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Dysfunctional islets of Langerhans are a hallmark of type 2 diabetes (T2D). We hypothesize that differences in islet gene expression alternative splicing which can contribute to altered protein function also participate in islet dysfunction. RNA sequencing (RNAseq) data from islets of obese diabetes-resistant and diabetes-susceptible mice were analyzed for alternative splicing and its putative genetic and epigenetic modulators. We focused on the expression levels of chromatin modifiers and SNPs in regulatory sequences. We identified alternative splicing events in islets of diabetes-susceptible mice amongst others in genes linked to insulin secretion, endocytosis or ubiquitin-mediated proteolysis pathways. The expression pattern of 54 histones and chromatin modifiers, which may modulate splicing, were markedly downregulated in islets of diabetic animals. Furthermore, diabetes-susceptible mice carry SNPs in RNA-binding protein motifs and in splice sites potentially responsible for alternative splicing events. They also exhibit a larger exon skipping rate, e.g., in the diabetes gene Abcc8, which might affect protein function. Expression of the neuronal splicing factor Srrm4 which mediates inclusion of microexons in mRNA transcripts was markedly lower in islets of diabetes-prone compared to diabetes-resistant mice, correlating with a preferential skipping of SRRM4 target exons. The repression of Srrm4 expression is presumably mediated via a higher expression of miR-326-3p and miR-3547-3p in islets of diabetic mice. Thus, our study suggests that an altered splicing pattern in islets of diabetes-susceptible mice may contribute to an elevated T2D risk.
Background: Patients with subjective cognitive decline (SCD) report memory deterioration and are at an increased risk of converting to Alzheimer's disease (AD) although psychophysical testing does not reveal any cognitive deficit.
Objective: Here, gustatory function is investigated as a potential predictor for an increased risk of progressive cognitive decline indicating higher AD risk in SCD.
Methods: Measures of smell and taste perception as well as neuropsychological data were assessed in patients with subjective cognitive decline (SCD): Subgroups with an increased likelihood of the progression to preclinical AD (SCD+) and those with a lower likelihood (SCD-) were compared to healthy controls (HC), patients with mild cognitive impairment and AD patients. The Sniffin' Sticks test contained 12 items with different qualities and taste was measured with 32 taste stripes (sweet, salty, bitter, sour) of different concentration.
Results: Only taste was able to distinguish between HC/SCD- and SCD+ patients.
Conclusion: This study provides a first hint of taste as a more sensitive marker than smell for detecting preclinical AD in SCD. Longitudinal observation of cognition and pathology are necessary to further evaluate taste perception as a predictor of pathological objective decline in cognition.
Background/objective: Negative emotional states, such as depression, anxiety, and stress challenge health care due to their long-term consequences for mental disorders. Accumulating evidence indicates that regular physical activity (PA) can positively influence negative emotional states. Among possible candidates, resilience and exercise tolerance in particular have the potential to partly explain the positive effects of PA on negative emotional states. Thus, the aim of this study was to investigate the association between PA and negative emotional states, and further determine the mediating effects of exercise tolerance and resilience in such a relationship. Method: In total, 1117 Chinese college students (50.4% female, Mage=18.90, SD=1.25) completed a psychosocial battery, including the 21-item Depression Anxiety Stress Scale (DASS-21), the Connor-Davidson Resilience Scale (CD-RISC), the Preference for and Tolerance of the Intensity of Exercise Questionnaire (PRETIE-Q), and the International Physical Activity Questionnaire short form (IPAQ-SF). Regression analysis was used to identify the serial multiple mediation, controlling for gender, age and BMI. Results: PA, exercise intensity-tolerance, and resilience were significantly negatively correlated with negative emotional states (Ps<.05). Further, exercise tolerance and resilience partially mediated the relationship between PA and negative emotional states. Conclusions: Resilience and exercise intensity-tolerance can be achieved through regularly engaging in PA, and these newly observed variables play critical roles in prevention of mental illnesses, especially college students who face various challenges. Recommended amount of PA should be incorporated into curriculum or sport clubs within a campus environment.
Introduction
Attempts to improve cognitive abilities via transcranial direct current stimulation (tDCS) have led to ambiguous results, likely due to the method's susceptibility to methodological and inter-individual factors. Conventional tDCS, i.e., using an active electrode over brain areas associated with the targeted cognitive function and a supposedly passive reference, neglects stimulation effects on entire neural networks.
Methods
We investigated the advantage of frontoparietal network stimulation (right prefrontal anode, left posterior parietal cathode) against conventional and sham tDCS in modulating working memory (WM) capacity dependent transfer effects of a single-session distractor inhibition (DIIN) training. Since previous results did not clarify whether electrode montage drives this individual transfer, we here compared conventional to frontoparietal and sham tDCS and reanalyzed data of 124 young, healthy participants in a more robust way using linear mixed effect modeling.
