10 levels were associated with PFS. Serum cytokine levels correlate with outcome in cHL and should be investigated further in risk-adapted cHL trials.

Clinical Perspectives of Theranostics.

Theranostics is a precision medicine which integrates diagnostic nuclear medicine and radionuclide therapy for various cancers throughout body using suitable tracers and treatment that target specific biological pathways or receptors. This review covers traditional theranostics for thyroid cancer and pheochromocytoma with radioiodine compounds. In addition, recent theranostics of radioimmunotherapy for non-Hodgkin lymphoma, and treatment of bone metastasis using bone seeking radiopharmaceuticals are described. Furthermore, new radiopharmaceuticals for prostatic cancer and pancreatic cancer have been added. Of particular, F-18 Fluoro-2-Deoxyglucose (FDG) Positron Emission Tomography (PET) is often used for treatment monitoring and estimating patient outcome. A recent clinical study highlighted the ability of alpha-radiotherapy with high linear energy transfer (LET) to overcome treatment resistance to beta--particle therapy. Theranostics will become an ever-increasing part of clinical nuclear medicine.

The Role of Protein Engineering in Biomedical Applications of Mammalian Synthetic Biology.

Engineered proteins with enhanced or altered functionality, generated for example by mutation or domain fusion, are at the core of nearly all synthetic biology endeavors in the context of precision medicine, also known as personalized medicine. From designer receptors sensing elevated blood markers to effectors rerouting signaling pathways to synthetic transcription factors and the customized therapeutics they regulate, engineered proteins play a crucial role at every step of novel therapeutic approaches using synthetic biology. Here, recent developments in protein engineering aided by advances in directed evolution, de novo design, and machine learning are discussed. Building on clinical successes already achieved with chimeric antigen receptor (CAR-) T cells and other cell-based therapies, these developments are expected to further enhance the capabilities of mammalian synthetic biology in biomedical and other applications.

Water-Splitting Based and Related Therapeutic Effects: Evolving Concepts, Progress, and Perspectives.

Water-splitting has been extensively studied especially for energy applications. It is often not paid with enough attention for biomedical applications. In fact, several innovative breakthroughs have been achieved in the past few years by employing water-splitting for treating cancer and other diseases. Interestingly, among these important works, only two reports have mentioned the term "water-splitting." For this reason, the importance of water-splitting for biomedical applications is significantly underestimated. This progress work is written with the aims to explain and summarize how the principle of water-splitting is employed to achieve therapeutic results not offered by conventional approaches. It is expected that this progress report will not only explain the importance of water-splitting to scientists in the biomedical fields, it should also draw attention from scientists working on energy applications of water-splitting.

Willingness to Pay for Health Improvements Using Stated Preferences: Prevention Versus Treatment.

OBJECTIVES: This study aimed to investigate whether there was a difference in willingness to pay (WTP) between prevention and treatment for health benefits of equal magnitude. METHODS: We used a web-based survey instrument in a sample of the Swedish general population to perform a contingent valuation study assessing the WTP for prevention and treatment. We analyzed the WTP as a continuous variable using a two-part regression model to adjust for a mass point around 0 and a skewed distribution among respondents with a positive WTP. RESULTS: The study found that people were less willing, on average, to pay at all for prevention than treatment, but those who were willing to pay for prevention had a higher WTP than for treatment. The latter effect was more substantial, and in total mean WTP for prevention was about 85% higher than for treatment. CONCLUSIONS: The findings from this study contribute to the ongoing discussion on the appropriate cost-effectiveness thresholds by adding prevention as a parameter affecting the demand-side value of health improvements. As such, it can provide support to decision makers in healthcare and in health promotion priority setting.

Concepts toward directing human astroplasticity to promote neuroregeneration.

Astrocytes exhibit dynamic and complex reactions to various insults. Recently, investigations into the transitions that occur during cellular specification, differentiation, maturation, and disease responses have provided insights into understanding the mechanisms that underlie these altered states of reactivity and function. Here we summarize current concepts in how astrocyte state transitions, termed astroplasticity, are regulated, as well as how this affects neural circuit function through extracellular signaling. We postulate that a promising future approach toward enhancing functional repair after injury and disease would be to steer astrocytes away from an inhibitory response and toward one that is beneficial to neuroplasticity and neuroregeneration. Toward this goal, we discuss emerging biotechnological advancements, with a focus on human pluripotent stem cell bioengineering, which has high potential for effective manipulation and control of astroplasticity. Highlights include innovations in cellular transdifferentiation techniques, nanomedicine, organoid and three-dimensional (3D) spheroid microcircuit development, and the use of biomaterials to influence the extracellular environment. Current barriers and future applications are also summarized in order to augment the design of future preclinical trials aimed toward astrocyte-targeted neuroregeneration with a concept termed astrocellular therapeutics. Developmental Dynamics 248:21-33, 2019. © 2018 Wiley Periodicals, Inc.

