Background
Multimorbidity and polypharmacy represent a major problem for elderly patients; improvement of medication schemes is important and listing approaches (e.g. Beers list) are considered to be ...potentially useful.
Objectives
The aim of this study was to perform expert consensus validation of the FORTA (Fit fOR The Aged) List, a drug classification combining positive and negative labelling of drugs chronically prescribed to elderly patients.
Methods
A two-round Delphi procedure was conducted involving 20 experts, 17 geriatric internists and 3 geriatric psychiatrists from Germany and Austria, evaluating the labels assigned to 190 substances or substance groups. These labels ranged from A (indispensable), B (beneficial), C (questionable) to D (avoid), depending on the state of evidence for safety, efficacy and overall age-appropriateness. The experts were also requested to suggest additional substances and indication areas for assessment and possible inclusion in the FORTA List. A weighted (corrected) consensus coefficient was generated for each substance to reflect (1) agreement with the original label, and (2) distribution among raters’ labels.
Results
The overall consensus for all items and raters was 92 % (corrected). For 54/190 items (28.4 %), a unanimous response was achieved as to the original author-based FORTA label choice. Twenty-four substances (12.6 %) fell short of the consensus cutoff and were re-evaluated in a second round. This yielded confirmation of 171/190, or 90 %, of the original author-based FORTA labels. A total of 35 new substances were also accepted for the FORTA List. Drugs used for dementia and dementia syndromes provoked particular response heterogeneity.
Conclusion
The FORTA List now reflects a wider consensus among experts, increasing its validity for clinical use. It represents a tool to improve the quality of drug prescription in older patients by identifying both inappropriate and omitted drugs, and thus overtreatment and undertreatment. The validation of FORTA’s impact on clinical endpoints has yielded promising preliminary results, to be corroborated in ongoing larger trials.
Hereditary pulmonary alveolar proteinosis (herPAP) constitutes a rare, life threatening lung disease characterized by the inability of alveolar macrophages to clear the alveolar airspaces from ...surfactant phospholipids. On a molecular level, the disorder is defined by a defect in the CSF2RA gene coding for the GM-CSF receptor alpha-chain (CD116). As therapeutic options are limited, we currently pursue a cell and gene therapy approach aiming for the intrapulmonary transplantation of gene-corrected macrophages derived from herPAP-specific induced pluripotent stem cells (herPAP-iPSC) employing transcriptional activator-like effector nucleases (TALENs). Targeted insertion of a codon-optimized CSF2RA-cDNA driven by the hybrid cytomegalovirus (CMV) early enhancer/chicken beta actin (CAG) promoter into the AAVS1 locus resulted in robust expression of the CSF2RA gene in gene-edited herPAP-iPSCs as well as thereof derived macrophages. These macrophages displayed typical morphology, surface phenotype, phagocytic and secretory activity, as well as functional CSF2RA expression verified by STAT5 phosphorylation and GM-CSF uptake studies. Thus, our study provides a proof-of-concept, that TALEN-mediated integration of the CSF2RA gene into the AAVS1 safe harbor locus in patient-specific iPSCs represents an efficient strategy to generate functionally corrected monocytes/macrophages, which in the future may serve as a source for an autologous cell-based gene therapy for the treatment of herPAP.
Nanoscale aluminium trihydroxide (ATH) is examined to its suitability for carbon fibre reinforced plastics (CFRP) as a novel flame retardant. In particular the influence of particle size and ...concentration of ATH to the fire behaviour of epoxy polymer matrices is determined. The particle size is adjusted by means of different dispersing techniques. By SEM images and viscosity measurements the homogeneity of the produced ATH dispersions for the liquid ones and of cured epoxy–ATH nanocomposites is determined. Based on these pre-results, selected ATH dispersions are used for the manufacturing of CFRP which are produced by the proved injection technology. The thermal stability of the ATH nanocomposite plates and the corresponding CFRP plates are analyzed by means of quantitative single difference thermoanalysis (QSDTA). The fire behaviour is characterised by using the OSU chamber test. Both tests indicate a reduced heat release rate by decreasing the ATH particle size, i.e. the thermal load decreases. A combined fire protection mechanism is discussed for the improved fire protection through ATH nanoparticles.
