Classification of Kudoa thyrsites infected and uninfected fish using a handheld near-infrared spectrophotometer, SIMCA and PLS-DA.

Kudoa thyrsites infection of marine fish typically results in myoliquefaction, which is only apparent 24 to 56 h post-mortem. The traditional methods for the detection of K. thyrsites infected fish are time-consuming and destructive, reducing its marketability. This poses a challenge for the fish industry to remove infected fish before it reaches the market or further processing activities. This study investigated the use of near-infrared (NIR) spectroscopy, in combination with soft independent modelling of class analogy (SIMCA) and partial least square discriminant analysis (PLS-DA), for discriminating K. thyrsites infected fish from uninfected fish. Performance of the classification models was evaluated by calculating the sensitivity, specificity and precision. A total of 334 fish samples (200 sardine, 64 hake and 70 kingklip) were used for this study. Infection of K. thyrsites was determined with the use of qPCR assays. Ninety per cent (90%) of the sardine samples, 78% of the hake samples and 37% of the kingklip samples were infected. Class groups of infected and uninfected fish samples were created for the purpose of generating SIMCA and PLS-DA classification models for each species of fish, as well as for a species independent data set. Principal component analysis (PCA) of NIR spectra did not show any clustering for infected and uninfected samples. Calibration and test sample sets were generated for the purpose of building and testing the SIMCA and PLD-DA classification models. SIMCA and PLS-DA were unable to classify test samples correctly into the two classes. The number of misclassifications (NMC) was higher for the SIMCA models than for the PLS-DA models, with more than 60% incorrectly classified. SIMCA classified most of the test samples into both classes. The precision for PLS-DA were 89% for sardine, 81% for hake, 0% for kingklip and 87% for species independent models, however, most samples were classified at infected. The use of NIR spectroscopy and classification models such as SIMCA and PLS-DA showed limited use as a method to distinguish between K. thyrsites infected and uninfected fish samples. Textural and chemical changes during extended frozen storage of the fish samples may have masked the effects associated with K. thyrsites infection. Further studies are suggested where NIR spectroscopy is used in combination with texture analysis and image spectroscopy.

Do new lakes behave like natural lakes regarding sediment composition and phosphorus fluxes?

Numerous new lakes have been established during the last few decades. Lakes established on former agricultural soils often have high legacy phosphorus (P)-content, which constitutes a risk for potential internal P-loading after the lake is formed. In this study, we compared the P release and sediment P-pools from 31 new lakes and 31 natural lakes, to assess their similarities and differences. A suite of other sediment characteristics was identified and compared for both natural and new lakes; catchment characteristics of the new lakes also were analyzed. P release from the sediment of new lakes was significantly lower than from natural lakes (13.2 mg P m-2 d-1) compared to new lakes (6.9 mg P m-2 d-1). The P release was found to be low when molar Fe:P ratios were above 10. A significant correlation was found between the content of mobile-P (loosely adsorbed P, iron-bound P, and leachable organic P) and TP in the sediment, irrespective of lake type. The composition of the mobile P-pool also differed, with the new non-excavated lakes showing a higher proportion of RP-BD; both new lake types had significantly (p = 0.021) lower proportions of nrP, compared to natural lakes in the uppermost 10 cm sediment. In addition, variance in P release and mobile-P content of new lakes could be explained in terms of the land use of the catchments. Most sediment characteristics of new lakes established without topsoil excavation reached the average levels of natural Danish lakes with respect to density, organic content and P content within 20-30 years, while excavated lakes showed no such tendencies.

Immunoglobulin G/immunoglobulin M autoantibody ratios in incomplete systemic lupus erythematosus.

