Metabolic Profile Reflects Stages of Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide, with fibrosis stage being the main predictor for clinical outcomes. Here, we present the metabolic profile of NAFLD patients with regards to fibrosis progression. We included all consecutive new referrals for NAFLD services between 2011 and 2019. Demographic, anthropometric and clinical features and noninvasive markers of fibrosis were recorded at baseline and at follow-up. Significant and advanced fibrosis were defined using liver stiffness measurement (LSM) as LSM ≥ 8.1 kPa and LSM ≥ 12.1 kPa, respectively. Cirrhosis was diagnosed either histologically or clinically. Fast progressors of fibrosis were defined as those with delta stiffness ≥ 1.03 kPa/year (25% upper quartile of delta stiffness distribution). Targeted and untargeted metabolic profiles were analysed on fasting serum samples using Proton nuclear magnetic resonance (1H NMR). A total of 189 patients were included in the study; 111 (58.7%) underwent liver biopsy. Overall, 11.1% patients were diagnosed with cirrhosis, while 23.8% were classified as fast progressors. A combination of metabolites and lipoproteins could identify the fast fibrosis progressors (AUROC 0.788, 95% CI: 0.703-0.874, p < 0.001) and performed better than noninvasive markers. Specific metabolic profiles predict fibrosis progression in patients with nonalcoholic fatty liver disease. Algorithms combining metabolites and lipids could be integrated in the risk-stratification of these patients.

The medial condylar wall is a reliable landmark to kinematically align the femoral component in medial UKA: an in-silico study.

PURPOSE: Kinematic alignment (KA) aligns the femoral implant perpendicular to the cylindrical axis in the frontal and axial plane. Identification of the kinematic axes when using the mini-invasive sub-quadricipital approach is challenging in unicompartmental knee arthroplasty (UKA). This study aims to assess if the orientation of condylar walls may be suitable for use as an anatomical landmark to kinematically align the femoral component in medial UKA. It was hypothesised that the medial wall of the medial condyle would prove to be a reliable anatomical landmark to set both the frontal and axial alignment of the femoral component in medial UKA. METHODS: 73 patients undergoing medial UKA had pre-operative CT imaging to generate 3D models. Those with osteophytes that impaired visualisation of the condylar walls were excluded. 28 patients were included in the study. The ideal KA was determined using the cylindrical axis in the frontal and axial plane. Simulations using the medial wall of the medial condyle (MWMC) and the lateral wall of the medial condyle (LWMC) were performed to set the frontal alignment. To set the axial alignment, the MWMC, LWMC, medial wall of the lateral condyle (MWLC), and medial diagonal line (MDL) anatomical landmarks were investigated. Differences between the ideal measured KA values and values obtained using landmarks were investigated. RESULTS: Use of the MWMC let to similar frontal alignment compared to the ideal KA (2.9° valgus vs 3.4° valgus, p = 0.371) with 46.4% (13/28) of measurements being [Formula: see text] 1.0° different from the ideal KA and only 1 simulation with greater than 4.0° difference. Use of the MWMC led to very similar axial alignments compared to the ideal KA (0.5° internal vs 0.0°, p = 0.960) with 75.0% (21/28) of measurements being [Formula: see text] 1.0o different from the ideal KA, and a maximum difference of 3.0°. Use of the MWLC and MDL was associated with significant statistical differences when compared to the ideal KA (p < 0.001 for both). CONCLUSIONS: The native orientation of the medial condylar wall seems to be a reliable anatomical landmark for aligning the femoral component in medial KA UKA in both the axial plane and frontal planes. Other assessed landmarks were shown to not be reliable. Clinical and radiographic assessments of the reliability of using the MWMC to set the frontal and axial orientation of the femoral component when performing a medial KA UKA are needed.

Which method for femoral component sizing when performing kinematic alignment TKA? An in silico study.