Induced pluripotent stem cells (iPSCs) represent an innovative source for the standardized in vitro generation of macrophages (Mφ). We here describe a robust and efficient protocol to obtain mature ...and functional Mφ from healthy as well as disease-specific murine iPSCs. With regard to morphology, surface phenotype, and function, our iPSC-derived Mφ (iPSC-Mφ) closely resemble their counterparts generated in vitro from bone marrow cells. Moreover, when we investigated the feasibility of our differentiation system to serve as a model for rare congenital diseases associated with Mφ malfunction, we were able to faithfully recapitulate the pathognomonic defects in GM-CSF signaling and Mφ function present in hereditary pulmonary alveolar proteinosis (herPAP). Thus, our studies may help to overcome the limitations placed on research into certain rare disease entities by the lack of an adequate supply of disease-specific primary cells, and may aid the development of novel therapeutic approaches for herPAP patients.
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•Myeloid differentiation of murine iPSCs into mature Mφ (iPSC-Mφ)•Functional iPSC-Mφ similar to bone marrow lineage-negative cell-derived Mφ•Disease modeling of defects in GM-CSF signaling and Mφ function present in herPAP
In this article, Lachmann and colleagues describe a highly efficient and robust protocol to obtain mature Mφ (iPSC-Mφ) from healthy as well as disease-specific murine iPSCs, which display characteristic morphology, surface phenotype, and functionality. Moreover, the protocol was applied to successfully model the pathognomonic defects in GM-CSF signaling and Mφ function present in hereditary pulmonary alveolar proteinosis (herPAP).
Levels of civic engagement are assumed to vary according to numerous social and psychological characteristics, but not much is known about online civic engagement. This study aimed to investigate ...differences and similarities in young people’s offline and online civic engagement and to clarify, based on Ajzen’s theory of planned behavior (TPB), associations between motivation for civic engagement, peer and parental norms, collective efficacy, and civic engagement. The sample consisted of 755 youth (native German, ethnic German Diaspora, and Turkish migrants) from two age groups (16–18 and 19–26; mean age 20.5 years; 52 % female). Results showed that ethnic group membership and age moderated the frequency of engagement behavior, with Turkish migrants taking part more than native Germans, who were followed by ethnic German Diaspora migrants. Analyses based on TPB showed good fit for a model relating intention for offline and online civic engagement to motivation for civic engagement, peer and parental norms, and collective efficacy. Ethnic group moderated the findings for offline civic engagement and questioned the universality of some model parameters (e.g., peer and parental norms). This study showed the utility of the TPB framework for studying civic engagement but also reveals that the predictive utility of peer and parental norms seems to vary depending on the group and the behavior under study. This study highlights the importance of including minority samples in the study of civic engagement in order to identify between-group similarities and differences.
Abstract
To decrease greenhouse gas emissions of the Swiss building stock, effective retrofit strategies are necessary. Due to the long-term operation of buildings, future developments and ...uncertainties need to be considered, which calls for assessing the robustness of retrofit decisions. Existing studies propose robustness metrics for decisions under deep uncertainty to be coupled with a scenario-based simulation approach. We review these metrics and present a simulation approach that includes current and future operational energy, emissions, and costs. We apply the seven identified metrics to retrofit decisions of a multifamily house located in Zurich, where future scenarios in terms of climate, occupancy, decarbonization, and cost development are included. The metrics are based on different assumptions and positions towards risk. We further find that the discriminatory power is different, confirming the Minimax Regret metric to be most suitable for the building context when looking at individual buildings. For the case study, we find that deep retrofit seems to be a robust decision from an environmental perspective. From a cost perspective, the electrification of the heating system with heat pumps and the installation of PV without a complete envelope retrofit proves to be most robust.
to further validate the FORTA (Fit fOR The Aged) concept, a bicentric randomised, controlled trial was run in two geriatric clinics.
patients (≥65 years, ≥3 drugs or ≥60 years, ≥6 drugs) with three ...relevant diseases and hospitalisation for ≥5 days were randomised. In the intervention, but not the control group, a FORTA team instructed ward physicians on FORTA. FORTA is the first positive/negative listing approach labelling medications used to treat chronic illnesses in older patients from A (indispensable), B (beneficial), C (questionable) to D (avoid). The primary end point was the FORTA score: sum of medication errors classified as over-, under- and mistreatment. Consecutive patients were randomised to the intervention and control ward; outcome assessment was blinded.