Implementation of Assisted Therapy With Dogs in the Therapeutic Approach to People With Autistic Spectrum Disorder.

A holistic intervention is needed for individuals who suffer from autism spectrum disorders. Our objective was to work with these individuals in a multidisciplinary manner through the use of animal-assisted therapy, finding improvements in the experimental group as compared with the control group in the different evaluated areas.

Recent trends in treatment of thalassemia.

Thalassemia is a common inherited monogenic disease. It is characterized by chronic hemolysis, ineffective erythropoiesis (IE) and iron overload. Despite advances in transfusion practices and chelation therapy, still many limitations in delivering these standard therapies exist. Challenges of currently available standard care and advances in understanding the underlying pathophysiological mechanisms in thalassemia stimulated research towards development of novel therapeutic targets. Agents reducing IE as Jak 2 inhibitors and Activin II receptor traps are promising and are currently in clinical trials. Other approaches targeting iron dysregulation as mini-hepcidins, exogenous transferrin and erythroferrone inhibitors are in preclinical studies. Gene therapy, a rapidly evolving field, has exhibited remarkable progress in recent years. Studies have focused on ß or γ-globin addition, over expression of endogenous γ-globin-activating transcription factors, silencing of γ-globin repressors and genome editing of ß-globin mutations or γ-globin repressors. In this article we provide an overview of emerging recent trends in treatment of thalassemia targeting IE, iron dysregulation and novel curative treatments as gene therapy and gene editing.

Defining and Managing High-Priced Cures: Healthcare Payers' Opinions.

OBJECTIVES: Recent regulatory approvals of potentially curative but high-cost treatments have made these therapies a focus of health policy discussions. Cures present new challenges to healthcare payers because they have high upfront costs but have life-long health benefits. The objectives of this study are to understand how healthcare payers define and manage cures. We investigated payers' views on key features of curative treatments and the affordability and value challenges they present. METHODS: We conducted semistructured interviews in 2016 with key informants in US payer organizations. Interviewees were directly involved in coverage determination for highly effective and curative therapies. RESULTS: We contacted 24 individuals and 18 participated. When asked what aspects of cures were important for coverage determination, an equal percentage of respondents (61% each) mentioned clinical and economic factors. In defining a cure, half of respondents included an economic element such as no downstream costs associated with the disease. When asked about challenges, 72% of respondents mentioned uncertainty regarding long-term outcomes and 56% mentioned membership churn and competition. CONCLUSIONS: Payers expressed a novel definition of a cure-which we call a "healthcare cost cure"-that captures both the clinical and economic consequences of treatment. This definition may be more pertinent in fragmentary financing systems that unevenly distribute cure costs and benefits across payers. Overall findings indicate that decision makers desire evidence to ensure that the long-term real-world consequences of covering cures match the expected benefits. Future policies need to balance upfront acquisition costs with downstream financial benefits.

Significance of Molecular Monitoring of T Cells for the Decision of Treatment Strategy for Epstein-Barr Virus-associated Hemophagocytic Lymphohistiocytosis.

A 17-year-old patient with Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis achieved first remission after immunochemotherapy (ICT). However, he had fever with an increase in soluble interleukin-2 receptor, but not in ferritin. Molecular analysis revealed augmented plasma and T-cell EBV loads and reappearance of clonal T cells. Despite achieving second remission, the T-cell EBV load at week 8 after second ICT was almost similar to that at week 8 after first ICT. Hence, cyclosporine was decreased over a 9-month period, with molecular monitoring of plasma and T cells. In this article, we describe how useful molecular monitoring was for detecting relapse and resuming ICT.

Guidelines on the Use of Therapeutic Apheresis in Clinical Practice - Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue.

