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Unc-51-like kinase 4 (ULK4) is a pseudokinase that has been linked to the development of several diseases. Even though sequence motifs required for ATP binding in kinases are lacking, ULK4 still tightly binds ATP and the presence of the co-factor is required for structural stability of ULK4. Here, we present a high-resolution structure of a ULK4-ATPγS complex revealing a highly unusual ATP binding mode in which the lack of the canonical VAIK motif lysine is compensated by K39, located N-terminal to αC. Evolutionary analysis suggests that degradation of active site motifs in metazoan ULK4 has co-occurred with an ULK4-specific activation loop, which stabilizes the C helix. In addition, cellular interaction studies using BioID and biochemical validation data revealed high confidence interactors of the pseudokinase and armadillo repeat domains. Many of the identified ULK4 interaction partners were centrosomal and tubulin-associated proteins and several active kinases suggesting interesting regulatory roles for ULK4.
Unc-51-like kinase 4 (ULK4) is a pseudokinase that has been linked to the development of several diseases. Even though sequence motifs required for ATP binding in kinases are lacking, ULK4 still tightly binds ATP and the presence of the cofactor is required for structural stability of ULK4. Here we present a high-resolution structure of a ULK4-ATPγS complex revealing a highly unusual ATP binding mode in which the lack of the canonical VAIK motif lysine is compensated by K39, located N-terminal to αC. Evolutionary analysis suggests that degradation of active site motifs in metazoan ULK4 has co-occurred with an ULK4 specific activation loop, which stabilizes the C-helix. In addition, cellular interaction studies using BioID and biochemical validation data revealed high confidence interactors of the pseudokinase and armadillo repeat domains. Many of the identified ULK4 interaction partners were centrosomal and tubulin associated proteins and several active kinases suggesting new roles for ULK4.
Highlights: Structure of the ULK4 ATP complex reveals a unique ATP binding mode.
Disease associated mutations modulate ATP binding and ULK4 stability
Degradation of active site motifs co-occurred in evolution with an ULK4 specific activation loop
BioID suggests a role of ULK4 regulating centrosomal and cytoskeletal functions,
Certain electron-rich 1,4-diborabenzene derivatives efficiently activate single, double, and triple bonds and thereby increasingly compete with transition metals in homogeneous catalysis. This review compares the activation of three model substrates (H2, H2C=CH2, CO2) by (i) 9,10-dihydro-9,10-diboraanthracene dianions, (ii) their neutral carbene-stabilized congeners, (iii) 1,3,2,5-diazadiborinines, and (iv) 1,4,2,5-diazadiborinines. Distinct structure-properties relationships become apparent, the most influential factors being (i) the steric demands of the B-bonded substituents, (ii) the charges on the B-doped (hetero)arenes, (iii) charge polarization as a result of additional N-doping, and (iv) the energies and nodal structures of the frontier orbitals. The observed reactions are explained by a transition metal-like activation mechanism. If the two boron atoms are chemically inequivalent, contributions of a B(+I)/B(+III) mixed-valence state determine the observed regioselectivities when polar substrates are added. The lessons learned from the conversions of the model substrates are subsequently used to rationalize the behavior of the B2 heterocycles also toward more sophisticated substrate molecules. Finally, catalytic cycles based on H2- and H−-transfers, hydroboration reactions, and CO2 reductions will be covered.
Formulation scientists have developed a toolkit of strategies that can improve the solubility and subsequent bioavailability of poorly soluble candidates. Amorphous formulations are especially appealing due to the significant improvement in solubility the amorphous form can provide, but must be stabilized for effective performance (Timpe, 2007).
2. The Importance of Drug Polymer Interactions in Precipitation Inhibition
Polymeric “precipitation inhibitors” have seen widespread usage in the literature (Warren, 2010). The precipitation inhibition effect of polymers on precipitations is related to interference with nucleation and crystal growth (Xu, 2013). Many techniques have been reported in the literature to predict these interactions, however, they are not suitable to screening due to API and time resources required, which are not amenable to early stage pharmaceutical development.
