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Im Rahmen dieser publikationsbasierten Dissertation wurden drei wissenschaftliche Arbeiten veröffentlicht. Als Erstautorenschaft wurde 2022 die Arbeit “Effectiveness of High-intensity Focused Ultrasound (HIFU) Therapy of Solid and Complex Benign Thyroid Nodules - A Long-term Follow up Two-center Study.” im Journal “Experimental and Clinical Endocrinology & Diabetes” veröffentlicht. Im Folgenden wird der Inhalt dieser Arbeit dargelegt. Ein kurzer Überblick über die Ergebnisse der anderen beiden mitpublizierten Arbeiten findet sich im Kapitel „Weitere Ergebnisse der Arbeitsgruppe“.
Durch die hohe Prävalenz benigner Schilddrüsenknoten sind deren Behandlungsalternativen von großem wissenschaftlichem Interesse. Dabei bildet die nebenwirkungsarme, minimalinvasive Thermoablation mittels high-intensity focused ultrasound (HIFU) eine attraktive Alternative zu herkömmlichen Verfahren wie der Schilddrüsenchirurgie oder der Radioiodtherapie. Bei der HIFU-Echotherapie werden die Schilddrüsenknoten auf 80 - 90 Grad Celsius erhitzt, sodass eine irreversible Koagulationsnekrose entsteht. Um den Therapieprozess und die Indikationsstellung von HIFU bei benignen Schilddrüsenknoten zu optimieren, ist es notwendig, genaue Studien durchzuführen.
Ziel der vorliegenden bizentrischen Langzeitstudie war, die Effektivität von HIFU-Echotherapien bei benignen Schilddrüsenknoten zu evaluieren und erstmalig den Einfluss der Knotenmorphologie auf den Therapieerfolg zu untersuchen. Vor der Therapie und in regelmäßigen Intervallen nach der Therapie wurden die Größe und die Morphologie der Schilddrüsenknoten mittels Ultraschall dokumentiert. In der retrospektiven Studie wurden Daten von 58 Patienten ausgewertet. Dabei wurde die Gesamtpopulation in eine Gruppe mit soliden und in eine Gruppe mit komplexen Knoten eingeteilt. Die durchschnittliche prozentuale Volumenreduktion in jeder Gruppe wurde mit dem Wilcoxon-Signed-Rank Test statistisch analysiert.
Die Gesamtpopulation zeigte eine Volumenreduktion der zuvor abladierten Knoten von 38.86 % nach 3 Monaten (Spannweite: 4.03 % - 91.16 %, p < 0.0001, n = 25), 42.7 % nach 6 Monaten (Spannweite: 7.36 % - 93.2 %, p < 0.0001, n = 18), 62.21 % nach 9 Monaten (Spannweite: 12.88 % - 93.2 %, p = 0.0078, n = 8) und 61.42 % nach 12 Monaten (Spannweite: 39.39 % - 93.2 %, p > 0.05, n = 4). Die soliden Knoten hatten eine Volumenreduktion von 49.98 % nach 3 Monaten (Spannweite: 4.03 % - 91.16 %, p = 0.0001, n = 15), 46.40 % nach 6 Monaten (Spannweite: 7.36 % - 93.2 %, p = 0.001, n = 11), 65.77 % nach 9 Monaten (Spannweite: 39.39 % - 93.2 %, p = 0.0156, n = 7) und 63.88 % nach 12 Monaten (Spannweite: 39.39 % - 93.2%, p > 0.05, n = 2). Komplexe Knoten hatten eine Volumenreduktion von 35.2 % nach 3 Monaten (Spannweite: 5.85 % - 68.63 %, p = 0.002, n = 10), 36.89 % nach 6 Monaten (Spannweite: 12.23 % - 68.63 %, p = 0.0156, n = 7) und 63.64 % nach 12 Monaten (Spannweite: 52,38 % - 73.91 %, p > 0.05, n = 2).
In der vorliegenden bizentrischen Langzeitstudie wurde deutlich, dass HIFU-Echotherapie eine effektive Behandlungsoption benigner Schilddrüsenknoten ist. Erstmalig gezeigt wurde der Trend, dass solide Knoten besser auf HIFU-Echotherapie ansprechen als komplexe Knoten.
Anhand der gewonnenen Ergebnisse und der neuen Erkenntnisse zum Einfluss der Knotenmorphologie auf die HIFU-Echotherapie benigner Schilddrüsenknoten kann HIFU als Therapieoption besser bewertet werden. Eine differenziertere Indikationsstellung in Bezug auf solide und komplexe Knoten wird ermöglicht und die HIFU-Echotherapie kann gegen andere thermoablative Verfahren abgewogen werden.
Highlights
• An airport can result in high particle concentrations in a distant residential area.
• The particle size distribution indicated the airport as the main source of particles.
• Lower air traffic during the COVID-19 pandemic lead to lower particle concentrations.
• The particle concentration showed high temporal variations.
Abstract
Exposure to ultrafine particles has a significant influence on human health. In regions with large commercial airports, air traffic and ground operations can represent a potential particle source. The particle number concentration was measured in a low-traffic residential area about 7 km from Frankfurt Airport with a Condensation Particle Counter in a long-term study. In addition, the particle number size distribution was determined using a Fast Mobility Particle Sizer.
The particle number concentrations showed high variations over the entire measuring period and even within a single day. A maximum 24 h-mean of 24,120 cm−3 was detected. Very high particle number concentrations were in particular measured when the wind came from the direction of the airport. In this case, the particle number size distribution showed a maximum in the particle size range between 5 and 15 nm. Particles produced by combustion in jet engines typically have this size range and a high potential to be deposited in the alveoli. During a period with high air traffic volume, significantly higher particle number concentrations could be measured than during a period with low air traffic volume, as in the COVID-19 pandemic.
A large commercial airport thus has the potential to lead to a high particle number concentration even in a distant residential area. Due to the high particle number concentrations, the critical particle size, and strong concentration fluctuations, long-term measurements are essential for a realistic exposure analysis.
Highlights
• Since there is only a low level of evidence, it is difficult to agree on state-of-the-art standards or to provide recommendations and guidelines.
• The value of combining several monitoring devices for dual or triple guidance must be challenged.
• The principle of fascial plane blocks is suitable to avoid traumatic needle-to-nerve contact. However, local toxicity must be regarded as a possible mechanism for nerve injuries.
• Block procedures might be conducted during sedation or general anesthesia when considering the individual patients' clinical situations and the expertise of the anesthesiologist.
• The quality of ultrasound equipment and education provided by the corresponding anesthesia department is highly relevant
• Mexican and German populations of L. sericata differ in their development times.
• Mexican L. sericata had a shorter development time at 20°C than German flies.
• At 30 °C, German L. sericata pupariated and eclosed earlier than the Mexican flies.
• Differences in study design make the comparison of developmental studies difficult.
Abstract
The cosmopolitan blow fly Lucilia sericata is often used in forensic case work for estimating the minimum postmortem interval (PMImin). For this, the age of immature specimens developing on the dead body is calculated by measuring the time taken to reach the sampled developmental stage at a given temperature. To test whether regional developmental data of L. sericata is valid on a global scale, the time taken to reach different developmental stages was compared between a population from Mexico and one from Germany at two different constant temperatures.
The German population of L. sericata was collected in Frankfurt/Main, while the Mexican population originated near Oaxaca de Juarez and was transported to Germany in the larval stage. Only the F1 generation was used to avoid adaption of the Mexican flies. Eggs were immediately placed at 20 °C and 30 °C. Five times 30 freshly eclosed larvae per replicate (n = 5) were then transferred to a cup of minced meat in separate containers. The larvae were checked every 8 h for migration, pupariation or emergence of adult flies. The time at which the first individual and 50 % of the specimens per container entered each of these stages, was recorded.
Significant differences in the time of development between the two populations were observed at both temperatures. At 20 °C, the first specimens of the Mexican population reached all developmental stages a little (< 1 day to < 2 days) earlier than the German L. sericata. At 30 °C, the Mexican flies also reached the post-feeding stage slightly earlier (0.2 days). However, at 30 °C, the German flies started pupariation significantly earlier (after 5 days) than the Mexican flies (6.9 days) and the adults from Germany also emerged earlier (10.5 days compared to 13.1 days). The same pattern was observed when looking at 50 % of the total number of specimens per container. A comparison with previously published developmental studies was difficult as the experimental design varied widely between studies. However, the results were within the range of most studies. Our study has shown that age estimation can vary widely depending on the population on which the reference data used for the calculations are based. This highlights the importance of using local and population-specific developmental data for estimating the age of blow flies in case work.