The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating and categorizing indications for the evidence-based use of therapeutic apheresis (TA) in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the committee has incorporated systematic review and evidence-based approaches in the grading and categorization of apheresis indications. This Eighth Edition of the JCA Special Issue continues to maintain this methodology and rigor in order to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Eighth Edition, like its predecessor, continues to apply the category and grading system definitions in fact sheets. The general layout and concept of a fact sheet that was introduced in the Fourth Edition, has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease entity or medical condition. The Eighth Edition comprises 84 fact sheets for relevant diseases and medical conditions, with 157 graded and categorized indications and/or TA modalities. The Eighth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease.

Heart Failure Care Dyadic Typology: Initial Conceptualization, Advances in Thinking, and Future Directions of a Clinically Relevant Classification System.

BACKGROUND: Heart failure (HF) dyadic self-care science is advancing rapidly, as evidenced by recent theoretical work, literature reviews, and multiple empiric studies. Typologies, once considered archaic, are now viewed as person-oriented classification systems that allow a whole-system view of information patterns. This whole-system view is particularly needed to understand complex tasks like dyadic HF self-care. PURPOSE: The purpose of this article is to review the initial conceptualization of an HF care dyadic typology and the present advances in our thinking and suggest future directions for this clinically relevant classification system. CONCLUSIONS: Development and testing of the typology across 5 studies resulted in a well-characterized, pragmatic and parsimonious, person-oriented classification system for understanding how patients and informal caregivers conduct patients' HF self-care at home. The 4 types are characterized as 2 individually oriented types-type I, patient oriented; type II, caregiver oriented; and 2 relationally oriented types-type III, collaboratively oriented; and type IV, incongruently oriented. We have devised a single-item measure of typology group that can be assessed in the clinical setting. Once this information is ascertained, the clinician can personalize the plan of care to the realities of the dyad. IMPLICATIONS: Dyads that disagree on who is responsible for self-care may forego or delay action, resulting in self-care failures with subsequent HF advancement, hospitalization, and mortality. As the HF dyadic self-care science has advanced, we have come to appreciate the complexity that arises when 2 individuals work together on 1 complex task-HF self-care.

The Effect of Different Intervention Approaches on Gross Motor Outcomes of Children With Autism Spectrum Disorder: A Meta-Analysis.

Despite the rising interest in intervention for children with autism spectrum disorder, the extent to which interventions are effective on gross motor outcomes is currently unknown. The purpose of this study was to analyze the effect of different intervention approaches on gross motor outcomes among children with autism spectrum disorder using meta-analysis. A total of 18 studies met the inclusion criteria for quantitative analysis. Pre- and posttest means and SDs were extracted to calculate effect sizes. Potential moderator variables were chosen based on important intervention characteristics. The results suggest that interventions have a large effect on gross motor outcomes among children with autism spectrum disorder (δ = 0.99, SE = 0.19, p < .001, 95% confidence interval [0.62, 1.36]). The interventions that were 16 total hours or longer had a significantly larger effect than those less than 16 hr. In addition, the interventions in experimental settings had significantly larger effects than the interventions in practical settings. Future interventions should consider intensity, including not only the duration of the intervention but also the intensity in which specific intervention goals are targeted.

Healing activities construct the objects of therapy: Medicine's way of seeking truth, organizing forms of reality, regulating patients' bodies, illness and culture?

In this paper, I will explore the concept that healing activities shape the objects of therapy and seek to construct those objects through therapeutic activities. Objects of therapy are the persons, patients, human bodies, diseases, physiological processes and personal suffering-that which clinical medicine constructs through its distinctive formative processes, practices and knowledge. The rationale for choice of philosophical sources namely, Cassirer, Foucault, the anthropological perspective of Good and the sociological account of Frank will be discussed. The claim articulated by Good will be examined and its relationship to culture, illness, medical knowledge, practice, truth, and science. I then focus on Frank's concepts of the patient and the body and how medical knowledge and practices affects it. The concept that the medicalization of the illness narrative silences the patient's voice requiring an ethic of listening will be emphasized, described and further supported by Charon's (2006, Narrative medicine: Honoring the stories of illness. New York, NY: Oxford University Press) and Cassell's (2015, The nature of suffering and the goals of medicine. New York, NY: Oxford University Press) thoughts on narrative of illness in clinical medicine. My position concludes that healing activities construct the objects of therapy: as the medical culture's way of seeking truth; as medicine's way of mediating and organizing forms of reality through culture and symbolic forms; and, as medicine's way of entering the body and constructing the disease. Lastly, I suggest that in spite of the remarkable progress in the control of disease, the failure to address the interpretation of illness meanings is a fundamental flaw in the work of "doctoring." The experience and meanings of illness are at the centre of clinical practice and is a moral, political, ethical and professional obligation. The person is a cultural construct, a complex and culturally shaped way of experiencing self and other, and cultural "work" is required to constitute the person who is the object of medical attention and it also necessitates the ethic of listening.