Results
The interaction of electrode montage and WM capacity resulted in systematic differences in transfer effects. While higher performance gains were observed with increasing WM capacity in the frontoparietal stimulation group, low WM capacity individuals benefited more in the sham condition. The conventional stimulation group showed subtle performance gains independent of WM capacity.
Discussion
Our results confirm our previous findings of WM capacity dependent transfer effects on WM by a single-session DIIN training combined with tDCS and additionally highlight the pivotal role of the specific electrode montage. WM capacity dependent differences in frontoparietal network recruitment, especially regarding the parietal involvement, are assumed to underlie this observation.
Brain activation during active balancing and its behavioral relevance in younger and older adults
(2022)
Age-related deterioration of balance control is widely regarded as an important phenomenon influencing quality of life and longevity, such that a more comprehensive understanding of the neural mechanisms underlying this process is warranted.
Specifically, previous studies have reported that older adults typically show higher neural activity during balancing as compared to younger counterparts, but the implications of this finding on balance performance remain largely unclear.
Using functional near-infrared spectroscopy (fNIRS), differences in the cortical control of balance between healthy younger (n = 27) and older (n = 35) adults were explored.
More specifically, the association between cortical functional activity and balance performance across and within age groups was investigated. To this end, we measured hemodynamic responses (i.e., changes in oxygenated and deoxygenated hemoglobin) while participants balanced on an unstable device.
As criterion variables for brain-behavior-correlations, we also assessed postural sway while standing on a free-swinging platform and while balancing on wobble boards with different levels of difficulty.
We found that older compared to younger participants had higher activity in prefrontal and lower activity in postcentral regions.
Subsequent robust regression analyses revealed that lower prefrontal brain activity was related to improved balance performance across age groups, indicating that higher activity of the prefrontal cortex during balancing reflects neural inefficiency.
We also present evidence supporting that age serves as a moderator in the relationship between brain activity and balance, i.e., cortical hemodynamics generally appears to be a more important predictor of balance performance in the older than in the younger. Strikingly, we found that age differences in balance performance are mediated by balancing-induced activation of the superior frontal gyrus, thus suggesting that differential activation of this region reflects a mechanism involved in the aging process of the neural control of balance.
Our study suggests that differences in functional brain activity between age groups are not a mere by-product of aging, but instead of direct behavioral relevance for balance performance.
Potential implications of these findings in terms of early detection of fall-prone individuals and intervention strategies targeting balance and healthy aging are discussed.
Coronary artery disease (CAD) is the leading cause of death worldwide.
Statins reduce morbidity and mortality of CAD. Intake of n-3 polyunsaturated fatty acid (n-3 PUFAs), particularly eicosapentaenoic acid (EPA), is associated with reduced morbidity and mortality in patients with CAD. Previous data indicate that a higher conversion of precursor fatty acids (FAs) to arachidonic acid (AA) is associated with increased CAD prevalence.
Our study explored the FA composition in blood to assess n-3 PUFA levels from patients with and without CAD. We analyzed blood samples from 273 patients undergoing cardiac catheterization. Patients were stratified according to clinically relevant CAD (n = 192) and those without (n = 81). FA analysis in full blood was performed by gas chromatography. Indicating increased formation of AA from precursors, the ratio of dihomo-gamma-linolenic acid (DGLA) to AA, the delta-5 desaturase index (D5D index) was higher in CAD patients. CAD patients had significantly lower levels of omega-6 polyunsaturated FAs (n-6 PUFA) and n-3 PUFA, particularly EPA, in the blood.
Thus, our study supports a role of increased EPA levels for cardioprotection.
Die interventionelle Behandlung des Vorhofflimmerns verursacht häufiger als in der Vergangenheit wahrgenommen eine Beeinträchtigung benachbarter Gewebe und Organe. Im Vordergrund der Betrachtungen dieser Arbeit stehen Schäden des Oesophagus, die aufgrund der schlechten Vorhersagbarkeit, des zeitlich verzögerten Auftretens und der fatalen Prognose bei Ausbildung einer atrio-oesophagealen Fistel besondere Relevanz haben.