Marjan van den Akker, Gesundheitswissenschaftlerin und Epidemiologin : Goethe, Deine Forscher
(2024)
Highlights
• Out of the six edible pumpkin seeds found in Cameroonian C. sativus showed most potent anti-proliferative effects on prostate cells.
• Its oil conserved almost all the effects of raw seeds and prevented benign prostatic hyperplasia (BPH).
• It exhibited potent anti-inflammatory activities in rat with BPH.
Abstract
Pumpkin seeds are claimed to treat prostate tumour/cancer. The in vitro (ability to inhibit cell growth through MTT assay) and in vivo (ability to prevent testosterone-induced BPH in rats at the doses of 125, 250, 500 and 1000 mg/kg BW) of six edible pumpkin seeds found in Cameroonian were assessed. The endpoints were cell growth arrest, prostate mass and volume, prostatic epithelium height, prostatic proteins, prostate specific antigen (PSA) and inflammatory cytokines. In vitro, C. sativus seeds exhibited the most potent antiproliferative effects on DU145 and PC3 prostate cancer cells and its oil conserved almost all the effects of raw seeds. Further, it prevented the increased of prostate relative mass and volume, prostate epithelium height, PSA and testosterone dose-dependently compared to normal rats. This effect is thought to be mediated through antiandrogenic, estrogenic and anti-inflammatory activities, evidenced by a decreased in IL-1β, IL-6 and TNFα level. Overall, this results justify its traditional use.
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
Beyond well-established difficulties with working memory in individuals with attention deficit hyperactivity disorder (ADHD), evidence is emerging that other memory processes may also be affected. We investigated, first, which memory processes show differences in adults and adolescents with ADHD in comparison to control participants, focusing on working and short-term memory, initial learning, interference, delayed and recognition memory. Second, we investigated whether ADHD severity, co-occurring depressive symptoms, IQ and physical fitness are associated with the memory performance in the individuals with ADHD.
We assessed 205 participants with ADHD (mean age 25.8 years, SD 7.99) and 50 control participants (mean age 21.1 years, SD 5.07) on cognitive tasks including the digit span forward (DSF) and backward (DSB), the Rey Auditory Verbal Learning Test (RAVLT), and the vocabulary and matrix reasoning subtests of the Wechsler Abbreviated Scale of Intelligence. Participants with ADHD were additionally assessed on ADHD severity, depression symptoms and cardiorespiratory fitness. A series of regressions were run, with sensitivity analyses performed when variables were skewed.
ADHD-control comparisons were significant for DSF, DSB, delayed and recognition memory, with people with ADHD performing less well than the control participants. The result for recognition memory was no longer significant in sensitivity analysis. Memory performance was not associated with greater ADHD or depression symptoms severity. IQ was positively associated with all memory variables except DSF. Cardiorespiratory fitness was negatively associated with the majority of RAVLT variables.
Individuals with ADHD showed difficulties with working memory, short-term memory and delayed memory, as well as a potential difficulty with recognition memory, despite preserved initial learning.
Highlights
• High resolution profile of C. pipiens' sugar diet has been obtained using UHPLC-MS.
• Artificial feeding using ornamental plants provides similar sugar profiles as observed in field collected mosquitoes.
• Metabolomic profiling found secondary metabolites and pollutants of anthropogenic use.
Abstract: Culex pipiens (Linnaeus, 1758) mosquitoes search plant sources of sugars to cope with the energetic demand of various physiological processes. The crop as part of the digestive system is devoted to the storage of sugar-based meal obtained from various nectars sources. The profiling of sugars and metabolites in the Culex pipiens’ crop is scarce, and only few studies used Liquid Chromatography – Mass Spectrometry (LC-MS), which provides broad detection for biomonitoring environmental substances and even contaminants in the sugar diet of mosquitoes populations.
Therefore, sugar and metabolite profiling were performed on crops obtained from mosquitoes exposed to plant nectar under laboratory or natural conditions by Ultra High-Performance LC-MS (UHPLC-MS). This method allowed us a precise quantitative and qualitative identification of sugar diet and associated environmental compounds in the crop of the mosquito C. pipiens. Under laboratory condition, mosquitoes were allowed to feed on either glucose solution, commercially-available flowers or field collected flowers. In addition, we collected mosquitoes from the field to compare those crop metabolomes with metabolome patterns occurring after nectar feeding in the lab.
The sugar quantities and quality obtained from the crops of mosquitoes collected in the field were similar to those crops obtained from mosquitoes that fed on commercially-available flowers and from field collected flowers with a limit of detection of 10 μg/L for sucrose, glucose and sucrose. Next to sugar compounds, we identified 2 types of amino acids, 12 natural products, and 9 pesticides.
Next to the diversity of sugar compounds, we could confirm that secondary metabolites and environmental pollutants are typically up taken from floral nectar sources by C. pipiens. The in-depth knowledge on mosquito–plant interactions may inspire the development and further optimization of mosquito trap systems and arboviral surveillance systems.
Highlights
• NCoR1 is the most highly expressed endothelial corepressor.
• Loss of NCoR1 promotes angiogenic function in endothelial cells.
• Loss of NCoR1 promotes a tip cell position during angiogenic sprouting.
Abstract
Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), silencing mediator of retinoid and thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCOR1 promotes RBPJk activity. Furthermore, NCoR1 depletion prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCOR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function.
Highlights
• TAM polarization induces CP RNA.
• CP RNA expression is regulated by HIF-2 and STAT1.
• CP RNA is transferred from TAMs to HT1080 cells.
• CP RNA is translated by HT1080 cells and protects from ferroptosis.
• Co-cultured HT1080 cells decrease iron and lipid peroxidation.
Abstract
Solid tumors are characterized by hypoxic areas, which are prone for macrophage infiltration. Once infiltrated, macrophages polarize to tumor associated macrophages (TAM) to support tumor progression. Therefore, the crosstalk between TAMs and tumor cells is of current interest for the development of novel therapeutic strategies. These may comprise induction of an iron- and lipid peroxidation-dependent form of cell death, known as ferroptosis. To study the macrophage - tumor cell crosstalk we polarized primary human macrophages towards a TAM-like phenotype, co-cultured them with HT1080 fibrosarcoma cells, and analyzed the tumor cell response to ferroptosis induction. In TAMs the expression of ceruloplasmin mRNA increased, which was driven by hypoxia inducible factor 2 and signal transducer and activator of transcription 1. Subsequently, ceruloplasmin mRNA was transferred from TAMs to HT1080 cells via extracellular vesicles. In tumor cells, mRNA was translated into protein to protect HT1080 cells from RSL3-induced ferroptosis. Mechanistically this was based on reduced iron abundance and lipid peroxidation. Interestingly, in naïve macrophages also hypoxia induced ceruloplasmin under hypoxia and a co-culture of HT1080 cells with hypoxic macrophages recapitulated the protective effect observed in TAM co-cultures. In conclusion, TAMs provoke tumor cells to release iron and thereby protect them from lipid peroxidation/ferroptosis.
The lipid content of skin plays a determinant role in its barrier function with a particularly important role attributed to linoleic acid and its derivatives. Here we explored the consequences of interfering with the soluble epoxide hydrolase (sEH) on skin homeostasis. sEH; which converts fatty acid epoxides generated by cytochrome P450 enzymes to their corresponding diols, was largely restricted to the epidermis which was enriched in sEH-generated diols. Global deletion of the sEH increased levels of epoxides, including the linoleic acid-derived epoxide; 12,13-epoxyoctadecenoic acid (12,13-EpOME), and increased basal keratinocyte proliferation. sEH deletion (sEH-/- mice) resulted in thicker differentiated spinous and corneocyte layers compared to wild-type mice, a hyperkeratosis phenotype that was reproduced in wild-type mice treated with a sEH inhibitor. sEH deletion made the skin sensitive to inflammation and sEH-/- mice developed thicker imiquimod-induced psoriasis plaques than the control group and were more prone to inflammation triggered by mechanical stress with pronounced infiltration and activation of neutrophils as well as vascular leak and increased 12,13-EpOME and leukotriene (LT) B4 levels. Topical treatment of LTB4 antagonist after stripping successfully inhibited inflammation and neutrophil infiltration both in wild type and sEH-/- skin. While 12,13-EpoME had no effect on the trans-endothelial migration of neutrophils, like LTB4, it effectively induced neutrophil adhesion and activation. These observations indicate that while the increased accumulation of neutrophils in sEH-deficient skin could be attributed to the increase in LTB4 levels, both 12,13-EpOME and LTB4 contribute to neutrophil activation. Our observations identify a protective role of the sEH in the skin and should be taken into account when designing future clinical trials with sEH inhibitors.