3. Mesoporous Silica: An Emerging Formulation Technology
Mesoporous silicon dioxide has emerged in recent years as a new option for stabilizing the amorphous form. Upon impregnation of the silica with a concentrated drug solution, the drug can be molecularly adsorbed and locally and sterically confined, preventing recrystallization (Ditzinger, 2018). Upon administration of mesoporous silica formulations to the body the amorphous formulation generates supersaturation which must be stabilized using precipitation inhibitors (Guzman, 2007).
4. Co-incorporation: A New Method to Combine Precipitation Inhibitors with Mesoporous Silica
There has been no systematic study of how best to incorporate precipitation inhibitors into mesoporous silica formulations. The current standard practice involves combining inhibitors in a physical mixture with the drug-loaded silica, either by pestle and mortar or overhead stirring. Due to the lack of a defined protocol, there is uncertainty about how reliably the precipitation inhibitor is combined with the drug-loaded silica on a batch to batch basis. In this work, a novel co-incorporated formulation of glibenclamide and the precipitation inhibitor, HPMCAS, onto mesoporous silica was described. By co-incorporating the precipitation inhibitor, the formulation significantly outperformed the commonly applied simple physical blend due to the formation of drug-polymer interactions in the solid state.
5. In Silico Pharmaceutics: A New Method to Select Precipitation Inhibitors for Mesoporous Silica
An approach that can incorporate understanding of the drug-polymer interactions with a quick and efficient screening process would be very useful. The COnductor like Screening MOdel for Real Solvents (COSMO-RS) is a quantum mechanical theory, which can be used to derive thermodynamic properties of interest. (Klamt, 1993, 1995, 2003). We proposed excess mixing enthalpies of drug and polymer could be calculated using the COSMO-RS theory. This new approach was applied to screen precipitation inhibitors for three model compounds, all of which showed a strong positive correlation between the rank assigned based on the calculated free enthalpy of mixing and the overall formulation performance.
6. Conclusion
This body of work aimed to improve the processes underpinning the design and development of mesoporous silica with precipitation inhibitors. Firstly, this involved two extensive literature reviews in the area of solubility enhancement formulation technologies and precipitation inhibition. Secondly, a mechanistic rational and experimental approach was developed to improve the formulation of precipitation inhibitors with mesoporous silica, the “co-incorporation” approach significantly improved process efficiency and formulation performance. Finally, combining insights from the aforementioned review, and learnings from the mechanistic analysis of the “co-incorporation” approach, an in silico screening protocol was developed to calculate the enthalpy of interaction between drug and polymer, to identify the most optimal precipitation inhibitor for a given formulation.
Mesoporous silica has emerged as an enabling formulation for poorly soluble active pharmaceutical ingredients (APIs). Unlike other formulations, mesoporous silica typically does not inhibit precipitation of supersaturated API therefore, a suitable precipitation inhibitor (PI) should be added to increase absorption from the gastrointestinal (GI) tract. However, there is limited research about optimal processes for combining PIs with silica formulations. Typically, the PI is added by simply blending the API-loaded silica mechanically with the selected PI. This has the drawback of an additional blending step and may also not be optimal with regard to release of drug and PI. By contrast, loading PI simultaneously with the API onto mesoporous silica, i.e. co-incorporation, is attractive from both a performance and practical perspective. The aim of this study was to demonstrate the utility of a co-incorporation approach for combining PIs with silica formulations, and to develop a mechanistic rationale for improvement of the performance of silica formulations using the co-incorporation approach. The results indicate that co-incorporating HPMCAS with glibenclamide onto silica significantly improved the extent and duration of drug supersaturation in single-medium and transfer dissolution experiments. Extensive spectroscopic characterization of the formulation revealed that the improved performance was related to the formation of drug-polymer interactions already in the solid state; the immobilization of API-loaded silica on HPMCAS plates, which prevents premature release and precipitation of API; and drug-polymer proximity on disintegration of the formulation, allowing for rapid onset of precipitation inhibition. The data suggests that co-incorporating the PI with the API is appealing for silica formulations from both a practical and formulation performance perspective.
The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome‐mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9‐engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.
