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A new method for time‐resolved X‐ray absorption near edge structure (XANES) spectroscopy that enables faster data acquisition and requires smaller sample quantities for high‐quality data, thus allowing the analysis of more samples in a shorter time is introduced. The method uses large bandwidth free electron laser pulses to measure laser‐excited XANES spectra in transmission mode. A beam‐splitting grating configuration allows simultaneous measurements of the spectra of the incoming X‐ray Free Electron Laser (XFEL) pulses and transmission XANES, which is crucial for compensating the pulse‐dependent intensity and spectrum fluctuations due to the self‐amplified spontaneous emission operation. The implementation of this new methodology is applied on a liquid solution of ammonium iron(III) oxalate jet and is compared to previous results, showing great improvements in the speed of acquisition and spectral resolution, and the ability to measure a large 2‐D spectral‐time map quickly. [ABSTRACT FROM AUTHOR]

The repair of airfoil blades is an enabling technology to extend the operational life of gas turbine engines. Directed energy deposition (DED) additive manufacturing (AM) provides the ability to add material by melting blown powder using a directed energy source. Seventeen Ti‐6Al‐4V airfoil blades were repaired using DED AM and analyzed to determine what effect the repair will have on the blade performance in high cycle vibration fatigue testing. Volumetric computed tomography (CT) was used to quantify the pores from the AM process. The blades were then subjected to vibrational bending fatigue, used to simulate turbine engine loading conditions, until failure. Only three blades failed in the repaired sections. The identified pore sizes and fatigue stress distribution in the blade were used to suggest that understanding the impact of internal and near surface level pores arising from the AM repair is critical towards the implementation of AM repair in aerospace components under fatigue loading. Highlights: Investigates directed energy deposition additive manufacturing repair for engine rotors.Examines defects in additive repairs using CT scans and image processing techniques.Studies the prediction of bending fatigue life based on porosity size and location. [ABSTRACT FROM AUTHOR]

To fully exploit ultra-short X-ray pulse durations routinely available at X-ray free-electron lasers to follow out-of-equilibrium dynamics, inherent arrival time fluctuations of the X-ray pulse with an external perturbing laser pulse need to be measured. In this work, two methods of arrival time measurement were compared to measure the arrival time jitter of hard X-ray pulses. The methods were photoelectron streaking by a THz field and a transient refractive index change of a semiconductor. The methods were validated by shot-to-shot correction of a pump-probe transient reflectivity measurement. An ultimate shot-to-shot full width at half-maximum error between the devices of 19.2 ± 0.1 fs was measured. [ABSTRACT FROM AUTHOR]

Many biotechnologies require direct contact between biomolecules and (semi)solid substrates. However, little information is available regarding site‐directed covalent surface immobilization of heterodimeric proteins. Integrins are heterodimeric, conformationally dependent membrane adhesion‐receptors, which are important in the (patho)biology of almost all human diseases. In this study, a biomimetic‐platform is developed for covalent and site‐directed immobilization of oriented integrin heterodimers onto most hydroxyl bearing surfaces, herein demonstrated on both glass‐slides and silica‐particles. This platform consists of a self‐assembled monolayer, upon which C‐terminal modified αIIbβ3 integrin extracellular domains are oriented and covalently anchored. As with cell surface integrins, the conformation of immobilized αIIbβ3 is switchable and can be modulated to the active ligand‐binding conformation by divalent cations. Furthermore, the αIIbβ3‐coupled silica particles display platelet‐mimetic hemostat function and co‐aggregate with platelets from both wild‐type and fibrinogen/von Willebrand factor double deficient mice, facilitating αIIbβ3‐non‐classical ligand discoveries. This work provides a biomaterial platform for functional multimeric protein‐substrate coupling, which should have broad impact on multiple fields of biology, biotechnology, and clinical diagnosis/therapy. [ABSTRACT FROM AUTHOR]

Electrochemical aptamer‐based (E‐AB) biosensors have demonstrated capabilities in monitoring molecules directly in undiluted complex matrices and in the body with the hopes of addressing personalized medicine challenges. This sensing platform relies on an electrode‐bound, redox‐reporter‐modified aptamer. The electrochemical signal is thought to originate from the aptamer undergoing a binding‐induced conformational change capable of moving the redox reporter closer to the electrode surface. While this is the generally accepted mechanism, it is notable that there is limited evidence demonstrating conformational change or distance‐dependent change in electron transfer rates in E‐AB sensors. In response, we investigate here the signal transduction of the well‐studied cocaine‐binding aptamer with different analytical methods and found that this sensor relies on a redox‐reporter ‐ ligand competition mechanism rather than a ligand‐induced structure formation mechanism. Our results show that the covalently bound redox reporter, methylene blue, binds at or near the ligand binding site on the aptamer resulting in a folded conformation of the cocaine‐binding aptamer. Addition of ligand then competes with the redox reporter for binding, altering its electron transfer rate. While we show this for the cocaine‐binding aptamer, given the prevalence of methylene blue in E‐AB sensors, a similar competition‐based may occur in other systems. [ABSTRACT FROM AUTHOR]

Summary: Equine primary hyperparathyroidism is rare compared with the condition in human medicine where it is often encountered and represents the most common explanation for hypercalcemia in the outpatient setting. Primary hyperparathyroidism results from a hyperfunctioning parathyroid gland and surgical treatment (parathyroidectomy) is typically curative. Successful surgical removal of a diseased parathyroid gland can be challenging in horses as both normal and hyperfunctioning glands are difficult to localise. Identification of surgical targets using ultrasonography and/or Technetium‐99 m sestimibi scintigraphy are useful for this purpose in both the human and equine contexts. However, these localisation approaches are not always effective. Moreover, not all patients are candidates for general anaesthesia and surgery and the costs associated with diagnostic localisation and parathyroidectomy may be prohibitive for some owners. This commentary presents information about primary hyperparathyroidism in the event that it is not treated and strives to review aspects of the disease when left untreated from the human medical context. [ABSTRACT FROM AUTHOR]

A 26‐year‐old mule gelding was evaluated for chronic weight loss and decreased appetite. The mule had been losing weight and intermittently hypophagic for approximately 7 months. Laboratory analysis of whole blood and plasma identified severe total hypercalcemia, marked hypophosphatemia, markedly increased parathyroid hormone concentration, and marked lymphocytosis. A sestimibi scan intended to identify parathyroid gland tissue was nondiagnostic. Results of flow cytometry and PCR for antigen receptor rearrangement (PARR) were consistent with a B cell lymphoproliferative disorder, likely chronic lymphocytic leukemia (CLL). Although not previously described concurrently, these conditions may sometimes arise together, complicating definition of the underlying mechanism for weight loss and hypercalcemia in aged equids. [ABSTRACT FROM AUTHOR]

