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Molecular profiling of patients with cytogenetically normal acute myeloid leukemia and hyperleukocytosis
No full textAcute myeloid leukemia (AML) with initial hyperleukocytosis is associated
with high early mortality and a poor prognosis. The aims of this study were to
delineate the underlying molecular landscape in the largest cytogenetic risk group,
cytogenetically normal acute myeloid leukemia (CN‐AML), and to assess the prognostic
relevance of recurrent mutations in the context of hyperleukocytosis and
clinical risk factors.
Methods: The authors performed a targeted sequencing of 49 recurrently mutated
genes in 56 patients with newly diagnosed CN‐AML and initial hyperleukocytosis of
≥100 G/L treated in the AMLCG99 study. The median number of mutated genes per
patient was 5. The most common mutations occurred in FLT3 (73%), NPM1 (75%),
and TET2 (45%).
Results: The predominant pathways affected by mutations were signaling (84% of
patients), epigenetic modifiers (75% of patients), and nuclear transport (NPM1; 75%)
of patients. AML with hyperleukocytosis was enriched for molecular subtypes that
negatively affected the prognosis, including a high percentage of patients presentin
An economic analysis of multi-level wind power regulation in Germany
No full textThis doctoral thesis examines the efficiency, effectiveness, and distributional outcomes of multi-level regulation of wind power deployment in Germany. The thesis is structured into three studies, employing both theoretical modeling and empirical analysis. The first study utilizes a game-theoretical model to analyze multi-level co-regulation and derives conditions under which regulatory decisions are efficiently coordinated. A key factor for achieving efficient coordination is the subnational burden sharing of financing costs for national support policies. Which specification of subnational burden sharing is efficient depends on the combination of regulatory instruments at both national and subnational levels. The second study empirically assesses how wind power expansion can be managed effectively, particularly through spatial planning instruments. A comprehensive evaluation of geodata on wind turbine installations and designated areas for wind power highlights not only the impact of the total area designated to wind power deployment but also the importance of zoning details -- such as the size and shape of individual designated areas. Additionally, the study quantifies the effects of further policy measures that influence land availability and the profitability of wind power projects. The third study investigates the share of potential business tax payments generated by wind turbines that remains within the hosting municipality. Using tax data from the past two decades, the study estimates that at most half of the potential business tax payments have remained on site. The findings indicate that the primary reason for this is the formula apportionment rule under the German business tax law, which predominantly allocates tax payments to the municipalities where wind turbine operators are headquartered. Overall, the findings of these three studies identify multiple avenues for improving the efficiency, effectiveness, and distributional outcomes of multi-level regulation of wind power deployment
“If anybody wants to judge me […] frankly, they can fuck off”: The Fulfords and Their Country House
No full text
Guideline-directed medical therapy in patients undergoing transcatheter edge-to-edge repair for secondary mitral regurgitation
No full textTriple guideline-directed medical therapy (GDMT) prescription was associated with a lower 2-year mortality compared to non-triple GDMT
prescription (A). Such association was observed in patients with concomitant comorbidities (B). CI, confidence interval; CKD, chronic kidney disease;
CMP, cardiomyopathy; HR, hazard ratio; MRA, mineralocorticoid receptor antagonists; M-TEER, mitral valve transcatheter edge-to-edge repair; RAS,
renin–angiotensin system; ResMR, residual mitral regurgitation; RV-Dys, right ventricular dysfunction; SMR, secondary mitral regurgitation
Utilizing 4D Printing to Design Smart Gastroretentive, Esophageal, and Intravesical Drug Delivery Systems
No full textThe breakthrough of 3D printing in biomedical research has paved the way for
the next evolutionary step referred to as four dimensional (4D) printing. This
new concept utilizes the time as the fourth dimension in addition to the x, y,
and z axes with the idea to change the configuration of a printed construct
with time usually in response to an external stimulus. This can be attained
through the incorporation of smart materials or through a preset smart
design. The 4D printed constructs may be designed to exhibit expandability,
flexibility, self-folding, self-repair or deformability. This review focuses on 4D
printed devices for gastroretentive, esophageal, and intravesical delivery. The
currently unmet needs and challenges for these application sites are tried to
be defined and reported on published solution concepts involving 4D printing.
In addition, other promising application sites that may similarly benefit from
4D printing approaches such as tracheal and intrauterine drug delivery are proposed
Orofacial conditions and oral health behavior of young athletes: A comparison of amateur and competitive sports
No full textPurpose: This retrospective cross-sectional
study aimed to evaluate oral health
status (dental, periodontal, and functional) and oral health behavior in young
German athletes including the comparison of competitive (CA) and amateur
sports (AA).
Methods: Data of CA (German national teams, perspective, and youth squads)
and AA aged between 18 and 30 years with an available oral examination in 2019
were included. Clinical examination: caries experience (DMF-T),
non-carious
wear (erosion, BEWE), partially erupted wisdom teeth, gingival inflammation
(PBI), plaque index, periodontal screening (PSI), and temporomandibular dysfunction
(TMD) screening. Questionnaires: oral health behavior and periodontal
symptoms.
