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Although the presence of FLT3 -ITD, as well as levels of the FLT3 -ITD allelic ratio, have been described as prognostic factors in acute myeloid leukemia (AML), little is known about how the FLT3 -ITD allelic ratio impacts patients' outcomes when receiving an allogeneic hematopoietic stem cell transplantation (HSCT). We analyzed 118 patients (median age at diagnosis 58.3, range 14.3-82.3 years) harboring FLT3 -ITD, of whom 94 patients were consolidated with an allogeneic HSCT and included in outcome analyses. A high FLT3 -ITD allelic ratio was associated with a higher white blood cell count, higher blood and bone marrow blasts, and worse ELN2017 risk at diagnosis. Patients with a high FLT3 -ITD allelic ratio more often had NPM1 mutations, while patients with a low allelic ratio more often had FLT3 -TKD mutations. Patients with a high FLT3 -ITD allelic ratio were less likely to achieve a measurable residual disease (MRD)-negative remission prior to allogeneic HSCT and had a trend for a shorter time to relapse. However, there was no distinct cumulative incidence of relapse, non-relapse mortality, or overall survival according to the FLT3 -ITD allelic ratio in transplanted patients. While co-mutated FLT3 -TKD was associated with better outcomes, the MRD status at HSCT was the most significant factor for outcomes. While our data indicates that an allogeneic HSCT may mitigate the adverse effect of a high FLT3 -ITD allelic ratio, comparative studies are needed to evaluate which FLT3 -ITD mutated patients benefit from which consolidation strategy.

Somatic mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are common in acute myeloid leukemia (AML). The prognostic impact of the presence of IDH mutations may be influenced by the comutational status, the specific location of the mutation (ie, IDH1 R132, IDH2 R140, and IDH2 R172) at diagnosis, and the dynamics of the mutation burden during disease course. Even though many patients with IDH-mutated AML are consolidated by hematopoietic stem cell transplantation (HSCT), the underlying biology and prognostic consequences remain largely unknown. Here, we present a large analysis of 292 patients with AML who received HSCT in complete remission (CR) or CR with incomplete peripheral recovery (CRi), in which we assessed the IDH mutation status at diagnosis and HSCT as a potential marker for measurable residual disease (MRD). About a quarter of all patients were IDH-mutated at diagnosis. The diagnostic presence of IDH mutations in AML did not have a significant prognostic impact when consolidated with HSCT. However, IDH1 R132 and IDH2 R172 MRD positivity in remission at HSCT associated with an increased risk of relapse, while IDH2 R140 mutations did not. The IDH2 R140 variant allele frequency (VAF) at diagnosis was higher, clustering around 50%, and the mutation clearance at HSCT in morphologic remission was much lower compared with IDH1 R132 and IDH2 R172. In our cohort, IDH2 R140 mutations behaved more like a clonal hematopoiesis-related aberration, while IDH1 R132 and IDH2 R172 harbored AML disease-specific features., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

For most acute myeloid leukemia (AML) patients an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of cure. The introduction of less toxic non-myeloablative conditioning (NMA) regimes enabled older and/or comorbid patients to be consolidated with an allogeneic HSCT. While the hematopoietic cell transplantation comorbidity index (HCT-CI) predicted outcomes in many younger patient cohorts its impact in older AML patients receiving NMA-HSCT remains unknown. Here we analyzed 289 AML patients 60 years or older (median age 66, range 60-77 years) undergoing NMA-HSCT (2 or 3 Gray total body irradiation and 3 days of fludarabine 30 mg/m 2 ). HCT-CI risk was low, intermediate, or high in 36%, 31%, and 33% of patients, respectively. Non-relapse mortality (NRM), cumulative incidence of relapse (CIR), and overall survival (OS) did not differ between HCT-CI groups. The HCT-CI also did not impact outcomes when considering the European LeukemiaNet 2017 risk at diagnosis or the measurable residual disease (MRD) status at HSCT. Notably, MRD-negative older NMA-transplanted AML patients had a beneficial OS of 49% after 5 years. Since a higher HCT-CI did not impair outcomes, age or comorbidities per se should not impede NMA-HSCT, presenting a feasible consolidation option for this group of AML patients., (© 2022. The Author(s).)

For most patients with acute myeloid leukemia (AML), an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of cure. Recently, the European LeukemiaNet (ELN) published updated recommendations on the diagnosis and risk classification in AML based on genetic factors at diagnosis as well as a dynamic adjustment (reclassification) according to the measurable residual disease (MRD) status for the favorable and intermediate risk groups. Validation of the ELN2022 risk classification has not been reported. We retrospectively analyzed 522 AML patients who received an HSCT at a median age of 59 (range 16-76) years. For patients with adequate material available and in remission prior to HSCT (n = 229), the MRD status was evaluated. Median follow-up after HSCT was 3.0 years. ELN2022 risk at diagnosis was in 22% favorable, in 26% intermediate, and in 52% adverse. ELN2022 risk at diagnosis is associated with the cumulative incidence of relapse/progression (CIR), event-free survival (EFS), and overall survival (OS) in the whole patient cohort, as well as the subgroup of patients transplanted in first remission. However, the risk stratification based on the ELN2022 classification did not significantly improve outcome prognostication in comparison to the ELN2017 classification. In our study, the newly added group of patients with myelodysplasia-related gene mutations did not have adverse outcomes. Re-classifying these patients into the intermediate risk group and adjusting the grouping for all AML patients by MRD at HSCT, led to a refined and improved risk stratification, which should be validated in independent studies., (© 2022. The Author(s).)

Malnutrition (MN) is a common primary or secondary complication in gastrointestinal diseases. The patient's nutritional status also influences muscle mass and function, which can be impaired up to the degree of sarcopenia. The molecular interactions in diseases leading to sarcopenia are complex and multifaceted, affecting muscle physiology, the intestine (nutrition), and the liver at different levels. Although extensive knowledge of individual molecular factors is available, their regulatory interplay is not yet fully understood. A comprehensive overall picture of pathological mechanisms and resulting phenotypes is lacking. In silico approaches that convert existing knowledge into computationally readable formats can help unravel mechanisms, underlying such complex molecular processes. From public literature, we manually compiled experimental evidence for molecular interactions involved in the development of sarcopenia into a knowledge base, referred to as the Sarcopenia Map. We integrated two diseases, namely liver cirrhosis (LC), and intestinal dysfunction, by considering their effects on nutrition and blood secretome. We demonstrate the performance of our model by successfully simulating the impact of changing dietary frequency, glycogen storage capacity, and disease severity on the carbohydrate and muscle systems. We present the Sarcopenia Map as a publicly available, open-source, and interactive online resource, that links gastrointestinal diseases, MN, and sarcopenia. The map provides tools that allow users to explore the information on the map and perform in silico simulations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hoch, Ehlers, Bannert, Stanke, Brauer, Caton, Lamprecht, Wolkenhauer, Jaster and Wolfien.)