Das Vorhofflimmern selbst ist nicht mit einer unmittelbaren vitalen Bedrohung verbunden, aber durch seine Komplikationen (z.B. Herzinsuffizienz, Schlaganfall) dennoch prognostisch relevant. Durch Antiarrhythmika gelingt keine Verbesserung der Rhythmuskontrolle (Arrhythmie-Freiheit), eine katheterinterventionelle Behandlung ist der medikamentösen Therapie überlegen. Durch eine frühzeitige und erfolgreiche Behandlung des Vorhofflimmerns konnte eine Verbesserung klinischer Endpunkte und der Prognose erreicht werden. Das Risiko einer invasiven Behandlung (insbesondere hinsichtlich des Auftretens prognoserelevanter Komplikationen) muss jedoch bei der Indikationsstellung und der Prozedur-Durchführung bedacht und gegenüber den günstigen Effekten der Behandlung abgewogen werden.
Untersuchungen zur Vermeidung der sehr seltenen atrio-oesophagealen Fisteln bedienen sich Surrogat-Parametern, hier bisher ausschließlich den ablationsinduzierten Schleimhaut-Läsionen des Oesophagus. Die Untersuchungen dieser Arbeit zeigen ein komplexeres Bild der (peri)-oesophagealen Schädigungen nach Vorhofflimmern-Ablation mit thermischen Energiequellen.
(1) Neue Definition der Oesophagus-Schäden: Oesophageale und perioesophageale Beeinträchtigungen treten sehr häufig auf (nach der hier verwendeten erweiterten Definition bei zwei Drittel der Patienten) und sind unabhängig von der verwendeten Ablationsenergie. Unterschiede finden sich in den Manifestationen der Oesophagus-Schäden für die verschiedenen Energie-Protokolle, ohne dass der Mechanismus hierfür aufgeklärt ist. Diese Arbeit beschreibt die unterschiedlichen Ausprägungen thermischer Oesophagus-Schäden, deren Determinanten und pathophysiologische Relevanz.
(2) Die Detektion (zum Teil subtiler) Oesophagus-Schäden ist maßgeblich von der Intensität der Nachsorge abhängig. Eine Beschränkung auf subjektive Schilderungen (z.B. Schmerzen beim Schluckakt, Sodbrennen) ist irreführend, die Mehrzahl der Veränderungen bleibt asymptomatisch, die Symptome der ausgebildeten atrio-oesophagealen Fistel (meist nach mehreren Wochen) bereits mit einer sehr schlechten Prognose belastet. Eine Endoskopie der Speiseröhre findet in den meisten elektrophysiologischen Zentren nicht oder nur bei anhaltenden Symptomen statt und kann ausschließlich Mukosa-Läsionen nachweisen. Damit wird das Ausmaß des oesophagealen und perioesophagealen Schadens bei Weitem unterschätzt. Veränderungen des perioesophagealen Raums, deren klinische Relevanz (noch) unklar ist, werden nicht erfasst, und damit ein Wandödem und Schäden im Gewebe zwischen linkem Vorhof und Speiseröhre (einschl. Nerven und Gefäßen) ignoriert.
Die Studien tragen auch zur Neubewertung etablierter Messgrößen und Risikofaktoren der Oesophagus-Schäden bei.
(3) Das Temperaturmonitoring im Oesophagus anhand der Maximalabweichungen ist erst für Extremwerte aussagekräftig und dadurch nicht hilfreich, Oesophagus-Läsionen zu vermeiden. Die komplexe Analyse der Temperatur-Rohdaten (bisher nur offline möglich) liefert in der AUC für RF-Ablationen einen prädiktiven Parameter für Oesophagus-Schäden, der eine Strukturierung der weiteren endoskopischen Diagnostik erlaubt. Ein vergleich¬barer Wert für die Cryoablationen konnte in den Analysen nicht gefunden werden.
(4) Eine chronische Entzündung des unteren Oesophagus-Drittels behindert nicht nur das Abheilen einer thermischen Oesophagus-Läsion, sondern kann das Auftreten solcher Läsionen durch die Ablation begünstigen. Die große Zahl vorbestehender Oesophagus-Veränderungen, die eine erhöhte Vulnerabilität anzeigen, und die Bedeutung für die Ent¬stehung thermischer Läsionen können der Ansatzpunkt präventiver Maßnahmen sein.
Ergänzend werden Ausprägungen der Oesophagus-Schäden durch umfangreiche Diagnostik erfasst und beschrieben, die aus pathophysiologischen Überlegungen relevant sein können.
(5) Die systematische Erweiterung der bildgebenden Diagnostik auf den perioesophagealen Raum durch Endosonographie zeigte, dass Schleimhaut-Läsionen alleine nur einen geringen Teil der Oesophagus-Schäden darstellen. Schleimhaut-Läsionen infolge einer instrumentellen Verletzung sind nicht mit dem Risiko der Ausbildung einer atrio-oesophagealen Fistel verbunden und unterstreichen die pathophysiologische Relevanz der perioesophagealen Veränderungen.