Background: Limited information is available regarding endothelial glycocalyx degradation during sepsis in horses. Plasma syndecan‐1 concentrations are increased in consequence of sepsis in other species and have been useful for prognostication. Objectives: To determine whether plasma syndecan‐1 levels are increased in adult horses affected with sepsis. Study design: Retrospective cohort study. Methods: Adult horses were assigned to one of three groups based on results of physical and laboratory examinations, clinical diagnosis, and results of previously described SIRS classification: Group 1 horses included healthy, nonseptic horses; Group 2 included horses in which clinical illness was identified but that were not considered to be septic; Group 3 included horses with a clinical diagnosis of sepsis. Plasma syndecan‐1 concentration was determined in blood obtained at admission into the hospital for each horse, using an equine specific ELISA. Data were analysed using ANOVA and linear regression (p ≤ 0.05). Results: One hundred and ninety‐one horses were included and divided into three groups. Scores for SIRS were highest for Group 3 horses and lowest in Groups 1 and 2. Plasma syndecan‐1 concentrations in Group 3 horses (50.73 ± 84.24 μg/ml; n = 42) were greater than those for Group 1 (15.69 ± 11.28 μg/ml; n = 66) and Group 2 (16.88 ± 15.30 μg/ml; n = 83). There was no difference regarding syndecan concentrations between Groups 1 and 2. Main limitations: Retrospective study design, solitary time point of measurement for each patient, and lack of a widely accepted consensus regarding definitive diagnosis of sepsis in adult horses. Conclusions: Circulating plasma levels of syndecan‐1, a biochemical marker of endothelial glycocalyx damage, are increased in septic adult horses. [ABSTRACT FROM AUTHOR]

Summary: Background: While surveillance improves the early detection of hepatocellular carcinoma (HCC), it is unclear whether this has improved prognosis in clinical practice. Aims: To investigate the characteristics and prognoses of patients with viral versus non‐viral HCC over the previous two decades in Japan, while HCC surveillance has been active. Methods: This multi‐centre study enrolled 6007 patients initially diagnosed with HCC between 2000 and 2020 at seven high‐volume academic centres. Patients were categorised based on dates of diagnosis: 2000–2006, 2007–2013 and 2014–2020. HCC characteristics and post‐diagnosis survival rates were compared between periods in patients with viral and non‐viral HCC. Results: The percentage of patients with non‐viral HCC increased during the study period. The maximal tumour size and percentage of patients with multinodular HCC decreased significantly over time in the viral HCC group but remained unchanged in the non‐viral HCC group. Liver function at diagnosis improved over time in both groups, but to a greater extent in the viral HCC group. Survival rates increased significantly with time in the viral HCC group, but not in the non‐viral HCC group. Conclusions: The prevalence of non‐viral HCC is increasing. Although the survival of patients with viral HCC improved significantly over the past two decades, there was no improvement in patients with non‐viral HCC. This was presumably due mainly to lower surveillance among patients with non‐viral HCC and failure to diagnose early‐stage HCC. [ABSTRACT FROM AUTHOR]

Infectious zoonotic diseases are a threat to wildlife conservation and global health. They are especially a concern for wild apes, which are vulnerable to many human infectious diseases. As ecotourism, deforestation, and great ape field research increase, the threat of human‐sourced infections to wild populations becomes more substantial and could result in devastating population declines. The endangered mountain gorillas (Gorilla beringei beringei) of the Virunga Massif in east‐central Africa suffer periodic disease outbreaks and are exposed to infections from human‐sourced pathogens. It is important to understand the possible risks of disease introduction and spread in this population and how human contact may facilitate disease transmission. Here we present and evaluate an individual‐based, stochastic, discrete‐time disease transmission model to predict epidemic outcomes and better understand health risks to the Virunga mountain gorilla population. To model disease transmission we have derived estimates for gorilla contact, interaction, and migration rates. The model shows that the social structure of gorilla populations plays a profound role in governing disease impacts with subdivided populations experiencing less than 25% of the outbreak levels of a single homogeneous population. It predicts that gorilla group dispersal and limited group interactions are strong factors in preventing widespread population‐level outbreaks of infectious disease after such diseases have been introduced into the population. However, even a moderate amount of human contact increases disease spread and can lead to population‐level outbreaks. Highlights: This disease model shows that the social structure of gorilla populations plays a profound role in governing disease impacts.Gorilla group dispersal and limited group interactions are strong factors in preventing widespread population‐level outbreaks of infectious disease.Human visitors can potentially have a dramatic effect on spreading infection throughout the gorilla population. [ABSTRACT FROM AUTHOR]

High‐grade dysplasia carries significant risk of transformation to hepatocellular carcinoma (HCC). Despite this, at the current standard of care, all non‐malignant hepatic nodules including high‐grade dysplastic nodules are managed similarly. This is partly related to difficulties in distinguishing high‐risk pathology in the liver. We aimed to identify chromosome arm‐level somatic copy number alterations (SCNAs) that characterise the transition of liver nodules along the cirrhosis–dysplasia–carcinoma axis. We validated our findings on an independent cohort using blood‐derived cell‐free DNA. A repository of non‐cancer DNA sequences obtained from patients with HCC (n = 389) was analysed to generate cut‐off thresholds aiming to minimise false‐positive SCNAs. Tissue samples representing stages from the multistep process of hepatocarcinogenesis (n = 184) were subjected to low‐pass whole genome sequencing. Chromosome arm‐level SCNAs were identified in liver cirrhosis, dysplastic nodules, and HCC to assess their discriminative capacity. Samples positive for 1q+ or 8q+ arm‐level duplications were likely to be either HCC or high‐grade dysplastic nodules as opposed to low‐grade dysplastic nodules or cirrhotic tissue with an odds ratio (OR) of 35.5 (95% CI 11.5–110) and 16 (95% CI 6.4–40.2), respectively (p < 0.0001). In an independent cohort of patients recruited from Nottingham, UK, at least two out of four alterations (1q+, 4q−, 8p−, and 8q+) were detectable in blood‐derived cell‐free DNA of patients with HCC (n = 22) but none of the control patients with liver cirrhosis (n = 9). Arm‐level SCNAs on 1q+ or 8q+ are associated with high‐risk liver pathology. These can be detected using low‐pass sequencing of cell‐free DNA isolated from blood, which may be a future early cancer screening tool for patients with liver cirrhosis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Summary: Within each individual, the adaptive immune system generates a repertoire of cells expressing receptors capable of recognizing diverse potential pathogens. The theoretical diversity of the T‐cell receptor (TCR) repertoire exceeds the actual size of the T‐cell population in an individual by several orders of magnitude – making the observation of identical TCRs in different individuals extremely improbable if all receptors were equally likely. Despite this disparity between the theoretical and the realized diversity of the repertoire, these 'public' receptor sequences have been identified in autoimmune, cancer and pathogen interaction contexts. Biased generation processes explain the presence of public TCRs in the naive repertoire, but do not adequately explain the different abundances of these public TCRs. We investigate and characterize the distribution of genomic TCR‐β sequences of naive CD8+ T cells from three genetically identical mice, comparing non‐productive (non‐functional sequences) and productive sequences. We find public TCR‐β sequences at higher abundances compared with unshared sequences in the productive, but not in the non‐productive, repertoire. We show that neutral processes such as recombination biases, codon degeneracy and generation probability do not fully account for these differences, and conclude that thymic or peripheral selection plays an important role in increasing the abundances of public TCR‐β sequences. [ABSTRACT FROM AUTHOR]