Evidence-based and comprehensible health information is a key element of evidence-based medicine and public health. The goal is informed decision-making based on realistic estimations of health risks and accurate expectations about benefits and harms of interventions. In Germany, standards of evidence-based risk information were poorly followed during the COVID-19 pandemic. Frequently, public information was biased, fragmentary and misleading. Pandemic-related threat scenarios induced emotional distress and unnecessary anxiety. A systematic and comprehensive evaluation of the pandemic measures is crucial, but still pending in Germany. A critical analysis of risk communication by experts, politicians and the media during the pandemic should be a key element of the evaluation process. Evaluation of decision making and media reporting during the pandemic should improve preparedness for future crises.
Highlights
• CD62p + exosomes were significantly increased in septic polytrauma-patients, while CD40+, as well as CD49e + exosomes were diminished.
• Exosomal IL-6 concentration in septic patients reflects the systemic IL-6.
• Exosomal IL-10 concentration seemed to be constant in patients and healthy controls.
• Decrease of miR-21 in exosomes was associated with the development of sepsis, while exosomal miR-93, miR-155 and miR-92a were not specifically altered.
Abstract
Sepsis as a severe systemic inflammation leads oftentimes to organ dysfunction and subsequently to death. In polytrauma patients, septic complications represent with 45% the predominant cause of late death and are responsible for extremely high costs in the healthcare system. Therefore, clinicians have to detect as early as possible the begin of sepsis to improve the patient's outcome. One new promising diagnostic tool to diagnose septic complications in polytraumatized patients are exosomes.
Plasma samples from polytraumatized patients (Injury Severity Score (ISS) ≥16) which developed sepsis (n = 10) and without sepsis (n = 10), were collected at emergency room (ER), 24h and 5 days after trauma. The EVs subpopulations were investigated by a bead-based multiplex flow cytometry measurement of surface epitopes and were compared with plasma EVs from healthy controls (n = 10). Moreover, exosomal cytokine concentrations were measured via high-sensitive ELISA and were correlated with systemic concentrations. For miRNA cargo analysis, we analysed the miRNAs miR-1298-5p, miR-1262, miR-125b-5p, miR-92a-3p, miR-93-5p, miR-155-5p and miR-21-5p and compared their exosomal concentrations by means of RT-qPCR.
CD62p + exosomes were significantly increased in septic polytrauma-patients (p ≤ 0.05), while CD40+exosomes, as well as CD49e + exosomes were diminished (p ≤ 0.05). Furthermore, we observed that the exosomal IL-6 concentration reflects the systemic IL-6 concentration (r2 = 0.63) and did not significantly alter between patients with and without sepsis. The exosomal IL-10 concentration seemed to be constant in all patients and healthy controls. We observed that a decrease of miR-21-5p in exosomes was associated with the development of sepsis (p ≤ 0.05), while exosomal miR-93-5p, miR-155-5p and miR-92a-3p were not specifically altered in septic patients.
Taken together, the present study in polytraumatized patients demonstrated that the development of sepsis is associated with an increase of CD62p + exosomes. Furthermore, the exosomal cargo was changed in septic patients: miR-21-5p was diminished.
Highlights
• Currently, China has the most publications, ahead of the USA and European countries.
• Research focuses are strictly separated into ecological and material science topics.
• Russia and Ukraine are among the frontrunners with a clear focus on materials science.
• The focus in PFAS research is shifting toward ecological issues.
• A national imbalance can be observed that leaves the low economies behind.
Abstract
The European Commission's current efforts to launch the largest proposal to restrict per- and polyfluoroalkyl substances (PFAS) in history reflect the dire global plight of PFAS accumulation in the environment and their health impacts. While there are existing studies on PFAS research, there is a lack of comprehensive analysis that both covers the entire research period and provides deep insights into global research patterns, incentives, and barriers based on various parameters. We have been able to demonstrate the increasing interest in PFAS research, although citation numbers are declining prematurely. Policy regulations based on proving and establishing the toxicity of PFASs have stimulated research in developed countries and vice versa, with increasing emphasis on ecological aspects. China, in particular, is investing increasingly in PFAS research, but without defining or implementing regulations - with devastating effects. The separation of industrial and environmental research interests is clear, with little involvement of developing countries, even though their exposure to PFAS is devastating. It, therefore, requires increased globally networked and multidisciplinary approaches to address PFAS contamination challenges.
Targeted protein degradation (TPD) has recently emerged as an exciting new drug modality. However, the strategy of developing small molecule-based protein degraders has evolved over the past two decades and has now established molecular tags that are already in clinical use, as well as chimeric molecules, PROteolysis TArgeting Chimeras (PROTACs), based mainly on ligand systems developed for the two E3 ligases CRBN and VHL. The large size of the human E3 ligase family suggests that PROTACs can be developed by targeting a large diversity of E3 ligases, some of which have restricted expression patterns with the potential to design disease- or tissue-specific degraders. Indeed, many new E3 ligands have been published recently, confirming the druggability of E3 ligases. This review summarises recent data on E3 ligases and highlights the challenges in developing these molecules into efficient PROTACs rivalling the established degrader systems.
Background: Trauma-related guilt and shame are crucial for the development and maintenance of PTSD (posttraumatic stress disorder). We developed an intervention combining cognitive techniques with loving-kindness meditations (C-METTA) that specifically target these emotions. C-METTA is an intervention of six weekly individual treatment sessions followed by a four-week practice phase.
Objective: This study examined C-METTA in a proof-of-concept study within a randomized wait-list controlled trial.
Method: We randomly assigned 32 trauma-exposed patients with a DSM-5 diagnosis to C-METTA or a wait-list condition (WL). Primary outcomes were clinician-rated PTSD symptoms (CAPS-5) and trauma-related guilt and shame. Secondary outcomes included psychopathology, self-criticism, well-being, and self-compassion. Outcomes were assessed before the intervention phase and after the practice phase.
Results: Mixed-design analyses showed greater reductions in C-METTA versus WL in clinician-rated PTSD symptoms (d = −1.09), guilt (d = −2.85), shame (d = −2.14), psychopathology and self-criticism.
Conclusion: Our findings support positive outcomes of C-METTA and might contribute to improved care for patients with stress-related disorders. The study was registered in the German Clinical Trials Register (DRKS00023470).
HIGHLIGHTS
C-METTA is an intervention that addresses trauma-related guilt and shame and combines cognitive interventions with loving-kindness meditations.
A proof-of-concept study was conducted examining C-METTA in a wait-list randomized controlled trial
C-METTA led to reductions in trauma-related guilt and shame and PTSD symptoms.
Background: Urachal cancer (UrC) is a rare disease with limited availability of representative incidence and clinical data. Although, the prevalence is accounting for less than 1% of bladder tumors, the 5-year survival rate is around only 50% for patients with resectable tumors, and even worse for patients with metastatic disease. Due to the lack of comprehensive prospective studies, our current knowledge of UrC is still limited.
Objective: The present study aimed to summarize the available registry-based studies with unselected UrC patients to evaluate its incidence and clinicopathological characteristics.
Material and methods: We conducted a systematic literature search of registry-based UrC publications on the 15th of May 2023 in 5 databases, which identified 4,748 publications. After duplicate removal and selection by 2 independent investigators, 6 publications proved to be appropriate for the final meta-analysis. Estimated incidence and clinicopathological parameters were extracted.
Results: Estimated incidence ranged between 0.022 and 0.060/ 100.000 person-years, with the highest occurrence in Japan and the lowest in Canada, while the random effect model calculated an overall incidence rate of 0.04 (95%CI: 0.03–0.05) 100.000 person-years. The median age at first diagnosis was 60 years (range: 58–64). The female to male ratio was 2:3. Lymph node or distant metastases were present in 9% and 14% of patients. The predominant tumour type was adenocarcinoma (86%) followed by urothelial carcinoma (12%) and squamous cell carcinoma (2%). The 5-year survival rate was 51.0% with 95%CI: 45.2–57.4.
Conclusions: Our study provides an up-to-date comparison of estimated incidence rates between 6 countries of 3 continents based on rigorously selected registry-based studies. The results suggest low incidence rates for UrC with considerable geographic differences. The present meta-analysis provides unbiased registry-based data on the incidence, clinicopathological parameters and survival of UrC.