INTRODUCTION: The kinematically alignment (KA) technique for TKA aims to reproduce the pre-arthritic knee anatomy, including both the femoro-tibial and femoro-patellar joints. An in silico study was conducted to compare 3 different femoral component sizing techniques to identify the anatomical landmark which allows closest restoration of the native trochlear anatomy. Our study's question was: what was the best method for sizing the femoral component when performing KA-TKA? It was hypothesized that sizing the femoral component by aiming to restore the groove height would be the best method to restore the native trochlear anatomy. METHODS: GMK sphere® (Medacta) femoral component 3D models were virtually kinematically aligned on 30 tri-dimensional (3D) bony osteoarthritis knee models. The femoral component was mediolaterally positioned to match distal native and prosthetic grooves. Three methods were used to size the femoral component: a conventional method with the anterior femoral cut flush to the femoral cortex (C-KATKA) and two alternative personalized methods aiming to recreate either the medial facet's height (ATM-KATKA) or the groove's height (ATG-KATKA). In-house analysis software was used to compare native and prosthetic trochlear articular surfaces and mediolateral implant overhangs. RESULTS: Compared with the C-KATKA, ATG-KATKA and ATM-KATKA techniques increased the component size by a mean of 0.90 (SD 0.31, min 0.5 to max 1.5) (p<0.001) and 1.02 (SD 0.31, min 0.5 to max 1.5) (p<0.001), respectively. C-KATKA technique substantially proximally understuffed the trochleae with maximum values of 7.11mm (SD 1.39, min 3.93mm to max 10.57mm) in the medial facet, 4.72mm (SD 1.27, min 1.46mm to max 6.86mm) in the lateral facet and 4.51mm (SD 1.40, min 1.92mm to max 7.30mm) in the groove, respectively. Alternative techniques understuffed medial facet with maximum values of 5.07mm (SD 1.29, min 2.83mm to max 8.34mm) and 4.70mm (SD 1.52, min 0.83mm to max 8.04mm) for ATG-KATKA and ATM-KATKA techniques, respectively. There was no significant understuffing of the groove or lateral facet for alternative techniques (ATM and ATG). The ATM-KATKA and ATG-KATKA techniques generated mediolateral implant overhang, mainly postero-lateral, with a rate of 90.0% and 86.7%, respectively. In this study, no mediolateral implant overhang was found for C-KATKA. DISCUSSION/CONCLUSION: The C-KATKA technique substantially understuffs the native trochlear articular surfaces in medial, lateral and groove parts. Alternative techniques (ATM-KATKA and ATG-KATKA) for sizing the femoral component better restore the native trochlear anatomy but also generate a high rate of postero-lateral implant overhangs. Would this postero-lateral implant overhang be clinically deleterious remains unknown? The aspect ratio of contemporary femoral TKA implants can probably be optimized to allow a better anatomical restoration of the anterior femoral compartment. LEVEL OF EVIDENCE: II, in silico study.

Science Policy to Advance a Climate Change and Health Research Agenda in the United States.

Climate change is thought to be one of the greatest public health threats of the 21st century and there has been a tremendous growth in the published literature describing the health implications of climate change over the last decade. Yet, there remain several critical knowledge gaps in this field. Closing these gaps is crucial to developing effective interventions to minimize the health risks from climate change. In this commentary, we discuss policy trends that have influenced the advancement of climate change and health research in the United States context. We then enumerate specific knowledge gaps that could be addressed by policies to advance scientific research. Finally, we describe tools and methods that have not yet been fully integrated into the field, but hold promise for advancing the science. Prioritizing this advancement offers the potential to improve public health-related policies on climate change.

Achievements and needs for the climate change scenario framework.

Long-term global scenarios have underpinned research and assessment of global environmental change for four decades. Over the past ten years, the climate change research community has developed a scenario framework combining alternative futures of climate and society to facilitate integrated research and consistent assessment to inform policy. Here we assess how well this framework is working and what challenges it faces. We synthesize insights from scenario-based literature, community discussions and recent experience in assessments, concluding that the framework has been widely adopted across research communities and is largely meeting immediate needs. However, some mixed successes and a changing policy and research landscape present key challenges, and we recommend several new directions for the development and use of this framework.