The policy studies literature is divided on how information processing takes place in policy processes. Punctuated equilibrium theory claims that policymakers tend to process information disproportionately, giving more weight to some incoming signals than to others. By contrast, thermostatic models of policymaking argue that policymakers respond in a more proportionate way. In this paper, we analyse information processing in the adoption of Total Allowable Catches (TACs) under the European Union’s (EU) Common Fisheries Policy. Based on a novel measure for the proportionality of information processing, it shows that over time TACs have become more closely aligned with incoming signals about fish stocks. This development can be explained through a combination of changing discourses around fisheries conservation and institutional adjustments in EU fisheries policy. This analysis has implications for the debate between punctuated equilibrium and thermostatic models of policymaking and our understanding of the effectiveness of EU fisheries policies.
Knowledge on the postmortem interval (PMI) of wild boar (Sus scrofa) carcasses is crucial in the event of an outbreak of African swine fever in a wild boar population. Therefore, a thorough understanding of the decomposition process of this species in different microhabitats is necessary. We describe the decomposition process of carcasses exposed in cages. Trial 1 compared a wild boar and a domestic pig (Sus scrofa domesticus) under similar conditions; Trial 2 was performed with three wild boar piglets in the sunlight, shade, or in a wallow, and Trial 3 with two adult wild boar in the sun or shade. The wild boar decomposed more slowly than the domestic pig, which shows that standards derived from forensic studies on domestic pigs are not directly applicable to wild boar. The carcasses exposed to the sun decomposed faster than those in the shade did, and the decomposition of the carcass in the wallow took longest. To assess the state of decomposition, we adapted an existing total body scoring system originally developed for humans. Based on our studies, we propose a checklist tailored to wild boar carcasses found in the field that includes the most important information for a reliable PMI estimation.
La Escuela de Frankfurt ha jugado un papel determinante en la recepción posterior del Empirismo Lógico. Sin embargo, la revisión histórica del Empirismo Lógico ha revelado que esta visión partía de ciertas simplificaciones que no hacían justicia a la diversidad y complejidad de posturas que el movimiento incluía. En El ataque más reciente a la Metafísica Horkheimer sostiene que el positivismo es necesariamente irreflexivo y ahistórico en su explicación de las ciencias, y que su carencia de una teoría social que las contextualice lo vuelve incapaz de criticar el rol de la ciencia y de la razón instrumental en su aceptación del orden establecido, comprometiéndolo con una visión conservadora de la política. Se problematizará la atribución hecha al Empirismo Lógico de sostener una concepción de “razón instrumental” generalizada, y se sostendrá que, desde la visión de Neurath, el carácter auto-reflexivo de la ciencia admite una consideración crítica de los fines y propósitos del conocimiento.
Background: Ever decreasing costs along with advances in sequencing and library preparation technologies enable even small research groups to generate chromosome-level assemblies today. Here we report the generation of an improved chromosome-level assembly for the Siamese fighting fish (Betta splendens) that was carried out during a practical university Master’s course. The Siamese fighting fish is a popular aquarium fish and an emerging model species for research on aggressive behaviour. We updated the current genome assembly by generating a new long-read nanopore-based assembly with subsequent scaffolding to chromosome-level using previously published HiC data.
Findings: The use of nanopore-based long-read data sequenced on a MinION platform (Oxford Nanopore Technologies) allowed us to generate a baseline assembly of only 1,276 contigs with a contig N50 of 2.1 Mbp, and a total length of 441 Mbp. Scaffolding using previously published HiC data resulted in 109 scaffolds with a scaffold N50 of 20.7 Mbp. More than 99% of the assembly is comprised in 21 scaffolds. The assembly showed the presence of 95.8% complete BUSCO genes from the Actinopterygii dataset indicating a high quality of the assembly.
Conclusion: We present an improved full chromosome-level assembly of the Siamese fighting fish generated during a university Master’s course. The use of ~35× long-read nanopore data drastically improved the baseline assembly in terms of continuity. We show that relatively in-expensive high-throughput sequencing technologies such as the long-read MinION sequencing platform can be used in educational settings allowing the students to gain practical skills in modern genomics and generate high quality results that benefit downstream research projects.
