Molecular basis of GDF15 induction and suppression by drugs in cardiomyocytes and cancer cells toward precision medicine.

GDF15 has recently emerged as a key driver of the development of various disease conditions including cancer cachexia. Not only the tumor itself but also adverse effects of chemotherapy have been reported to contribute to increased GDF15. Although regulation of GDF15 transcription by BET domain has recently been reported, the molecular mechanisms of GDF15 gene regulation by drugs are still unknown, leaving uncertainty about the safe and effective therapeutic strategies targeting GDF15. We screened various cardiotoxic drugs and BET inhibitors for their effects on GDF15 regulation in human cardiomyocytes and cancer cell lines and analyzed in-house and public gene signature databases. We found that DNA damaging drugs induce GDF15 in cardiomyocytes more strongly than drugs with other modes of action. In cancer cells, GDF15 induction varied depending on drug- and cell type-specific gene signatures including mutations in PI3KCA, TP53, BRAF and MUC16. GDF15 suppression by BET inhibition is particularly effective in cancer cells with low activity of the PI3K/Akt axis and high extracellular concentrations of pantothenate. Our findings provide insights that the risk for GDF15 overexpression and concomitant cachexia can be reduced by a personalized selection of anticancer drugs and patients for precision medicine.

Reclassification of Clostridium aurantibutyricum Hellinger 1944 and Clostridium roseum (ex McCoy and McClung 1935) Cato et al. 1988.

Clostridium aurantibutyricum, Clostridium felsineum and Clostridium roseum share a very high similarity based on multi-locus sequence analysis. In this study, their correct taxonomic status was determined using genomic and phenotypic investigations. Average nucleotide identity based on MUMmer alignment of the genomes and in silico DNA-DNA hybridization resulted in values of 98.55-100 and 78.7-100 %, respectively, strongly indicating that all strains are members of the same species. In addition, morphological investigations, fatty acid analyses and substrate utilization tests revealed no striking differences between the strains. Therefore, we propose the reclassification of C. aurantibutyricum and C. roseum as later heterotypic synonyms of C. felsineum. The type strain is lodged in several culture collections (ATCC 17788T=DSM 794T=NCIMB 10690T).

Therapeutic alliance in psychotherapy across online and face-to-face settings: A quantitative analysis.

Lockdown enacted by government in response to the Covid-19 pandemic in Austria forced psychotherapy practice into an online-only setting for several months in 2020. Although there is evidence supporting the effectiveness of psychotherapy in remote settings, research investigating therapeutic alliance in online psychotherapy is still limited, with a specific need for research in assessing possible effects of changes in therapeutic setting from face-to-face to online and vice versa. We measured therapeutic alliance in client-therapist dyads using the Helping Alliance Questionnaire (HAQ) at the Adult Outpatient Clinic of Sigmund Freud University, Vienna. Eighty-seven dyads completed HAQ twice, assessing three time-points: after switching from face-to-face to online therapy, providing a retrospective assessment of their alliance before the setting change as well as a concurrent account of their experience during online therapy, then another assessment after switching back to face-to-face setting after lockdown restrictions were lifted. Data were analysed by fitting a multilevel linear model, where the variables person (client/therapist) and time (before online therapy; online therapy; back to face-to-face) were nested within the client-therapist dyad. We found a statistically significant small improvement in the quality of therapeutic alliance over time, but no differences due to change in therapeutic setting. Separate analysis of HAQ sub-scales revealed that clients rated their relationship statistically significantly higher than their therapists with medium effect size, while there were no differences in success ratings over time and settings, nor between clients and therapists. The findings support the feasibility of online therapy in terms of therapeutic alliance in general, and alternating between face-to-face and online therapy settings in particular.

Heat Treatment Influencing Porosity and Tensile Properties of Field Assisted Sintered AlSi7Mg0.6.

In this study, an attempt was made to improve the mechanical properties and in particular the strength of a precipitation-hardenable aluminum alloy while still maintaining high ductility. For this purpose, AlSi7Mg0.6 (A357) powder with an average particle diameter of d50 = 40 µm was consolidated using field assisted sintering technique (FAST), and two material conditions were compared: an as-sintered and an underaging heat treated condition (T61). Mechanical properties were determined using tensile tests and hardness measurements. In addition, the microstructure was investigated by optical microscopy. Further, porosity and density were analyzed after the different heat treatments. By the underaging heat treatment, the surface hardness was increased by 100% and the yield strength was increased by 80% compared to the as-sintered material. However, the elongation to failure dropped to one third of that of the as-sintered material. Presumably, this effect was a result of an increased porosity due to the heat treatment. It is assumed that the observed pores were generated by artefacts from the FAST process used to manufacture the samples. The internal gas pressure and equilibrium diffusion supported by heat treatment temperature, and the reduction in surface energy caused by coalescent micropores, led to the enlargement of previously undetectable inhomogeneities in the as-sintered material that resulted in pores in the heat-treated sintered alloy.

"The Adjunct Faculty Are Our Lifeblood" An Institution's Response to Deliver Value to Volunteer Community Faculty.