Production of human monoclonal antibody in eggs of chimeric chickens.

The tubular gland of the chicken oviduct is an attractive system for protein expression as large quantities of proteins are deposited in the egg, the production of eggs is easily scalable and good manufacturing practices for therapeutics from eggs have been established. Here we examined the ability of upstream and downstream DNA sequences of ovalbumin, a protein produced exclusively in very high quantities in chicken egg white, to drive tissue-specific expression of human mAb in chicken eggs. To accommodate these large regulatory regions, we established and transfected lines of chicken embryonic stem (cES) cells and formed chimeras that express mAb from cES cell-derived tubular gland cells. Eggs from high-grade chimeras contained up to 3 mg of mAb that possesses enhanced antibody-dependent cellular cytotoxicity (ADCC), nonantigenic glycosylation, acceptable half-life, excellent antigen recognition and good rates of internalization.

Differential evidence of natural selection on two leading sporozoite stage malaria vaccine candidate antigens.

Experimental malaria vaccines based on two sporozoite stage candidate antigens of Plasmodium falciparum, the circumsporozoite protein (CSP) and thrombospondin-related adhesive protein (TRAP), have undergone clinical trials of efficacy. The relevance of naturally existing polymorphism in these molecules remains unknown. Sequence polymorphism in the genes encoding these antigens was studied in a Gambian population (sample of 48 trap and 44 csp gene sequences) to test for signatures of selection that would result from naturally acquired immunity. Allele frequency distributions were analyzed and compared with data from another population (in Thailand). Patterns of non-synonymous and synonymous polymorphism in P. falciparum and in Plasmodium vivax were compared with divergence from related species. Results indicate that polymorphism in TRAP is under strong selection for amino acid sequence diversity and that allele frequencies are under balancing selection within the Gambian P. falciparum population. There was no such evidence for CSP, calling into question the idea that most polymorphisms in this gene are under immune selection. There was a weak trend for regions known to encode T cell epitopes to have slightly higher indices suggesting balancing selection. Overall, the results predict more allele-specific immunity to TRAP than to CSP and should be considered in design and efficacy testing of vaccine candidates based on these antigens.

The receptor for type I IFNs is highly expressed on peripheral blood B cells and monocytes and mediates a distinct profile of differentiation and activation of these cells.

Type I interferons (IFNs) are potent regulators of both innate and adaptive immunity. All type I IFNs bind to the same heterodimeric cell surface receptor composed of IFN-alpha receptor (IFNAR-1) and IFN-alpha/beta receptor (IFNAR-2) polypeptides. This study revealed that type I IFN receptor levels vary considerably on hematopoietic cells, with monocytes and B cells expressing the highest levels. Overnight treatment of peripheral blood mononuclear cells (PBMCs) with IFN-alpha2b or IFN-beta led to increased expression on monocytes and B cells of surface markers commonly associated with activated antigen-presenting cells (APCs), such as CD38, CD86, MHC class I, and MHC class II. Five-day exposure of adherent monocytes to granulocyte-macrophage colony-stimulating factor (GM-CSF) plus IFN-alpha or IFN-beta caused the development of potent allostimulatory cells with morphology similar to that of myeloid dendritic cells (DCs) obtained from culture with GM-CSF and interleukin-4 (IL-4) but with distinct cell surface marker profiles and activity. In contrast to IL-4-derived DCs, IFN-alpha-derived DCs were CD14+, CD1a-, CD123+, CD32+, and CD38+ and expressed high levels of CD86 and MHC class II. Development of these cells was completely blocked by an antibody to IFNAR-1. Furthermore, activity of the type I IFN-derived DC in a mixed lymphocyte reaction (MLR) was consistently more potent than that of IL-4-derived DCs, especially at high responder/stimulator ratios. This MLR activity was abrogated by the addition of anti-IFNAR-1 antibody at the start of the DC culture. In contrast, there was no effect of anti-IFNAR-1 on IL-4-derived DCs, indicating that this is a distinct pathway of DC differentiation. These results suggest a potential role for anti-IFNAR-1 immunotherapy in autoimmune diseases, such as systemic lupus erythematosus (SLE), in which the action of excessive type I IFN on B cells and myeloid DCs may play a role in disease pathology.