Objective: Obesity, often associated with non-alcoholic fatty liver disease (NAFLD), is characterized by an imbalance between energy expenditure and food intake, which is also reflected by desensitization of fibroblast growth factor 21 (FGF21). FGF21 is strongly influenced, among others, by TNFα, which is known to be upregulated in obesity-induced inflammation. Successful long-term treatments of NAFLD might be dietary modification, exercise, or fasting., Materials and Methods: Whether succeeded NAFLD recovery is linked with improved FGF21 sensitivity and finally reverted FGF21 resistance was the focus of the present study. For this purpose, mice received a high-fat diet (HFD) for 6 months to establish obesity. Afterward, the mice were subjected to three different weight loss interventions, namely, dietary change to low-fat diet (LFD), treadmill training, and/or time-restricted feeding for additional 6 months, whereas one group remained on HFD., Results: In addition to the expected decrease in NAFLD activity with dietary change, this was also observed in the HFD group with additional time-restricted feeding. There was also an associated decrease in hepatic TNFα and FGF21 expression and an increase in ß-klotho expression, demonstrated mainly by using principal component analysis. Pearson correlation analysis shows that independent of any intervention, TNFα expression decreased with improved NAFLD recovery. This was accompanied with higher FGF21 sensitivity, as expressed by an increase in β-klotho and FGFR1c expression and concomitantly decreased FGF21 levels., Conclusion: In summary, we conclude that successful NAFLD therapy is associated with a reversion of the TNFα-triggered FGF21-resistant state or desensitization., Competing Interests: HG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen Cilag, as well as research funding from Fresenius Medical Care. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Power Guerra, Leyens, Müller, Brauer, Janowitz, Schlick, Pilz, Grabe, Vollmar and Kuhla.)

Allogeneic hematopoietic stem cell transplantation (HSCT) offers the best chance for relapse-free survival to most patients with acute myeloid leukemia (AML). It may be performed during complete remission or delayed until after the first relapse because of relevant treatment-related morbidity and mortality. The measurable residual disease (MRD) status at HSCT adds refined prognostic information to the assigned European LeukemiaNet (ELN) 2017 genetic risk at diagnosis. We analyzed 580 patients with AML who underwent allogeneic HSCT during either the first (79%) or second (21%) remission. Although, because of common treatment strategies, some adverse risk characteristics, such as monosomal or complex karyotypes, were less frequent in patients who underwent transplant in the second remission, those patients had worse outcomes compared with patients who had transplant in the first remission. The MRD status at HSCT was an independent prognostic factor, irrespective of the number of remissions at HSCT. Notably, patients who were MRD+ who underwent HSCT in the first remission and those who were MRD- and underwent transplant in the second remission had similar outcomes. In the clinically highly relevant group of individuals who had ELN2017 intermediate risk, the MRD status provided the highest prognostic value with very dismal outcomes for patients who were MRD+ and underwent second-remission transplants. The adverse outcomes of patients who are MRD+ and of those who undergo transplant in the second remission should be considered when planning consolidation treatment, to avert an allogeneic HSCT in MRD+ second remission when possible., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Recent trends in 3D cell culturing has placed organotypic tissue models at another level. Now, not only is the microenvironment at the cynosure of this research, but rather, microscopic geometrical parameters are also decisive for mimicking a tissue model. Over the years, technologies such as micromachining, 3D printing, and hydrogels are making the foundation of this field. However, mimicking the topography of a particular tissue-relevant substrate can be achieved relatively simply with so-called template or morphology transfer techniques. Over the last 15 years, in one such research venture, we have been investigating a micro thermoforming technique as a facile tool for generating bioinspired topographies. We call them MatriGrid ® s. In this research account, we summarize our learning outcome from this technique in terms of the influence of 3D micro morphologies on different cell cultures that we have tested in our laboratory. An integral part of this research is the evolution of unavoidable aspects such as possible label-free sensing and fluidic automatization. The development in the research field is also documented in this account.

Real-time monitoring of bioanalytes in organotypic cell cultivation devices is a major research challenge in establishing stand-alone diagnostic systems. Presently, no general technical facility is available that offers a plug-in system for bioanalytics in diversely available organotypic culture models. Therefore, each analytical device has to be tuned according to the microfluidic and interface environment of the 3D in vitro system. Herein, we report the design and function of a 3D automated culture and analysis device (3D-ACAD) which actively perfuses a custom-made 3D microbioreactor, samples the culture medium and simultaneously performs capillary-based flow ELISA. A microstructured MatriGrid ® has been explored as a 3D scaffold for culturing HepaRG cells, with albumin investigated as a bioanalytical marker using flow ELISA. We investigated the effect of acetaminophen (APAP) on the albumin secretion of HepaRG cells over 96 h and compared this with the albumin secretion of 2D monolayer HepaRG cultures. Automated on-line monitoring of albumin secretion in the 3D in vitro mode revealed that the application of hepatotoxic drug-like APAP results in decreased albumin secretion. Furthermore, a higher sensitivity of the HepaRG cell culture in the automated 3D-ACAD system to APAP was observed compared to HepaRG cells cultivated as a monolayer. The results support the use of the 3D-ACAD model as a stand-alone device, working in real time and capable of analyzing the condition of the cell culture by measuring a functional analyte. Information obtained from our system is compared with conventional cell culture and plate ELISA, the results of which are presented herein.

Seaweeds are macroalgae, which can be of many different morphologies, sizes, colors, and chemical profiles. They include brown, red, and green seaweeds. Brown seaweeds have been more investigated and exploited in comparison to other seaweed types for their use in animal feeding studies due to their large sizes and ease of harvesting. Recent in vitro and in vivo studies suggest that plant secondary compound-containing seaweeds (e.g., halogenated compounds, phlorotannins, etc.) have the potential to mitigate enteric methane (CH 4 ) emissions from ruminants when added to the diets of beef and dairy cattle. Red seaweeds including Asparagopsis spp. are rich in crude protein and halogenated compounds compared to brown and green seaweeds. When halogenated-containing red seaweeds are used as the active ingredient in ruminant diets, bromoform concentration can be used as an indicator of anti-methanogenic properties. Phlorotannin-containing brown seaweed has also the potential to decrease CH 4 production. However, numerous studies examined the possible anti-methanogenic effects of marine seaweeds with inconsistent results. This work reviews existing data associated with seaweeds and in vitro and in vivo rumen fermentation, animal performance, and enteric CH 4 emissions in ruminants. Increased understanding of the seaweed supplementation related to rumen fermentation and its effect on animal performance and CH 4 emissions in ruminants may lead to novel strategies aimed at reducing greenhouse gas emissions while improving animal productivity., Competing Interests: We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, and there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the content of this paper., (© 2021 Chinese Association of Animal Science and Veterinary Medicine. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd.)