BACKGROUND AND OBJECTIVES: Because of the importance of and increasing competition for unpaid community faculty's time, we qualitatively evaluated the adjunct community faculty experience in order to identify mechanisms to improve the recruitment, training, and retention of these faculty members. METHODS: The authors captured community faculty and key stakeholder opinion through interviews, focus groups, and a survey to elucidate their perspective of roles, responsibilities, facilitators, and barriers for providing quality teaching and learning experiences. After evaluating the data, we created an impact/effort matrix to guide suggested changes. RESULTS: Key medical education stakeholders reported adjunct community faculty members were critical to delivery of the medical school curriculum and shared methods and barriers for retaining members. Adjunct community faculty focus groups revealed two major themes: (1) personal experience and motivation, and (2) individual advantages and institutional barriers that influence being a faculty member. The survey and impact/effort matrix led to interventions including an Office of Community Faculty to implement recruitment and retention programs and provide more comprehensive oversight, a clinical scheduling hub, improved access to specialists for community faculty, and awards to recognize the critical contributions of community faculty members. CONCLUSIONS: As competition for community placements increases, including community faculty voices to inform action is an effective investment that enables an institution to direct resources towards interventions that maximize their support and engagement. Including community faculty perspectives also increases faculty's ability to participate in training the next generation of physicians.

Application Options of the Sustainable Child Development Index (SCDI)-Assessing the Status of Sustainable Development and Establishing Social Impact Pathways.

The needs of children and their vulnerability to diseases, violence and poverty are different from those of adults. The Sustainable Child Development Index (SCDI) was thus developed in previous work to evaluate the status of sustainable development for countries with a focus on children and triple-bottom-line thinking. This study proposes application options to put the SCDI into practice. The SCDI can be performed similarly to existing development indices, for comparing and tracing the performance of sustainable development on different geographic levels and between population groups. In addition, the SCDI can be integrated into existing social sustainability assessment approaches (e.g., Social Life Cycle Assessment and Social Organizational Life Cycle Assessment) and databases (e.g., The Social Hotspots Database) to take children into account and enhance impact assessment of social sustainability assessment approaches. As an exemplification, this study demonstrates the application of the SCDI framework to support the development of social impact pathways. Due to the importance of tertiary education in reducing poverty, a preliminary social impact pathway addressing completion of tertiary education was established. By putting the SCDI into practice, the SCDI can support decision making in child as well as sustainable development policies.

Biodiversity impact assessment (BIA+) - methodological framework for screening biodiversity.

For the past 20 years, the life cycle assessment (LCA) community has sought to integrate impacts on biodiversity into the LCA framework. However, existing impact assessment methods still fail to do so comprehensively because they quantify only a few impacts related to specific species and regions. This paper proposes a methodological framework that will allow LCA practitioners to assess currently missing impacts on biodiversity on a global scale. Building on existing models that seek to quantify the impacts of human activities on biodiversity, the herein proposed methodological framework consists of 2 components: a habitat factor for 14 major habitat types and the impact on the biodiversity status in those major habitat types. The habitat factor is calculated by means of indicators that characterize each habitat. The biodiversity status depends on parameters from impact categories. The impact functions, relating these different parameters to a given response in the biodiversity status, rely on expert judgments. To ensure the applicability for LCA practitioners, the components of the framework can be regionalized on a country scale for which LCA inventory data is more readily available. The weighting factors for the 14 major habitat types range from 0.63 to 1.82. By means of area weighting of the major habitat types in a country, country-specific weighting factors are calculated. In order to demonstrate the main part of the framework, examples of impact functions are given for the categories "freshwater eutrophication" and "freshwater ecotoxicity" in 1 major habitat type. The results confirm suitability of the methodological framework. The major advantages are the framework's user-friendliness, given that data can be used from LCA databases directly, and the complete inclusion of all levels of biodiversity (genetic, species, and ecosystem). It is applicable for the whole world and a wide range of impact categories. Integr Environ Assess Manag 2018;14:282-297. © 2017 SETAC.

Macular xanthophylls and ω-3 long-chain polyunsaturated fatty acids in age-related macular degeneration: a randomized trial.

IMPORTANCE: It has been shown that the functionality of the macula lutea depends on the nutritional uptake of lutein and zeaxanthin and that it is inversely associated with the risk of age-related macular degeneration (AMD). Additionally, ω-3 long-chain polyunsaturated fatty acids (LC-PUFAs) may also be protective. OBJECTIVE: To investigate the effect of a 12-month intervention with macular xanthophylls and ω-3 LC-PUFAs on xanthophylls and fatty acids in plasma, antioxidant capacity, and optical density of the macular pigment of patients with nonexudative AMD. DESIGN: The LUTEGA study was a randomized, double-blind, placebo-controlled, parallel clinical trial that was conducted for 12 months. SETTING: University Eye Hospital and Institute of Nutrition, Friedrich Schiller University Jena, Germany. PARTICIPANTS: A total of 172 individuals with nonexudative AMD. INTERVENTION: Individuals were enrolled and randomly divided as follows: placebo group, group 1 (a capsule containing 10 mg of lutein, 1 mg of zeaxanthin, 100 mg of docosahexaenoic acid, and 30 mg of eicosapentaenoic acid administered each day), and group 2 (same substances but twice the dose used in group 1). One hundred forty-five participants completed the study successfully. MAIN OUTCOME MEASURES: Plasma xanthophyll concentrations and fatty acid profiles, optical density of the macular pigment, and antioxidant capacity in plasma (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid [Trolox] equivalent antioxidant capacity and photochemiluminescence). RESULTS: The concentrations of the administered carotenoids in plasma as well as the optical density of the macular pigment increased significantly in the groups randomized to receive supplementary macular xanthophylls and ω-3 LC-PUFAs after 1 month of intervention and remained at this level through the end of the study. Use of the double dose resulted in a beneficial alteration of the fatty acid profile in the plasma of patients with AMD in comparison with the dose in group 1. The lipophilic antioxidant capacity in plasma was significantly elevated with the intervention. CONCLUSIONS AND RELEVANCE: A supplement containing a fixed combination of lutein, zeaxanthin, and ω-3 LC-PUFAs during 12 months significantly improved plasma antioxidant capacity, circulating macular xanthophyll levels, and the optical density of the macular pigment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00763659.