Hazard prioritization in ecological risk assessment through spatial analysis of toxicant gradients.

The analysis of spatial relationships among the distribution of environmental stressors and observed or predicted adverse effects may be a useful method of prioritizing hazards in regional ecological risk assessment (ERA). Geographic information systems were used to compare the spatial distribution of toxicant concentrations in sediments of Chesapeake Bay with the distribution of areas in the basin where ecological impacts have historically been observed. Toxicants were then prioritized based upon the strength of their spatial association with the high impact areas. This method of hazard identification/prioritization was validated against the Chesapeake Bay Program's lists of toxics of concern and toxics of potential concern (TOC and TOPC, respectively). Of the 18 toxicants on the TOC/TOPC lists that were considered in the current study, 15 (83%) were identified as priority contaminants in the current study, 11 (73%) of which were either of primary or secondary concern. The use of spatial analysis tools in ERA may lead to more rapid and rigorous methods for prioritizing environmental risks.

Spatial patterns in benthic biodiversity of Chesapeake Bay, USA (1984-1999): association with water quality and sediment toxicity.

Non-point-source pollution is an increasing source of stress to aquatic, estuarine, and marine ecosystems. Such pollution may be of unknown etiology, distributed over extensive spatial scales, and comprised of multiple stressors. Current stressor-based paradigms for ecological risk assessment (ERA) may be insufficient to characterize risk from multiple stressors at regional spatial scales, necessitating the use of effects-based approaches. Historical data (1984-1999) for benthic macroinvertebrate biodiversity in Chesapeake Bay, USA, were incorporated into a geographic information system (GIS) and spatial analysis tools were used to model zones within the bay predicted to be of low or high anthropogenic impact. Data for benthic water quality and sediment toxicant concentrations from each of these zones were subsequently analyzed and compared to identify associations between benthic biodiversity and potential stressors. A number of stressors were significantly associated with high-impact zones, including increased nitrogen and phosphorus concentrations, low dissolved oxygen, heavy metals, pesticides, polycyclic aromatic hydrocarbons, and polychlorinated biphenyls. The spatial autocorrelation among multiple stressors suggests that traditional stressor-based approaches to ERA may result in the a priori exclusion of ecologically relevant stressors. Considering the effects of individual stressors rather than net effects of multiple stressors may result in underestimation of risk. The GISs are a useful tool for integrating multiple data sets in support of comprehensive regional ERA.

Indirect effects in aquatic ecotoxicology: implications for ecological risk assessment.

Understanding toxicant effects at higher levels of biological organization continues to be a challenge in ecotoxicology and ecological risk assessment. This is due in part to a tradition in ecotoxicology of considering the direct effects of toxicants on a limited number of model test species. However, the indirect effects of toxicity may be a significant factor influencing the manner in which ecosystem structure and function respond to anthropogenic stressors. Subsequently, failure to incorporate indirect effects into risk assessment paradigms may be a significant source of uncertainty in risk estimates. The current paper addresses the importance of indirect effects in an ecotoxicological context. Laboratory, mesocosm, and whole ecosystem research into indirect effects is reviewed. The implications of indirect effects for ecological risk assessment and potential areas of profitable future research are also discussed.

Observed winter warming of the Chesapeake Bay estuary (1949-2002): implications for ecosystem management.