OBJECTIVE: Immunoglobulin G (IgG) autoantibodies in systemic lupus erythematosus (SLE) are considered pathogenic, whereas immunoglobulin M (IgM) autoantibodies may have protective effects. The aim of this study was to identify whether IgG/IgM autoantibody ratios differ between patients with incomplete systemic lupus erythematosus (iSLE), patients with SLE, and healthy controls (HCs), and whether IgG/IgM autoantibody ratios relate to progression from iSLE to SLE. METHOD: This prospective cohort study included 34 iSLE patients, 41 SLE patients, and 11 HCs. IgG and IgM anti-dsDNA, anti-Ro52, and anti-Ro60 were measured by fluoro-enzyme immunoassay in serum samples obtained at baseline in all groups and in follow-up samples of up to 5 years for iSLE patients. Correlations between IgG/IgM autoantibody ratios, interferon signature, and clinical parameters were also assessed. RESULTS: At baseline, IgG anti-dsDNA, anti-Ro52, anti-Ro60, and IgM anti-dsDNA were elevated in iSLE and SLE patients. IgG/IgM anti-dsDNA and anti-Ro52 ratios were similar between groups, while IgG/IgM anti-Ro60 ratios were significantly elevated in iSLE and SLE patients compared to HCs. IgG/IgM autoantibody ratios were not correlated with interferon signature or clinical parameters. IgG/IgM ratios at baseline were similar and remained relatively stable during a median follow-up of 18 months in non-progressors and six iSLE patients who progressed to SLE. CONCLUSION: IgG anti-dsDNA, anti-Ro52, anti-Ro60, and IgM anti-dsDNA were elevated in iSLE and SLE patients, which was not apparent from the respective IgG/IgM ratios only. IgG/IgM autoantibody ratios remained relatively stable over up to 5 years in iSLE non-progressors and six patients who progressed to SLE.

An agent-based framework to study forced migration: A case study of Ukraine.

The ongoing Russian aggression against Ukraine has forced over eight million people to migrate out of Ukraine. Understanding the dynamics of forced migration is essential for policy-making and for delivering humanitarian assistance. Existing work is hindered by a reliance on observational data which is only available well after the fact. In this work, we study the efficacy of a data-driven agent-based framework motivated by social and behavioral theory in predicting outflow of migrants as a result of conflict events during the initial phase of the Ukraine war. We discuss policy use cases for the proposed framework by demonstrating how it can leverage refugee demographic details to answer pressing policy questions. We also show how to incorporate conflict forecast scenarios to predict future conflict-induced migration flows. Detailed future migration estimates across various conflict scenarios can both help to reduce policymaker uncertainty and improve allocation and staging of limited humanitarian resources in crisis settings.

A 10-year prospectus for mathematical epidemiology.

There is little significant work at the intersection of mathematical and computational epidemiology and detailed psychological processes, representations, and mechanisms. This is true despite general agreement in the scientific community and the general public that human behavior in its seemingly infinite variation and heterogeneity, susceptibility to bias, context, and habit is an integral if not fundamental component of what drives the dynamics of infectious disease. The COVID-19 pandemic serves as a close and poignant reminder. We offer a 10-year prospectus of kinds that centers around an unprecedented scientific approach: the integration of detailed psychological models into rigorous mathematical and computational epidemiological frameworks in a way that pushes the boundaries of both psychological science and population models of behavior.

Lipschitz continuity under toric equivalence for asynchronous Boolean networks.

Mathematical models rooted in network representations are becoming increasingly more common for capturing a broad range of phenomena. Boolean networks (BNs) represent a mathematical abstraction suited for establishing general theory applicable to such systems. A key thread in BN research is developing theory that connects the structure of the network and the local rules to phase space properties or so-called structure-to-function theory. While most theory for BNs has been developed for the synchronous case, the focus of this work is on asynchronously updated BNs (ABNs) which are natural to consider from the point of view of applications to real systems where perfect synchrony is uncommon. A central question in this regard is sensitivity of dynamics of ABNs with respect to perturbations to the asynchronous update scheme. Macauley & Mortveit [Nonlinearity 22, 421-436 (2009)] showed that the periodic orbits are structurally invariant under toric equivalence of the update sequences. In this paper and under the same equivalence of the update scheme, the authors (i) extend that result to the entire phase space, (ii) establish a Lipschitz continuity result for sequences of maximal transient paths, and (iii) establish that within a toric equivalence class the maximal transient length may at most take on two distinct values. In addition, the proofs offer insight into the general asynchronous phase space of Boolean networks.

