Transcriptome analysis by GeneTrail revealed regulation of functional categories in response to alterations of iron homeostasis in Arabidopsis thaliana

<p>Abstract</p> <p>Background</p> <p>High-throughput technologies have opened new avenues to study biological processes and pathways. The interpretation of the immense amount of data sets generated nowadays needs to be facilitated in order to enable biologists to identify complex gene networks and functional pathways. To cope with this task multiple computer-based programs have been developed. GeneTrail is a freely available online tool that screens comparative transcriptomic data for differentially regulated functional categories and biological pathways extracted from common data bases like KEGG, Gene Ontology (GO), TRANSPATH and TRANSFAC. Additionally, GeneTrail offers a feature that allows screening of individually defined biological categories that are relevant for the respective research topic.</p> <p>Results</p> <p>We have set up GeneTrail for the use of <it>Arabidopsis thaliana</it>. To test the functionality of this tool for plant analysis, we generated transcriptome data of root and leaf responses to Fe deficiency and the Arabidopsis metal homeostasis mutant <it>nas4x-1</it>. We performed Gene Set Enrichment Analysis (GSEA) with eight meaningful pairwise comparisons of transcriptome data sets. We were able to uncover several functional pathways including metal homeostasis that were affected in our experimental situations. Representation of the differentially regulated functional categories in Venn diagrams uncovered regulatory networks at the level of whole functional pathways. Over-Representation Analysis (ORA) of differentially regulated genes identified in pairwise comparisons revealed specific functional plant physiological categories as major targets upon Fe deficiency and in <it>nas4x-1</it>.</p> <p>Conclusion</p> <p>Here, we obtained supporting evidence, that the <it>nas4x-1 </it>mutant was defective in metal homeostasis. It was confirmed that <it>nas4x-1 </it>showed Fe deficiency in roots and signs of Fe deficiency and Fe sufficiency in leaves. Besides metal homeostasis, biotic stress, root carbohydrate, leaf photosystem and specific cell biological categories were discovered as main targets for regulated changes in response to - Fe and <it>nas4x-1</it>. Among 258 differentially expressed genes in response to - Fe and <it>nas4x-1 </it>five functional categories were enriched covering metal homeostasis, redox regulation, cell division and histone acetylation. We proved that GeneTrail offers a flexible and user-adapted way to identify functional categories in large-scale plant transcriptome data sets. The distinguished feature that allowed analysis of individually assembled functional categories facilitated the study of the <it>Arabidopsis thaliana </it>transcriptome.</p

Neonatal care delivery for low birth weight infants in the context of continuum of care in Ghana

Introduction and Aims: Effectively coordinated care linkages have high tendency of minimising adverse events associated with low birth weight (LBW) infants. In Ghana, however, linkages across health settings and family support structures are not clearly laid-out. This study elicited the continuum of care for LBW infants to understand how linkages can be strengthened to optimise quality of care. Methods: This study adopted a constructivist grounded theory design. Data collection took place in a municipality in Ghana between 2020 - 2021 with families, health professionals and managers providing care in clinical and community-based facilities. Audio recorded in-depth interviews were analysed using initial and focused coding, constant comparative analysis, theoretical memos, and diagramming until theoretical sufficiency was determined. Results: Analysis of 25 interviews generated an interpretive theory showing that referral, discharge, and review processes were not systematically planned and documented. Neonatal care knowledge was lacking due to insufficient investments in coordination and trainings with awareness creation on newborn health thought to reduce misconceptions. Motivated staff, implementation of care guidelines and staff supervision were identified as enabling factors. Mothers lacked financial and practical support and needed assistance in balancing their hope and confidence and empowerment to care for their LBW infants. To overcome these challenges, early bonding and family involvement were helpful. Discussion: A coordinated care process, family, and community involvement through adoption of a family system approach is necessary. Implementing guidelines, providing training opportunities, involving stakeholders, and promoting committed leadership can improve quality in the care continuum

Smoking Cessation Program for Inpatients with Substance Use Disorder: A Quasi-Randomized Controlled Trial of Feasibility and Efficacy

Aims: The present study investigated the feasibility, acceptance and efficacy of a newly developed cognitive behavioral program for smoking cessation/reduction ('Rethink your Smoking' program, RSP) in inpatients with substance use disorder (SUD). Method: One hundred ninety-nine inpatients with SUD were randomly assigned to either the RSP (n = 101) or a minimal intervention (MI) program (n = 98). In addition, participants were offered optional nicotine replacement therapy. Data from a group of patients with SUD without any intervention (control group, n = 78) were included in the analyses for comparison. Assessments were performed at admission, discharge and follow-up after 3 and 6 months. Results: RSP proved to be feasible and was well accepted by participants. Patients in both interventions showed lower scores for physical nicotine dependence and number of cigarettes smoked per day and higher scores for various motivational parameters at discharge and 3 months later. Both interventions were superior to no intervention, but no differences were found between the RSP and MI. Conclusion: A smoking cessation/reduction program is feasible for substance-dependent in-patients undergoing detoxification. Although the RSP appears to be effective in terms of harm reduction in in-patients with SUD, more cost-and time-efficient programs might also be suitable for this population. (C) 2016 S. Karger AG, Base

Health-system drivers influencing the continuum of care linkages for low-birth-weight infants at the different care levels in Ghana