Background: For most patients with acute myeloid leukemia (AML) harboring a trisomy 8 an allogeneic hematopoietic stem cell transplantation (HSCT) is a suitable and recommended consolidation therapy. However, comparative outcome analyses between patients with and without trisomy 8 undergoing allogeneic HSCT have not been performed so far., Methods: We retrospectively analyzed clinical features, outcomes, and measurable residual disease (MRD) of 659 AML (12%, n = 81, with a trisomy 8) patients subjected to allogeneic HSCT as a consolidation therapy., Results: The presence of a trisomy 8 associated with a trend for higher age at diagnosis, AML of secondary origin, lower white blood cell counts at diagnosis, worse ELN2017 genetic risk, wild-type NPM1 , and mutated IDH1/2 and JAK2 . Outcomes after allogeneic HSCT in the entire cohort did not differ between patients with a sole trisomy 8, trisomy 8 with additional cytogenetic aberrations or without a trisomy 8. A trisomy 8 did not affect outcomes within the three ELN2017 risk groups. In accordance with findings in unselected patient cohorts, persistent MRD at allogeneic HSCT in patients with a trisomy 8 identified individuals with a higher risk of relapse following allogeneic HSCT., Conclusions: Outcomes of trisomy 8 patients after allogeneic HSCT did not compare unfavorably to that of other AML patients following allogeneic HSCT. Rather than the presence or absence of a trisomy 8, additional genetic aberrations and MRD at HSCT define outcome differences and aid in informed treatment decisions.

Objective: Anthroposophic painting therapy (APT) is a specific form of art therapy that aims to activate self-healing capacities through painting aquarelles., Methods: The Anthroposophic Art Therapy Assessment-Paint' (AART-ASSESS-P) was developed to measure pictorial expression and validated in the framework of a comprehensive cohort design study. The validation study examined 68 breast cancer patients with fatigue. Art therapists made pre- and post-assessments of spontaneously drawn water-color paintings with a preliminary version of the AART-ASSESS-P (58 items). Inter-rater reliability (IRR) for the items was examined with Cohen's weighted Kappa (κw). Additionally, a reliability- and factor analysis (FA) were conducted. Convergence criteria were patients' self-report measures: the Satisfaction with Painting Therapy, Inner Correspondence with Painting Therapy and the Self-Regulation Questionnaire., Results: IRR for the items was heterogeneous (κ w = 0.09-0.89, Mean κ w = 0.40, SD = 0.17). Thirty-six items were excluded due to insufficient IRR and item-total correlation (κ w = < 0.30, ρ item-total < 0.30). A FA with 22 items revealed 5 subscales: Shape Development (6 items), Shape Arrangement (6 items), Order and Symmetry (5 items), Color Application (3 items), and Color Quality (2 items) explaining 61% of total variance. Psychometric properties for the AART-ASSESS-P were satisfying with Cronbach's alpha coefficients (r α  = 0.60-0.81) across subscales. Due to weak inter-subscale correlations (r = 0.18-0.48, p < 0.05) and the ambiguity of face validity a sum-score was not formed. Correlations between subscales and self-reports were small (all p < 0.05)., Conclusion: The AART-ASSESS-P is the first reliable instrument to measure pictorial expression during APT., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The SRSF2 mutations are frequently found in acute myeloid leukemia (AML) and mostly affect the P95 residue. Mutations in this splicing factor mediate abnormal splicing associated with exon skipping events, including EZH2 as a crucial target. While SRSF2 mutations are enriched in secondary AML and associated with worse outcomes following chemotherapy consolidation, very little is known about the associated biological and clinical implications in AML patients consolidated with allogeneic hematopoietic stemcell transplantation (HSCT). Here we retrospectively analyzed 263 adult AML patients who received an allogeneic HSCT regarding the biological and clinical implications of the SRSF2 mutation status at diagnosis and in morphologic remission at HSCT. We found 12.5% of the patients to be SRSF2 mutated at diagnosis. Mutated patients had increased EZH2 missplicing events with P95H likely driving this pathobiology most effectively. However, the amount of EZH2 missplicing events, as a functional surrogate marker did not associate with relevant biological or clinical characteristics. We observed a persistence of mutations in remission before HSCT in the majority (93%) of SRSF2 mutated AML patients. Importantly, the variant allele frequency (VAF) levels of SRSF2 mutations in remission at HSCT did not correlate with outcomes following HSCT consolidation, limiting the applicability of SRSF2 mutations as a marker for residual AML disease. Following allogeneic HSCT SRSF2 mutated AML patients experienced a 2-year overall survival of 77%, indicating that SRSF2 mutated AML patients may benefit from HSCT consolidation., (© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Animal manure can be a source of antibiotic-resistant genes (ARGs) and pharmaceutical residues; however, few studies have evaluated the presence of ARG in pasture-raised animal production systems. The objective of this study was to examine changes in microbiome diversity and the presence of antibiotic residues (ABRs) on three farms that contained a diverse range of animal species: pasture-raised poultry (broiler and layer), swine, and beef cattle. Total bacterial communities were determined using 16S rRNA microbiome analysis, while specific ARGs (sulfonamide [Sul; Sul1] and tetracycline [Tet; TetA]) were enumerated by qPCR (real-time PCR). Results indicated that the ARG abundances (Sul1 [P < 0.05] and TetA [P < 0.001]) were higher in layer hen manures (16.5 × 10-4 and 1.4 × 10-4 µg kg-1, respectively) followed by broiler chickens (2.9 × 10-4 and 1.7 × 10-4 µg kg-1, respectively), swine (0.22 × 10-4 and 0.20 × 10-4 µg kg-1, respectively) and beef cattle (0.19 × 10-4 and 0.02 × 10-4 µg kg-1, respectively). Average fecal TetA ABR tended to be greater (P = 0.09) for broiler chickens (11.4 µg kg-1) than for other animal species (1.8 to 0.06 µg kg-1), while chlortetracycline, lincomycin, and oxytetracycline ABRs were similar among animal species. Furthermore, fecal microbial richness and abundances differed significantly (P < 0.01) both among farms and specific species of animal. This study indicated that the microbial diversity, ABR, ARG concentrations, and types in feces varied from farm-to-farm and from animal species-to-animal species. Future studies are necessary to perform detailed investigations of the horizontal transfer mechanism of antibiotic-resistant microorganisms (ARMs) and ARG., (Published by Oxford University Press on behalf of the American Society of Animal Science 2021.)