ADAMTS13: origins, applications, and prospects.

ADAMTS13 is an enzyme that acts by cleaving prothrombotic von Willebrand factor (VWF) multimers from the vasculature in a highly regulated manner. In pathologic states such as thrombotic thrombocytopenic purpura (TTP) and other thrombotic microangiopathies (TMAs), VWF can bind to the endothelium and form large multimers. As the anchored VWF chains grow, they provide a greater surface area to bind circulating platelets (PLTs), generating unique thrombi that characterize TTP. This results in microvasculature thrombosis, obstruction of blood flow, and ultimately end-organ damage. Initial presentations of TTP usually occur in an acute manner, typically developing due to an autoimmune response toward, or less commonly a congenital deficiency of, ADAMTS13. Triggers for TMAs that can be associated with ADAMTS13 deficiency, including TTP, have been linked to events that place a burden on hemostatic regulation, such as major trauma and pregnancy. The treatment plan for cases of suspected TTP consists of emergent therapeutic plasma exchange that is continued on a daily basis until normalization of PLT counts. However, a subset of these patients does not respond favorably to standard therapies. These patients necessitate a better understanding of their diseases for the advancement of future therapeutic options. Given ADAMTS13's key role in the cleavage of VWF and the prevention of PLT-rich thrombi within the microvasculature, future treatments may include anti-VWF therapeutics, recombinant ADAMTS13 infusions, and ADAMTS13 expression via gene therapy.

Single index methods for evaluation of marker-guided treatment rules based on multivariate marker panels.

Clinical practice may be enhanced by use of person-level information that could guide treatment choice and lead to better outcomes for both treated individuals and for the population. The scientific challenge is to identify and validate those factors that can reliably be used to target treatment, and to accurately quantify the expected treatment benefit as a function of candidate markers. Our proposal is to explicitly focus on smooth non-parametric evaluation of a canonical single index score that estimates the expected treatment benefit associated with patient characteristics. Our methods intentionally decouple the model used to generate the treatment benefit score from the methods that are adopted to evaluate the performance of the resulting single index score. We are motivated by the practical issue that model performance can not realistically be evaluated for every specific covariate value due to intrinsic sparseness. However, direct validation of a scalar treatment benefit score obtained through model-based dimension reduction is feasible, and we believe should be the focus of validation efforts. We also show that the canonical single index treatment benefit score can be used for selecting subsets of patients with enriched expected treatment response since patients can be easily ordered and grouped based on the scalar score. Our biomedical motivation comes from a recent randomized trial of steroid injections for low back pain where baseline clinical and imaging data are candidate measures for guiding therapeutic choice.

A multi-source adaptive platform design for testing sequential combinatorial therapeutic strategies.

Traditional paradigms for clinical translation are challenged in settings where multiple contemporaneous therapeutic strategies have been identified as potentially beneficial. Platform trials have emerged as an approach for sequentially comparing multiple trials using a single protocol. The Ebola virus disease outbreak in West Africa represents one recent example which utilized a platform design. Specifically, the PREVAIL II master protocol sequentially tested new combinations of therapies against the concurrent, optimal standard of care (oSOC) strategy. Once a treatment demonstrated sufficient evidence of benefit, the treatment was added to the oSOC for all future comparisons (denoted as segments throughout the manuscript). In the interest of avoiding bias stemming from population drift, PREVAIL II considered only within-segment comparisons between the oSOC and novel treatments and failed to leverage data from oSOC patients in prior segments. This article describes adaptive design methodology aimed at boosting statistical power through Bayesian modeling and adaptive randomization. Specifically, the design uses multi-source exchangeability models to combine data from multiple segments and adaptive randomization to achieve information balance within a segment. When compared to the PREVAIL II design, we demonstrate that our proposed adaptive platform design improves power by as much as 51% with limited type-I error inflation. Further, the adaptive platform effectuates more balance with respect to the distribution of acquired information among study arms, with more patients randomized to experimental regimens.