A large number of studies have documented 20th century climate variability and change at the global, hemispheric, and regional levels. However, understanding the implications of climate change for environmental management necessitates information at the level of the ecosystem. Historical monitoring data from the Chesapeake Bay estuary were used to identify temporal patterns of estuarine temperature anomalies in the surface (/=15 m) between 1949 and 2002. Data indicated a trend in surface and subsurface warming of +0.16 degrees C and +0.21 degrees C per decade, respectively, driven by warming during winter and spring. These trends suggest warming of the estuary since the mid-20th century of approximately 0.8-1.1 degrees C. Estuarine temperatures correlated well with other independent data records for sea surface and surface air temperatures in the region and to a lesser extent, the northern hemisphere. Gross long-term temperature variability in the estuary was consistent with North Atlantic climate variability associated with the prolonged positive North Atlantic Oscillation/Arctic Oscillation and increased anthropogenic radiative forcing, although localized environmental drivers likely are important as well. A simple spatial analysis revealed strong seasonal latitudinal and longitudinal gradients in estuarine temperature as well as a north-south gradient in long-term temperature trends. Continued warming of the estuary will have important implications for ecosystem structure and function as well as attempts to manage existing challenges such as eutrophication and benthic hypoxia. However, such management efforts must be cognizant of the effects of various climate and nonclimate drivers of environmental variability and change operating over different spatial and temporal scales.

Multiple stressor effects on benthic biodiversity of Chesapeake Bay: implications for ecological risk assessment.

In natural aquatic systems, there is frequently overlap in the spatial distribution of both natural and anthropogenic stressors, particularly at regional geographic scales. Yet the proportional risk associated with individual stressors, their cumulative effects and the manner in which they interact to affect aquatic ecology is frequently unknown, limiting the robustness of multiple-stressor ecological risk assessments (ERA). The current study used historical environmental monitoring data (1984-1999) to identify a combination of natural and anthropogenic stressors that best accounted for observed patterns of benthic biodiversity in Chesapeake Bay. Geographic information systems (GIS) were used to geographically link spatially heterogeneous databases for benthic biodiversity, water quality and sediment toxicant concentrations. Single and multiple variable regression techniques were subsequently used to develop a statistical model to explain observed patterns of benthic biodiversity. Combinations of natural stressors alone accounted for as much as 34% of the variation in benthic biodiversity, and combinations of anthropogenic toxicants accounted for as much as 48% of the variation. The consideration of both natural and anthropogenic stressors resulted in a statistical model that accounted for approximately 73% of the observed variation in benthic biodiversity of Chesapeake Bay. These results suggest that benthic biodiversity in Chesapeake Bay is a function of complex interactions among water quality characteristics and anthropogenic toxicants. Therefore, new risk assessment methodologies are required to assess the risk of multiple stressors at regional scales.

Risk-based analysis of environmental monitoring data: application to heavy metals in North Carolina surface waters.

The state of North Carolina's Department of Environment and Natural Resources (NCDENR) conducts routine water quality monitoring throughout the state to assess the health of aquatic systems. The current study reports the results of a retrospective (1990-2000) ecological risk assessment of six heavy metals (arsenic, cadmium, copper, lead, mercury, and zinc) in 17 North Carolina basins that was conducted to estimate the risk of heavy metal toxicity to freshwater organisms and assess the sufficiency of NCDENR's monitoring data to identify water-quality-related ecological threats. Acute and chronic ecotoxicological thresholds (ETs) were calculated for each metal based upon the 10th percentile of species sensitivity distributions and were normalized for water hardness. Statewide probabilities (expressed as percentages) of a random sample exceeding acute or chronic ETs among the six metals ranged from 0.01% to 12.19% and 0.76% to 21.21%, respectively, with copper having the highest and arsenic and mercury the lowest risk. Basin-specific probabilities varied significantly depending upon water hardness and presumably watershed development. Although the majority of specific sites where data were collected were at low risk for metal toxicity, some specific sites had a high probability of toxic events associated with one or more metals. Analytical detection limits for metals were frequently higher than estimated chronic ET, limiting the ability to assess the risk of chronic toxicity in soft-water basins. Results suggest risk-based criteria may be useful for assessing and validating the sufficiency of monitoring programs and prioritizing management goals.