Whilst the benefit of direct‐acting antiviral agents (DAAs) in achieving sustained virological response (SVR) is now well‐accepted, their impact on liver function, particularly in relation to achievement of SVR, has not been well documented. We studied 2394 patients with chronic HCV infection, 1276 receiving DAAs and 1118 interferon‐based therapy. Liver function was assessed by the albumin‐bilirubin (ALBI) score or grade. Overall survival according to SVR status and baseline ALBI grade was examined. We also studied time to first decompensation according to ALBI grade, as well as longitudinal changes in ALBI score over time according to SVR. Among the patients receiving DAAs, 89% achieved SVR (Japan = 99%, UK = 78%). Amongst the decompensated patients in the UK cohort, three distinct risk groups according to ALBI grade at baseline were observed. The UK patients receiving DAAs, who had predominantly decompensated disease, showed clear evidence of improvement of liver function detectable within 2 years of the start of treatment, especially in those achieving SVR. These early changes in liver function were very similar to those observed in the first 2‐3 years after interferon‐based therapy. DAAs improve liver function especially in those with decompensated disease who achieve SVR. Experience with interferon‐based therapy suggests that failure to achieve SVR is associated with long‐term decline in liver function and, in contrast, patients who do achieve SVR can expect long‐term disease improvement and subsequent stabilization of liver function. Our initial analysis suggests that those receiving DAAs are likely, in the long term, to follow a similar course. [ABSTRACT FROM AUTHOR]

As global temperatures continue to rise, assessment of how species within ecological communities respond to shifts in temperature has become increasingly important. However, such assessments require detailed long‐term observations or ecosystem‐level manipulations that allow for interactions among species and the potential for species dispersal and exchange with the regional species pool.We examined the effects of experimental whole‐stream warming on a larval black fly assemblage in southwest Iceland. We used a paired‐catchment design, in which we studied the warmed stream and a nearby reference stream for 1 year prior to warming and 2 years during warming and estimated population abundance, biomass, secondary production, and growth rates for larvae of three black fly species.Experimental warming by 3.8°C had contrasting effects on the three black fly species in the assemblage. The abundance, biomass, growth, and production of Prosimulium ursinum decreased in the experimental stream during the warming manipulation. Despite increasing in the reference stream, the abundance, biomass, and production of another species, Simulium vernum, decreased in the experimental stream during warming.In contrast, warming had an overall positive effect on Simulium vittatum. While warming had little effect on the growth of overwintering cohorts of S. vittatum, warming led to an additional cohort during the summer months and increased its abundance, biomass, and production. Overall, family‐level production was enhanced by warming, despite variation in species‐level responses.Our study illustrates that the effects of climate warming are likely to differ even among closely related species. Moreover, our study highlights the need for further investigation into the uneven effects of warming on individual species and how those variable effects influence food web dynamics and ecosystem function. [ABSTRACT FROM AUTHOR]

Summary: Background: We conducted a prospective study using gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid–enhanced magnetic resonance imaging (Gd‐EOB‐MRI) to determine whether sustained virological response (SVR) by direct‐acting anti‐viral (DAA) drugs suppresses hepatocarcinogenesis in patients with hepatitis C virus (HCV) infection. Aim: To use serial Gd‐EOB‐MRI to assess the impact of DAAs on hepatocarcinogenesis. Methods: Between February 2008 and December 2018, 1083 consecutive patients with HCV infection underwent Gd‐EOB‐MRI. Of these, 719 patients were enrolled, including 210 patients in the 'Non‐DAA group', who did not receive DAAs before the introduction of DAAs, and 509 patients in the 'DAA group', who achieved SVR after the introduction of DDAs. Factors associated with hepatocarcinogenesis were analysed by a Cox proportional hazard model. In addition, hepatocarcinogenesis was classified into two types, 'multistep' and 'de novo', on the basis of Gd‐EOB‐MRI findings. Factors associated with each type were analysed by Fine and Gray proportional hazards models. Results: Hepatocarcinogenesis was observed in 67 of 719 (9.3%) patients. Factors associated with hepatocarcinogenesis were male gender, albumin‐bilirubin (ALBI) grade 2 or 3, Lens culinaris agglutinin–reactive fraction of alpha‐fetoprotein (AFP‐L3) ≥5%, the presence of nonhypervascular hypointense nodules (NHHNs) and Non‐DAA group. Of 67 patients, multistep hepatocarcinogenesis occurred in 58 patients (86.6%) and de novo hepatocarcinogenesis occurred in nine patients (13.4%). Factors associated with multistep hepatocarcinogenesis were male gender and Non‐DAA group. Conclusion: The eradication of HCV by DAA therapy reduces multistep hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

Climate warming is predicted to alter routing and flows of energy through food webs because of the critical and varied effects of temperature on physiological rates, community structure, and trophic dynamics. Few studies, however, have experimentally assessed the net effect of warming on energy flux and food web dynamics in natural intact communities. Here, we test how warming affects energy flux and the trophic basis of production in a natural invertebrate food web by experimentally heating a stream reach in southwest Iceland by ~4°C for 2 yr and comparing its response to an unheated reference stream. Previous results from this experiment showed that warming led to shifts in the structure of the invertebrate assemblage, with estimated increases in total metabolic demand but no change in annual secondary production. We hypothesized that elevated metabolic demand and invariant secondary production would combine to increase total consumption of organic matter in the food web, if diet composition did not change appreciably with warming. Dietary composition of primary consumers indeed varied little between streams and among years, with gut contents primarily consisting of diatoms (72.9%) and amorphous detritus (19.5%). Diatoms dominated the trophic basis of production of primary consumers in both study streams, contributing 79–86% to secondary production. Although warming increased the flux of filamentous algae within the food web, total resource consumption did not increase as predicted. The neutral net effect of warming on total energy flow through the food web was a result of taxon‐level variation in responses to warming, a neutral effect on total invertebrate production, and strong trophic redundancy within the invertebrate assemblage. Thus, food webs characterized by a high degree of trophic redundancy may be more resistant to the effects of climate warming than those with more diverse and specialized consumers. [ABSTRACT FROM AUTHOR]

We did not detect the profilin allergen Ara h 5, consistent with previous work.[7] Dust sample 3 contained poor coverage of the most abundant allergens (Ara h 1, 2, and 3). We have confirmed the presence of the clinically important peanut allergens Ara h 1, 2, 3, and 6 in peanut containing dust samples using MS analysis which offers more specific, sequence-specific, detection than ELISA method. The effect of thermal processing on the behaviour of peanut allergen peptide targets used in multiple reaction monitoring mass spectrometry experiments. [Extracted from the article]