From 1945 to the early 1960s, the US government undertook numerous atomic and hydrogen bomb tests. These full-scale explosions were recorded on film from various angles, and at different speeds. Indeed, it soon became required to obtain images of the very first milli-seconds of the expanding phase of the atomic fireball. Ultrahigh-speed cameras able to produce such images were specifically developed for that purpose. This article explores the different “media-temporalities” that intersect in those images. I focus on the “micro-processes happening on a technical level that are very fast,” and more specifically the ones that go into the “Rapatronic camera” designed by Harold Edgerton (head of the US national defense contractor company EG&G) to record the atomic fireball early formation. The scientific slow-motion films and high-speed photographic images operate at the junction of the micro-scale temporality of the atomic explosions’ early phases, and the macro-scale temporality of the political and ecological implications of these explosions. I argue that these films are the objects and inscriptions of micro-temporalities, macro-history and geological times.
Importance Coronavirus disease 2019 (COVID-19) continues to cause considerable morbidity and mortality worldwide. Case reports of hospitalized patients suggest that COVID-19 prominently affects the cardiovascular system, but the overall impact remains unknown.
Objective To evaluate the presence of myocardial injury in unselected patients recently recovered from COVID-19 illness.
Design, Setting, and Participants In this prospective observational cohort study, 100 patients recently recovered from COVID-19 illness were identified from the University Hospital Frankfurt COVID-19 Registry between April and June 2020.
Exposure Recent recovery from severe acute respiratory syndrome coronavirus 2 infection, as determined by reverse transcription–polymerase chain reaction on swab test of the upper respiratory tract.
Main Outcomes and Measures Demographic characteristics, cardiac blood markers, and cardiovascular magnetic resonance (CMR) imaging were obtained. Comparisons were made with age-matched and sex-matched control groups of healthy volunteers (n = 50) and risk factor–matched patients (n = 57).
Results Of the 100 included patients, 53 (53%) were male, and the mean (SD) age was 49 (14) years. The median (IQR) time interval between COVID-19 diagnosis and CMR was 71 (64-92) days. Of the 100 patients recently recovered from COVID-19, 67 (67%) recovered at home, while 33 (33%) required hospitalization. At the time of CMR, high-sensitivity troponin T (hsTnT) was detectable (greater than 3 pg/mL) in 71 patients recently recovered from COVID-19 (71%) and significantly elevated (greater than 13.9 pg/mL) in 5 patients (5%). Compared with healthy controls and risk factor–matched controls, patients recently recovered from COVID-19 had lower left ventricular ejection fraction, higher left ventricle volumes, and raised native T1 and T2. A total of 78 patients recently recovered from COVID-19 (78%) had abnormal CMR findings, including raised myocardial native T1 (n = 73), raised myocardial native T2 (n = 60), myocardial late gadolinium enhancement (n = 32), or pericardial enhancement (n = 22). There was a small but significant difference between patients who recovered at home vs in the hospital for native T1 mapping (median [IQR], 1119 [1092-1150] ms vs 1141 [1121-1175] ms; P = .008) and hsTnT (4.2 [3.0-5.9] pg/dL vs 6.3 [3.4-7.9] pg/dL; P = .002) but not for native T2 mapping. None of these measures were correlated with time from COVID-19 diagnosis (native T1: r = 0.07; P = .47; native T2: r = 0.14; P = .15; hsTnT: r = −0.07; P = .50). High-sensitivity troponin T was significantly correlated with native T1 mapping (r = 0.33; P < .001) and native T2 mapping (r = 0.18; P = .01). Endomyocardial biopsy in patients with severe findings revealed active lymphocytic inflammation. Native T1 and T2 were the measures with the best discriminatory ability to detect COVID-19–related myocardial pathology.
Conclusions and Relevance In this study of a cohort of German patients recently recovered from COVID-19 infection, CMR revealed cardiac involvement in 78 patients (78%) and ongoing myocardial inflammation in 60 patients (60%), independent of preexisting conditions, severity and overall course of the acute illness, and time from the original diagnosis. These findings indicate the need for ongoing investigation of the long-term cardiovascular consequences of COVID-19.
