A systematic review and meta-analysis of childhood health utilities

Background: A common feature of most reviews or catalogues of health utilities has been their focus on adult health states or derivation of values from adult populations. More generally, utility measurement in or on behalf of children has been constrained by a number of methodological concerns. The objective of this study was to conduct the first comprehensive systematic review and meta-analysis of primary utility data for childhood conditions and descriptors and to determine the effects of methodological factors on childhood utilities. Methods: The review followed PRISMA guidelines. PubMed, Embase, Web of Science, PsycINFO, EconLit, CINAHL and Cochrane Library were searched for primary studies reporting health utilities for childhood conditions or descriptors using direct or indirect valuation methods. The Pediatric Economic Database Evaluation (PEDE) was also searched for cost-utility analyses with primary utility values. Mean or median utilities for each of the main samples were catalogued, whilst weighted averages of utilities for each health condition were estimated, by valuation method. Mixed-effects meta-regression using hierarchical linear modelling was conducted for the most common valuation methods to estimate the utility decrement for each health condition category relative to general childhood population health, as well as the independent effects of methodological factors. Results: The literature searches resulted in 272 eligible studies. These yielded 3,414 utilities when all sub-groups were considered, covering all ICD-10 chapters relevant to childhood health, 19 valuation methods, 12 respondent types, 8 modes of administration, and data from 36 countries. A total of 1,191 utility values were obtained when only main study samples were considered and these were catalogued by health condition or descriptor, and methodological characteristics. 1,073 mean utilities for main samples were used for fixed-effects meta-analysis by health condition and valuation method. Mixed-effects meta-regressions estimated that 53 of 76 ICD-10 delineated health conditions valued using the HUI3 were associated with statistically significant utility decrements relative to general population health, whilst 38 of 57 valued using a Visual Analogue Scale (VAS) were associated with statistically significant VAS decrements. For both methods, parental proxy-assessment was associated with overestimation of values, whilst adolescents reported lower values than children under 12 years. VAS responses were more heavily influenced by mode of administration than the HUI3

Private specificities of CD8 T cell responses control patterns of heterologous immunity

CD8 T cell cross-reactivity between viruses can play roles in protective heterologous immunity and damaging immunopathology. This cross-reactivity is sometimes predictable, such as between lymphocytic choriomeningitis virus (LCMV) and Pichinde virus, where cross-reactive epitopes share six out of eight amino acids. Here, however, we demonstrate more subtle and less predictable cross-reactivity between LCMV and the unrelated vaccinia virus (VV). Epitope-specific T cell receptor usage differed between individual LCMV-infected C57BL/6 mice, even though the mice had similar epitope-specific T cell hierarchies. LCMV-immune mice challenged with VV showed variations, albeit in a distinct hierarchy, in proliferative expansions of and down-regulation of IL-7Rα by T cells specific to different LCMV epitopes. T cell responses to a VV-encoded epitope that is cross-reactive with LCMV fluctuated greatly in VV-infected LCMV-immune mice. Adoptive transfers of splenocytes from individual LCMV-immune donors resulted in nearly identical VV-induced responses in each of several recipients, but responses differed depending on the donor. This indicates that the specificities of T cell responses that are not shared between individuals may influence cross-reactivity with other antigens and play roles in heterologous immunity upon encounter with another pathogen. This variability in cross-reactive T cell expansion that is unique to the individual may underlie variation in the pathogenesis of infectious diseases

Development of a Civil Infrastructure Resilience Assessment Framework

Recent disruptive events, such as earthquakes or floods, have caused severe damage to civil infrastructural systems. Thus, there is a need to extend the focus of traditional design practices to consider resilience-based design approaches which can help in defining preventive actions and measures to mitigate the consequences caused by such disruptive events. This paper presents a Civil Infrastructure Resilience Assessment Framework (CIRAF) to assess the seismic fragility and resilience of a single or interconnected civil infrastructural systems following a disruptive event. Once the information regarding the infrastructural system, hazards, fragility databases, components damage state correlation, recovery models, and upgrade models are identified, then the framework can be used to quantify the loss of functionality, recovery time, repair cost, and overall resilience following an extreme event. Bayesian models are used to evaluate the probability of failure of a system, which consists of layers of sub-systems and components. A state-of-the-art engineering tool is also developed using the framework that would enable the stakeholders to compare different upgrade strategies through an easy to use web interface and thus easing the decision-making process. A simplified infrastructural system consisting of 3 components is illustrated in this paper using the CIRAF framework

Long-Lasting Impairments in Quadriceps Mitochondrial Health, Muscle Size, and Phenotypic Composition Are Present After Non-Invasive Anterior Cruciate Ligament Injury