Background: The 'Prediction Of Survival in Advanced Sorafenib‐treated HCC' (PROSASH) model addressed the heterogeneous survival of patients with hepatocellular carcinoma (HCC) treated with sorafenib in clinical trials but requires validation in daily clinical practice. This study aimed to validate, compare and optimize this model for survival prediction. Methods: Patients treated with sorafenib for HCC at five tertiary European centres were retrospectively staged according to the PROSASH model. In addition, the optimized PROSASH‐II model was developed using the data of four centres (training set) and tested in an independent dataset. These models for overall survival (OS) were then compared with existing prognostic models. Results: The PROSASH model was validated in 445 patients, showing clear differences between the four risk groups (OS 16.9‐4.6 months). A total of 920 patients (n = 615 in training set, n = 305 in validation set) were available to develop PROSASH‐II. This optimized model incorporated fewer and less subjective parameters: the serum albumin, bilirubin and alpha‐foetoprotein, and macrovascular invasion, extrahepatic spread and largest tumour size on imaging. Both PROSASH and PROSASH‐II showed improved discrimination (C‐index 0.62 and 0.63, respectively) compared with existing prognostic scores (C‐index ≤0.59). Conclusions: In HCC patients treated with sorafenib, individualized prediction of survival and risk group stratification using baseline prognostic and predictive parameters with the PROSASH model was validated. The refined PROSASH‐II model performed at least as good with fewer and more objective parameters. PROSASH‐II can be used as a tool for tailored treatment of HCC in daily practice and to define pre‐planned subgroups for future studies. [ABSTRACT FROM AUTHOR]

Background & Aims: It remains controversial whether the eradication of hepatitis C virus (HCV) by interferon (IFN)‐free anti‐HCV therapy using direct‐acting antivirals (DAAs) suppresses or promotes hepatocellular carcinoma (HCC) development. We investigated the influence of HCV eradication by DAA therapy on HCC development, by observing changes of non‐hypervascular hypointense nodules (NHHNs) by gadolinium‐ethoxybenzyl‐diethylenetriamine pentaacetic acid‐enhanced magnetic resonance imaging (EOB‐MRI). Methods: A total of 401 patients treated with DAA therapy who did not have a history of HCC were enrolled in this prospective cohort study. All patients underwent EOB‐MRI prior to the start of DAA therapy and were followed up periodically after therapy. The progression of NHHNs detected at baseline to typical HCC, as indicated by hypervascularization and the incidence of newly emergent NHHNs, was analyzed. Results: In comparison of patients who achieved sustained virologic response (SVR) with propensity score‐matched patients with persistent HCV infection, there was no difference in the incidence of hypervascularization of NHHNs to typical HCC among patients who had NHHNs at baseline. Among patients who did not have NHHNs at baseline, the incidence of the new emergence of NHHNs did not differ between study patients and propensity score–matched patients with persistent HCV infection. Conclusions: During a 2‐year observation period after SVR, the eradication of HCV by IFN‐free DAA therapy did not suppress or enhance HCC development. (UMIN000017020). See Editorial on Page 446 [ABSTRACT FROM AUTHOR]

Background: Three flaviviruses (equine pegivirus [EPgV]; Theiler's disease–associated virus [TDAV]; non‐primate hepacivirus [NPHV]) and equine parvovirus (EqPV‐H) are present in equine blood products; the TDAV, NPHV, and EqPV‐H have been suggested as potential causes of serum hepatitis. Objective: To determine the prevalence of these viruses in horses with equine serum hepatitis. Animals: Eighteen horses diagnosed with serum hepatitis, enrolled from US referral hospitals. Methods: In the prospective case study, liver, serum, or both samples were tested for EPgV, TDAV, NPHV, and EqPV‐H by PCR. Results: Both liver tissue and serum were tested for 6 cases, serum only for 8 cases, and liver only for 4 cases. Twelve horses received tetanus antitoxin (TAT) 4‐12.7 weeks (median = 8 weeks), 3 horses received commercial equine plasma 6‐8.6 weeks, and 3 horses received allogenic stem cells 6.4‐7.6 weeks before the onset of hepatic failure. All samples were TDAV negative. Two of 14 serum samples were NPHV‐positive. Six of 14 serum samples were EPgV‐positive. All liver samples were NPHV‐negative and EPgV‐negative. EqPV‐H was detected in the serum (N = 8), liver (N = 4), or both samples (N = 6) of all 18 cases. The TAT of the same lot number was available for virologic testing in 10 of 12 TAT‐associated cases, and all 10 samples were EqPV‐H positive. Conclusions and Clinical Importance: We demonstrated EqPV‐H in 18 consecutive cases of serum hepatitis. EPgV, TDAV, and NPHV were not consistently present. This information should encourage blood product manufacturers to test for EqPV‐H and eliminate EqPV‐H–infected horses from their donor herds. [ABSTRACT FROM AUTHOR]

Background: A novel equine parvovirus (EqPV‐H) was recently discovered in the equine liver with Theiler's disease. Objectives: To determine the prevalence of EqPV‐H infection in naturally occurring Theiler's disease cases and in‐contact horses in the absence of historical equine biologic product administration. Animals Ten cases of Theiler's disease from 6 separate properties were included in the study, based on the criteria of acute onset of clinical signs of liver failure with laboratory or histopathologic findings characteristic of Theiler's disease and no history of receiving an equine biologic product within the preceding 4 months. In addition, 37 in‐contact horses from 4 of the 6 properties were screened for EqPV‐H infection and hepatitis. Methods: In prospective case series, cases were diagnosed with Theiler's disease by the attending veterinarian and were tested for EqPV‐H by PCR of liver or serum. In‐contact horses were assessed via serum chemistry and PCR at the attending veterinarian's discretion. Hepatitis was defined as serum gamma‐glutamyltransferase activity above reference interval. The association of EqPV‐H with hepatitis was determined by Fisher's exact test. Results: Nine of 10 (90%) Theiler's disease cases and 54% of tested in‐contact horses were EqPV‐H positive. Hepatitis was significantly associated with EqPV‐H infection (P = .036). Conclusions and Clinical Importance: Although further study is required to identify EqPV‐H as the causative agent of Theiler's disease, EqPV‐H appears strongly associated with cases of fatal Theiler's disease and subclinical hepatitis in horses in contact with those cases. The prevalence of EqPV‐H infection on affected properties can be high. [ABSTRACT FROM AUTHOR]

Abstract: Climate warming is affecting the structure and function of river ecosystems, including their role in transforming and transporting carbon (C), nitrogen (N), and phosphorus (P). Predicting how river ecosystems respond to warming has been hindered by a dearth of information about how otherwise well‐studied physiological responses to temperature scale from organismal to ecosystem levels. We conducted an ecosystem‐level temperature manipulation to quantify how coupling of stream ecosystem metabolism and nutrient uptake responded to a realistic warming scenario. A ~3.3°C increase in mean water temperature altered coupling of C, N, and P fluxes in ways inconsistent with single‐species laboratory experiments. Net primary production tripled during the year of experimental warming, while whole‐stream N and P uptake rates did not change, resulting in 289% and 281% increases in autotrophic dissolved inorganic N and P use efficiency (UE), respectively. Increased ecosystem production was a product of unexpectedly large increases in mass‐specific net primary production and autotroph biomass, supported by (i) combined increases in resource availability (via N mineralization and N2 fixation) and (ii) elevated resource use efficiency, the latter associated with changes in community structure. These large changes in C and nutrient cycling could not have been predicted from the physiological effects of temperature alone. Our experiment provides clear ecosystem‐level evidence that warming can shift the balance between C and nutrient cycling in rivers, demonstrating that warming will alter the important role of in‐stream processes in C, N, and P transformations. Moreover, our results reveal a key role for nutrient supply and use efficiency in mediating responses of primary producers to climate warming. [ABSTRACT FROM AUTHOR]