Therapierefraktärer Schmerz ist ein weit verbreitetes, äußerst belastendes Leitsymptom rheumatischer Erkrankungen. Viele Betroffene weichen daher bei Versagen der Standardmedikation selbstständig auf Cannabis oder die strukturell verwandte Substanz Palmitoylethanolamid (PEA) als Add-On- oder Alternativtherapie aus, obwohl dies in Deutschland bisher nur eingeschränkt zulässig ist. Die deutsche Gesetzgebung ist diesbezüglich nicht eindeutig, weshalb Ärzt:innen in ihrer Entscheidung, Cannabis zu verschreiben, auf Leitlinien, Fallberichte und Expert:innenmeinungen zurückgreifen müssen. Dies führt zu schwierigen Einzelfallentscheidungen, da sich die derzeitige Datenlage zu Cannabis-based Medicine (CBM) bzw. PEA und Rheuma als mangelhaft darstellt und die Leitlinien dementsprechend keine klaren Empfehlungen enthalten. Ziel der vorliegenden Arbeit ist es, die vorhandene Evidenz zusammenzufassen, zu ordnen und anhand der Hill-Kriterien den möglichen kausalen Zusammenhang zwischen der Einnahme von CBM bzw. PEA und der analgetischen Wirkung bei Rheumaschmerzen zu prüfen.
Highlights
• Artificial intelligence systems for mechanically ventilated patients are increasing.
• The clinical and financial impact of these models are often unexamined.
• We developed a generic health-economic model for artificial intelligence systems.
• This model assesses the cost-effectiveness for many different scenarios.
• The developed framework is easily adjustable to other (clinical) situations.
Abstract
Purpose: The health and economic consequences of artificial intelligence (AI) systems for mechanically ventilated intensive care unit patients often remain unstudied. Early health technology assessments (HTA) can examine the potential impact of AI systems by using available data and simulations. Therefore, we developed a generic health-economic model suitable for early HTA of AI systems for mechanically ventilated patients.
Materials and methods: Our generic health-economic model simulates mechanically ventilated patients from their hospitalisation until their death. The model simulates two scenarios, care as usual and care with the AI system, and compares these scenarios to estimate their cost-effectiveness.
Results: The generic health-economic model we developed is suitable for estimating the cost-effectiveness of various AI systems. By varying input parameters and assumptions, the model can examine the cost-effectiveness of AI systems across a wide range of different clinical settings.
Conclusions: Using the proposed generic health-economic model, investors and innovators can easily assess whether implementing a certain AI system is likely to be cost-effective before an exact clinical impact is determined. The results of the early HTA can aid investors and innovators in deployment of AI systems by supporting development decisions, informing value-based pricing, clinical trial design, and selection of target patient groups.
Understanding the underlying mechanisms that link psychopathology and physical comorbidities in schizophrenia is crucial since decreased physical fitness and overweight pose major risk factors for cardio-vascular diseases and decrease the patients’ life expectancies. We hypothesize that altered reward anticipation plays an important role in this. We implemented the Monetary Incentive Delay task in a MR scanner and a fitness test battery to compare schizophrenia patients (SZ, n = 43) with sex- and age-matched healthy controls (HC, n = 36) as to reward processing and their physical fitness. We found differences in reward anticipation between SZs and HCs, whereby increased activity in HCs positively correlated with overall physical condition and negatively correlated with psychopathology. On the other handy, SZs revealed stronger activity in the posterior cingulate cortex and in cerebellar regions during reward anticipation, which could be linked to decreased overall physical fitness. These findings demonstrate that a dysregulated reward system is not only responsible for the symptomatology of schizophrenia, but might also be involved in physical comorbidities which could pave the way for future lifestyle therapy interventions.
We provide in this paper a comprehensive comparison of various transfer learning strategies and deep learning architectures for computer-aided classification of adult-type diffuse gliomas. We evaluate the generalizability of out-of-domain ImageNet representations for a target domain of histopathological images, and study the impact of in-domain adaptation using self-supervised and multi-task learning approaches for pretraining the models using the medium-to-large scale datasets of histopathological images. A semi-supervised learning approach is furthermore proposed, where the fine-tuned models are utilized to predict the labels of unannotated regions of the whole slide images (WSI). The models are subsequently retrained using the ground-truth labels and weak labels determined in the previous step, providing superior performance in comparison to standard in-domain transfer learning with balanced accuracy of 96.91% and F1-score 97.07%, and minimizing the pathologist's efforts for annotation. Finally, we provide a visualization tool working at WSI level which generates heatmaps that highlight tumor areas; thus, providing insights to pathologists concerning the most informative parts of the WSI.
MicroRNAs (miRNAs) are critical post-transcriptional regulators in many biological processes. They act by guiding RNA-induced silencing complexes to miRNA response elements (MREs) in target mRNAs, inducing translational inhibition and/or mRNA degradation. Functional MREs are expected to predominantly occur in the 3’ untranslated region and involve perfect base-pairing of the miRNA seed. Here, we generate a high-resolution map of miR-181a/b-1 (miR-181) MREs to define the targeting rules of miR-181 in developing murine T-cells. By combining a multi-omics approach with computational high-resolution analyses, we uncover novel miR-181 targets and demonstrate that miR-181 acts predominantly through RNA destabilization. Importantly, we discover an alternative seed match and identify a distinct set of targets with repeat elements in the coding sequence which are targeted by miR-181 and mediate translational inhibition. In conclusion, deep profiling of MREs in primary cells is critical to expand physiologically relevant targetomes and establish context-dependent miRNA targeting rules.
Key Points:
* Deep profiling identifies novel targets of miR-181 associated with global gene regulation.
* miR-181 MREs in repeat elements in the coding sequence act through translational inhibition.
* High-resolution analysis reveals an alternative seed match in functional MREs.
Highlights
• Deletion of SPPL3 promotes resistance of malignant B cells to NK cell cytotoxicity
• Loss of SPPL3 blocks ligand binding to NK receptors via increased N-glycosylation
• B3GNT2 deletion reduces LacNAc addition and restores SPPL3-KO cell sensitivity to NK cells
• SPPL3-deficient cells are enriched in tetra-antennary N-glycans with LacNAc elongations
Summary
Natural killer (NK) cells are primary defenders against cancer precursors, but cancer cells can persist by evading immune surveillance. To investigate the genetic mechanisms underlying this evasion, we perform a genome-wide CRISPR screen using B lymphoblastoid cells. SPPL3, a peptidase that cleaves glycosyltransferases in the Golgi, emerges as a top hit facilitating evasion from NK cytotoxicity. SPPL3-deleted cells accumulate glycosyltransferases and complex N-glycans, disrupting not only binding of ligands to NK receptors but also binding of rituximab, a CD20 antibody approved for treating B cell cancers. Notably, inhibiting N-glycan maturation restores receptor binding and sensitivity to NK cells. A secondary CRISPR screen in SPPL3-deficient cells identifies B3GNT2, a transferase-mediating poly-LacNAc extension, as crucial for resistance. Mass spectrometry confirms enrichment of N-glycans bearing poly-LacNAc upon SPPL3 loss. Collectively, our study shows the essential role of SPPL3 and poly-LacNAc in cancer immune evasion, suggesting a promising target for cancer treatment.
PET probes targeting fibroblasts are frequently used for varying applications in oncology. In recent years, the clinical spectrum has been expanded towards cardiovascular medicine, e.g., after myocardial infarction, in aortic stenosis or as a non-invasive read-out of atherosclerosis. We herein provide a brief overview of the current status of this PET radiotracer in the context of cardiovascular disease, including translational and clinical evidence. In addition, we will also briefly discuss future applications, e.g., the use of fibroblast-targeting PET to investigate bilateral organ function along the cardiorenal axis.
Lifestyle factors—such as diet, physical activity (PA), smoking, and alcohol consumption—have a significant impact on mortality as well as healthcare costs. Moreover, they play a crucial role in the development of type 2 diabetes mellitus (DM2). There also seems to be a link between lifestyle behaviours and insulin resistance, which is often a precursor of DM2. This study uses an enhanced Healthy Living Index (HLI) integrating accelerometric data and an Ecological Momentary Assessment (EMA) to explore differences in lifestyle between insulin-sensitive (IS) and insulin-resistant (IR) individuals. Moreover, it explores the association between lifestyle behaviours and inflammation. Analysing data from 99 participants of the mPRIME study (57 women and 42 men; mean age 49.8 years), we calculated HLI scores—ranging from 0 to 4— based on adherence to specific low-risk lifestyle behaviours, including non-smoking, adhering to a healthy diet, maximally moderate alcohol consumption, and meeting World Health Organization (WHO) PA guidelines. Insulin sensitivity was assessed using a Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and C-reactive protein (CRP) levels were used as a proxy for inflammation. Lifestyle behaviours, represented by HLI scores, were significantly different between IS and IR individuals (U = 1529.0; p = 0.023). The difference in the HLI score between IR and IS individuals was mainly driven by lower adherence to PA recommendations in the IR group. Moreover, reduced PA was linked to increased CRP levels in the IR group (r = −0.368, p = 0.014). Our findings suggest that enhancing PA, especially among individuals with impaired insulin resistance, holds significant promise as a preventive strategy.