Short linear motifs (SLiMs) located in disordered regions of multidomain proteins are important for the organization of protein–protein interaction networks. By dynamic association with their binding partners, SLiMs enable assembly of multiprotein complexes, pivotal for the regulation of various aspects of cell biology in higher organisms. Despite their importance, there is a paucity of molecular tools to study SLiMs of endogenous proteins in live cells. LC3 interacting regions (LIRs), being quintessential for orchestrating diverse stages of autophagy, are a prominent example of SLiMs and mediate binding to the ubiquitin-like LC3/GABARAP family of proteins. The role of LIRs ranges from the posttranslational processing of their binding partners at early stages of autophagy to the binding of selective autophagy receptors (SARs) to the autophagosome. In order to generate tools to study LIRs in cells, we engineered high affinity binders of LIR motifs of three archetypical SARs: OPTN, p62, and NDP52. In an array of in vitro and cellular assays, the engineered binders were shown to have greatly improved affinity and specificity when compared with the endogenous LC3/GABARAP family of proteins, thus providing a unique possibility for modulating LIR interactions in living systems. We exploited these novel tools to study the impact of LIR inhibition on the fitness and the responsiveness to cytarabine treatment of THP-1 cells – a model for studying acute myeloid leukemia (AML). Our results demonstrate that inhibition of LIR of a single autophagy receptor is insufficient to sensitize the cells to cytarabine, while simultaneous inhibition of three LIR motifs in three distinct SARs reduces the IC50 of the chemotherapeutic.
Background: Meta-analysis of observational studies concluded that soft drinks may increase the risk of depression, while high consumption of coffee and tea may reduce the risk. Objectives were to explore the associations between the consumption of soft drinks, coffee or tea and: (1) a history of major depressive disorder (MDD) and (2) the severity of depressive symptoms clusters (mood, cognitive and somatic/vegetative symptoms). Methods: Cross-sectional and longitudinal analysis based on baseline and 12-month-follow-up data collected from four countries participating in the European MooDFOOD prevention trial. In total, 941 overweight adults with subsyndromal depressive symptoms aged 18 to 75 years were analyzed. History of MDD, depressive symptoms and beverages intake were assessed. Results: Sugar-sweetened soft drinks were positively related to MDD history rates whereas soft drinks with non-nutritive sweeteners were inversely related for the high vs. low categories of intake. Longitudinal analysis showed no significant associations between beverages and mood, cognitive and somatic/vegetative clusters. Conclusion: Our findings point toward a relationship between soft drinks and past MDD diagnoses depending on how they are sweetened while we found no association with coffee and tea. No significant effects were found between any studied beverages and the depressive symptoms clusters in a sample of overweight adults.
We explore the tilted-pulse-front excitation technique to control the superradiant emission of terahertz (THz) pulses from large-area photonconductive semiconductor switches. Two cases are studied. First, a photoconductive antenna emitting into free space, where the propagation direction of the optically generated THz beam is controlled by the choice of the tilt angle of the pump pulse front. Second, a THz waveguide structure with an integrated photoconductive window for the generation of THz radiation, where the injection of the THz radiation into a waveguide mode is optimized by the pulse front tilt. By providing long interaction lengths, such a waveguide-based optical-pump/THz-probe set-up may provide a new platform for the study of diverse short-lived optically induced excitations.
Background and Aims: Monocyte chemotactic protein-1 (MCP-1) is a potent chemoattractant for monocytes. It is involved in pathogenesis of several inflammatory diseases. Hepatic MCP-1 is a readout of macrophage activation. While inflammation is a major driver of liver disease progression, the origin and role of circulating MCP-1 as a biomarker remains unclear.
Methods: Hepatic CC-chemokine ligand 2 (CCL2) expression and F4/80 staining for Kupffer cells were measured and correlated in a mouse model of chronic liver disease (inhalative CCl4 for 7 weeks). Next, hepatic RNA levels of CCL2 were measured in explanted livers of 39 patients after transplantation and correlated with severity of disease. Changes in MCP-1 were further evaluated in a rat model of experimental cirrhosis and acute-on-chronic liver failure (ACLF). Finally, we analyzed portal and hepatic vein levels of MCP-1 in patients receiving transjugular intrahepatic portosystemic shunt insertion for complications of portal hypertension.