Ensembles of realistic power distribution networks.

The power grid is going through significant changes with the introduction of renewable energy sources and the incorporation of smart grid technologies. These rapid advancements necessitate new models and analyses to keep up with the various emergent phenomena they induce. A major prerequisite of such work is the acquisition of well-constructed and accurate network datasets for the power grid infrastructure. In this paper, we propose a robust, scalable framework to synthesize power distribution networks that resemble their physical counterparts for a given region. We use openly available information about interdependent road and building infrastructures to construct the networks. In contrast to prior work based on network statistics, we incorporate engineering and economic constraints to create the networks. Additionally, we provide a framework to create ensembles of power distribution networks to generate multiple possible instances of the network for a given region. The comprehensive dataset consists of nodes with attributes, such as geocoordinates; type of node (residence, transformer, or substation); and edges with attributes, such as geometry, type of line (feeder lines, primary or secondary), and line parameters. For validation, we provide detailed comparisons of the generated networks with actual distribution networks. The generated datasets represent realistic test systems (as compared with standard test cases published by Institute of Electrical and Electronics Engineers (IEEE)) that can be used by network scientists to analyze complex events in power grids and to perform detailed sensitivity and statistical analyses over ensembles of networks.

The impact of climate change and eutrophication on phosphorus forms in sediment: Results from a long-term lake mesocosm experiment.

Characteristics of bottom sediments in lake mesocosms 11 years after starting the experiment were studied in order to determine the effects of nutrient loading, temperature increase and vegetation type on concentration and vertical distribution of phosphorus (P) forms. The experimental setup consisted of 24 outdoor flow-through mesocosms with two nutrient treatments - low (L) and high (H) and 3 temperature levels - ambient (T0), heated by 2-4 °C (T1) and 3-6 °C (T2) in four replicates. Thickness of the organic sediment was measured and the sediment analysed for dry weight, organic matter, and P fractions (according to a sequential extraction scheme) and organic P compounds (by 31P nuclear magnetic resonance spectroscopy). Higher nutrient loading led to increased sediment accumulation and higher concentration of total P and most P fractions, except P bound to aluminium and humic matter. The dominant vegetation type covaried with nutrient levels. Vertical gradients in Ca bound P and mobile P in low nutrient mesocosms was perhaps a result of P coprecipitation with calcite on macrophytes and P uptake by roots indicating that in macrophyte-rich lakes, plants can be important modifiers of early P diagenesis. Temperature alone did not significantly affect sediment accumulation rate but the interaction effect between nutrient and temperature treatments was significant. At high nutrient loading, sediment thickness decreased with increasing temperature, but at low nutrient loading, it increased with warming. The effect of warming on sediment composition became obvious only in nutrient enriched mesocosms showing that eutrophication makes shallow lake ecosystems more susceptible to climate change.

The combined effects of macrophytes (Vallisneria denseserrulata) and a lanthanum-modified bentonite on water quality of shallow eutrophic lakes: A mesocosm study.

Establishment of submerged macrophyte beds and application of chemical phosphorus inactivation are common lake restoration methods for reducing internal phosphorus loading. The two methods operate via different mechanisms and may potentially supplement each other, especially when internal phosphorous loading is continuously high. However, their combined effects have so far not been elucidated. Here, we investigated the combined impact of the submerged macrophyte Vallisneria denseserrulata and a lanthanum-modified bentonite (Phoslock®) on water quality in a 12-week mesocosm experiment. The combined treatment led to stronger improvement of water quality and a more pronounced reduction of porewater soluble reactive phosphorus than each of the two measures. In the combined treatment, total porewater soluble reactive phosphorus in the top 10 cm sediment layers decreased by 78% compared with the control group without Phoslock® and submerged macrophytes. Besides, in the upper 0-1 cm sediment layer, mobile phosphorus was transformed into recalcitrant forms (e.g. the proportion of HCl-P increased to 64%), while in the deeper layers, (hydr)oxides-bound phosphorus species increased 17-28%. Phoslock®, however, reduced the clonal growth of V. denseserrulata by 35% of biomass (dry weight) and 27% of plant density. Our study indicated that Phoslock® and submerged macrophytes may complement each other in the early stage of lake restoration following external nutrient loading reduction in eutrophic lakes, potentially accelerating the restoration process, especially in those lakes where the internal phosphorus loading is high.