The ICH M13A draft bioequivalence guideline allows the exclusion of very low plasma profiles from the statistical evaluation in exceptional cases, i.e., if such phenomenon occurs due to non-compliance of subjects (not swallowing the product). Moreover, the draft ICH guideline requests additional bioequivalence studies for medicinal products with pH-dependent solubility after concomitant administration of gastric pH modifying preparations, e.g., proton pump inhibitors. Both regulations are scientifically sound, however, would need further specification. Main problem in this context is that compounds with very low solubility and slow intrinsic dissolution in the intestinal environment will cause significant bioavailability problems if their solid oral dosage forms are emptied from the stomach undisintegrated. Also very low plasma profiles may result under these circumstances. Such cases can occur accidentally and are not resultant of non-compliance. Thus, limitation for one case per study only as suggested in the guideline is not justified.
• Mexican and German populations of L. sericata differ in their development times.
• Mexican L. sericata had a shorter development time at 20°C than German flies.
• At 30 °C, German L. sericata pupariated and eclosed earlier than the Mexican flies.
• Differences in study design make the comparison of developmental studies difficult.
Abstract
The cosmopolitan blow fly Lucilia sericata is often used in forensic case work for estimating the minimum postmortem interval (PMImin). For this, the age of immature specimens developing on the dead body is calculated by measuring the time taken to reach the sampled developmental stage at a given temperature. To test whether regional developmental data of L. sericata is valid on a global scale, the time taken to reach different developmental stages was compared between a population from Mexico and one from Germany at two different constant temperatures.
The German population of L. sericata was collected in Frankfurt/Main, while the Mexican population originated near Oaxaca de Juarez and was transported to Germany in the larval stage. Only the F1 generation was used to avoid adaption of the Mexican flies. Eggs were immediately placed at 20 °C and 30 °C. Five times 30 freshly eclosed larvae per replicate (n = 5) were then transferred to a cup of minced meat in separate containers. The larvae were checked every 8 h for migration, pupariation or emergence of adult flies. The time at which the first individual and 50 % of the specimens per container entered each of these stages, was recorded.
Significant differences in the time of development between the two populations were observed at both temperatures. At 20 °C, the first specimens of the Mexican population reached all developmental stages a little (< 1 day to < 2 days) earlier than the German L. sericata. At 30 °C, the Mexican flies also reached the post-feeding stage slightly earlier (0.2 days). However, at 30 °C, the German flies started pupariation significantly earlier (after 5 days) than the Mexican flies (6.9 days) and the adults from Germany also emerged earlier (10.5 days compared to 13.1 days). The same pattern was observed when looking at 50 % of the total number of specimens per container. A comparison with previously published developmental studies was difficult as the experimental design varied widely between studies. However, the results were within the range of most studies. Our study has shown that age estimation can vary widely depending on the population on which the reference data used for the calculations are based. This highlights the importance of using local and population-specific developmental data for estimating the age of blow flies in case work.
Ziel der Arbeit ist es die Eigenschaften und die Häufigkeit von Rezidiven der primär und sekundär therapierten Basalzellkarzinome der MKPG, insbesondere in Abhängigkeit der Lokalisation und des Resektionsstatus zu evaluieren und mit den Ergebnissen der Literatur zu vergleichen, um ein optimiertes chirurgisches Vorgehen zu sichern.
On the current psychotherapeutic situation for persons with pornography use disorder in Germany
(2023)
Background and aims: For the first time, the ICD-11 provides the diagnosis compulsive sexual behavior disorder (CSBD) that can be assigned for pornography use disorder (PUD). This study aimed to estimate the prevalence of PUD and associated consequences in Germany, to identify the psychotherapy demand among likely PUD (lPUD) cases and the treatment supply in different psychotherapeutic settings, to survey psychotherapists' level of expertise regarding PUD, and to identify predictors for psychotherapy demand.
Methods: Four studies were conducted: 1. Online study in the general population (n = 2070; m = 48.9%, f = 50.8%, d = 0.2%), 2. Survey among practicing psychotherapists (n = 983), 3. Survey of psychotherapists in psychotherapeutic outpatient clinics (n = 185), 4. Interviews with psychotherapeutic inpatient clinics (n = 28).
Results: The estimated prevalence of lPUD in the online study was 4.7% and men were 6.3 times more often affected than women. Compared to individuals without PUD, individuals with lPUD more often indicated negative consequences in performance-related areas. Among lPUD cases, 51.2% of men and 64.3% of women were interested in a specialized PUD treatment. Psychotherapists reported 1.2%–2.9% of lPUD cases among their patients. 43.2%–61.5% of psychotherapists stated to be poorly informed about PUD. Only 7% of psychotherapeutic inpatient clinics provided specific treatments to patients with PUD. While, among other factors, negative consequences attributed to lPUD were predictive for psychotherapy demand, weekly pornography consumption, subjective well-being, and religious attachment were not.
Discussion and conclusions: Although PUD occurs quite often in Germany, availability of mental health care services for PUD is poor. Specific PUD treatments are urgently needed.
Zur bisherigen Basisdiagnostik bei klinischem Verdacht eines PCa wird den aktuellen Leitlinien zufolge, neben einer fundierten Anamnese und körperlicher Untersuchung, die Bestimmung des PSA-Wertes gezählt. Seit nun mehr als zwei Jahrzehnten hat sich die PSA-Bestimmung zur Früherkennung, aber auch der Überwachung von Patienten mit bereits diagnostiziertem PCa bewährt. Ob die Bestimmung des PSA-Wertes die PCa-spezifische Mortalität adäquat widerspiegelt, wird allerdings in zahlreichen Expertenkreisen weiterhin kontrovers diskutiert. Anlässlich dessen soll die Erforschung neuer Biomarker dazu dienen, das Risiko eines aggressiven PCa gezielter zu erfassen und behandeln zu können. Die Arbeitsgruppe von Tsaur et al. hat in vorausgegangenen Studien auf das vielversprechende Potential von sE-Cadherin als möglichen Biomarker beim PCa hingewiesen [92]. Basierend darauf wurde in der vorliegenden Arbeit untersucht, wie sich das Serumprotein sE-Cadherin auf PCa-Zelllinien vor allem in Hinblick auf die Metastasierung des PCa am in vitro Modell auswirkt. Die Experimente erfolgten an den beiden Androgen-resistenten Zellen PC3 und DU145 sowie der Androgen-sensitiven Zelllinie LNCaP nach Behandlung mit sE-Cadherin. Unbehandelte Zellen dienten jeweils als Kontrolle. Die ersten Versuche beschäftigten sich damit, eine Arbeitskonzentration des sE-Cadherins zu etablieren, welche nachfolgend für alle weiteren Versuche genutzt werden konnte. Die Arbeitskonzentration von sE-Cadherin wurde auf 5 µg/ml festgelegt. Mithilfe des MTT-Assays wurde nachfolgend das Zellwachstum untersucht. Auswirkungen von sE-Cadherin auf den Zellzyklus der genannten PCa-Zelllinien wurden mithilfe der fluoreszenzaktivierten Zellanalyse (FACS) nach erfolgter Zell-Synchronisation evaluiert. Der Einfluss von sE-Cadherin auf die einzelnen Schritte der Metastasierung wurde durch Migrations- und Invasions- sowie Adhäsions-Versuchen an Zellmatrixproteinen (immobilisiertes Kollagen und Fibronektin) untersucht. Mithilfe der Durchflusszytometrie konnte die Beeinflussung von sE-Cadherin auf die Integrinoberflächenprofile analysiert werden. Zur Evaluation relevanter Signalwege erfolgten Western-Blot-Versuche, in denen der Expressionsstatus von Integrin-assoziierten Signalproteinen untersucht wurde. Blockade-Studien dienten der Überprüfung der funktionellen Relevanz einzelner Integrine. Die Behandlung der PCa-Zellen mit sE-Cadherin in der Konzentration von 5 µg/ml führte zur signifikanten Abnahme des Tumorwachstums. Die Zellzyklus-Analyse zeigte einen vermehrten Zell-Arrest in der G0/G1-Phase sowie Abnahme der S-Phase. Des Weiteren führte die sE-Cadherin-Applikation bei allen drei PCa-Zelllinien zur Abnahme der Adhäsionsfähigkeit an Kollagen und Fibronektin. Im Gegensatz dazu konnte gleichzeitig eine Erhöhung der chemotaktischen Bewegung beobachtet werden. Unter der sE-Cadherin-Behandlung kam es zur signifikanten Veränderung der Oberflächenprofile der Integrin-Subtypen α3 und β1. Dessen physiologische Relevanz konnte in Blockadestudien überprüft werden. Es zeigte sich, dass beide Subtypen, jedoch insbesondere β1, in die Adhäsion und Chemotaxis involviert sind. Abschließend kann in Zusammenschau der Experimente und dessen Resultate geschlussfolgert werden, dass sE-Cadherin maßgeblich das Metastasierungspotenzial der verschiedenen Prostatakarzinomzellen steigert, indem es das Zellwachstum stagnieren lässt und gleichzeitig das Herablösen der Tumorzellen von der extrazellulären Matrix sowie den Anschluss an das Blut-/Lymphabflusssystem erleichtert.