Secondary or therapy-related acute myeloid leukemia (s/tAML) differs biologically from de novo disease. In general s/tAML patients have inferior outcomes after chemotherapy, compared to de novo cases and often receive allogeneic stem cell transplantation (HSCT) for consolidation. The European LeukemiaNet (ELN) risk stratification system is commonly applied in AML but the clinical significance is unknown in s/tAML. We analyzed 644 s/tAML or de novo AML patients receiving HSCT. s/tAML associated with older age and adverse risk, including higher ELN risk. Overall, s/tAML patients had similar cumulative incidence of relapse (CIR), but higher non-relapse mortality (NRM) and shorter overall survival (OS). In multivariate analyses, after adjustment for ELN risk and pre-HSCT measurable residual disease status, disease origin did not impact outcomes. Within the ELN favorable risk group, CIR was higher in s/tAML compared to de novo AML patients likely due to a different distribution of genetic aberrations, which did not translate into shorter OS. Within the ELN intermediate and adverse group outcomes were similar in de novo and s/tAML patients. Thus, not all s/tAML have a dismal prognosis and outcomes of s/tAML after allogeneic HSCT in remission are comparable to de novo patients when considering ELN risk.

The nutritional status at diagnosis, as well as weight loss during chemotherapy, are important factors for morbidity and mortality in cancer patients. They might also influence outcomes in patients with acute myeloid leukemia (AML) receiving allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the body mass index (BMI) at diagnosis, prior to HSCT, and the BMI difference (ΔBMI = BMI HSCT -BMI diagnosis ) in 662 AML patients undergoing allogeneic HSCT. Patients being obese at AML diagnosis had significantly higher nonrelapse mortality (NRM) and shorter overall survival (OS) after HSCT, but no distinct cumulative incidence of relapse than nonobese patients. Weight loss during chemotherapy (ΔBMI > -2) was a strong predictor for higher NRM and shorter OS in univariate and multivariate analyses. These results were observed across all European LeukemiaNet (ELN) 2017 risk groups but especially in patients with favorable or intermediate ELN2017 risk and patients transplanted in morphologic complete remission. Only in patients being obese at AML diagnosis, weight loss did not result in adverse outcomes. ΔBMI > -2 represents a strong, independent, and modifiable risk factor for AML patients treated with HSCT. Nutritional monitoring and supplementation during disease course might improve patients' outcomes., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Magnesium and zinc ions play various key roles in the human body, being involved, among others, in skeletal development and wound healing. Zinc is also known to have antimicrobial properties. While low concentrations can stimulate cells in vitro, high concentrations of magnesium or zinc introduced into bioactive glasses significantly reduce glass degradation and ion release and inhibit apatite precipitation. On the other hand, magnesium and zinc ions improve the high temperature processing of bioactive glasses, even when present at low concentrations only. Results here show that by substituting small amounts of Mg or Zn for Ca, ion release remains high enough to allow for apatite precipitation. In addition, magnesium and zinc containing bioactive glasses are shown to be very susceptible to changes in particle size and relative surface area. For a given magnesium or zinc content in the glass, ion release and apatite formation can be enhanced dramatically by reducing the particle size, reaching comparable levels as Bioglass 45S5 of the same particle size range. Taken together, these findings suggest that when introducing these ions into bioactive glasses, ideally low Mg or Zn for Ca substitution as well as small particle sizes are used. This way, bioactive glasses combining good high temperature processing with fast ion release and apatite precipitation can be obtained, providing the potential additional benefit of releasing magnesium or zinc ions in therapeutic concentrations.

For most acute myeloid leukemia (AML) patients, an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of sustained remissions and long-term survival. At diagnosis, high expression of the AML-associated genes BAALC (brain and acute leukemia, cytoplasmic) and MN1 (meningioma-1) were repeatedly linked to inferior outcomes in patients consolidated with chemotherapy while data for patients receiving HSCT remain limited. Using clinically applicable digital droplet PCR assays, we analyzed the diagnostic BAALC/ABL1 and MN1/ABL1 copy numbers in 302 AML patients. High BAALC/ABL1 and MN1/ABL1 copy numbers associated with common adverse prognostic factors at diagnosis. However, while high diagnostic copy numbers of both genes associated with shorter event free survival (EFS) and overall survival (OS) in patients receiving chemotherapy, there was no prognostic impact in patients undergoing HSCT. Our data suggests that the adverse prognostic impact of high BAALC and MN1 expression are mitigated by allogeneic HSCT. But preHSCT BAALC/ABL1 and MN1/ABL1 assessed in remission prior to HSCT remained prognosticators for EFS and OS independent of the diagnostic expression status. Whether allogeneic HSCT may improve survival for AML patients with high diagnostic BAALC or MN1 expression should be investigated prospectively and may improve informed decisions towards individualized consolidation options in AML.