An Assessment of the Multifunctionality of Integrated Buffer Zones in Northwestern Europe.

Integrated buffer zones (IBZs) have recently been introduced in the Northwestern Europe temperate zone to improve delivery of ecosystem services compared with the services associated with long-established vegetated buffer zones. A common feature of all the studied IBZ sites is that tile drainage, which previously discharged directly into the streams, is now intercepted within the IBZ. Specifically, the design of IBZs combines a pond, where soil particles present in drain water or surface runoff can be deposited, and a planted subsurface flow infiltration zone. Together, these two components should provide an optimum environment for microbial processes and plant uptake of nutrients. Nutrient reduction capacities, biodiversity enhancement, and biomass production functions were assessed with different emphasis across 11 IBZ sites located in Denmark, Great Britain, and Sweden. Despite the small size of the buffer zones (250-800 m) and thus the small proportion of the drained catchment (mostly <1%), these studies cumulatively suggest that IBZs are effective enhancements to traditional buffer zones, as they (i) reduce total N and P loads to small streams and rivers, (ii) act as valuable improved habitats for aquatic and amphibian species, and (iii) offer economic benefits by producing fast-growing wetland plant biomass. Based on our assessment of the pilot sites, guidance is provided on the implementation and management of IBZs within agricultural landscapes.

Matrix binding of T-2 toxin: structure elucidation of reaction products and indications on the fate of a relevant food-borne toxin during heating.

This study deals with the influence of food matrix components on the degradation of the mycotoxins T-2 toxin (T-2) and HT-2 toxin (HT-2) and with the binding of T-2 to starch during thermal food processing. Both mycotoxins were heated in a simulated food environment and subsequently analyzed via HPLC-HRMS to generate degradation curves and to draw conclusions regarding the thermal degradation under food processing conditions. Thermal degradation increased generally with increasing time and temperature with a maximum degradation rate of 93% (T-2) and 99% (HT-2). Furthermore, HRMS data were exploited to screen the samples for degradation products. In model heating experiments, T-2 was bound to 1-O-methyl-α-D-glucopyranoside, a model compound that was used to simulate starch. The formed reaction products were isolated and identified by NMR, giving detailed insights into a potential binding of T-2 to starch. In the next step, further model heating experiments were performed, which proved the covalent binding of T-2 to starch. Finally, the amount of matrix-bound T-2 was estimated roughly in a semi-quantitative approach in the model heating experiments as well as during cookie-making via GC-MS analysis of the isovaleric acid ester moiety of T-2, released after alkaline hydrolysis.

Attractor Stability in Finite Asynchronous Biological System Models.