Bei über der Hälfte der Patienten mit einer operationsbedürftigen MI liegt gleichzeitig eine Insuffizienz der TK vor. In den meisten Fällen handelt es sich hierbei um eine funktionelle Insuffizienz welche aus einer RV-Pathologie, bedingt durch eine Volumen- oder Druckbelastung resultiert. In der Vergangenheit bestand die Überzeugung eine konservative Behandlung der TI sei ausreichend und nach Beheben der ursächlichen Grunderkrankung sei diese selbstlimitierend. Neuere Studien konnten jedoch belegen, dass eine bestehende TI auch nach operativer Versorgung einer ursächlichen LV-pathologie keine ausreichende Rückbildungstendenz aufweist, sondern im Verlauf sogar noch progredient ist. Die persistierende TI führt zu einer deutlich erhöhten Morbidität und Mortalität. Ist eine zweizeitige Operation an der TK im Verlauf erforderlich, so ist die Früh- und Spätmortalität deutlich erhöht und die Langzeitergebnisse sind schlecht. Diese Ergebnisse haben dazu geführt, dass die Indikation zur operativen Versorgung der TI ≥ 2 zu einem früheren Zeitpunkt und weniger restriktiv gestellt wird. Jedoch weisen die aktuellen ESC/EACTS-Guidelines insbesondere hinsichtlich der Versorgung einer TI < 2 nur einen niedrigen Evidenz-Grad auf, der richtige Operationszeitpunkt bleibt weiterhin umstritten. Der Grund für eine eher zurückhaltende Einstellung ist vor allem die Angst vor einer erhöhten Morbidität und Mortalität durch den additiven Eingriff. Zudem sind kaum Studien zu einer operativen Versorgung einer TI < 2 vorhanden. Ziel der vorliegenden Arbeit war daher der Gewinn weiterer Erkenntnisse, dieses bis dato kaum untersuchten Patientengutes, insbesondere hinsichtlich der peri- und postoperativen Mortalität, sowie der Auswirkungen der prophylaktischen TKR im Langzeitverlauf. Im Rahmen dieser monozentrischen, prospektiven Studie wurden 264 Patienten eingeschlossen, welche sich im Zeitraum von 2009 bis 2015 einer TKR im Rahmen einer MKR an der Klinik für Thorax- Herz- und thorakaler Gefäßchirurgie des Universitätsklinikums Frankfurt am Main unterzogen. Das Patientenkollektiv wurde nachfolgend in zwei Gruppen unterteilt, nach dem Schweregrad der präoperativ bestehenden TI in eine „prophylaktische” pTKR-Gruppe bei einer TI < 2 und eine „therapeutische” tTKR-Gruppe bei einer TI ≥ 2. Primärer Endpunkt war die Erfassung der Früh- und Spätmortalität. Sekundäres Endziel war die Untersuchung des postoperativen Verlaufes der TI, sowie der Verlauf der kardialen Funktion. Die 30-Tages-Mortalität betrug 12% in der pTKR-Gruppe und 17% in der tTKR-Gruppe. Der wichtigste Einflussfaktor war die EKZ-Dauer. Der Unterschied zwischen den beiden Gruppen war statistisch nicht signifikant. Im Vergleich zu anderen Studien zeigte sich eine höhere 30-Tages-Mortalität, jedoch handelte es sich bei diesen zumeist um einen isolierten Eingriff an der Mitralklappe, mit einer deutlich kürzeren EKZ. Hinsichtlich der Gesamtmortalität zeigte sich ein 1-, 5- und 7-Jahres-Überleben in der pTKR-Gruppe von 81%, 66% und 56%, sowie 65%, 52% und 41% in der tTKR-Gruppe. Die höhere Gesamtmortalität dieser Studie im Vergleich zu anderen Arbeiten ist durch das deutlich ältere und multimorbide Patientenkollektiv erklärt. Bei dem Vergleich von Patienten, welche im Rahmen dieser Studie eine prophylaktische TKR erhielten gegenüber den Patienten, bei welchen im Rahmen von Vergleichsarbeiten bewusst auf eine TKR verzichtet wurde (NTKR-Gruppe), zeigte sich ein verbessertes Langzeitüberleben der pTKR-Gruppe. Bei den Arbeiten, bei welchen kein Überlebensvorteil unserer pTKR-Gruppe, gegenüber deren NTKR-Gruppe gezeigt werden konnte, zeigten sich dennoch positive Effekte der begleitenden Klappenoperation. Die erhöhte Frühsterblichkeit dieser Arbeit ist dem Umstand geschuldet, dass durch die zur Indikationsstellung herangezogenen Risikofaktoren ein Hochrisikokollektiv selektioniert wurde, mit einer konsekutiv erhöhten Sterblichkeit auch abhängig vom Ausmass der TI. Bereits in der Vergangenheit konnte eine Verbesserung des Langzeitüberlebens durch die Durchführung einer TKR bei einer TI ≥ 2, gegenüber dem Verzicht auf diese nachgewiesen werden. Anhand des Vergleiches von anderen Arbeiten mit der vorliegenden Arbeit konnte dieser Überlebensvorteil auch für die Durchführung einer pTKR bei einer TI < 2 gezeigt werden. Zudem konnte dargelegt werden, dass es sich bei der begleitenden pTKR um eine effektive und dauerhafte Methode zur Vermeidung einer Klappeninsuffizienz handelt. Somit konnte gezeigt werden, dass auch bei Patienten mit einer TI < 2 eine additiven TKR die Entwicklung einer späten TI verhindert.
Hintergrund: Der Rettungsdienst versorgt täglich viele Patient/-innen in unterschiedlichen Umgebungen und ist damit auch potentieller Überträger nosokomialer Infektionen. Zur Händehygiene, als entscheidende Säule der Infektionsprophylaxe, liegen bislang nur wenige Daten aus dem Rettungsdienst vor.
Methoden: Prospektive multizentrische Studie mit Fragebogen zur Selbst- und Fremdeinschätzung der Compliance und beeinflussender Faktoren (abgeleitet von der WHO Perception Survey for Health-Care Workers) sowie direkte Compliance-Beobachtung nach WHO-Standard bei Rettungsdienstpersonal zweier Berufsfeuerwehren in Deutschland.
Ergebnisse: Es wurden 207 Fragebögen eingereicht und während ca. 66h Beobachtungszeit wurden 674 Händedesinfektionsgelegenheiten protokolliert. Der präventive Effekt der HH wurde allgemein von den Mitarbeitenden anerkannt. Die Selbsteinschätzung (MW: 80%) und beobachtete Compliance-Rate (38%) zeigten eine deutliche Diskrepanz und die Compliance variierte zwischen den verschiedenen Indikationen. Besonders niedrig zeigte sich die Compliance rund um die Durchführung aseptischer Tätigkeiten. Hier zeichnete sich ein geringes Risikobewusstsein für nicht sichtbare Verunreinigungen ab. Hürden für die Umsetzung der Händehygiene stellten vor allem die Vorrangigkeit anderer Maßnahmen, Unterbrechung des Arbeitsablaufes und Zeitmangel dar.
Schlussfolgerungen: Die beobachtete Compliance-Rate im Rettungsdienst lag unterhalb der innerklinischen Durchschnittswerte. Insbesondere die Compliance im Rahmen aseptischer Tätigkeiten muss dringend gesteigert werden. Dies erfordert einen multimodalen Lösungsansatz, der die Optimierung der Ausbildung, Algorithmen, Materialverfügbarkeit und Praktikabilität der Händedesinfektion im Rettungsdienst beinhaltet.