Background: Low birth weight (LBW) is associated with short and long-term consequences including neonatal mortality and disability. Effective linkages in the continuum of care (CoC) for newborns at the health facility, community (primary care) and home care levels have a high tendency of minimizing adverse events associated with LBW. But it is unclear how these linkages work and what factors influence the CoC process in Ghana as literature is scarce on the views of health professionals and families of LBW infants regarding the CoC. Therefore, this study elicited the drivers influencing the CoC for LBW infants in Ghana and how linkages in the CoC could be strengthened to optimize quality of care. Methods: A constructivist grounded theory study design was used. Data was collected between September 2020 to February 2021. A total of 25 interviews were conducted with 11 family members of LBW infants born in a secondary referral hospital in Ghana, 9 healthcare professionals and 7 healthcare managers. Audio recordings were transcribed verbatim, analyzed using initial and focused coding. Constant comparative techniques, theoretical memos, and diagramming were employed until theoretical saturation was determined. Results: Emerging from the analysis was a theoretical model describing ten major themes along the care continuum for LBW infants, broadly categorized into health systems and family-systems drivers. In this paper, we focused on the former. Discharge, review, and referral systems were neither well-structured nor properly coordinated. Efficient dissemination and implementation of guidelines and supportive supervision contributed to higher staff motivation while insufficient investments and coordination of care activities limited training opportunities and human resource. A smooth transition between care levels is hampered by procedural, administrative, logistics, infrastructural and socio-economic barriers. Conclusion: A coordinated care process established on effective communication across different care levels, referral planning, staff supervision, decreased staff shuffling, routine in-service training, staff motivation and institutional commitment are necessary to achieve an effective care continuum for LBW infants and their families

Experiences of families and health professionals along the care continuum for low-birth weight neonates : a constructivist grounded theory study

Aims: To explore the experiences of health professionals and families concerning supporting low-birth weight (LBW) infants along the continuum of care (CoC) in Ghana with the goal to unveil new strategies to improve the quality of neonatal care. Design: A constructivist grounded theory. Method: Simultaneous data collection and analysis among health professionals alongside families with LBW infants from September 2020 to April 2021. The study used constructivist grounded theory strategies for data collection and analysis. Results: The analysis of 25 interviews resulted in a theoretical model describing 10 themes along the CoC for LBW infants, categorized into health and family systems drivers. In this paper, we focus on the latter. Early bonding and family involvement were empowering. Mothers needed assistance in balancing hope and confidence which enabled them to render special care to their LBW infants. Providing mothers with financial and domestic support as well as creating awareness on newborn health in communities were important. Conclusion: To achieve family involvement, a coordinated CoC must entail key players and be culturally inclusive. It must be applied at all levels in the CoC process in a non-linear faction. This can help LBW infants to thrive and to reach their full developmental potential. Impact: The theoretical model developed shows the importance of family involvement through family systems care for a comprehensive response in addressing needs of health professionals and families with LBW infants and bridging the fragmentations in the neonatal CoC in Ghana. Context-tailored research on family systems care in the neonatal period is necessary to achieve a quality CoC for LBW infants and their families. Patient or Public Contribution: Caregivers and providers participated by granting in-depth interviews. Care providers further contributed through their feedback on preliminary findings

The price of tumor control

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Phosphatidylinositol 3-Kinase -Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study

PurposeWe report the first-in-human phase Ia study to our knowledge (ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase (PI3K)-selective inhibitor.Patients and MethodsIn the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer received alpelisib 400 mg once daily.ResultsOne hundred thirty-four patients received treatment. Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed; half-life was 7.6 hours at 400 mg once daily with minimal accumulation. Objective tumor responses were observed at doses 270 mg once daily; overall response rate was 6.0% (n = 8; one patient with endometrial cancer had a complete response, and seven patients with cervical, breast, endometrial, colon, and rectal cancers had partial responses). Stable disease was achieved in 70 (52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease control rate (complete and partial responses and stable disease) was 58.2%. In patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, median progression-free survival was 5.5 months. Frequently mutated genes ( 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS (22.4%), ARID1A (13.2%), and FBXW7 (10.5%).ConclusionAlpelisib demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA-altered solid tumors, supporting the rationale for selective PI3K inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors

Establishing a Mental Health Surveillance in Germany: Development of a framework concept and indicator set

In the course of the recognition of mental health as an essential component of population health, the Robert Koch Institute has begun developing a Mental Health Surveillance (MHS) system for Germany. MHS aims to continuously report data for relevant mental health indicators, thus creating a basis for evidence-based planning and evaluation of public health measures. In order to develop a set of indicators for the adult population, potential indicators were identified through a systematic literature review and selected in a consensus process by international and national experts and stakeholders. The final set comprises 60 indicators which, together, represent a multidimensional public health framework for mental health across four fields of action. For the fifth field of action ‘Mental health promotion and prevention’ indicators still need to be developed. The methodology piloted proved to be practicable. Strengths and limitations will be discussed regarding the search and definition of indicators, the scope of the indicator set as well as the participatory decision-making process. Next steps in setting up the MHS will be the operationalisation of the single indicators and their extension to also cover children and adolescents. Given assured data availability, the MHS will contribute to broadening our knowledge on population mental health, supporting a targeted promotion of mental health and reducing the disease burden in persons with mental disorders