(6) Eine funktionelle Diagnostik thermischer Schäden des perioesophagealen Vagus-Plexus identifiziert Patienten mit Oesophagus-Schäden, die bildgebend nicht erfasst wurden, jedoch in ihren Auswirkungen (Nahrungsretention und gastro-oesophagealer Reflux) zur Läsionsprogression beitragen können.
Myasthenia gravis is an autoimmune disease affecting neuromuscular transmission and causing skeletal muscle weakness. Additionally, systemic inflammation, cognitive deficits and autonomic dysfunction have been described.
However, little is known about myasthenia gravis-related reorganization of the brain. In this study, we thus investigated the structural and functional brain changes in myasthenia gravis patients.
Eleven myasthenia gravis patients (age: 70.64 +/- 9.27; 11 males) were compared to age-, sex- and education-matched healthy controls (age: 70.18 +/- 8.98; 11 males). Most of the patients (n = 10, 0.91%) received cholinesterase inhibitors.
Structural brain changes were determined by applying voxel-based morphometry using high-resolution T-1-weighted sequences. Functional brain changes were assessed with a neuropsychological test battery (including attention, memory and executive functions), a spatial orientation task and brain-derived neurotrophic factor blood levels.
Myasthenia gravis patients showed significant grey matter volume reductions in the cingulate gyrus, in the inferior parietal lobe and in the fusiform gyrus. Furthermore, myasthenia gravis patients showed significantly lower performance in executive functions, working memory (Spatial Span, P = 0.034, d = 1.466), verbal episodic memory (P = 0.003, d = 1.468) and somatosensory-related spatial orientation (Triangle Completion Test, P = 0.003, d = 1.200).
Additionally, serum brain-derived neurotrophic factor levels were significantly higher in myasthenia gravis patients (P = 0.001, d = 2.040). Our results indicate that myasthenia gravis is associated with structural and functional brain alterations. Especially the grey matter volume changes in the cingulate gyrus and the inferior parietal lobe could be associated with cognitive deficits in memory and executive functions.
Furthermore, deficits in somatosensory-related spatial orientation could be associated with the lower volumes in the inferior parietal lobe. Future research is needed to replicate these findings independently in a larger sample and to investigate the underlying mechanisms in more detail.
Klaus et al. compared myasthenia gravis patients to matched healthy control subjects and identified functional alterations in memory functions as well as structural alterations in the cingulate gyrus, in the inferior parietal lobe and in the fusiform gyrus.
Risikokommunikation spielt eine zentrale Rolle in Public-Health-Notlagen: Sie muss informierte Entscheidungen ermöglichen, schützendes bzw. lebenserhaltendes Verhalten fördern und das Vertrauen in öffentliche Institutionen bewahren. Zudem müssen Unsicherheiten über wissenschaftliche Erkenntnisse transparent benannt werden, irrationale Ängste und Gerüchte entkräftet werden. Risikokommunikation sollte die Bevölkerung partizipativ einbeziehen. Ihre Risikowahrnehmung und -kompetenz müssen kontinuierlich erfasst werden. In der aktuellen Pandemie der Coronavirus-Krankheit 2019 (COVID-19) ergeben sich spezifische Herausforderungen für die Risikokommunikation.
Der Wissensstand zu vielen wichtigen Aspekten, die COVID-19 betreffen, war und ist oftmals unsicher oder vorläufig, z. B. zu Übertragung, Symptomen, Langzeitfolgen und Immunität. Die Kommunikation ist durch wissenschaftliche Sprache sowie eine Vielzahl von Kennzahlen und Statistiken geprägt, was die Verständlichkeit erschweren kann. Neben offiziellen Mitteilungen und Einschätzungen von Expertinnen und Experten wird über COVID-19 in großem Umfang in sozialen Medien kommuniziert, dabei werden auch Fehlinformationen und Spekulationen verbreitet; diese „Infodemie“ erschwert die Risikokommunikation.
Nationale wie internationale Forschungsprojekte sollen helfen, die Risikokommunikation zu COVID-19 zielgruppenspezifischer und effektiver zu machen. Dazu gehören u. a. explorative Studien zum Umgang mit COVID-19-bezogenen Informationen, das COVID-19 Snapshot Monitoring (COSMO), ein regelmäßig durchgeführtes Onlinesurvey zu Risikowahrnehmung und Schutzverhalten sowie eine interdisziplinäre qualitative Studie, die die Konzeption, Umsetzung und Wirksamkeit von Risikokommunikationsstrategien vergleichend in 4 Ländern untersucht.
Background:
From birth to young adulthood, health and development of young people are strongly linked to their living situation, including their family's socioeconomic position (SEP) and living environment. The impact of regional characteristics on development in early childhood beyond family SEP has been rarely investigated. This study aimed to identify regional predictors of global developmental delay at school entry taking family SEP into consideration.