We present mathematical techniques for exhaustive studies of long-term dynamics of asynchronous biological system models. Specifically, we extend the notion of [Formula: see text]-equivalence developed for graph dynamical systems to support systematic analysis of all possible attractor configurations that can be generated when varying the asynchronous update order (Macauley and Mortveit in Nonlinearity 22(2):421, 2009). We extend earlier work by Veliz-Cuba and Stigler (J Comput Biol 18(6):783-794, 2011), Goles et al. (Bull Math Biol 75(6):939-966, 2013), and others by comparing long-term dynamics up to topological conjugation: rather than comparing the exact states and their transitions on attractors, we only compare the attractor structures. In general, obtaining this information is computationally intractable. Here, we adapt and apply combinatorial theory for dynamical systems from Macauley and Mortveit (Proc Am Math Soc 136(12):4157-4165, 2008. https://doi.org/10.1090/S0002-9939-09-09884-0 ; 2009; Electron J Comb 18:197, 2011a; Discret Contin Dyn Syst 4(6):1533-1541, 2011b. https://doi.org/10.3934/dcdss.2011.4.1533 ; Theor Comput Sci 504:26-37, 2013. https://doi.org/10.1016/j.tcs.2012.09.015 ; in: Isokawa T, Imai K, Matsui N, Peper F, Umeo H (eds) Cellular automata and discrete complex systems, 2014. https://doi.org/10.1007/978-3-319-18812-6_6 ) to develop computational methods that greatly reduce this computational cost. We give a detailed algorithm and apply it to (i) the lac operon model for Escherichia coli proposed by Veliz-Cuba and Stigler (2011), and (ii) the regulatory network involved in the control of the cell cycle and cell differentiation in the Caenorhabditis elegans vulva precursor cells proposed by Weinstein et al. (BMC Bioinform 16(1):1, 2015). In both cases, we uncover all possible limit cycle structures for these networks under sequential updates. Specifically, for the lac operon model, rather than examining all [Formula: see text] sequential update orders, we demonstrate that it is sufficient to consider 344 representative update orders, and, more notably, that these 344 representatives give rise to 4 distinct attractor structures. A similar analysis performed for the C. elegans model demonstrates that it has precisely 125 distinct attractor structures. We conclude with observations on the variety and distribution of the models' attractor structures and use the results to discuss their robustness.

Evaluation of dried amorphous ferric hydroxide CFH-12® as agent for binding bioavailable phosphorus in lake sediments.

Metal hydroxides formed from aluminum (Al) and iron (Fe) salts can be used as phosphorus (P) adsorbents in lake restoration, but the application entails problems in low-alkaline lakes due to acid producing hydrolysis and potential formation of toxic metal ions. Therefore, we tested the potential of applying CFH-12® (Kemira) - a dried, amorphous Fe-oxide with no pH effect - in lake restoration. Since Fe3+ may become reduced in lake sediments and release both Fe2+ and any associated P we also evaluated the redox sensitivity of CFH-12® in comparison with freshly formed Fe(OH)3. CFH-12® was added to undisturbed sediment cores from three Danish lakes relative to the size of their mobile P pool (molar Fe:PMobile dose ratio of ~10:1), and P and Fe fluxes across the sediment-water interface were compared with those from untreated cores and cores treated with freshly formed Fe(OH)3. Under anoxic conditions, we found that CFH-12® significantly reduced the P efflux from the sediments (by 43% in Lake Sønderby, 70% in Lake Hampen and 60% in Lake Hostrup) while the Fe2+ efflux remained unchanged relative to the untreated cores. Cores treated with freshly formed Fe(OH)3 retained more P, but released significantly more Fe2+, indicating continued Fe3+ reduction. Finally, experiments with pure phases showed that CFH-12® adsorbed less P than freshly formed Fe(OH)3 in the short term, but was capable of adsorbing up to 70% of P adsorbed by Fe(OH)3 over 3months. With product costs only 30% higher than Al salts we find that CFH-12® has potential for use in restoration of low-alkaline lakes.

Nitrogen and Phosphorus Removal from Agricultural Runoff in Integrated Buffer Zones.

Integrated buffer zones (IBZs) represent a novel form of edge-of-field technology in Northwest Europe. Contrary to the common riparian buffer strips, IBZs collect tile drainage water from agricultural fields by combining a ditch-like pond (POND), where soil particles can settle, and a flow-through filter bed (FILTERBED) planted with Alnus glutinosa (L.), a European alder (black alder). The first experimental IBZ facility was constructed and thoroughly tested in Denmark for its capability to retain various nitrogen (N) and phosphorus (P) species within the first three years after construction. We calculated the water and nutrient budget for the total IBZ and for the two compartments, POND and FILTERBED, separately. Furthermore, a tracer experiment using sodium bromide was conducted in order to trace the water flow and estimate the hydraulic residence time in the FILTERBEDs. The monthly average removal efficiency amounted to 10-67% for total N and 31-69% for total P, with performance being highest during the warm season. Accordingly, we suggest that IBZs may be a valuable modification of dry buffer strips in order to mitigate the adverse impacts of high nutrient loading from agricultural fields on the aquatic environment.