Background & Aims Biliary tract cancer is a rare tumour entity characterized by a poor prognosis. We aimed to identify prognostic factors and create a prognostic score to estimate survival. Methods Clinical data of the training set, consisting of 569 patients treated from 2000 to 2010 at Hannover Medical School, were analysed. A prognostic model defining three prognostic risk groups was derived from Cox regression analyses. The score was applied and validated in an independent cohort of 557 patients from four different German centres. Results Median overall survival ( OS) was 14.5 months. If complete resection was performed, the patients had a significantly improved OS (23.9 months; n=242) as compared to patients with non-resectable tumours (9.1 months; n=329, P<.0001). Based on univariable and multivariable analyses of clinical data, a prognostic model was created using variables available before treatment. Those were age, metastasis, C-reactive protein ( CRP), international normalized ratio ( INR) and bilirubin. The prognostic score distinguished three groups with a median OS of 21.8, 8.6 and 2.6 months respectively. The validation cohort had a median OS of 20.2, 14.0 and 6.5 months respectively. The prognostic impact of the score was independent of the tumour site and of treatment procedures. Conclusions Here, we identified prognostic factors and propose a prognostic score to estimate survival, which can be applied to all patients independent of tumour site and before initial treatment. Further validation in prospective trials is required. [ABSTRACT FROM AUTHOR]

A central question at the interface of food-web and climate change research is how secondary production, or the formation of heterotroph biomass over time, will respond to rising temperatures. The metabolic theory of ecology ( MTE) hypothesizes the temperature-invariance of secondary production, driven by matched and opposed forces that reduce biomass of heterotrophs while increasing their biomass turnover rate (production : biomass, or P: B) with warming. To test this prediction at the whole community level, we used a geothermal heat exchanger to experimentally warm a stream in southwest Iceland by 3.8°C for two years. We quantified invertebrate community biomass, production, and P : B in the experimental stream and a reference stream for one year prior to warming and two years during warming. As predicted, warming had a neutral effect on community production, but this result was not driven by opposing effects on community biomass and P: B. Instead, warming had a positive effect on both the biomass and production of larger-bodied, slower-growing taxa (e.g., larval black flies, dipteran predators, snails) and a negative effect on small-bodied taxa with relatively high growth rates (e.g., ostracods, larval chironomids). We attribute these divergent responses to differences in thermal preference between small- vs. large-bodied taxa. Although metabolic demand vs. resource supply must ultimately constrain community production, our results highlight the potential for idiosyncratic community responses to warming, driven by variation in thermal preference and body size within regional species pools. [ABSTRACT FROM AUTHOR]

How ecological communities respond to predicted increases in temperature will determine the extent to which Earth's biodiversity and ecosystem functioning can be maintained into a warmer future. Warming is predicted to alter the structure of natural communities, but robust tests of such predictions require appropriate large-scale manipulations of intact, natural habitat that is open to dispersal processes via exchange with regional species pools. Here, we report results of a two-year whole-stream warming experiment that shifted invertebrate assemblage structure via unanticipated mechanisms, while still conforming to community-level metabolic theory. While warming by 3.8 °C decreased invertebrate abundance in the experimental stream by 60% relative to a reference stream, total invertebrate biomass was unchanged. Associated shifts in invertebrate assemblage structure were driven by the arrival of new taxa and a higher proportion of large, warm-adapted species (i.e., snails and predatory dipterans) relative to small-bodied, cold-adapted taxa (e.g., chironomids and oligochaetes). Experimental warming consequently shifted assemblage size spectra in ways that were unexpected, but consistent with thermal optima of taxa in the regional species pool. Higher temperatures increased community-level energy demand, which was presumably satisfied by higher primary production after warming. Our experiment demonstrates how warming reassembles communities within the constraints of energy supply via regional exchange of species that differ in thermal physiological traits. Similar responses will likely mediate impacts of anthropogenic warming on biodiversity and ecosystem function across all ecological communities. [ABSTRACT FROM AUTHOR]

Neuroma management is an unresolved problem. Biomaterials to limit unwanted axonal growth could be a tool to manage neuroma. Hyaluronic acid/carboxymethyl cellulose (HA/CMC) is an antiadhesive, biodegradable material that is nontoxic to nerve. The purpose of this study was to evaluate the efficacy of this biomaterial to limit axonal growth. Rats received a sciatic nerve transection and repair with a short conduit (5 mm) containing HA/CMC, fibrin, or nothing (empty conduit). In another study, nerve was transected and either left undisturbed or wrapped with HA/CMC around the proximal and distal ends. In a final study, nerve was transected and repaired with an HA/CMC wrap. Four weeks following the procedures, nerves were harvested and assessed using histomorphometry to measure axonal regeneration. Axonal regeneration following transection was significantly inhibited by direct axonal contact with HA/CMC, whether within a conduit or wrapped around the transected proximal nerve end. Axonal regeneration following epineurial repair was not affected by HA/CMC wrapped around nerve, demonstrating axonal growth inhibition due to direct contact of regenerating axons with HA/CMC. These studies demonstrate the efficacy of HA/CMC to limit axonal outgrowth by contact with regenerating axons. HA/CMC barriers may prove to be a tool to prevent neuroma formation by inhibiting axonal growth. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 568-574, 2017. [ABSTRACT FROM AUTHOR]

Background and Aims The albumin-bilirubin (ALBI) grade is a recently emerging alternative of the Child-Pugh (CP) grade. The Cancer of the Liver Italian Program (CLIP) was demonstrated to be a useful prognostic model for hepatocellular carcinoma (HCC) in large prospective cohorts. We aimed to investigate the feasibility of substituting the CP grade by the ALBI grade in the CLIP system and compare the prognostic performance with other existing staging systems. Methods A large cohort of 1973 Chinese patients with HCC was recruited to evaluate the prognostic performance of CP-based CLIP (CP-CLIP) and ALBI-based CLIP (ALBI-CLIP) systems and nine other staging systems by homogeneity likelihood chi-square, c-index, and corrected Akaike information criterion. Results The ALBI-CLIP system provided comparable prognostic performance than the CP-CLIP system, which was indicated by homogeneity likelihood chi-squares (ALBI-CLIP 1186.35 vs CP-CLIP 1145.54), c-indices (ALBI-CLIP 0.789 vs CP-CLIP 0.785) and AICs (ALBI-CLIP 15 493.47 vs CP-CLIP 15 534.28). Among 11 staging systems, ALBI-CLIP and CP-CLIP systems were associated with the highest homogeneity chi-squares and c-indices, and the lowest corrected Akaike information criterion. Patients in ALBI-CLIP score 0-4 had better median survival than those in corresponding CP-CLIP score. Conclusions The ALBI grade performs as well as the CP grade when integrating into the CLIP system. ALBI-CLIP and CP-CLIP systems are the most accurate prognostic models among 11 existing staging systems. [ABSTRACT FROM AUTHOR]