Method:
We used representative, population-based data from mandatory school entry examinations of the German federal state of Brandenburg in 2018/2019 with n=22,801 preschool children. By applying binary multilevel models, we hierarchically analyzed the effect of regional deprivation defined by the German Index of Socioeconomic Deprivation (GISD) and rurality operationalized as inverted population density of the children's school district on global developmental delay (GDD) while adjusting for family SEP (low, medium and high)
Results:
Family SEP was significantly and strongly linked to GDD. Children with the highest family SEP showed a lower odds for GDD compared to a medium SEP (female: OR=4.26, male: OR=3.46) and low SEP (female: OR=16.58, male: OR=12.79). Furthermore, we discovered a smaller, but additional and independent effect of regional socioeconomic deprivation on GDD, with a higher odds for children from a more deprived school district (female: OR=1.35, male: OR=1.20). However, rurality did not show a significant link to GDD in preschool children beyond family SEP and regional deprivation.
Conclusion:
Family SEP and regional deprivation are risk factors for child development and of particular interest to promote health of children in early childhood and over the life course.
The investigation of protein structures, functions and interactions often requires modifications to adapt protein properties to the specific application. Among many possible methods to equip proteins with new chemical groups, the utilization of orthogonal aminoacyl-tRNA synthetase/tRNA pairs enables the site-specific incorporation of non-canonical amino acids at defined positions in the protein. The open nature of cell-free protein synthesis reactions provides an optimal environment, as the orthogonal components do not need to be transported across the cell membrane and the impact on cell viability is negligible. In the present work, it was shown that the expression of orthogonal aminoacyl-tRNA synthetases in CHO cells prior to cell disruption enhanced the modification of the pharmaceutically relevant adenosine A2a receptor. For this purpose, in complement to transient transfection of CHO cells, an approach based on CRISPR/Cas9 technology was selected to generate a translationally active cell lysate harboring endogenous orthogonal aminoacyl-tRNA synthetase.
Following stroke, neuronal death takes place both in the infarct region and in brain areas distal to the lesion site including the hippocampus. The hippocampus is critically involved in learning and memory processes and continuously generates new neurons. Dysregulation of adult neurogenesis may be associated with cognitive decline after a stroke lesion. In particular, proliferation of precursor cells and the formation of new neurons are increased after lesion. Within the first week, many new precursor cells die during development. How dying precursors are removed from the hippocampus and to what extent phagocytosis takes place after stroke is still not clear. Here, we evaluated the effect of a prefrontal stroke lesion on the phagocytic activity of microglia in the dentate gyrus (DG) of the hippocampus. Three-months-old C57BL/6J mice were injected once with the proliferation marker BrdU (250 mg/kg) 6 hr after a middle cerebral artery occlusion or sham surgery. The number of apoptotic cells and the phagocytic capacity of the microglia were evaluated by means of immunohistochemistry, confocal microscopy, and 3D-reconstructions. We found a transient but significant increase in the number of apoptotic cells in the DG early after stroke, associated with impaired removal by microglia. Interestingly, phagocytosis of newly generated precursor cells was not affected. Our study shows that a prefrontal stroke lesion affects phagocytosis of apoptotic cells in the DG, a region distal to the lesion core. Whether disturbed phagocytosis might contribute to inflammatory- and maladaptive processes including cognitive impairment following stroke needs to be further investigated.
Introduction Airway infection with pathogens and its associated pulmonary exacerbations (PEX) are the major causes of morbidity and premature death in cystic fibrosis (CF). Preventing or postponing chronic infections requires early diagnosis. However, limitations of conventional microbiology-based methods can hamper identification of exacerbations and specific pathogen detection. Analyzing volatile organic compounds (VOCs) in breath samples may be an interesting tool in this regard, as VOC-biomarkers can characterize specific airway infections in CF. Areas covered We address the current achievements in VOC-analysis and discuss studies assessing VOC-biomarkers and fingerprints, i.e. a combination of multiple VOCs, in breath samples aiming at pathogen and PEX detection in people with CF (pwCF). We aim to provide bases for further research in this interesting field. Expert opinion Overall, VOC-based analysis is a promising tool for diagnosis of infection and inflammation with potential to monitor disease progression in pwCF. Advantages over conventional diagnostic methods, including easy and non-invasive sampling procedures, may help to drive prompt, suitable therapeutic approaches in the future. Our review shall encourage further research, including validation of VOC-based methods. Specifically, longitudinal validation under standardized conditions is of interest in order to ensure repeatability and enable inclusion in CF diagnostic routine.