Methane gas from livestock production activities is a significant source of greenhouse gas (GHG) emissions which have been shown to influence climate change. New technologies offer a potential to manipulate the rumen biome through genetic selection reducing CH 4 production. Methane production may also be mitigated to varying degrees by various dietary intervention strategies. Strategies to reduce GHG emissions need to be developed which increase ruminant production efficiency whereas reducing production of CH 4 from cattle, sheep, and goats. Methane emissions may be efficiently mitigated by manipulation of natural ruminal microbiota with various dietary interventions and animal production efficiency improved. Although some CH 4 abatement strategies have shown efficacy in vivo, more research is required to make any of these approaches pertinent to modern animal production systems. The objective of this review is to explain how anti-methanogenic compounds (e.g., plant tannins) affect ruminal microbiota, reduce CH 4 emission, and the effects on host responses. Thus, this review provides information relevant to understanding the impact of tannins on methanogenesis, which may provide a cost-effective means to reduce enteric CH 4 production and the influence of ruminant animals on global GHG emissions., (© 2020 Chinese Association of Animal Science and Veterinary Medicine. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.mam.2020.100894. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Acute inflammation is a protective reaction by the immune system in response to invading pathogens or tissue damage. Ideally, the response should be localized, self-limited, and returning to homeostasis. If not resolved, acute inflammation can result in organ pathologies leading to chronic inflammatory phenotypes. Acute inflammation and inflammation resolution are complex coordinated processes, involving a number of cell types, interacting in space and time. The biomolecular complexity and the fact that several biomedical fields are involved, make a multi- and interdisciplinary approach necessary. The Atlas of Inflammation Resolution (AIR) is a web-based resource capturing an essential part of the state-of-the-art in acute inflammation and inflammation resolution research. The AIR provides an interface for users to search thousands of interactions, arranged in inter-connected multi-layers of process diagrams, covering a wide range of clinically relevant phenotypes. By mapping experimental data onto the AIR, it can be used to elucidate drug action as well as molecular mechanisms underlying different disease phenotypes. For the visualization and exploration of information, the AIR uses the Minerva platform, which is a well-established tool for the presentation of disease maps. The molecular details of the AIR are encoded using international standards. The AIR was created as a freely accessible resource, supporting research and education in the fields of acute inflammation and inflammation resolution. The AIR connects research communities, facilitates clinical decision making, and supports research scientists in the formulation and validation of hypotheses. The AIR is accessible through https://air.bio.informatik.uni-rostock.de., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Hematopoietic stem cell transplantation is successfully applied since the late 1950s; however, its efficacy still needs to be increased. A promising strategy is to transplant high numbers of pluripotent hematopoietic stem cells (HSCs). Therefore, an improved ex vivo culture system that supports proliferation and maintains HSC pluripotency would override possible limitations in cell numbers gained from donors. To model the natural HSC niche in vitro, we optimized the HSC medium composition with a panel of cytokines and valproic acid and used an artificial 3D bone marrow-like scaffold made of polydimethylsiloxane (PDMS). This 3D scaffold offered a suitable platform to amplify human HSCs in vitro and, simultaneously, to support their viability, multipotency and ability for self-renewal. Silicon oxide-covering of PDMS structures further improved amplification of CD34+ cells, although the conservation of naïve HSCs was better on non-covered 3D PDMS. Finally, we found that HSC cultivated on non-covered 3D PDMS generated most pluripotent colonies within colony forming unit assays. In conclusion, by combining biological and biotechnological approaches, we optimized in vitro HSCs culture conditions, resulting in improved amplification, multipotency maintenance and vitality of HSCs., Competing Interests: The authors have declared that no competing interests exist.

Objective: This work focuses on the influence of poly(acrylic acid) (PAA) architecture (linear or branched) on setting behavior and compressive strength of glass ionomer cements (GICs)., Methods: Branched and linear poly(acrylic acid)s were synthesized according to the Strathclyde methodology or by free radical polymerization. They were characterized by 1 H-NMR spectroscopy and size exclusion chromatography to determine their molecular weight and size distribution. GIC setting was characterized by oscillating rheometry and time-dependent FTIR spectroscopy. In addition, compressive strength was tested on cylindrical samples (6 × 4 mm; n = 8/cement composition) after storage in deionized water at 37 °C for one day., Results: We used two different routes to prepare PAA. One direct route in order to provide straightforward access to branched PAA and a two-step approach in order to get more control about the PAA molecular weight using tert-butyl acrylate (tBA) for polymerization with subsequent deprotection. Using the second approach we obtained several linear PAA of which a mixture was used in order to mimic the molecular weight and size distribution of branched PAA. This allowed the direct comparison of properties relying only on the polymer architecture. Comparing linear PAA to branched samples in general led to faster setting but at the same time decreased the compressive strength. Increasing molecular weight of branched PAA resulted in even faster GIC setting while increasing compressive strength and this correlates well with the trends reported for linear PAA in literature. Mixing of branched and linear PAA, however, turned out to be an effective way of tailoring GIC properties., Significance: our results suggest that both molecular weight and dispersity need to be considered when choosing suitable PAA architecture for obtaining specific GIC properties., (Copyright © 2020 The Academy of Dental Materials. Published by Elsevier Inc. All rights reserved.)

The goal of this pilot study was to track patient outcomes after an expedited discharge after enhanced recovery after surgery (ERAS) pathway for pancreaticoduodenectomy (PD). A quantitative content analysis approach was used. All PD patients in a single academic medical center between February 2017 and June 2018 were called twice by specialized physician extenders after discharge. A semi-structured interview approach was used to identify patient's symptoms or concerns, proactively educate them, and provide outpatient management when indicated. A detailed narrative of the conversation was documented. Ninety patients (mean age 66.3; 58.1% males) were included in the study. Of all, 88.9 per cent of the patients received follow-up phone calls in accordance with our PD ERAS protocol. Among the 80 patients called, 71 (88.8%) reported at least one symptom, issue, or self-care need. The most common issues involved bowel movements and nutrition. A total of 147 interventions were performed to address patient needs including medication management, local care coordination, and outpatient referral to a healthcare provider. The intervention led to the identification of 15 patients for earlier evaluation. This identification was associated with the total number of reported symptoms ( X ² = 15.6, P = 0.004). Most patients require additional care after discharge after traditional ERAS pathways. ERAS transitional care protocols uncovered an unmet need for additional patient support after PD.

Two sets of in vitro rumen fermentation experiments were conducted to determine effects of diets that included wet distiller's grains plus solubles (WDGS) and tannin-rich peanut skin (PS) on the in vitro digestibility, greenhouse gas (GHG) and other gas emissions, fermentation rate, and microbial changes. The objectives were to assess associative effects of various levels of PS or WDGS on the in vitro digestibility, GHG and other gas emissions, fermentation rate, and microbial changes in the rumen. All gases were collected using an ANKOM Gas Production system for methane (CH4), carbon dioxide (CO2), nitrous oxide (N2O), and hydrogen sulfide (H2S) analyses. Cumulative ruminal gas production was determined using 250 mL ANKOM sampling bottles containing 50 mL of ruminal fluid (pH 5.8), 40 mL of artificial saliva (pH 6.8), and 6 g of mixed diets after a maximum of 24 h of incubation. Fermenters were flushed with CO2 gas and held at 39 °C in a shaking incubator for 24 h. Triplicate quantitative real-time polymerase chain reaction (qPCR) analyses were conducted to determine microbial diversity. When WDGS was supplied in the diet, in the absence of PS, cumulative CH4 production increased (P < 0.05) with 40% WDGS. In the presence of PS, production of CH4 was reduced but the reduction was less at 40% WDGS. In the presence of PS, ruminal lactate, succinate, and acetate/propionate (A/P) ratio tended to be less with a WDGS interaction (P < 0.01). In the presence of PS and with 40% WDGS, average populations of Bacteroidetes, total methanogens, Methanobrevibacter sp. AbM4, and total protozoa were less. The population of total methanogens (R2 = 0.57; P < 0.01), Firmicutes (R2 = 0.46: P < 0.05), and Firmicutes/Bacteroidetes (F/B) ratio (R2 = 0.46; P < 0.03) were strongly correlated with ruminal CH4 production. Therefore, there was an associative effect of tannin-rich PS and WDGS, which suppressed methanogenesis both directly and indirectly by modifying populations of ruminal methanogens., (Published by Oxford University Press on behalf of the American Society of Animal Science 2019.)