Results: 88 CA (w = 51%, 20.6 ± 3.5 years) of endurance sports and 57 AA
(w = 51%, 22.2 ± 2.1 years) were included. DMF-T
was comparable (CA: 2.7 ± 2.2,
AA: 2.3 ± 2.2; p = 0.275) with more D-T
in CA (0.6 ± 1.0) than AA (0.3 ± 0.7;
p = 0.046; caries prevalence: CA: 34%, AA: 19%; p = 0.06). Both groups had low
severity of erosion (BEWE about 3.5). CA had more positive TMD screenings
(43% vs. 25%; p = 0.014). In both groups, all athletes showed signs of gingival
inflammation, but on average of low severity (PBI <1). More CA needed complex
periodontal treatment than AA (maximum PSI = 3 in 40% vs. 12%; p < 0.001).
Oral health behavior was comparable (daily tooth brushing; regular dental check-ups
in >70%).
Conclusions: Young German athletes (CA and AA) generally showed signs of
gingival inflammation and needed to improve their oral health behavior. CA
showed slightly increased oral findings (more D-T,
periodontal and TMD screening
findings) than AA, but similar oral health behavior. This may imply an increased
dental care need in competitive sports
A non-canonical function of eukaryotic elongation factor 1A1: Regulation of interleukin-6 expression
No full textInterleukin-6 is one of the most prominent triggers of inflammatory processes. We have shown recently that
heteroarylketones (HAKs) interfere with stimulated interleukin-6 expression in astrocytes by suppression of
STAT3 phosphorylation at serine 727. Surprisingly, this effect is not based on the inhibition of STAT3-relevant
kinases. Therefore, we here used the structurally modified HAK compound biotin-HAK-3 in a reverse chemical
approach to identify the relevant molecular target in UV-mediated cross-linking experiments. Employing
streptavidin-specific 2D-immunoblotting followed by mass spectrometry we identified nine proteins putatively
interacting with biotin-HAK-3. After co-immunoprecipitation, co-immunofluorescence, surface plasmon resonance
analyses and RNAi-mediated knock-down, the eukaryotic elongation factor 1A1 (eEF1A1) was verified
as the relevant target of HAK bioactivity. eEF1A1 forms complexes with STAT3 and PKCδ, which are crucial for
STAT3S727 phosphorylation and for NF-κB/STAT3-enhanced interleukin-6 expression. Furthermore, the intracellular
HAK accumulation is strongly dependent on eEF1A1 expression. Taken together, the results reveal a novel
molecular mechanism for a non-canonical role of eEF1A1 in signal transduction via direct modulation of
kinase-dependent phosphorylation events
Early-Outcome Differences between Acute and Chronic Periprosthetic Joint Infections: A Retrospective Single-Center Study
No full textPeriprosthetic joint infections (PJI) are serious complications after arthroplasty, associated with high morbidity, mortality, and complex treatment processes. The outcomes of different PJI entities are largely unknown. The aim of this study was to access the early outcomes of different PJI entities. A retrospective, single-center study was conducted. The characteristics and outcomes of patients with PJI treated between 2018 and 2019 were evaluated 12 months after the completion of treatment. Primary endpoints were mortality, relapse free survival (RFS) and postoperative complications (kidney failure, sepsis, admission to ICU). A total of 115 cases were included [19.1% early (EI), 33.0% acute late (ALI), and 47.8% chronic infections (CI)]. Patients with ALI were older (p = 0.023), had higher ASA scores (p = 0.031), preoperative CRP concentrations (p = 0.011), incidence of kidney failure (p = 0.002) and sepsis (p = 0.026). They also tended towards higher in-house mortality (ALI 21.1%, 13.6% EI, 5.5% CI) and admission to ICU (ALI 50.0%, 22.7% EI, 30.9% CI). At 12 months, 15.4% of patients with EI had a relapse, compared to 38.1% in ALI and 36.4% in CI. There are differences in patient characteristics and early outcomes between PJI entities. Patients with EI have better early clinical outcomes. Patients with ALI require special attention during follow-up because they have higher occurrences of relapses and postoperative complications than patients with EI and CI
Nicotinamide as potential biomarker for Alzheimer’s disease: A translational study based on metabolomics
No full textIntroduction: The metabolic routes altered in Alzheimer's disease (AD) brain are poorly understood. As the metabolic pathways are evolutionarily conserved, the metabolic profiles carried out in animal models of AD could be directly translated into human studies. Methods: We performed untargeted Nuclear Magnetic Resonance metabolomics in hippocampus of McGill-R-Thy1-APP transgenic (Tg) rats, a model of AD-like cerebral amyloidosis and the translational potential of these findings was assessed by targeted Gas Chromatography-Electron Impact-Mass Spectrometry in plasma of participants in the German longitudinal cohort AgeCoDe. Results: In rat hippocampus 26 metabolites were identified. Of these 26 metabolites, nine showed differences between rat genotypes that were nominally significant. Two of them presented partial least square-discriminant analysis (PLS-DA) loadings with the larger absolute weights and the highest Variable Importance in Projection (VIP) scores and were specifically assigned to nicotinamide adenine dinucleotide (NAD) and nicotinamide (Nam). NAD levels were significantly decreased in Tg rat brains as compared to controls. In agreement with these results, plasma of AD patients showed significantly reduced levels of Nam in respect to cognitively normal participants. In addition, high plasma levels of Nam showed a 27% risk reduction of progressing to AD dementia within the following 2.5 years, this hazard ratio is lost afterwards. Discussion: To our knowledge, this is the first report showing that a decrease of Nam plasma levels is observed couple of years before conversion to AD, thereby suggesting its potential use as biomarker for AD progression