Kraft und Kognition
(2023)
Die in den letzten Jahren aus Querschnittstudien gewonnenen empirischen Erkenntnisse deuten auf einen Zusammenhang zwischen muskulärer Kraftleistungsfähigkeit und kognitiver Leistungsfähigkeit hin [10]. Diese Beobachtung wird von Längsschnittstudien gestützt, bei denen in Folge gezielter Krafttrainingsinterventionen, welche typischerweise zur Steigerung der muskulären Kraftleistungsfähigkeit führen, Verbesserungen der kognitiven Leistungsfähigkeit dokumentiert werden konnten [11]. Die zugrundeliegenden Mechanismen, die den Zusammenhang zwischen muskulärer Kraftleistungsfähigkeit und kognitiver Leistungsfähigkeit begründen, sind jedoch noch nicht vollständig bekannt und bedürfen weiterer Forschung [10,12]. Vor diesem Hintergrund hatten die im Rahmen dieser Dissertation durchgeführten Forschungsarbeiten das übergeordnete Ziel, die Mechanismen zu untersuchen, welche den Zusammenhang zwischen der muskulären Kraftleistungsfähigkeit und der kognitiven Leistungsfähigkeit erklären können. In dieser Arbeit wurden dazu unterschiedliche Populationen (junge Menschen und ältere Menschen ohne und mit leichten kognitiven Störungen) unter Anwendung verschiedener untersuchungsmethodischer Ansätze (systematische Literaturrecherche, Doppelaufgabenparadigma und funktionelle Nahinfrarotspektroskopie) untersucht. Aufgrund der im Rahmen dieser Dissertation durchgeführten Forschungsarbeiten, die konsekutiv aufeinander aufbauen, konnten folgende Haupterkenntnisse gewonnen werden:
• Um einen umfassenden Überblick über die aktuelle Evidenzlage zum Thema Kraftleistungsfähigkeit und kognitiver Leistungsfähigkeit sowie den zugrundeliegenden neuronalen Korrelaten zu erlangen, wurde eine systematische Literaturrecherche zu diesem Forschungsthema durchgeführt. Die Ergebnisse dieser systematischen Literaturrecherche dokumentieren, dass ein gezieltes Krafttraining neben der Steigerung der kognitiven Leistungsfähigkeit zu funktionellen und strukturellen Veränderungen des Gehirns, insbesondere in frontalen Gehirnregionen, führen kann [13]. Ferner zeigen die Ergebnisse dieser systematischen Literaturrecherche, bei der eine begrenzte Anzahl verfügbarer Studien (n = 18) identifiziert wurde, den Bedarf weiterer Forschungsarbeiten zu diesem Themenfeld an [13].
• Zur Überprüfung der Hypothese, dass zur Ausführung von Krafttrainingsübungen höhere kognitive Prozesse benötigt werden, wurde in einer experimentellen Studie bei jüngeren gesunden Erwachsenen das Doppelaufgabenparadigma bei der Krafttrainingsübung Knie-beuge angewendet. Die in dieser Studie beobachteten Doppelaufgabenkosten bei der Ausführung der Krafttrainingsübung Kniebeuge (im Vergleich zur Kontrollbedingung Stehen) deuten auf die Beteiligung höherer kognitiver Prozesse zur Lösung dieser Bewegungsaufgabe hin und bestätigen die aufgestellte Hypothese [14].
• Um die Hypothese zu untersuchen, dass spezifische neuronale Korrelate (funktionelle Gehirnaktivität) den Zusammenhang zwischen muskulärer Kraftleistungsfähigkeit und kognitiver Leistungsfähigkeit vermitteln, wurde bei jungen gesunden Erwachsenen der Zusammenhang zwischen der Ausprägung der maximalen Handgriffkraft (normalisiert auf den Body-Mass-Index) und der kortikalen hämodynamischen Antwortreaktion untersucht, die bei der Durchführung eines standardisierten kognitiven Tests mittels funktioneller Nahinfrarotspektroskopie in präfrontalen Gehirnarealen gemessen wurde. Im Rahmen dieser Querschnittsstudie konnte die initiale Hypothese nicht vollständig bestätigt werden, da zwar Zusammenhänge zwischen maximaler Handgriffkraft und kognitiver Leistungsfähigkeit mit Parametern der hämodynamischen Antwortreaktion beobachtet wurden, aber die Ausprägung der maximalen Handgriffkraft nicht im Zusammenhang mit der Kurzeitgedächtnisleistung stand [16].