Background & Aims The Albumin-Bilirubin ( ALBI) grade was proposed as an objective means to evaluate liver function in patients with Hepatocellular Carcinoma ( HCC). ALBI grade 1 vs 2 were proposed as stratification factors within the Child Pugh ( CP) A class. However, the original publication did not provide comparison with the subclassification by points (5-15) within the CP classification. Methods We retrospectively analysed data from patients treated with sorafenib for HCC from 17 centres in United Kingdom and France. Overall survival ( OS) was analysed using the Kaplan -Meier method and a Cox regression model. Discriminatory abilities of the classifications were assessed with the log likelihood ratio, Harrell's C statistics and Akaike information criterion. Results Data from 1019 patients were collected, of which 905 could be assessed for both scores. 92% of ALBI grade 1 were CP A5 while ALBI 2 included a broad range of CP scores of which 44% were CP A6. Median OS was 10.2, 7.0 and 3.6 months for CP scores A5, A6 and >A6, respectively ( P < 0.001), Hazard Ratio ( HR) = 1.60 (95% CI: 1.35-1.89, P < 0.001) for A6 vs A5. Median OS was 10.9, 6.6 and 3.0 months for ALBI grade 1, 2 and 3, respectively ( P < 0.001), HR = 1.68 (1.43-1.97, P < 0.001) for grade 2 vs 1. Discriminatory abilities of CP and ALBI were similar in the CP A population, but better for CP in the overall population. Conclusions Our findings support the use CP class A as an inclusion criterion, and ALBI as a stratification factor in trials of systemic therapy. [ABSTRACT FROM AUTHOR]

Background and Aim The Japan Integrated Staging (JIS) for hepatocellular carcinoma (HCC) has been extensively studied in hepatitis virus C-endemic Japanese population but seldom evaluated outside Japan, while albumin-bilirubin (ALBI)-based JIS (ALBI-T) has never been externally validated. We evaluate the prognostic significance of the ALBI-T score among Chinese patients with hepatitis virus B (HBV)-related HCC, and to explore its potential therapeutic application in selecting patients for appropriate treatments in addition to the Barcelona Clinic Liver Cancer (BCLC) recommendation. Methods A cohort of 1222 HBV-associated HCC patients was evaluated to compare the prognostic performance of JIS and ALBI-T scores by homogeneity likelihood chi-square and corrected Akaike information criterion. In the subgroup analysis of each BCLC stage, Kaplan-Meier method and log-rank statistics were used to compare overall survival of patients undergoing different treatment options. Results The ALBI-T score showed better prognostic performance than the JIS score, which were indicated by homogeneity likelihood chi-squares (ALBI-T 580.12 vs JIS 536.35) and Akaike information criteria (ALBI-T 9836.57 vs JIS 9880.23). Treatment options significantly influenced prognosis among patients of the same BCLC stage. With the use of ALBI-T score 4 as the cutoff, the current study identified that a portion of patients (14.7%, 25.2% and 28.6% of BCLC stage B, C and D, respectively) undergoing unnecessary therapy without survival advantage. Conclusions The ALBI-T score is applicable to Chinese patients with HBV-related HCC to provide reasonable prognostic information as well as potentially helping clinicians to avoid offering non-beneficial aggressive treatments. [ABSTRACT FROM AUTHOR]

Background and Aims The albumin-bilirubin (ALBI) grade is a recently reported, simpler, more objective, and evidence-based alternative to the Child-Pugh (CP) score for hepatocellular carcinoma (HCC). We aimed to study whether ALBI grade could substitute for CP score in Barcelona Clinic Liver Cancer (BCLC) for HCC. Methods An international multicentre cohort ( n = 3696) was accrued to compare the prognostic performance of the CP-based and ALBI-based BCLC system, in terms of homogeneity, discriminatory ability, and monotonicity of gradients that were numerically reflected by homogeneity likelihood, linear trend chi-squares, and c-indices, respectively. Results The ALBI grade performed as well as CP score when integrated into the BCLC staging system in terms of predicting clinical outcome of HCC regardless of regions, etiology, and treatment options. CP-based and ALBI-based BCLC systems were highly concordant with weighted kappa value of 0.917. All restaged patients showed significantly different clinical outcomes compared with their original stage classification. In particular, ALBI-based BCLC upstaged 83 (2.2%) patients from lower CP-based BC LC stages to ALBI-based BCLC stage D, whose median overall survival was only 3 months. Conclusions The overall prognostic performance of ALBI-based and CP-based BCLC systems was similar. It also potentially allows more precise patient selection for clinical trials on systemic agents. [ABSTRACT FROM AUTHOR]

Although much effort has been devoted to quantifying how warming alters carbon cycling across diverse ecosystems, less is known about how these changes are linked to the cycling of bioavailable nitrogen and phosphorus. In freshwater ecosystems, benthic biofilms (i.e. thin films of algae, bacteria, fungi, and detrital matter) act as biogeochemical hotspots by controlling important fluxes of energy and material. Understanding how biofilms respond to warming is thus critical for predicting responses of coupled elemental cycles in freshwater systems. We developed biofilm communities in experimental streamside channels along a gradient of mean water temperatures (7.5-23.6 °C), while closely maintaining natural diel and seasonal temperature variation with a common water and propagule source. Both structural (i.e. biomass, stoichiometry, assemblage structure) and functional (i.e. metabolism, N2-fixation, nutrient uptake) attributes of biofilms were measured on multiple dates to link changes in carbon flow explicitly to the dynamics of nitrogen and phosphorus. Temperature had strong positive effects on biofilm biomass (2.8- to 24-fold variation) and net ecosystem productivity (44- to 317-fold variation), despite extremely low concentrations of limiting dissolved nitrogen. Temperature had surprisingly minimal effects on biofilm stoichiometry: carbon:nitrogen (C:N) ratios were temperature-invariant, while carbon:phosphorus (C:P) ratios declined slightly with increasing temperature. Biofilm communities were dominated by cyanobacteria at all temperatures (>91% of total biovolume) and N2-fixation rates increased up to 120-fold between the coldest and warmest treatments. Although ammonium-N uptake increased with temperature (2.8- to 6.8-fold variation), the much higher N2-fixation rates supplied the majority of N to the ecosystem at higher temperatures. Our results demonstrate that temperature can alter how carbon is cycled and coupled to nitrogen and phosphorus. The uncoupling of C fixation from dissolved inorganic nitrogen supply produced large unexpected changes in biofilm development, elemental cycling, and likely downstream exports of nutrients and organic matter. [ABSTRACT FROM AUTHOR]