The influence of lake water alkalinity and humic substances on particle dispersion and lanthanum desorption from a lanthanum modified bentonite.

A 12 days laboratory study on potential desorption of Lanthanum (La) from a commercial La modified clay (Phoslock) was conducted using lake water from 17 Danish lakes with alkalinities between 0.02 and 3.7 meq L-1 and varying concentrations of DOC and humic acids (HA's). A similar study was conducted in artificial lake water with alkalinities from 0 to 2.5 meq L-1in order to exclude interference from dissolved HA's. To test if La in solution (FLa) was associated with fine particles, the water samples were filtered sequentially through three filter sizes (1.2 µm, 0.45 µm and 0.2 µm), and finally, ultracentrifugation was used in an attempt to separate colloidal La from dissolved La. The study showed that higher FLa (up to 2.5 mg L-1 or 14% of the total La in the Phoslock) concentrations were found in soft water lakes compared to hard water lakes, probably due to dispersion of the clay at low alkalinities. In addition, this study showed that HA's seem to increase the FLa concentrations in soft water lakes, most likely through complexation of La retained in the Phoslock matrix. In summary, we conclude that elevated La concentrations in lake water after a Phoslock treatment should only be expected in soft water lakes rich in DOC and HA's.

Detoxification and elimination of nicotine by nectar-feeding birds.

Many dilute nectars consumed by bird pollinators contain secondary metabolites, potentially toxic chemicals produced by plants as defences against herbivores. Consequently, nectar-feeding birds are challenged not only by frequent water excess, but also by the toxin content of their diet. High water turnover, however, could be advantageous to nectar consumers by enabling them to excrete secondary metabolites or their transformation products more easily. We investigated how the alkaloid nicotine, naturally present in nectar of Nicotiana species, influences osmoregulation in white-bellied sunbirds Cinnyris talatala and Cape white-eyes Zosterops virens. We also examined the metabolic fate of nicotine in these two species to shed more light on the post-ingestive mechanisms that allow nectar-feeding birds to tolerate nectar nicotine. A high concentration of nicotine (50 µM) decreased cloacal fluid output and increased its osmolality in both species, due to reduced food intake that led to dehydration. White-eyes excreted a higher proportion of the ingested nicotine-containing diet than sunbirds. However, sugar concentration did not affect nicotine detoxification and elimination. Both species metabolised nicotine, excreting very little unchanged nicotine. Cape white-eyes mainly metabolised nicotine through the cotinine metabolic pathway, with norcotinine being the most abundant metabolite in the excreta, while white-bellied sunbirds excreted mainly nornicotine. Both species also utilized phase II conjugation reactions to detoxify nicotine, with Cape white-eyes depending more on the mercapturic acid pathway to detoxify nicotine than white-bellied sunbirds. We found that sunbirds and white-eyes, despite having a similar nicotine tolerance, responded differently and used different nicotine-derived metabolites to excrete nicotine.

The importance of catchment vegetation for alkalinity, phosphorus burial and macrophytes as revealed by a recent paleolimnological study in a soft water lake.

