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Background: Protection against airborne infection is currently, due to the COVID-19-associated restrictions, ubiquitously applied during public transport use, work and leisure time. Increased carbon dioxide re-inhalation and breathing resistance may result thereof and, in turn, may negatively impact metabolism and performance.
Objectives: To deduce the impact of the surgical mask and filtering face piece type 2 (FFP2) or N95 respirator application on gas exchange (pulse-derived oxygen saturation (SpO2), carbon dioxide partial pressure (PCO2), carbon dioxide exhalation (VCO2) and oxygen uptake (VO2)), pulmonary function (respiratory rate and ventilation) and physical performance (heart rate HR, peak power output Wpeak).
Methods: Systematic review with meta-analysis. Literature available in Medline/Pubmed, the Cochrane Library and the Web of Knowledge with the last search on the 6th of May 2021. Eligibility criteria: Randomised controlled parallel group or crossover trials (RCT), full-text availability, comparison of the acute effects of ≥ 1 intervention (surgical mask or FFP2/N95 application) to a control/comparator condition (i.e. no mask wearing). Participants were required to be healthy humans and > 16 years of age without conditions or illnesses influencing pulmonary function or metabolism. Risk of bias was rated using the crossover extension of the Cochrane risk of bias assessment tool II. Standardised mean differences (SMD, Hedges' g) with 95% confidence intervals (CI) were calculated, overall and for subgroups based on mask and exercise type, as pooled effect size estimators in our random-effects meta-analysis.
Results: Of the 1499 records retrieved, 14 RCTs (all crossover trials, high risk of bias) with 25 independent intervention arms (effect sizes per outcome) on 246 participants were included. Masks led to a decrease in SpO2 during vigorous intensity exercise (6 effect sizes; SMD = − 0.40 [95% CI: − 0.70, − 0.09], mostly attributed to FFP2/N95) and to a SpO2-increase during rest (5 effect sizes; SMD = 0.34 [95% CI: 0.04, 0.64]); no general effect of mask wearing on SpO2 occurred (21 effect sizes, SMD = 0.34 [95% CI: 0.04, 0.64]). Wearing a mask led to a general oxygen uptake decrease (5 effect sizes, SMD = − 0.44 [95% CI: − 0.75, − 0.14]), to slower respiratory rates (15 effect sizes, SMD = − 0.25 [95% CI: − 0.44, − 0.06]) and to a decreased ventilation (11 effect sizes, SMD = − 0.43 [95% CI: − 0.74, − 0.12]). Heart rate (25 effect sizes; SMD = 0.05 [95% CI: − 0.09, 0.19]), Wpeak (9 effect sizes; SMD = − 0.12 [95% CI: − 0.39, 0.15]), PCO2 (11 effect sizes; SMD = 0.07 [95% CI: − 0.14, 0.29]) and VCO2 (4 effect sizes, SMD = − 0.30 [95% CI: − 0.71, 0.10]) were not different to the control, either in total or dependent on mask type or physical activity status.
Conclusion: The number of crossover-RCT studies was low and the designs displayed a high risk of bias. The within-mask- and -intensity-homogeneous effects on gas exchange kinetics indicated larger detrimental effects during exhausting physical activities. Pulse-derived oxygen saturation was increased during rest when a mask was applied, whereas wearing a mask during exhausting exercise led to decreased oxygen saturation. Breathing frequency and ventilation adaptations were not related to exercise intensity. FFP2/N95 and, to a lesser extent, surgical mask application negatively impacted the capacity for gas exchange and pulmonary function but not the peak physical performance.
Registration: Prospero registration number: CRD42021244634
Hintergrund: Dehntrainings sind eine Maßnahme der betrieblichen Gesundheitsförderung (BGF) für Büroangestellte zur Prävention von muskuloskeletalen Erkrankungen (MSE). Sie können zu Beweglichkeitszuwächsen führen und auf psychischer Ebene entspannen. Ziel der Studie war es, ein standardisiertes und individualisiertes Dehntraining am Gerät, das „five-Business“, auf MSE, Lebensqualität und Beweglichkeit zu untersuchen. Dies ist eine Zusammenfassung der international publizierten Ergebnisse.
Methodik: In diese Untersuchung wurden 252 Proband(innen) eingeschlossen, 156 in die Interventionsgruppe (IG), 96 in die Kontrollgruppe (KG). Die IG absolvierte für 12 Wochen 22–24 Trainingseinheiten am „five-Business“, möglichst zweimal wöchentlich. Die Datenerhebung erfolgte mittels sportmotorischer bzw. Range-of-motion(ROM)-Tests, dem Nordic Questionnaire (NQ) und dem SF-36-Fragebogen in Form einer Prä-Post-Untersuchung.