Background and Aims The BALAD score is developed to provide an objective determination of prognosis for hepatocellular carcinoma ( HCC) by incorporating five serum markers, namely albumin, bilirubin, alpha-fetoprotein ( AFP), agglutinin-reactive alpha-fetoprotein ( AFP- L3), and des-γ-carboxy prothrombin. We aim to study the applicability of BALAD score and prognostication of the three tumor markers in hepatitis B virus-related HCC. Methods Patients with newly diagnosed HCC were prospectively enrolled. All of the baseline characteristics and serum albumin and bilirubin level were documented at baseline. The levels of the three tumor markers ( AFP, AFP- L3, and des-γ-carboxy prothrombin) were determined in archival serum samples. Patients were followed up for survivals according to local practice. The prognostic performances of the three markers and BALAD score were studied in association with overall survival ( OS). Results A total of 198 patients with hepatitis B-related HCC were recruited. AFP and AFP- L3 levels were independent prognostic factors. The number of elevated tumor markers was also predictive of worse OS. BALAD score could stratify the cohort into different patient groups with distinct median OS. The median OS of BALAD score of 0, 1, 2, 3, and 4 was not reached, 26.6, 8.3, 2.6, and 1.9 months, respectively ( P < 0.0001). BALAD score could further stratify outcomes in each Barcelona Clinic Liver Cancer ( BCLC) subgroup. In particular, BALAD score of 3-4 had median OS of 2.6 months only in BCLC stage C patients. Conclusion BALAD score is applicable in the population of hepatitis B virus-related HCC. The combined use of BALAD score and BCLC staging system could help identify more suitable candidates for clinical trial. [ABSTRACT FROM AUTHOR]

Recent school science curriculum developments in many countries emphasise that scientists derive evidence for their claims through different approaches; that such practices are bound up with disciplinary knowledge; and that the quality of data should be appreciated. This position paper presents an understanding of the validity of data as a set of conceptual relationships, illustrating the application of the network of ideas and their inter-relationships necessary for the ‘thinking behind the doing’ with examples from practice. We explore ways in which this understanding of data is inherently related to underpinning disciplinary ideas. We suggest how the recognition of a conceptual basis for understanding the quality of data represents an ontological shift with respect to widespread characterisations of scientific practices which addresses some long-standing issues in science education research, policy, curricula and practice. [ABSTRACT FROM AUTHOR]

Background & Aims Hepatocellular carcinoma ( HCC) is the second most common cause of cancer deaths worldwide. The global HCC BRIDGE study was a multiregional, large-scale, longitudinal cohort study undertaken to improve understanding of real-life management of patients with HCC, from diagnosis to death. Methods Data were collected retrospectively from January 2005 to September 2012 by chart reviews of eligible patients newly diagnosed with HCC at participating institutions. Results Forty-two sites in 14 countries contributed final data for 18 031 patients. Asia accounted for 67% of patients, Europe for 20% and North America for 13%. As expected, the most common risk factor was hepatitis C virus in North America, Europe and Japan, and hepatitis B virus in China, South Korea and Taiwan. The most common Barcelona Clinic Liver Cancer stage at diagnosis was C in North America, Europe, China and South Korea, and A in Taiwan and Japan. Across all stages, first HCC treatment was most frequently transarterial chemoembolization in North America, Europe, China and South Korea, percutaneous ethanol injection or radiofrequency ablation in Japan and resection in Taiwan. Survival from first HCC treatment varied significantly by region, with median overall survival not reached for Taiwan and 60, 33, 31, 24 and 23 months for Japan, North America, South Korea, Europe and China respectively ( P < 0.0001). Conclusions Initial results from the BRIDGE study confirm previously reported regional trends in patient demographic characteristics and HCC risk factors, document the heterogeneity of treatment approaches across regions/countries and underscore the need for earlier HCC diagnosis worldwide. [ABSTRACT FROM AUTHOR]

Variation in resource supply can cause variation in temperature dependences of metabolic processes (e.g., photosynthesis and respiration). Understanding such divergence is particularly important when using metabolic theory to predict ecosystem responses to climate warming. Few studies, however, have assessed the effect of temperature-resource interactions on metabolic processes, particularly in cases where the supply of limiting resources exhibits temperature dependence. We investigated the responses of biomass accrual, gross primary production (GPP), community respiration (CR), and N2 fixation to warming during biofilm development in a streamside channel experiment. Areal rates of GPP, CR, biomass accrual, and N2 fixation scaled positively with temperature, showing a 32- to 71-fold range across the temperature gradient (~7°-24°C). Areal N2-fixation rates exhibited apparent activation energies (1.5-2.0 eV; 1 eV ¼ ;1.6 3 10-19 J) approximating the activation energy of the nitrogenase reaction. In contrast, mean apparent activation energies for areal rates of GPP (2.1-2.2 eV) and CR (1.6-1.9 eV) were 6.5- and 2.7-fold higher than estimates based on metabolic theory predictions (i.e., 0.32 and 0.65 eV, respectively) and did not significantly differ from the apparent activation energy observed for N2 fixation. Mass-specific activation energies for N2 fixation (1.4-1.6 eV), GPP (0.3-0.5 eV), and CR (no observed temperature relationship) were near or lower than theoretical predictions. We attribute the divergence of areal activation energies from those predicted by metabolic theory to increases in N2 fixation with temperature, leading to amplified temperature dependences of biomass accrual and areal rates of GPP and R. Such interactions between temperature dependences must be incorporated into metabolic models to improve predictions of ecosystem responses to climate change. [ABSTRACT FROM AUTHOR]

Understanding and predicting how global warming affects the structure and functioning of natural ecosystems is a key challenge of the 21st century. Isolated laboratory and field experiments testing global change hypotheses have been criticized for being too small-scale and overly simplistic, whereas surveys are inferential and often confound temperature with other drivers. Research that utilizes natural thermal gradients offers a more promising approach and geothermal ecosystems in particular, which span a range of temperatures within a single biogeographic area, allow us to take the laboratory into nature rather than vice versa. By isolating temperature from other drivers, its ecological effects can be quantified without any loss of realism, and transient and equilibrial responses can be measured in the same system across scales that are not feasible using other empirical methods. Embedding manipulative experiments within geothermal gradients is an especially powerful approach, informing us to what extent small-scale experiments can predict the future behaviour of real ecosystems. Geothermal areas also act as sentinel systems by tracking responses of ecological networks to warming and helping to maintain ecosystem functioning in a changing landscape by providing sources of organisms that are preadapted to different climatic conditions. Here, we highlight the emerging use of geothermal systems in climate change research, identify novel research avenues, and assess their roles for catalysing our understanding of ecological and evolutionary responses to global warming. [ABSTRACT FROM AUTHOR]