Introduction: Despite rigorous rehabilitation aimed at restoring muscle health, anterior cruciate ligament (ACL) injury is often hallmarked by significant long-term quadriceps muscle weakness. Derangements in mitochondrial function are a common feature of various atrophying conditions, yet it is unclear to what extent mitochondria are involved in the detrimental sequela of quadriceps dysfunction after ACL injury. Using a preclinical, non-invasive ACL injury rodent model, our objective was to explore the direct effect of an isolated ACL injury on mitochondrial function, muscle atrophy, and muscle phenotypic transitions. Methods: A total of 40 male and female, Long Evans rats (16-week-old) were exposed to non-invasive ACL injury, while 8 additional rats served as controls. Rats were euthanized at 3, 7, 14, 28, and 56 days after ACL injury, and vastus lateralis muscles were extracted to measure the mitochondrial respiratory control ratio (RCR; state 3 respiration/state 4 respiration), mitochondrial reactive oxygen species (ROS) production, fiber cross sectional area (CSA), and fiber phenotyping. Alterations in mitochondrial function and ROS production were detected using two-way (sex:group) analyses of variance. To determine if mitochondrial characteristics were related to fiber atrophy, individual linear mixed effect models were run by sex. Results: Mitochondria-derived ROS increased from days 7 to 56 after ACL injury (30–100%, P \u3c 0.05), concomitant with a twofold reduction in RCR (P \u3c 0.05). Post-injury, male rats displayed decreases in fiber CSA (days 7, 14, 56; P \u3c 0.05), loss of IIa fibers (day 7; P \u3c 0.05), and an increase in IIb fibers (day 7; P \u3c 0.05), while females displayed no changes in CSA or phenotyping (P \u3e 0.05). Males displayed a positive relationship between state 3 respiration and CSA at days 14 and 56 (P \u3c 0.05), while females only displayed a similar trend at day 14 (P = 0.05). Conclusion: Long-lasting impairments in quadriceps mitochondrial health are present after ACL injury and play a key role in the dysregulation of quadriceps muscle size and composition. Our preclinical data indicate that using mitoprotective therapies may be a potential therapeutic strategy to mitigate alterations in muscle size and characteristic after ACL injury

Synthetic nano-fibrillar extracellular matrices with predesigned macroporous architectures

Scaffolding plays a pivotal role in tissue engineering. To mimic the architecture of a natural extracellular matrix component—collagen, nona-fibrous matrices have been created with synthetic biodegradable polymers in our laboratory using a phase-separation technique. To improve the cell seeding, distribution, mass transport, and new tissue organization, three-dimensional macroporous architectures are built in the nano-fibrous matrices. Water-soluble porogen materials are first fabricated into three-dimensional negative replicas of the desired macroporous architectures. Polymer solutions are then cast over the porogen assemblies in a mold, and are thermally phase-separated to form nano-fibrous matrices. The porogen materials are leached out with water to finally form the synthetic nano-fibrous extracellular matrices with predesigned macroporous architectures. In this way, synthetic polymer matrices are created with architectural features at several levels, including the anatomical shape of the matrix, macroporous elements (100 Μm to millimeters), interfiber distance (microns), and the diameter of the fibers (50–500 nm). These scaffolding materials circumvent the concerns of pathogen transmission and immuno-rejection associated with natural collagen. With the flexibility in the design of chemical structure, molecular weight, architecture, degradation rate, and mechanical properties, these novel synthetic matrices may serve as superior scaffolding for tissue engineering. © 2000 John Wiley & Sons, Inc. J Biomed Mater Res, 52, 430–438, 2000.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34418/1/25_ftp.pd

Clonal exhaustion as a mechanism to protect against severe immunopathology and death from an overwhelming CD8 T cell response

The balance between protective immunity and immunopathology often determines the fate of the virus-infected host. How rapidly virus is cleared is a function of initial viral load, viral replication rate, and efficiency of the immune response. Here, we demonstrate, with three different inocula of lymphocytic choriomeningitis virus (LCMV), how the race between virus replication and T cell responses can result in different disease outcomes. A low dose of LCMV generated efficient CD8 T effector cells, which cleared the virus with minimal lung and liver pathology. A high dose of LCMV resulted in clonal exhaustion of T cell responses, viral persistence, and little immunopathology. An intermediate dose only partially exhausted the T cell responses and resulted in significant mortality, and the surviving mice developed viral persistence and massive immunopathology, including necrosis of the lungs and liver. This suggests that for non-cytopathic viruses like LCMV, hepatitis C virus, and hepatitis B virus, clonal exhaustion may be a protective mechanism preventing severe immunopathology and death