Ergebnisse: Nach der Intervention gaben im NQ signifikant weniger Proband(innen) der IG Beschwerden im oberen Rücken (p < 0,001) im Vergleich zur KG an; keine signifikanten Unterschiede wurden bei Beschwerden im Nacken, Schultern, Hüfte und dem unteren Rücken gefunden. Der mit dem SF-36 erhobene allgemeine Gesundheitszustand und die gesundheitsbezogene Lebensqualität haben sich (nach subjektiven Angaben) signifikant verbessert (Summenscore IG: p = 0,005). In den ROM-Tests waren die Prä-Post-Differenzen bei IG-Proband(innen) in der Sagittalebene (Finger-Boden-Abstand und Retroflexion; p < 0,001) und im modifizierten Schultertest nach Janda auf der linken Seite (p = 0,003) signifikant größer.
Diskussion: Trotz des in Zeitdauer und Häufigkeit relativ geringen Trainingsaufwandes wurden sowohl auf körperlicher als auch auf psychischer Ebene relevante Verbesserungen erzielt, so dass das „five-Business“-Dehntraining als BGF-Maßnahme empfohlen werden kann.
Murine acetaminophen-induced acute liver injury (ALI) serves as paradigmatic model for drug-induced hepatic injury and regeneration. As major cause of ALI, acetaminophen overdosing is a persistent therapeutic challenge with N-acetylcysteine clinically used to ameliorate parenchymal necrosis. To identify further treatment strategies that serve patients with poor N-acetylcysteine responses, hepatic 3′mRNA sequencing was performed in the initial resolution phase at 24 h/48 h after sublethal overdosing. This approach disclosed 45 genes upregulated (≥5-fold) within this time frame. Focusing on C5aR1, we observed in C5aR1-deficient mice disease aggravation during resolution of intoxication as evidenced by increased liver necrosis and serum alanine aminotransferase. Moreover, decreased hepatocyte compensatory proliferation and increased caspase-3 activation at the surroundings of necrotic cores were detectable in C5aR1-deficient mice. Using a non-hypothesis-driven approach, herein pro-regenerative/-resolving effects of C5aR1 were identified during late acetaminophen-induced ALI. Data concur with protection by the C5a/C5aR1-axis during hepatectomy and emphasize the complex role of inflammation during hepatic regeneration and repair.
Behandlung von Hepatitis-C-Infektionen im Zeitalter direkt wirkender antiviraler Medikamente (DAAs)
(2022)
Die chronische Hepatitis-C-Infektion kann unbehandelt zu schwerwiegenden und potenziell lebensbedrohlichen leberassoziierten Komplikationen führen. Grundsätzlich stellt damit jede chronische Infektion mit dem Hepatitis-C-Virus (HCV) eine Indikation zur antiviralen Therapie dar. Besonders dringlich ist sie jedoch bei Patient*innen mit fortgeschrittener Lebererkrankung. In diesem Beitrag werden Indikation, Therapieziele und Grundprinzipien der direkt antiviralen Therapie beschrieben. Verschiedene Therapieregime und Möglichkeiten der Überwachung von Therapie und Therapieerfolg werden vorgestellt.
Heutzutage wird die chronische HCV-Infektion interferonfrei mit direkt antiviral wirksamen Medikamenten („direct acting antivirals“ – DAA) behandelt, wobei die Wahl der Medikamente von HCV-Genotyp, Vortherapie und Fibrosestatus abhängt. Patient*innen mit kompensierter Leberzirrhose und solche ohne Leberzirrhose weisen unter Behandlung vergleichbar hohe Viruseradikationsraten auf. Auch bei dekompensierter Leberzirrhose oder dialysepflichtiger Niereninsuffizienz und selbst bei Kindern ab einem Alter von 3 Jahren ist heutzutage eine sichere und hocheffiziente antivirale Behandlung möglich. Medikamenteninteraktionen sind zu beachten, können aber einfach und schnell im Internet überprüft werden. Auch wenn sich die Prognose nach HCV-Eradikation deutlich verbessert, sollten Patient*innen mit fortgeschrittener Leberfibrose bzw. einer Leberzirrhose lebenslang weiterbeobachtet werden, um die Entstehung eines hepatozellulären Karzinoms rechtzeitig zu erkennen (HCC-Surveillance).
Trotz der Relevanz des Themas Suizidalität und gut bekannter Risikofaktoren gibt es bisher keine deutsche Leitlinie zur Suizidalität im Erwachsenenalter. In diesem Beitrag werden zunächst die Geschichte und die Hintergründe der Arbeit mit Leitlinien beschrieben. Der aktuelle Stand der Leitlinien für psychische Erkrankungen in Deutschland wird dargestellt und auf suizidpräventive Inhalte hin untersucht. Die Notwendigkeit evidenzbasierter Suizidprävention und einer spezifischen Leitlinie zur Suizidprävention bei Erwachsenen wird diskutiert.