Low temperature cofired ceramics (LTCC) provide a technology for the 3-dimensional integration of sensor arrays into bioreactors covering dimensions of several hundred micrometers. Since optical control in such assemblies is not possible, the in situ detection of cell adhesion on impedance electrodes with high spatial resolution would deliver crucial information. A current limitation is the increasing impedance of microelectrodes with decreasing diameter. This study evaluates the suitability of thick film gold electrodes, pristine and coated with electropolymerized poly(3,4-ethylenedioxythiophene) (PEDOT), for the detection of cell adhesion on the electrode surface. The impedance as criterion for cell attachment is measured with a recording system for electroactive cells with the aim of improving usability. Two cell cultures with different adhesion characteristic are used for adhesion assessment on planar test chips. The impedance increase measured on individual PEDOT coated electrodes due to tight contact of cells reaches a factor of 6.8 in cultures of well-adherent HepG2 cells. Less adhered NG108-15 cells produce a maximum impedance increase by a factor of 2.6. Since the electrode impedance is significantly reduced by PEDOT coating, a reduction of the electrode diameter to values below 100 µm and spatially resolved detection is possible. The results encourage further studies using PEDOT coated thick film electrodes as bio-electronic-interfaces. We presume that such miniaturized electrodes are suitable for 3-dimensional recordings in electroactive cell cultures, providing information of local cell adhesion at the same time.

Background: Aspirin is a well-established therapy for the secondary prevention of cardiovascular events. However, its role in the primary prevention of cardiovascular disease is unclear, especially in older persons, who have an increased risk., Methods: From 2010 through 2014, we enrolled community-dwelling men and women in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia, or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo. The primary end point was a composite of death, dementia, or persistent physical disability; results for this end point are reported in another article in the Journal. Secondary end points included major hemorrhage and cardiovascular disease (defined as fatal coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal stroke, or hospitalization for heart failure)., Results: Of the 19,114 persons who were enrolled in the trial, 9525 were assigned to receive aspirin and 9589 to receive placebo. After a median of 4.7 years of follow-up, the rate of cardiovascular disease was 10.7 events per 1000 person-years in the aspirin group and 11.3 events per 1000 person-years in the placebo group (hazard ratio, 0.95; 95% confidence interval [CI], 0.83 to 1.08). The rate of major hemorrhage was 8.6 events per 1000 person-years and 6.2 events per 1000 person-years, respectively (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001)., Conclusions: The use of low-dose aspirin as a primary prevention strategy in older adults resulted in a significantly higher risk of major hemorrhage and did not result in a significantly lower risk of cardiovascular disease than placebo. (Funded by the National Institute on Aging and others; ASPREE ClinicalTrials.gov number, NCT01038583 .).

Background: Aspirin-exacerbated respiratory disease (AERD) is characterized by chronic eosinophilic rhinosinusitis, nasal polyps, asthma, and respiratory sensitivity to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). In addition to sensitivity to aspirin and NSAIDs, the majority of patients with AERD have been reported to have respiratory intolerance associated with the consumption of alcohol., Methods: A multicenter prospective cohort study was performed. Patients with AERD confirmed by aspirin challenge were eligible to participate. Those who described themselves as able to tolerate alcohol consumption were excluded. Patients underwent aspirin desensitization following endoscopic sinus surgery. A questionnaire was distributed to patients before and after desensitization to determine pre-desensitization and post-desensitization symptoms associated with alcohol ingestion., Results: Forty-five patients were enrolled and 37 patients completed the study. The most common pre-desensitization symptoms were nasal congestion (95.6%), rhinorrhea (46.7%), and wheezing (40%). Improvement in the ability to tolerate alcohol was noted in 86.5% of participants (95% confidence interval [CI], 75.5% to 97.5%) and 70.3% of participants (95% CI, 55.5% to 85.0%) described desensitization to be "very helpful" or "extremely helpful" for their ability to tolerate alcohol., Conclusion: The majority of patients with AERD who experience respiratory symptoms with alcohol consumption describe improvement in this domain following aspirin desensitization., (© 2018 ARS-AAOA, LLC.)

Micrometer-scale biochemical or topographical patterning is commonly used to guide the cell attachment and growth, but the ability to combine these patterns into an integrated surface with defined chemical and geometrical characteristics still remains a technical challenge. Here, we present a technical solution for simultaneous construction of 3D morphologies, in the form of channels, on porous membranes along with precise transfer of extracellular matrix proteins into the channels to create patterns with geometrically restricting features. By combining the advantages of microthermoforming and microcontact printing, this technique offers a unique patterning process that provides spatiotemporal control over morphological and chemical feature in a single step. By use of our 3D-microcontact printing (3DμCP), determined microstructures like channels with different depths and widths even with more complex patterns can be fabricated. Collagen, fibronectin, and laminin were successfully transferred inside the predesigned geometries, and the validity of the process was confirmed by antibody staining. Cells cultivated on 3DμCP patterned polycarbonate membrane have shown selective adhesion and growth. This technique offers a novel tool for creating freeform combinatorial patterning on the thermoformable surface.

Nutrient management on US dairy farms must balance an array of priorities, some of which conflict. To illustrate nutrient management challenges and opportunities across the US dairy industry, the USDA Agricultural Research Service Dairy Agroecosystems Working Group (DAWG) modeled 8 confinement and 2 grazing operations in the 7 largest US dairy-producing states using the Integrated Farm System Model (IFSM). Opportunities existed across all of the dairies studied to increase on-farm feed production and lower purchased feed bills, most notably on large dairies (>1,000 cows) with the highest herd densities. Purchased feed accounted for 18 to 44% of large dairies' total operating costs compared with 7 to 14% on small dairies (<300 milk cows) due to lower stocking rates. For dairies with larger land bases, in addition to a reduction in environmental impact, financial incentives exist to promote prudent nutrient management practices by substituting manure nutrients or legume nutrients for purchased fertilizers. Environmental priorities varied regionally and were principally tied to facility management for dry-lot dairies of the semi-arid western United States (ammonia-N emissions), to manure handling and application for humid midwestern and eastern US dairies (nitrate-N leaching and P runoff), and pasture management for dairies with significant grazing components (nitrous oxide emissions). Many of the nutrient management challenges identified by DAWG are beyond slight modifications in management and require coordinated solutions to ensure an environmentally and economically sustainable US dairy industry., (The Authors. Published by FASS Inc. and Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).)