Results: In this mouse model of fibrotic hepatitis, hepatic expression of CCL2 (P = 0.009) and the amount of F4/80 positive cells in the liver (P < 0.001) significantly increased after induction of hepatitis by CCl4 compared to control animals. Moreover, strong correlation of hepatic CCL2 expression and F4/80 positive cells were seen (P = 0.023). Furthermore, in human liver explants, hepatic transcription levels of CCL2 correlated with the MELD score of the patients, and thus disease severity (P = 0.007). The experimental model of ACLF in rats revealed significantly higher levels of MCP-1 plasma (P = 0.028) and correlation of hepatic CCL2 expression (R = 0.69, P = 0.003). Particularly, plasma MCP-1 levels did not correlate with peripheral blood monocyte CCL2 expression. Finally, higher levels of MCP-1 were observed in the hepatic compared to the portal vein (P = 0.01) in patients receiving TIPS. Similarly, a positive correlation of MCP-1 with Child-Pugh score was observed (P = 0.018). Further, in the presence of ACLF, portal and hepatic vein levels of MCP-1 were significantly higher compared to patients without ACLF (both P = 0.039).
Conclusion: Circulating levels of MCP-1 mainly derive from the injured liver and are associated with severity of liver disease. Therefore, liver macrophages contribute significantly to disease progression. Circulating MCP-1 may reflect the extent of hepatic macrophage activation.
Alcoholism is one of the leading and increasingly prevalent reasons of liver associated morbidity and mortality worldwide. Alcoholic hepatitis (AH) constitutes a severe disease with currently no satisfying treatment options. Lipoxin A4 (LXA4), a 15-lipoxygenase (ALOX15)-dependent lipid mediator involved in resolution of inflammation, showed promising pre-clinical results in the therapy of several inflammatory diseases. Since inflammation is a main driver of disease progression in alcoholic hepatitis, we investigated the impact of endogenous ALOX15-dependent lipid mediators and exogenously applied LXA4 on AH development. A mouse model for alcoholic steatohepatitis (NIAAA model) was tested in Alox12/15+/+ and Alox12/15−/− mice, with or without supplementation of LXA4. Absence of Alox12/15 aggravated parameters of liver disease, increased hepatic immune cell infiltration in AH, and elevated systemic neutrophils as a marker for systemic inflammation. Interestingly, i.p. injections of LXA4 significantly lowered transaminase levels only in Alox12/15−/− mice and reduced hepatic immune cell infiltration as well as systemic inflammatory cytokine expression in both genotypes, even though steatosis progressed. Thus, while LXA4 injection attenuated selected parameters of disease progression in Alox12/15−/− mice, its beneficial impact on immunity was also apparent in Alox12/15+/+ mice. In conclusion, pro-resolving lipid mediators may be beneficial to reduce inflammation in alcoholic hepatitis.
Bei der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) handelt es sich um eine hochprävalente Erkrankung, die bisher insbesondere im Erwachsenenalter nur unzureichend berücksichtigt wurde. Neben den Kernsymptomen bestehend aus Einschränkungen in der Aufmerksamkeit sowie einem erhöhten Maß an Hyperaktivität und Impulsivität gilt es, Komorbiditäten und Beeinträchtigungen zu berücksichtigen, die mit dieser Erkrankung einhergehen. In früheren Studien konnte bereits nachgewiesen werden, dass sowohl Kinder als auch Erwachsene mit einer ADHS vermehrte Unfälle und infolgedessen eine erhöhte Rate an stationären Behandlungen aufweisen. Zusätzlich besteht bei ADHS-Betroffenen ein höheres Risiko, frühzeitig zu versterben, wobei Unfälle als unnatürliche Todesursache den häufigsten Grund darstellen. Bisher existieren auf internationaler Ebene einige Studien, die sich mit den Zusammenhängen von adulter ADHS und Unfallraten beschäftigten. Eine differenzierte Betrachtung, die eine deutsche Population einschließt und den Einfluss des Geschlechts auf das Unfallgeschehen bei ADHS-Betroffenen untersucht, wurde bisher nicht realisiert. Aus diesen Gründen führten wir eine Querschnittsstudie auf unfallchirurgischen Stationen an zwei Kliniken in Frankfurt am Main durch. Im Rahmen der Studie sollte die Prävalenz von adulter ADHS bei stationär betreuten Unfallopfern ermittelt und mögliche unfallcharakteristische Unterschiede zwischen den Geschlechtern der ADHS-Positivkohorte erfasst werden.