Nur durch gezielte Suizidpräventionsstrategien und Interventionen für die jeweiligen Risikogruppen und unter Beachtung von Alters- und Geschlechtsspezifität kann für alle Betroffenen eine flächendeckende, gut erreichbare, bedarfs- und versorgungsgerechte, finanzierbare sowie nachhaltige medizinische Versorgung auf einem hohen Niveau sichergestellt werden. Dies gilt für den ambulanten und den stationären Bereich sowie für deren Schnittstellen. Bei Suizidalität handelt es sich um ein diagnoseübergreifendes, in unterschiedlichen Versorgungskontexten auftretendes Syndrom mit komplexem Behandlungsbedarf, weshalb intersektorale und multiprofessionelle Aspekte in einer entsprechenden Leitlinie besonders zu adressieren sind. Wissenschaftliche Evidenz und interdisziplinärer Konsens unter Expertinnen und Experten zum Umgang mit suizidalem Verhalten in der medizinischen Versorgung können dazu beitragen, Morbidität und Mortalität im Zusammenhang mit Suizidalität zu reduzieren. Im August 2021 wurde die Finanzierung einer S3-Leitlinie „Umgang mit Suizidalität“ vom Innovationsfonds des Gemeinsamen Bundesausschusses bewilligt.
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.
Incidence of an intracellular multiplication niche among Acinetobacter baumannii clinical isolates
(2022)
The spread of antibiotic-resistant Acinetobacter baumannii poses a significant threat to public health worldwide. This nosocomial bacterial pathogen can be associated with life-threatening infections, particularly in intensive care units. A. baumannii is mainly described as an extracellular pathogen with restricted survival within cells. This study shows that a subset of A. baumannii clinical isolates extensively multiply within nonphagocytic immortalized and primary cells without the induction of apoptosis and with bacterial clusters visible up to 48 h after infection. This phenotype was observed for the A. baumannii C4 strain associated with high mortality in a hospital outbreak and the A. baumannii ABC141 strain, which was isolated from the skin but was found to be hyperinvasive. Intracellular multiplication of these A. baumannii strains occurred within spacious single membrane-bound vacuoles, labeled with the lysosomal associate membrane protein (LAMP1). However, these compartments excluded lysotracker, an indicator of acidic pH, suggesting that A. baumannii can divert its trafficking away from the lysosomal degradative pathway. These compartments were also devoid of autophagy features. A high-content microscopy screen of 43 additional A. baumannii clinical isolates highlighted various phenotypes, and (i) the majority of isolates remained extracellular, (ii) a significant proportion was capable of invasion and limited persistence, and (iii) three more isolates efficiently multiplied within LAMP1-positive vacuoles, one of which was also hyperinvasive. These data identify an intracellular niche for specific A. baumannii clinical isolates that enables extensive multiplication in an environment protected from host immune responses and out of reach of many antibiotics.
IMPORTANCE Multidrug-resistant Acinetobacter baumannii isolates are associated with significant morbidity and mortality in hospitals worldwide. Understanding their pathogenicity is critical for improving therapeutic management. Although A. baumannii can steadily adhere to surfaces and host cells, most bacteria remain extracellular. Recent studies have shown that a small proportion of bacteria can invade cells but present limited survival. We have found that some A. baumannii clinical isolates can establish a specialized intracellular niche that sustains extensive intracellular multiplication for a prolonged time without induction of cell death. We propose that this intracellular compartment allows A. baumannii to escape the cell’s normal degradative pathway, protecting bacteria from host immune responses and potentially hindering antibiotic accessibility. This may contribute to A. baumannii persistence, relapsing infections, and enhanced mortality in susceptible patients. A high-content microscopy-based screen confirmed that this pathogenicity trait is present in other clinical A. baumannii isolates. There is an urgent need for new antibiotics or alternative antimicrobial approaches, particularly to combat carbapenem-resistant A. baumannii. The discovery of an intracellular niche for this pathogen, as well as hyperinvasive isolates, may help guide the development of antimicrobial therapies and diagnostics in the future.
The entire chemical modification repertoire of yeast ribosomal RNAs and the enzymes responsible for it have recently been identified. Nonetheless, in most cases the precise roles played by these chemical modifications in ribosome structure, function and regulation remain totally unclear. Previously, we demonstrated that yeast Rrp8 methylates m1A645 of 25S rRNA in yeast. Here, using mung bean nuclease protection assays in combination with quantitative RP-HPLC and primer extension, we report that 25S/28S rRNA of S. pombe, C. albicans and humans also contain a single m1A methylation in the helix 25.1. We characterized nucleomethylin (NML) as a human homolog of yeast Rrp8 and demonstrate that NML catalyzes the m1A1322 methylation of 28S rRNA in humans. Our in vivo structural probing of 25S rRNA, using both DMS and SHAPE, revealed that the loss of the Rrp8-catalyzed m1A modification alters the conformation of domain I of yeast 25S rRNA causing translation initiation defects detectable as halfmers formation, likely because of incompetent loading of 60S on the 43S-preinitiation complex. Quantitative proteomic analysis of the yeast Δrrp8 mutant strain using 2D-DIGE, revealed that loss of m1A645 impacts production of specific set of proteins involved in carbohydrate metabolism, translation and ribosome synthesis. In mouse, NML has been characterized as a metabolic disease-associated gene linked to obesity. Our findings in yeast also point to a role of Rrp8 in primary metabolism. In conclusion, the m1A modification is crucial for maintaining an optimal 60S conformation, which in turn is important for regulating the production of key metabolic enzymes.