Background: Respiratory muscle weakness contributes to exercise intolerance in patients with heart failure with a preserved ejection fraction (HFpEF)-a condition characterized by multiple comorbidities with few proven treatments. We aimed, therefore, to provide novel insight into the underlying diaphragmatic alterations that occur in HFpEF by using an obese cardiometabolic rat model and further assessed whether exercise training performed only after the development of overt HFpEF could reverse impairments., Methods and Results: Obese ZSF1 rats (n=12) were compared with their lean controls (n=8) at 20 weeks, with 3 additional groups of obese ZSF1 rats compared at 28 weeks following 8 weeks of either sedentary behavior (n=13), high-intensity interval training (n=11), or moderate-continuous training (n=11). Obese rats developed an obvious HFpEF phenotype at 20 and 28 weeks. In the diaphragm at 20 weeks, HFpEF induced a shift towards an oxidative phenotype and a fiber hypertrophy paralleled by a lower protein expression in MuRF1 and MuRF2, yet mitochondrial and contractile functional impairments were observed. At 28 weeks, neither the exercise training regimen of high-intensity interval training or moderate-continuous training reversed any of the diaphragm alterations induced by HFpEF., Conclusions: This study, using a well-characterized rat model of HFpEF underpinned by multiple comorbidities and exercise intolerance (ie, one that closely resembles the patient phenotype), provides evidence that diaphragm alterations and dysfunction induced in overt HFpEF are not reversed following 8 weeks of aerobic exercise training. As such, whether alternative therapeutic interventions are required to treat respiratory muscle weakness in HFpEF warrants further investigation., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

The aim of this study was to evaluate the degradation of completely demineralized dentin specimens in contact with a filler-free or 2 ion-releasing resins containing micrometer-sized particles of Bioglass 45S5 (BAG) or fluoride-containing phosphate-rich bioactive glass (BAG-F). Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) were also used to evaluate the remineralization induced by the experimental ion-releasing resin-based materials. Dentin beams were totally demineralized in H 3 PO 4 (10%) and placed in direct contact with a filler-free (RESIN) or 2 experimental ion-releasing resins (BAG or BAG-F) and immersed in artificial saliva (AS) up to 30 d. Further specimens were also processed and submitted to FTIR and SEM analysis to evaluate the remineralization induced by such ion-releasing resins before and after AS immersion. BAG and BAG-F alkalinized the incubation media. A significant decrease of the dry mass was observed between the specimens of all groups stored for 3 and 30 d in AS. However, the fluoride-containing phosphate-rich bioactive glass incorporated into a resin-based material (BAG-F) showed greater ability in reducing the solubilization of C-terminal cross-linked telopeptide (ICTP) and C-terminal telopeptide (CTX) after prolonged AS storage. Moreover, after 30 d of AS storage, BAG-F showed the greatest remineralizing effect on the stiffness of the completely demineralized dentin matrices. In conclusion, fluoride-containing phosphate-rich bioactive glass incorporated as micrometer-sized filler in dental composites may offer greater beneficial effects than Bioglass 45S5 in reducing the enzyme-mediated degradation and remineralization of demineralized dentin.

High grazing pressure can lead to soil erosion in pastures, causing increased sediment delivery to waterways. The objectives of this research were to evaluate the impact of grazing management and buffer strips on soil erosion by assessing soil physical properties, hydrology, and sediment loads from pastures fertilized with broiler litter. Field studies were conducted for 12 yr on 15 small watersheds. Five management strategies were evaluated: hayed (H), continuously grazed (CG), rotationally grazed (R), rotationally grazed with a buffer strip (RB), and rotationally grazed with a fenced riparian buffer (RBR). Broiler litter was applied every year at a rate of 5.6 Mg ha. Bulk density and penetration resistance were highest for CG watersheds. Runoff volumes, sediment concentrations, and loads were lowest for the H and RBR treatments and highest for CG. Average runoff amounts were 48, 84, 77, 60, and 81 mm yr for the H, R, RB, RBR, and CG treatments, respectively. Annual average sediment loads were 25, 30, 58, 71, and 110 kg ha for H, RBR, R, RB, and CG, respectively. The Revised Universal Soil Loss Equation, Version 2 was reasonably effective at predicting soil loss for the R, RB, and RBR treatments, but it greatly overpredicted soil loss from the CG and H treatments. Converting a pasture to a hay field or using rotational grazing in conjunction with a fenced riparian buffer appear to be effective options for reducing soil erosion and runoff to waterways from pasture soils., (Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.)

This brief report summarizes the process used by the University of Vermont to obtain transgender-inclusive health insurance coverage from their insurer, and the subsequent positive changes in Vermont state law regarding transgender health insurance coverage. The role of universities as change agents and applicability of this process to other universities are briefly discussed.