• Zur Untersuchung der Annahme, dass eine vorliegende neurologische Erkrankung (im Speziellen eine leichte kognitive Störung), die typischerweise mit Veränderungen von spezifischen neuronalen Korrelaten (z.B. des Hippokampus‘ [17-19] und des präfrontalen Kortex‘ [20,21]) einhergeht, einen Einfluss auf die Assoziation zwischen muskulärer Kraftleistungsfähigkeit und kognitiver Leistungsfähigkeit hat, wurde in einer Querschnittsstudie der Zusammenhang zwischen der Ausprägung der maximalen Handgriffkraft (normalisiert auf den Body-Mass-Index) und der Ausprägung der exekutiven Funktionen bei älteren Erwachsenen mit amnestischem und nicht-amnestischem Subtyp der leichten kognitiven Störung sowie gesunden älteren Erwachsenen untersucht. In dieser Querschnittsstudie wurde nur bei älteren Erwachsenen mit dem amnestischen Subtyp der leichten kognitiven Störung ein Zusammenhang zwischen maximaler Handgriffkraft und exekutiven Funktionen beobachtet. Solch eine Korrelation existiert jedoch nicht bei älteren Erwachsenen mit dem non-amnestischen Subtyp der leichten kognitiven Störung oder bei gesunden älteren Erwachsenen [24].
• In einem Perspektivenartikel wurde aufgezeigt, wie durch die theoriegeleitete Nutzung physiologischer Effekte, die bei einer speziellen Krafttrainingsmethode durch die Moderation des peripheren Blutflusses mittels Manschetten oder Bändern auftreten, insbesondere Populationen mit niedriger mechanischer Belastbarkeit von den positiven Effekten des Krafttrainings auf die Gehirngesundheit profitieren könnten [25].
Insgesamt deuten die Ergebnisse der in dieser Dissertation zusammengeführten und aufeinander aufbauenden Forschungsarbeiten auf das Vorhandensein von gemeinsamen neuronalen Korrelaten (z.B. frontaler Kortex) hin, die sowohl für die muskuläre Kraftleistungsfähigkeit als auch für höhere kognitive Prozesse eine wichtige Rolle spielen [26]. Betrachtet man die in der vorliegenden Dissertation gewonnenen Erkenntnisse im Verbund mit den bereits in der Literatur existieren-den empirischen Belegen, unterstützen sie die Sichtweise, dass eine relativ hohe muskuläre Kraftleistungsfähigkeit und deren Erhalt durch gezielte Krafttrainingsinterventionen über die Lebenspanne positive Effekte auf die (Gehirn-)Gesundheit haben können [27].
Objective
For an effective control of the SARS-CoV-2 pandemic with vaccines, most people in a population need to be vaccinated. It is thus important to know how to inform the public with reference to individual preferences–while also acknowledging the societal preference to encourage vaccinations. According to the health care standard of informed decision-making, a comparison of the benefits and harms of (not) having the vaccination would be required to inform undecided and skeptical people. To test evidence-based fact boxes, an established risk communication format, and to inform their development, we investigated their contribution to knowledge and evaluations of COVID-19 vaccines.
Methods
We conducted four studies (1, 2, and 4 were population-wide surveys with N = 1,942 to N = 6,056): Study 1 assessed the relationship between vaccination knowledge and intentions in Germany over three months. Study 2 assessed respective information gaps and needs of the population in Germany. In parallel, an experiment (Study 3) with a mixed design (presentation formats; pre-post-comparison) assessed the effect of fact boxes on risk perceptions and fear, using a convenience sample (N = 719). Study 4 examined how effective two fact box formats are for informing vaccination intentions, with a mixed experimental design: between-subjects (presentation formats) and within-subjects (pre-post-comparison).
Results
Study 1 showed that vaccination knowledge and vaccination intentions increased between November 2020 and February 2021. Study 2 revealed objective information requirements and subjective information needs. Study 3 showed that the fact box format is effective in adjusting risk perceptions concerning COVID-19. Based on those results, fact boxes were revised and implemented with the help of a national health authority in Germany. Study 4 showed that simple fact boxes increase vaccination knowledge and positive evaluations in skeptics and undecideds.
Conclusion
Fact boxes can inform COVID-19 vaccination intentions of undecided and skeptical people without threatening societal vaccination goals of the population
Nonparametric goodness-of-fit testing for parametric covariate models in pharmacometric analyses
(2021)
The characterization of covariate effects on model parameters is a crucial step during pharmacokinetic/pharmacodynamic analyses. Although covariate selection criteria have been studied extensively, the choice of the functional relationship between covariates and parameters, however, has received much less attention. Often, a simple particular class of covariate-to-parameter relationships (linear, exponential, etc.) is chosen ad hoc or based on domain knowledge, and a statistical evaluation is limited to the comparison of a small number of such classes. Goodness-of-fit testing against a nonparametric alternative provides a more rigorous approach to covariate model evaluation, but no such test has been proposed so far. In this manuscript, we derive and evaluate nonparametric goodness-of-fit tests for parametric covariate models, the null hypothesis, against a kernelized Tikhonov regularized alternative, transferring concepts from statistical learning to the pharmacological setting. The approach is evaluated in a simulation study on the estimation of the age-dependent maturation effect on the clearance of a monoclonal antibody. Scenarios of varying data sparsity and residual error are considered. The goodness-of-fit test correctly identified misspecified parametric models with high power for relevant scenarios. The case study provides proof-of-concept of the feasibility of the proposed approach, which is envisioned to be beneficial for applications that lack well-founded covariate models.