ABSTRACT Glial cell-line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor known to enhance motor nerve regeneration following its delivery. However, recent studies have determined that extended GDNF delivery to regenerating axons can entrap motor axons at the site of GDNF delivery. This entrapment leads to reduced motor axons available to reinnervate muscle. To address this issue, we designed a cell-based GDNF expression system that can temporally regulate protein expression using an inducible gene excision mechanism to prevent entrapment at the site of expression. To design this system for regulation of GDNF expression, we transduced two lentiviral vectors, one containing a constitutively active GDNF transgene flanked by two loxP sites, and the other containing a tetracycline-inducible cre transgene along with its constitutively active transactivator, into Schwann cells (SCs). These SCs over-express GDNF, but expression can be suppressed through the administration of tetracycline family antibiotics, such as doxycycline. The engineered SCs produced significantly more GDNF as compared to untransduced controls, as measured by enzyme-linked immunosorbent assay (ELISA). Following doxycycline treatment, these SCs produced significantly lower levels of GDNF and induced less neurite extension as compared to untreated SCs. Engineered SCs treated with doxycycline showed a marked increase in Cre recombinase expression, as visualized by immunohistochemistry (IHC), providing evidence of a mechanism for the observed changes in GDNF expression levels and biological activity. This cell-based GDNF expression system could have potential for future in vivo studies to provide a temporally controlled GDNF source to promote axon growth. Biotechnol. Bioeng. 2014;111: 1886-1894. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objective (i) To report the successful treatment of 10 cases of equine periocular squamous cell carcinoma ( PSCC) with surgical excision and photodynamic therapy ( PDT) using verteporfin. (ii) To evaluate time to first tumor recurrence between PDT-treated horses and horses treated with surgical excision and cryotherapy. Methods A total of 24 equine PSCC cases were included: group 1 ( n = 14) had excision and cryotherapy (1993-2003), group 2 ( n = 10), excision and local PDT (2006-2010). Evaluated data: signalment, treatment method, tumor location, size, and time to first recurrence. Groups were compared via chi-square test for categorical variables and Wilcoxon rank-sum test for numeric variables. Time to tumor recurrence was examined using Kaplan- Meier product-limit survival analysis. Results Of 24 cases, nine breeds were affected. Mean age at treatment in years: 14 (range 5-24) in group 1; 11 (range 8-18) in group 2. Median tumor size: 163 mm2 (range 20-625 mm2) in group 1; 195 mm2 (range 45-775 mm2) in group 2. Signalment, tumor laterality, and size were not significantly different between groups. Time to recurrence was significantly different between groups (Logrank test, P = 0.0006). In group 1, 11/14 horses had tumor regrowth with median time to recurrence in months: 10 (range 1-44). In group 2 (minimum follow-up of 25 months; range 25-50), no horse demonstrated tumor recurrence after one treatment with excision and PDT. Conclusions This represents the first report of local PDT using verteporfin for treatment of equine PSCC. Following surgery, the likelihood of tumor recurrence was significantly reduced with local PDT compared with cryotherapy. [ABSTRACT FROM AUTHOR]

The adaptive immune system requires a diverse T-cell repertoire to be able to respond to a wide variety of pathogens. Worryingly, the repertoire diversity declines dramatically in old age. As thymic output generates novel T cells, the conventional view holds that a decrease in this output with age is responsible for the loss in the repertoire. However, many additional factors affect the repertoire such as homeostatic turnover and antigen-dependent expansion in response to infection. Mathematical models taking a population biology perspective are important tools for understanding how the interplay between these factors affects the immune repertoire. These models suggest that thymic decline is not a major factor but rather that some combination of virus-induced proliferation and T-cell-intrinsic genetic or epigenetic changes gives rise to the oligoclonal expansions that cause the decline in T-cell diversity. We also discuss consequences for strategies to rejuvenate the immune repertoire in old age. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: This study evaluated whether Schwann cells (SCs) from different nerve sources transplanted into cold-preserved acellular nerve grafts (CP-ANGs) would improve functional regeneration compared with nerve isografts. Methods: SCs isolated and expanded from motor and sensory branches of rat femoral and sciatic nerves were seeded into 14mm CP-ANGs. Growth factor expression, axonal regeneration, and functional recovery were evaluated in a 14-mm rat sciatic injury model and compared with isografts. Results: At 14 days, motor or sensory-derived SCs increased expression of growth factors in CP-ANGs versus isografts. After 42 days, histomorphometric analysis found CP-ANGs with SCs and isografts had similar numbers of regenerating nerve fibers. At 84 days, muscle force generation was similar for CP-ANGs with SCs and isografts. SC source did not affect nerve fiber counts or muscle force generation. Conclusions: SCs transplanted into CP-ANGs increase functional regeneration to isograft levels; however SC nerve source did not have an effect. Muscle Nerve 49: 267-276, 2014 [ABSTRACT FROM AUTHOR]

Introduction: We sought to determine whether supplementation of acellular nerve allografts (ANAs) with Schwann cells overexpressing GDNF (G-SCs) would enhance functional recovery after peripheral nerve injury. Methods: SCs expanded in vitro were infected with a lentiviral vector to induce GDNF overexpression. Wild-type SCs (WT-SCs) and G-SCs were seeded into ANAs used to repair a 14-mm nerve gap defect. Animals were harvested after 6 and 12 weeks for histomorphometric and muscle force analysis. Results: At 6 weeks, histomorphometry revealed that ANAs supplemented with G-SCs promoted similar regeneration compared with isograft at midgraft. However, G-SCs failed to promote regeneration into the distal stump. At 12 weeks, ANAs with G-SCs had lower maximum and specific force production compared with controls. Conclusions: The combined results suggest that consistent overexpression of GDNF by G-SCs trapped axons in the graft and prevented functional regeneration. Muscle Nerve, 2013 [ABSTRACT FROM AUTHOR]

Various international and national regulations hold polluters liable for the cleanup of released hazardous substances and the restoration/rehabilitation of natural resources to preincident baseline conditions, a process often referred to as natural resource damage assessment and restoration (NRDAR). Here, we, the authors, describe how global climate change (GCC) will challenge each of the steps of NRDAR processes and offer eight recommendations to improve these processes in light of GCC. First, we call for a better understanding of the net effects of GCC and contaminants on natural resources. Second, we urge facilities and environmental managers to plan for GCC-related factors that are expected to increase the probability of contaminant releases. Third, we suggest re-evaluating definitions of baseline and reference conditions given that GCC will alter both their trajectories and variability. Fourth, we encourage long-term monitoring to improve the quantification of baseline conditions that will change as climate changes. This will enhance the accuracy of injury assessments, the effectiveness of restoration, and the detection of early warning signs that ecosystems are approaching tipping points. Fifth, in response to or anticipation of GCC, restoration projects may need to be conducted in areas distant from the site of injury or focused on functionally equivalent natural resources; thus, community involvement in NRDAR processes will be increasingly important. Sixth, we promote using NRDAR restoration projects as opportunities to mitigate GCC-related impacts. Seventh, we recommend adaptive management approaches to NRDAR processes and communication of successes and failures widely. Finally, we recommend focusing on managing the stressors that might be exacerbated by GCC, such as pollution and habitat loss, because there is a long history of successfully mitigating these stressors, which can be more easily managed on local scales than climate change. We believe that adoption of these recommendations will lead to a more efficacious NRDAR process, despite the challenges posed by climate change. Environ. Toxicol. Chem. 2013;32:93-101. © 2012 SETAC [ABSTRACT FROM AUTHOR]