Bioactive glasses (BG) are suitable for bone regeneration applications as they bond with bone and can be tailored to release therapeutic ions. Fluoride, which is widely recognized to prevent dental caries, is efficacious in promoting bone formation and preventing osteoporosis-related fractures when administered at appropriate doses. To take advantage of these properties, we created BG incorporating increasing levels of fluoride whilst holding their silicate structure constant, and tested their effects on human osteoblasts in vitro. Our results demonstrate that, whilst cell proliferation was highest on low-fluoride-containing BG, markers for differentiation and mineralization were highest on BG with the highest fluoride contents, a likely effect of a combination of surface effects and ion release. Furthermore, osteoblasts exposed to the dissolution products of fluoride-containing BG or early doses of sodium fluoride showed increased alkaline phosphatase activity, a marker for bone mineralization, suggesting that fluoride can direct osteoblast differentiation. Taken together, these results suggest that BG that can release therapeutic levels of fluoride may find use in a range of bone regeneration applications., (Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Investigations of humans with disorders of sex development (DSDs) resulted in the discovery of many of the now-known mammalian sex-determining genes, including SRY, RSPO1, SOX9, NR5A1, WT1, NR0B1, and WNT4. Here, the locus for an autosomal sex-determining gene was mapped via linkage analysis in two families with 46,XY DSD to the long arm of chromosome 5 with a combined, multipoint parametric LOD score of 6.21. A splice-acceptor mutation (c.634-8T>A) in MAP3K1 segregated with the phenotype in the first family and disrupted RNA splicing. Mutations were demonstrated in the second family (p.Gly616Arg) and in two of 11 sporadic cases (p.Leu189Pro, p.Leu189Arg)-18% prevalence in this cohort of sporadic cases. In cultured primary lymphoblastoid cells from family 1 and the two sporadic cases, these mutations altered the phosphorylation of the downstream targets, p38 and ERK1/2, and enhanced binding of RHOA to the MAP3K1 complex. Map3k1 within the syntenic region was expressed in the embryonic mouse gonad prior to, and after, sex determination. Thus, mutations in MAP3K1 that result in 46,XY DSD with partial or complete gonadal dysgenesis implicate this pathway in normal human sex determination., (Copyright © 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Shiitake mushrooms have a reputation as a healthy food. Growers may be able to use the presence of health-promoting constituents as a marketing tool to promote sales of their products for premium prices. There are few reports on the effects of management protocols for log-grown shiitakes on the concentrations of constituents to guide growers. This paper summarizes several studies that examined the effects of shiitake strains, mushroom cap development, and length of saprophytic association on the concentrations of a high molecular weight polysaccharide fraction that includes lentinan (HMWP). Concentrations of HMWP in mushrooms varied as much as 8-fold during fruiting among the 12 strains tested in these studies. Results also indicate that the concentrations of HMWP in shiitake mushrooms are influenced by the fungal phenotype and the characteristics of the environment. General trends showed that (1) mushrooms harvested at more immature stages of development (during bud break or before veil break) tended to have higher concentrations of HMWP and (2) the initial harvests of mushrooms from an inoculated log tend to have higher concentrations of HMWP than subsequent harvests. Results suggest that growers interested in maximizing the HMWP content of their mushrooms should use shiitake strains NN-430 and 569-430.

Nonsyndromic orofacial clefts are a common complex birth defect caused by genetic and environmental factors and/or their interactions. A previous genome-wide linkage scan discovered a novel locus for cleft lip with or without cleft palate (CL/P) at 9q22-q33. To identify the etiologic gene, we undertook an iterative and complementary fine mapping strategy using family-based CL/P samples from Colombia, USA and the Philippines. Candidate genes within 9q22-q33 were sequenced, revealing 32 new variants. Concurrently, 397 SNPs spanning the 9q22-q33 2-LOD-unit interval were tested for association. Significant SNP and haplotype association signals (P = 1.45E - 08) narrowed the interval to a 200 kb region containing: FOXE1, C9ORF156 and HEMGN. Association results were replicated in CL/P families of European descent and when all populations were combined the two most associated SNPs, rs3758249 (P = 5.01E - 13) and rs4460498 (P = 6.51E - 12), were located inside a 70 kb high linkage disequilibrium block containing FOXE1. Association signals for Caucasians and Asians clustered 5' and 3' of FOXE1, respectively. Isolated cleft palate (CP) was also associated, indicating that FOXE1 plays a role in two phenotypes thought to be genetically distinct. Foxe1 expression was found in the epithelium undergoing fusion between the medial nasal and maxillary processes. Mutation screens of FOXE1 identified two family-specific missense mutations at highly conserved amino acids. These data indicate that FOXE1 is a major gene for CL/P and provides new insights for improved counseling and genetic interaction studies.

Applications of manures to agricultural fields have increased soil test values for P to high levels in parts of the USA and thus increased the likelihood that P will be transported to surface water and degrade its quality. Waste paper applications to soils with high STP (soil test P) may decrease the risk of P transport to surface water by decreasing DRP (dissolved reactive P) by the formation of insoluble Al-P complexes and providing organic matter to improve infiltration. A field experiment was conducted near Booneville, AR (USA) to assess the effects of different rates of a waste paper product addition on STP, soil bulk density, and total soil C with a soil with approximately 45 mg Bray1-P kg-1 soil (dry weight). A Leadvale silt loam soil (fine-silty, siliceous, thermic Typic Fragiudult) was amended with 0, 22, 44, or 88 Mg waste paper product ha-1 to supply approximately 90, 170, or 350 kg Al ha-1, respectively. One year after additions, there was a strong negative correlation between waste paper product application rates and soil bulk density, and a strong positive correlation between rates and total soil C content. Soil bulk density and total C 2 yr after additions, and soil DRP and Bray1-P were not affected by waste paper additions. These results support the hypothesis that decreases in DRP in runoff from soils receiving waste paper additions were probably due to changes in soil organic matter and bulk density, rather than changes in the chemical forms of soil P.

Background: General health-related questionnaires on quality of life do not satisfactorily distinguish between healthy and sick people. One of the reasons cited for this lack is too much mental influence. This is why we developed a questionnaire on endogenous regulation (eR) that reflects the regulatory state of various vegetative functions., Objective: The current study examines whether the short version eR questionnaire is able to distinguish between healthy people and internal medicine patients., Patients and Methods: 408 participants were included in the study (284 females, 124 males). Among these were patients with colorectal cancer (n = 49), breast cancer (n = 95), diabetes mellitus (type 1: n = 20, type 2: n = 40), coronary disease (n = 39), rheumatoid illnesses (n = 28) and multimorbid patients (n = 22) as well as a healthy control group (n = 115). In addition to the eR questionnaire the study also used the Hospital Anxiety and Depression Scale (HADS), the short questionnaire on self-regulation and questions on the vegetative status., Results: The healthy control group showed the highest eR, with an estimated average of M = 29.8. Patients with breast cancer, diabetes mellitus type 2, coronary disease and rheumatoid illnesses reveal a significantly lowered eR. Multimorbid patients show the lowest eR. Patients with cancer of the colon and diabetes type 1 were measured at M = 27.9 and M = 27.3 respectively and showed no significantly lowered estimated average compared to the control group. A high eR significantly correlates (p < 0.002) with the following parameters: low levels of anxiety (r = 49) and depression (r = 0.36), high self-regulation (r = 0.34), morning type (r = 0.40), less congestive perspiration (r = 0.38), less shivering (r = 0.23), dysmenorrhoea (r = 0.38) and allergies (r = 0.17)., Conclusion: Healthy people show the highest, multimorbid patients the lowest eR. Consistent relations to health, illness, heat regulation and personality presence have been shown. Further studies to clarify clinical relevance are necessary.

The objective of the experiment was to determine the effectiveness of copper oxide wire particles (COWP) in pregnant ewes and safety to lambs. COWP have been used recently as an anthelmintic in small ruminants to overcome problems associated with nematode resistance to chemical dewormers. Doses of COWP (