four hundred and nine patients (age 81.5 years, 64% female, hospitalisation 17.4 days) were included. The primary end point was significantly (P < 0.0001) more reduced in the intervention versus control groups (2.7 ± 2.25 versus 1 ± 1.8, mean ± SD, intergroup comparison of admission/discharge differences). Over- and under-treatment scores and use of A (increase) and D (decrease) drugs were significantly improved (P < 0.01). The total number of adverse drug reactions (ADRs) was significantly reduced by FORTA (P < 0.05, number needed to treat is 5). Activities of daily living and renal failure improved significantly (P < 0.05). Blood pressure remained constant in the intervention, but decreased significantly in the control group.
applying FORTA to hospitalised geriatric patients leads to improvement of medication quality and may improve secondary clinical end points (e.g. ADRs). The concept is amenable to successful communication and implementation. Registration (DRKS-ID): DRKS00000531.
DFG-German Research Foundation (WE 1184/15-1).
Pluripotent stem cells, including induced pluripotent stem cells (iPSCs), have the capacity to differentiate towards all three germ layers and have been highlighted as an attractive cell source for ...the field of regenerative medicine. Thus, stable expression of therapeutic transgenes in iPSCs, as well as thereof derived progeny of hematopoietic lineage, may lay the foundation for innovative cell replacement therapies.
We have utilized human iPSC lines genetically modified by lentiviral vector technology or targeted integration of reporter genes to evaluate transgene expression during hematopoietic specification and differentiation towards macrophages.
Use of lentiviral vectors equipped with an ubiquitous chromatin opening element (CBX3-UCOE) as well as zinc finger nuclease-mediated targeting of an expression cassette into the human adeno-associated virus integration site 1 (AAVS1) safe harbor resulted in stable transgene expression in iPSCs. When iPSCs were differentiated along the myeloid pathway into macrophages, both strategies yielded sustained transgene expression during the hematopoietic specification process including mature CD14+ and CD11b+ macrophages.
Combination of human iPSC technology with either lentiviral vector technology or designer nuclease-based genome editing allows for the generation of transgenic iPSC-derived macrophages with stable transgene expression which may be useful for novel cell and gene replacement therapies.
Objective: In recent years, cefotaximases of the CTX-M type have become a predominant cause of resistance to extended-spectrum cephalosporins in Gram-negative bacteria. Although most enzymes provide ...higher levels of resistance to cefotaxime than to ceftazidime, mutants with enhanced catalytic efficiency against ceftazidime have recently been described. This report identifies another ceftazidime-resistant mutant of the CTX-M class of enzymes. Methods: Two ceftazidime-resistant strains, Escherichia coli IFI-1 and Klebsiella pneumoniae IFI-2, were isolated from a 46-year-old man during treatment of postoperative peritonitis with ceftazidime. Susceptibility testing, mating-out assays, isoelectric focusing as well as PCR and sequencing techniques were carried out to investigate the underlying mechanism of resistance. Results: E. coli IFI-1 and K. pneumoniae IFI-2 exhibited a clavulanic acid-inhibited substrate profile that included extended-spectrum cephalosporins. Notably, both strains had up to a 32-fold higher level of resistance to ceftazidime than to cefotaxime. Further characterization revealed that a novel blaCTX-M gene encoding a β-lactamase with a pI of 8.9 was implicated in this resistance: CTX-M-23. Along with the substitutions D114N and S140A, CTX-M-23 differed from CTX-M-1, the most closely related enzyme, by a P167T replacement in the active-site omega loop, which has not previously been observed in other CTX-M enzymes. By analogy with what was observed with certain TEM/PSE/BPS-type β-lactamases, the amino acid substitution in the omega loop may explain ceftazidime resistance, which has only rarely been reported for other CTX-M enzymes. Conclusion: The emergence of a new ceftazidime-resistant CTX-M-type mutant provides evidence that these enzymes are able to broaden their substrate spectrum towards ceftazidime, probably due to substitutions in the active-site omega loop.
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