Mithilfe der etablierten Adult ADHD Self-Report Scale (ASRS v1.1) der WHO wurden alle Unfallopfer, die den Einschlusskriterien entsprachen, auf adulte ADHS gescreent. Bei der Auswertung des ASRS verwendeten wir zwei unterschiedliche Methoden, die bereits in früheren Studien zur Anwendung kamen. Durch einen eigens erstellten Unfallfragebogen konnten Unfallcharakteristika sowie psychische Komorbiditäten der ADHSPositivkohorte erfasst werden. Zusätzlich erhoben wir zum Vergleich die Unfallcharakteristika bei einer nicht von ADHS betroffenen Kontrollgruppe. Bei einem Teil der positiv gescreenten Patienten wurde eine ausführliche Testung in der ADHS Spezialambulanz des Universitätsklinikums Frankfurt am Main vorgenommen. Mittels diagnostischer Interviews und weiteren Selbstauskunftsfragebögen (DIVA, HASE) konnte eine definitive ADHS-Diagnose gestellt und das positive Screeningergebnis verifiziert werden.
Wir stellten fest, dass die Prävalenz adulter ADHS unter Unfallopfern mit 6,89 % bzw. 8,68 % in Abhängigkeit der ASRS Auswertungskriterien im Vergleich zu der Prävalenz der adulten ADHS in der Allgemeinbevölkerung erhöht war. Des Weiteren gab es mehr Männer mit einem positiven ADHS-Screeningergebnis und einem Unfallgeschehen. Es konnten keine signifikanten geschlechtsspezifischen Unterschiede in den Unfallcharakteristika und Unfallorten in der ADHS Positivkohorte festgestellt werden. Auch in dem Vorhandensein psychischer Komorbiditäten unterschieden sich die beiden Geschlechtergruppen der ADHS-Positivkohorte nicht. Unabhängig der Geschlechterzugehörigkeit wurden die meisten Unfälle der ADHS-Positivkohorte im Straßenverkehr verzeichnet und als selbstverschuldet eingestuft. Es konnten signifikant mehr Unfälle außerhalb des Straßenverkehrs in der nicht von ADHS betroffenen Kontrollgruppe im Vergleich zu der ADHS Positivkohorte nachgewiesen werden. Insgesamt war nur bei 14 % aller positiv gescreenten Patienten eine ADHS-Erkrankung bereits bekannt und diagnostiziert worden.
Auf Grundlage der Ergebnisse dieser Studie lässt sich schlussfolgern, dass Menschen mit einer ADHS-Symptomatik vermehrt auf unfallchirurgischen Stationen anzutreffen sind und im Einklang mit früheren Forschungsergebnissen ein erhöhtes Unfall- und Verletzungsrisiko aufweisen. Darüber hinaus folgern wir aus unseren Ergebnissen, dass sich Männer und Frauen mit einer ADHS-Erkrankung hinsichtlich Symptomatik, Komorbidität und spezifischer Unfallcharakteristika ähnlicher sein könnten, als dass sie sich in diesen Bereichen unterscheiden. Im Hinblick auf die geringen vorbestehenden ADHS-Diagnosen in der Positivkohorte erscheint eine Etablierung eines Screeningsystems bei Patienten sinnvoll, die im Rahmen von Unfallgeschehen gehäuft stationär betreut werden müssen. Da ADHS-Betroffene ein erhöhtes Risiko für multiple Unfälle zu haben scheinen, könnte unter diesen Voraussetzungen eine adulte ADHS-Symptomatik früher erkannt und negative Folgen wie eine erhöhte Unfallrate reduziert werden. Methodologische Limitierungen bestanden in unserer Erhebung durch eine geringe Anzahl an ausführlichen Testungen zur Verifizierung der ADHS-Diagnose sowie dem Informationsgewinn auf der Basis einer Selbstauskunft. Um Ergebnisse aussagekräftiger zu gestalten und auch kleinere Unfälle zu erfassen, erscheint eine Ausweitung der Testung in Ambulanzen sinnvoll.