Lebensqualität, kognitive Leistung und multisensorische Integrationsleistung bei NMOSD Patienten
(2023)
Die Neuromyelitis-optica-Spektrum-Erkrankung (NMOSD) ist eine entzündliche Autoimmunerkrankung des zentralen Nervensystems (ZNS), die schubweise auftritt und meist in den Anfängen aufgrund der symptomatischen Ähnlichkeit mit der Multiplen Sklerose (MS) verwechselt wird. Primär manifestiert sich die NMOSD in Form von Sehstörungen und sensomotorische Lähmungserscheinungen. Im Krankheitsverlauf treten aber auch bei einem Großteil der Patienten kognitive Defizite auf, wobei vorwiegend das Gedächtnis, die Informationsverarbeitung und die Aufmerksamkeit betroffen sind, die nicht in Routineuntersuchungen erfasst werden. Kognitive Beeinträchtigungen wurden bereits bei der MS beschrieben. Ebenso spielt eine verminderte Lebensqualität bei beiden Erkrankungen eine große Rolle. Analog zu Untersuchungen bei MS Patienten, die gezeigt haben, dass kognitive Beeinträchtigungen mitunter ursächlich für die niedrige Lebensqualität sind, wird in dieser Arbeit postuliert, dass auch bei NMOSD Patienten das Ausmaß an kognitiven Dysfunktionen mit dem Grad an Einbußen in der Lebensqualität zusammenhängt. Ferner sollen weitere Prädiktoren ermittelt werden, welche einen Einfluss auf die Lebensqualität haben, wie bereits bestätigt körperliche Einschränkungen. Es wird erwartet, dass NMOSD Patienten von einer verminderten Lebensqualität berichten, die von den schlechteren Ergebnissen in den neuropsychologischen Tests vorhergesagt werden kann.
Zur Untersuchung der Kognition wurde in der vorliegenden Arbeit neben etablierten neuropsychologischen Tests auch die multisensorische Integrationsleistung mithilfe des SiFI Paradigmas angewandt, welche bereits bei MS Patienten und Patienten mit leichten kognitiven Defiziten (mild cognitive impairment; MCI) auffällige Daten lieferte und für eine Testung der globalen Kognitionsleistung genutzt werden konnte. Der Grund für den Einsatz der SiFI waren die nachgewiesenen Hirnkorrelate bei multisensorischer Integration, welche ebenfalls bereits bei kognitiver Dysfunktion festgestellt wurden, wie Atrophien, Konnektivitätsstörungen und Auffälligkeiten in der Transmission bestimmter Neurotransmitter. Ziel dieser Anwendung ist eine Implementierung der SiFI in den Klinikalltag zur erleichterten Erfassung kognitiver Defizite. Viele bekannte neuropsychologischen Tests sind entweder zu teuer, zu lang, abhängig von der sprachlichen Fähigkeit oder für die Patienten zu anstrengend. Die SiFI wäre daher eine gute Alternative als Marker kognitiver Defizite.
20 NMOSD Patienten wurden zu ihrer Lebensqualität (EQ-5D) sowie ihrem psychopathologischen Zustand (SCL-90-R) befragt und es wurde eine umfassende neuropsychologische Testung durchgeführt. Zur Diagnostik der multisensorischen Integrationsleistung wurde die SiFI Aufgabe herangezogen. Die Ergebnisse deuten auf eine verminderte kognitive Leistung mit mittelhohen Werten in den Fragebögen zur Lebensqualität. NMOSD Patienten nahmen die Illusion in der SiFI Aufgabe bei längeren Intervallen wahr, vergleichbar mit MS und MCI Patienten. Dies deutet auf eine verzögerte Integration sensorischer Informationen.
Angefangen mit einem Einblick über die Erkrankung und Darstellung des bisherigen Wissenschaftsstands zu den einzelnen Konstrukten und ihrer Zusammenhänge wird das Studiendesign vorgestellt und die Ergebnisse angegeben und interpretiert. Abschließend folgen eine kritische Beurteilung und Zusammenfassung der vorliegenden Daten mit Ausblick auf weitere Forschungsziele.
Background Vasoplegic syndrome is frequently observed during cardiac surgery and resembles a complication of high mortality and morbidity. There is a clinical need for therapy and prevention of vasoplegic syndrome during complex cardiac surgical procedures. Therefore, we investigated different strategies in a porcine model of vasoplegia.
Methods We evaluated new medical therapies and prophylaxis to avoid vasoplegic syndrome in a porcine model. After induction of anesthesia, cardiopulmonary bypass was established through median sternotomy and central cannulation. Prolonged aortic cross-clamping (120 min) simulated a complex surgical procedure. The influence of sevoflurane-guided anesthesia (sevoflurane group) and the administration of glibenclamide (glibenclamide group) were compared to a control group, which received standard anesthesia using propofol. Online hemodynamic assessment was performed using PiCCO® measurements. In addition, blood and tissue samples were taken to evaluate hemodynamic effects and the degree of inflammatory response.
Results Glibenclamide was able to break through early vasoplegic syndrome by raising the blood pressure and systemic vascular resistance as well as less need of norepinephrine doses. Sevoflurane reduced the occurrence of the vasoplegic syndrome in the mean of stable blood pressure and less need of norepinephrine doses.
Conclusion Glibenclamide could serve as a potent drug to reduce effects of vasoplegic syndrome. Sevoflurane anesthesia during cardiopulmonary bypass shows less occurrence of vasoplegic syndrome and therefore could be used to prevent it in high-risk patients.
Clinical Perspective; what is new?
* to our knowledge, this is the first randomized in vivo study evaluating the hemodynamic effects of glibenclamide after the onset of vasoplegic syndrome
* furthermore according to literature research, there is no study showing the effect of sevoflurane-guided anesthesia on the occurrence of a vasoplegic syndrome
Clinical Perspective; clinical implications?
to achieve better outcomes after complex cardiac surgery there is a need for optimized drug therapy and prevention of the vasoplegic syndrome
To understand the neural mechanisms underlying brain function, neuroscientists aim to quantify causal interactions between neurons, for instance by perturbing the activity of neuron A and measuring the effect on neuron B. Recently, manipulating neuron activity using light-sensitive opsins, optogenetics, has increased the specificity of neural perturbation. However, using widefield optogenetic interventions, multiple neurons are usually perturbed, producing a confound -- any of the stimulated neurons can have affected the postsynaptic neuron making it challenging to discern which neurons produced the causal effect. Here, we show how such confounds produce large biases in interpretations. We explain how confounding can be reduced by combining instrumental variables (IV) and difference in differences (DiD) techniques from econometrics. Combined, these methods can estimate (causal) effective connectivity by exploiting the weak, approximately random signal resulting from the interaction between stimulation and the absolute refractory period of the neuron. In simulated neural networks, we find that estimates using ideas from IV and DiD outperform naive techniques suggesting that methods from causal inference can be useful to disentangle neural interactions in the brain.
Die vorliegende Arbeit stellt eine auf datenwissenschaftlichen Methoden beruhende Analyse des aktuellen Wissens über mögliche kausale Zusammenhänge zwischen therapeutischen Morphinapplikationen mit Todesfällen dar, welche auf computergestützter Extraktion von Information aus frei verfügbaren Wissensdatenbanken und der Analyse der darin enthaltenen numerischen Information besteht. Die Relevanz der vorliegenden Analyse ergibt sich aus dem weltweit breiten Einsatz von Morphin zur Behandlung starker Schmerzen und der immer wieder vorkommenden Todesfälle während einer Morphintherapie, die regelmäßig zu Gerichtsverfahren mit den verschreibenden Ärzten als Angeklagte führen.
Morphin ist ein Opioid und zählt zu den starken Analgetika der WHO Stufe III. Bei der Applikation von Morphin kann es neben der gewünschten Analgesie auch zur Abflachung der Ventilation bis hin zum fatalen Atemstillstand kommen. In der Literatur wird die Inzidenz von Morphin-assoziierten Todesfällen mit 0,3 bis 4% angegeben. So kommt es in einigen Fällen auch zu strafrechtlichen Ermittlungen und Gerichtsverfahren mit dem Verdacht der vorsätzlichen Tötung oder sogar des Mordes. Die Frage, ob eine Morphinapplikation Ursache für den Tod eines Patienten war, ist nicht einfach zu beantworten, was mit einigen Besonderheiten von Opioid-Analgetika im Allgemeinen und von Morphin im Besonderen zusammenhängt. Für Morphin existieren z.B. keine genau definierten maximalen Dosen. Es wurden bisher lediglich Empfehlungen ausgesprochen, abhängig auch davon, ob ein Patient noch „opioid-naiv“ ist oder bereits Opioide einnimmt und damit ein Gewöhnungseffekt eingetreten ist, welcher neben der Analgesie die Gefahr des Atemstillstandes verringert. Grundsätzlich gilt immer, die Dosis so gering wie möglich und so hoch wie nötig zu halten. Die Dosis wird an die Schmerzintensität adaptiert, wobei nach keine maximal erlaubte Dosis existiert. Besonders bei terminal kranken Patienten ist die Kausalität zwischen therapeutischer Morphinapplikation und dem Tode oft fraglich, und es werden regelmäßig Gutachten eingeholt, die meistens von Rechtsmedizinern, Anästhesisten und klinischen Pharmakologen erstellt werden.