This study investigated whether transcutaneous auricular vagus nerve stimulation (taVNS) enhances reversal learning and augments noradrenergic biomarkers (i.e., pupil size, cortisol, and salivary alpha-amylase [sAA]). We also explored the effect of taVNS on respiratory rate and cardiac vagal activity (CVA). Seventy-one participants received stimulation of either the cymba concha (taVNS) or the earlobe (sham) of the left ear. After learning a series of cue-outcome associations, the stimulation was applied before and throughout a reversal phase in which cue-outcome associations were changed for some (reversal), but not for other (distractor) cues. Tonic pupil size, salivary cortisol, sAA, respiratory rate, and CVA were assessed at different time points. Contrary to our hypothesis, taVNS was not associated with an overall improvement in performance on the reversal task. Compared to sham, the taVNS group performed worse for distractor than reversal cues. taVNS did not increase tonic pupil size and sAA. Only post hoc analyses indicated that the cortisol decline was steeper in the sham compared to the taVNS group. Exploratory analyses showed that taVNS decreased respiratory rate but did not affect CVA. The weak and unexpected effects found in this study might relate to the lack of parameters optimization for taVNS and invite to further investigate the effect of taVNS on cortisol and respiratory rate.
Macrophages in pathologically expanded dysfunctional white adipose tissue are exposed to a mix of potential modulators of inflammatory response, including fatty acids released from insulin-resistant adipocytes, increased levels of insulin produced to compensate insulin resistance, and prostaglandin E-2 (PGE(2)) released from activated macrophages. The current study addressed the question of how palmitate might interact with insulin or PGE(2) to induce the formation of the chemotactic pro-inflammatory cytokine interleukin-8 (IL-8). Human THP-1 cells were differentiated into macrophages. In these macrophages, palmitate induced IL-8 formation. Insulin enhanced the induction of IL-8 formation by palmitate as well as the palmitate-dependent stimulation of PGE(2) synthesis. PGE(2) in turn elicited IL-8 formation on its own and enhanced the induction of IL-8 release by palmitate, most likely by activating the EP4 receptor. Since IL-8 causes insulin resistance and fosters inflammation, the increase in palmitate-induced IL-8 formation that is caused by hyperinsulinemia and locally produced PGE(2) in chronically inflamed adipose tissue might favor disease progression in a vicious feed-forward cycle.
Genetic engineering has provided humans the ability to transform organisms by direct manipulation of genomes within a broad range of applications including agriculture (e.g., GM crops), and the pharmaceutical industry (e.g., insulin production). Developments within the last 10 years have produced new tools for genome editing (e.g., CRISPR/Cas9) that can achieve much greater precision than previous forms of genetic engineering. Moreover, these tools could offer the potential for interventions on humans and for both clinical and non-clinical purposes, resulting in a broad scope of applicability. However, their promising abilities and potential uses (including their applicability in humans for either somatic or heritable genome editing interventions) greatly increase their potential societal impacts and, as such, have brought an urgency to ethical and regulatory discussions about the application of such technology in our society. In this article, we explore different arguments (pragmatic, sociopolitical and categorical) that have been made in support of or in opposition to the new technologies of genome editing and their impact on the debate of the permissibility or otherwise of human heritable genome editing interventions in the future. For this purpose, reference is made to discussions on genetic engineering that have taken place in the field of bioethics since the 1980s. Our analysis shows that the dominance of categorical arguments has been reversed in favour of pragmatic arguments such as safety concerns. However, when it comes to involving the public in ethical discourse, we consider it crucial widening the debate beyond such pragmatic considerations. In this article, we explore some of the key categorical as well sociopolitical considerations raised by the potential uses of heritable genome editing interventions, as these considerations underline many of the societal concerns and values crucial for public engagement. We also highlight how pragmatic considerations, despite their increasing importance in the work of recent authoritative sources, are unlikely to be the result of progress on outstanding categorical issues, but rather reflect the limited progress on these aspects and/or pressures in regulating the use of the technology.