The land use within a catchment may markedly affect the environmental conditions in a lake and the storage capability of its sediments. This study investigated how changes in the dominant catchment vegetation (from local stands of deciduous trees over extensive heathland with some agriculture to mainly coniferous forest) occurring during the last ca. 200years were reflected in the sediments of a soft water lake and how these changes influenced the lake ecosystem. Pollen, macrofossils, metals, different phosphorus (P) forms, organic matter, carbon and nitrogen contents were determined in short sediment cores. This novel combination of proxies revealed that 1) the reduction of deciduous trees in the watershed seemingly reduced the calcium (Ca) supply to the lake and thereby its buffering capacity. This development was accompanied by decreased abundances of Ca-dependent species and subsequent increases in acidophilic species. 2) The sedimentary contents of organic matter, non-reactive P and humic-bound P were evidently higher in sediments deposited during the time when deciduous trees were abundant, which is probably linked to a stabilising effect by Ca. 3) An erosion event clearly reduced the amounts of macrofossils of isoetid species and characeans, indicating a reduction in their maximum distribution depth because of lower water transparency. Overall, the results of our paleolimnological study are of importance within lake management by convincingly showing how land use changes may (irreversibly) affect environmental conditions and species composition in soft water lakes and the storage of organic matter and P in their sediments.

Phosphate adsorption to iron sludge from waterworks, ochre precipitation basins and commercial ferrihydrite at ambient freshwater phosphate concentrations.

Measures such as storm water ponds, constructed wetlands and buffer strips along streams are used to reduce diffuse phosphorus (P) loading to surface waters. These systems often retain particulate P well, whereas the retention of dissolved P is less efficient and might require addition of P adsorbents. In this study, we screened waterwork ochre sludge (WWS) originating from groundwater treatment and ochre sludge from ochre precipitation basins along streams for their applicability as P adsorbents at ambient P concentrations. We compared with a commercial ferric hydroxide (CFH 12™) for which adsorption properties is well described. The adsorption capacity of 9 products was measured over 24 h at different P concentrations (5-2000 µg L-1), a range that covers Danish drainage water and stormwater. WWS desorbed phosphate at concentrations below 50-200 µg P L-1 and should only be considered for use in systems with a constantly high load of dissolved P. High affinity combined with little or no desorption characterized the commercial product and the ochre sludge from the precipitation basins, rendering these useful for treating drainage water and storm water. The study underlines that waste products may act as potentially effective P adsorbers at environmentally relevant P levels.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy.

Voriconazole, a triazole antifungal agent, demonstrates wide interpatient variability in serum concentrations, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 ultrarapid metabolizers have decreased trough voriconazole concentrations, delaying achievement of target blood concentrations; whereas poor metabolizers have increased trough concentrations and are at increased risk of adverse drug events. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of voriconazole for treatment based on CYP2C19 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).

Exposure to persistent organic pollutants and sperm DNA methylation changes in Arctic and European populations.

Persistent organic pollutants (POPs), such as PCBs (polychlorinated biphenyls) and DDT [1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane], are environmental contaminants with potential endocrine disrupting activity. DNA methylation levels in peripheral blood lymphocytes have been associated with serum concentrations of POPs in Greenland Inuit and Korean populations. Greenland Inuits are characterized by the highest worldwide POP levels. In this cross-sectional study we evaluated the relationship between serum POP concentrations and DNA methylation levels in sperm of non-occupationally exposed fertile men from Greenland, Warsaw (Poland), and Kharkiv (Ukraine). Serum levels of PCB-153 [1,2,4-trichloro-5-(2,4,5-trichlorophenyl)benzene], as a proxy of the total PCBs body burden, and of p,p'-DDE [1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene], the main metabolite of DDT were measured. Sperm DNA methylation level was assessed globally by flow cytometric (FCM) immunodetection of 5-methyl-cytosines and at specific repetitive DNA sequences (Alu, LINE-1, Satα) by PCR-pyrosequencing after bisulfite conversion. Multivariate linear regression analysis was applied to investigate correlations between serum POP concentrations and DNA methylation. No consistent associations between exposure to POPs and sperm DNA methylation at repetitive DNA sequences were detected. A statistically significant global decrease in methylation was associated with exposure to either POP by FCM analysis. This is the first study to investigate environmental exposure to POPs and DNA methylation levels considering sperm as the target cells. Although POP exposure appears to have a limited negative impact on sperm DNA methylation levels in adult males, the global hypomethylation detected by one of the methods applied suggests that further investigation is warranted.