In diesen Gutachten müssen viele Faktoren, die die Wirkungen von Morphin bis hin zum letalen Ausgang beeinflussen können, diskutiert wurden, und die daher Hauptinhalt der vorliegenden Arbeit sind. Dazu gehören die verabreichten Morphindosen und die Konzentrationen von Morphin und seiner Metabolite im Blut, aber auch Charakteristika des Patienten, wie Alter, Vorerkrankungen wie z.B. Leber- oder Niereninsuffizienz, Komedikationen, oder pharmakogenetische Faktoren. Darüber hinaus spielt für die zeitliche Zuordnung einer Morphingabe mit dem Tode die verzögerte Verteilung Morphins an seinen Wirkort (das zentrale Nervensystem) eine wichtige Rolle.
Eine weitere Schwierigkeit, die sich bei Morphin-assoziierten Toden darstellt, ist die oft zur Debatte stehende verabreichte Morphindosis, die nachträglich aus den gemessenen Konzentrationen im Blut des Verstorbenen rekonstruiert werden soll, was oft nicht sicher möglich ist. Die postmortal gemessenen Konzentrationen von Morphin unterliegen relevanten Veränderungen aufgrund postmortaler Flüssigkeitsumverteilung oder des Zerfalls von Morphin, aber auch als Folge von Veränderungen während der Lagerung der Proben.
In unserer Analyse und Auswertung der vorhandenen Literatur zu diesen Themen kamen wir zu dem Ergebnis, dass es gegenwärtig praktisch sehr schwer ist, eine Morphindosis oder -konzentration sicher mit dem Tod eines Patienten in Verbindung zu bringen. Somit bleibt jeder Todesfall individuell und kontext-abhängig und erfordert die Berücksichtigung weiterer Aspekte bei der der strafrechtlichen Aufarbeitung. Zudem kamen wir zu dem Entschluss, dass angesichts dieser bereits seit langen bekannten Problemen mit Morphin und aber auch anderen Opioiden (siehe “opioid crisis” in den USA), die Entwicklung von sichereren stark wirksamen Analgetika als Ersatz für Opioide dringlich ist.
Graph data is an omnipresent way to represent information in machine learning. Especially, in neuroscience research, data from Diffusion-Tensor Imaging (DTI) and functional Magnetic Resonance Imaging (fMRI) is commonly represented as graphs. Exploiting the graph structure of these modalities using graph-specific machine learning applications is currently hampered by the lack of easy-to-use software. PHOTONAI Graph aims to close the gap between domain experts of machine learning, graph experts and neuroscientists. Leveraging the rapid machine learning model development features of the Python machine learning API PHOTONAI, PHOTONAI Graph enables the design, optimization, and evaluation of reliable graph machine learning models for practitioners. As such, it provides easy access to custom graph machine learning pipelines including, hyperparameter optimization and algorithm evaluation ensuring reproducibility and valid performance estimates. Integrating established algorithms such as graph neural networks, graph embeddings and graph kernels, it allows researchers without significant coding experience to build and optimize complex graph machine learning models within a few lines of code. We showcase the versatility of this toolbox by building pipelines for both resting–state fMRI and DTI data in the hope that it will increase the adoption of graph-specific machine learning algorithms in neuroscience research.
Control of cell proliferation is critical for the lymphocyte life cycle. However, little is known on how stage-specific alterations in cell-cycle behavior drive proliferation dynamics during T-cell development. Here, we employed in vivo dual-nucleoside pulse labeling combined with determination of DNA replication over time as well as fluorescent ubiquitination-based cell-cycle indicator mice to establish a quantitative high-resolution map of cell-cycle kinetics of thymocytes. We developed an agent-based mathematical model of T-cell developmental dynamics. To generate the capacity for proliferative bursts, cell-cycle acceleration followed a 'stretch model', characterized by simultaneous and proportional contraction of both G1 and S phase. Analysis of cell-cycle phase dynamics during regeneration showed tailored adjustments of cell-cycle phase dynamics. Taken together, our results highlight intrathymic cell-cycle regulation as an adjustable system to maintain physiologic tissue homeostasis and foster our understanding of dysregulation of the T-cell developmental program.
Neuroendokrine Tumoren (NET) sind eine seltene Krankheit mit einem breitgefächerten heterogenen Erscheinungsbild, wodurch sich die Diagnose der Tumoren aus einer Vielzahl aus Gründen häufig um Jahre verzögert (1). In dieser Arbeit analysierten wir einen großen Datensatz in einem tertiären Referenzzentrum (UKF) von 1984-2019, um die Symptomatik vor der Diagnose des Tumors sowie den Zeitraum von der Tumormanifestation bis zur Diagnose weiter zu klären. Für die deskriptiven Analysen kamen SPSS, Cox-Regression und Log-Rank-Test zur Anwendung.
Insgesamt schloss die retrospektive Studie 488 gastroenteropankreastische (GEP)-NET mit 486 Patienten ≥ 18 Jahren ein, wovon knapp mehr als die Hälfte männlich (52,9%) waren. Das mittlere Alter bei Erstdiagnose (ED) betrug 58 Jahre (477/486, 9 unbekannt). Die häufigsten Primärtumorlokalisationen stellten Pankreas (143/488 Patienten) und Dünndarm (145/488 Patienten) dar. Die Mehrheit der NET waren langsam wachsende G1-Tumoren mit einem Ki67 < 3% (155/330). Die Hälfte der Patienten entwickelten im Verlauf Fernmetastasen, wobei die meisten bereits bei der ED vorlagen und insbesondere die Leber als Metastasierungsorgan dominierte. Bei mehr als 60% der Patienten konnten Angaben zur klinischen Symptomatik vor der ED detektiert werden, wovon wiederum mehr als die Hälfte symptomatisch waren. 42% der symptomatischen Patienten zeigten NET-spezifische Symptome (Bauchschmerzen 77/128; 60,2%, Durchfall 51/128; 39,8%, Flush 19/128; 14,8%, Karzinoidsyndrom 8/128; 6,3% Tachykardie 6/128; 4,7%). In der primären bildgebenden Diagnostik dominierten konventionelle Bildgebungen wie Sonographie und Computertomographie (CT), wobei nuklearmedizinische Diagnostik eine Seltenheit darstellte. Mehr als 30% der Tumoren wurden als Zufallsbefunde im Rahmen einer bildgebenden Diagnostik oder Operation diagnostiziert. Die Mehrheit der Patienten stellte sich initial außerhalb unserer Klinik vor, nur etwa 15% wurden innerhalb unserer Klinik insbesondere in der Gastroenterologie vorstellig, wo der NET diagnostiziert wurde.
Die Phase von der Tumormanifestation bis zur ED aller NET betrug im Median 17 Tage. Das Vorhandensein von Fernmetastasen sowie Symptomen führte zu keiner signifikanten Kürzung der Phase und einer schnelleren ED des NET (Median 65,5 vs. 90 Tage, p = 0,4).
Protein post-translational modification with ubiquitin (Ub) is a versatile signal regulating almost all aspects of cell biology, and an increasing range of diseases is associated with impaired Ub modification. In this light, the Ub system offers an attractive, yet underexplored route to the development of novel targeted treatments. A promising strategy for small molecule intervention is posed by the final components of the enzymatic ubiquitination cascade, E3 ligases, as they determine the specificity of the protein ubiquitination pathway. Here, we present UbSRhodol, an autoimmolative Ub-based probe, which upon E3 processing liberates the pro-fluorescent dye, amenable to profile the E3 transthiolation activity for recombinant and in cell-extract E3 ligases. UbSRhodol enabled detection of changes in transthiolation efficacy evoked by enzyme key point mutations or conformational changes, and offers an excellent assay reagent amenable to a high-throughput screening setup allowing the identification of small molecules modulating E3 activity.