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Nirmatrelvir-ritonavir (Paxlovid), an oral antiviral treatment, is authorized for adults with mild-to-moderate COVID-19 who are at increased risk for progression to severe illness. However, real-world evidence on the benefit of Paxlovid, according to vaccination status, age group, and underlying health conditions, is limited. To examine the benefit of Paxlovid in adults aged ≥18 years in the United States, a large electronic health record (EHR) data set (Cosmos

Acute graft-versus-host disease (aGVHD) is a major limitation of the therapeutic potential of allogeneic hematopoietic cell transplantation. Lipopolysaccharides (LPS) derived from intestinal gram-negative bacteria are well-known aGVHD triggers and amplifiers. Here, we explored the LPS metabolism in aGVHD mouse models using an innovative quantification method. We demonstrated that systemic LPS accumulation after transplantation was due, at least partly, to a defect in its clearance through lipoprotein-mediated transport to the liver (i.e., the so-called reverse LPS transport). After transplantation, reduced circulating HDL concentration impaired LPS neutralization and elimination through biliary flux. Accordingly, HDL-deficient (Apoa1

Functional Near Infrared Spectroscopy (fNIRS) may be a suitable, simple, and cost-effective brain imaging technique for detecting divergent neuronal patterns at an early stage of neurodegeneration. In course of Mild Cognitive Impairment (MCI) or Alzheimer's disease (AD), a deficit in visual-spatial processing, located in the parietal cortex, is a reliable risk factor. Earlier, we established the application of the clock-hand-angle-discrimination task (ADT) during fNIRS to identify neuronal correlates of the visual-spatial processing in a healthy elderly sample. In this analysis, we aimed to measure and find out differences in the hemodynamic response in MCI participants compared to matched healthy controls. As expected, MCI participants showed more errors over all conditions of pointer length and a higher reaction time in the long and middle pointer length condition. Moreover, results revealed a significant reduction of cortical activation in MCI patients. There was a generally increased activity in both the right as compared to the left hemisphere and the superior parietal brain region as compared to the inferior parietal brain region in both groups. In summary, fNIRS can be implemented in the measurement of visual-spatial processing in MCI patients and healthy elderly based on ADT. MCI participants had difficulties to cope with the ADT. Since neuronal hypoactivity occurs with concomitant behavioral deficits, an additional analysis was performed on a subgroup of MCI patients who performed as well as the control group in behavior. This subgroup analysis also showed a hypoactivation of the parietal cortex, without evidence of a compensatory activation. Therefore, we assume that MCI patients are characterized by a deficit in the parietal cortex. Overall, these findings confirm our hypothesis that hemodynamic deficits in visual-spatial processing, localized in the parietal cortex, are reliable and early diagnostic markers for cognitive decline in risk groups for the development of AD.

Fungal infections caused by the ancient lineage Mucorales are emerging and increasingly reported in humans. Comprehensive surveys on promising attributes from a multitude of possible virulence factors are limited and so far, focused on Mucor and Rhizopus. This study addresses a systematic approach to monitor phagocytosis after physical and enzymatic modification of the outer spore wall of Lichtheimia corymbifera, one of the major causative agents of mucormycosis. Episporic modifications were performed and their consequences on phagocytosis, intracellular survival and virulence by murine alveolar macrophages and in an invertebrate infection model were elucidated. While depletion of lipids did not affect the phagocytosis of both strains, delipidation led to attenuation of LCA strain but appears to be dispensable for infection with LCV strain in the settings used in this study. Combined glucano-proteolytic treatment was necessary to achieve a significant decrease of virulence of the LCV strain in Galleria mellonella during maintenance of the full potential for spore germination as shown by a novel automated germination assay. Proteolytic and glucanolytic treatments largely increased phagocytosis compared to alive resting and swollen spores. Whilst resting spores barely (1–2%) fuse to lysosomes after invagination in to phagosomes, spore trypsinization led to a 10-fold increase of phagolysosomal fusion as measured by intracellular acidification. This is the first report of a polyphasic measurement of the consequences of episporic modification of a mucormycotic pathogen in spore germination, spore surface ultrastructure, phagocytosis, stimulation of Toll-like receptors (TLRs), phagolysosomal fusion and intracellular acidification, apoptosis, generation of reactive oxygen species (ROS) and virulence.

Background Meningioma is the most common primary brain tumor in adults. In recent years, several non-neurofibromin 2 mutations, i.e., AKT1, SMO, TRAF7, and KLF4 mutations, specific for meningioma have been identified. This study aims to analyze the clinical impact and imaging characteristics of the KLF4K409Q mutation in meningioma. Methods Clinical, neuropathologic, and imaging data of 170 patients who underwent meningioma resection between 2013 and 2018 were retrospectively collected and tumors were analyzed for the presence of the KLF4K409Q mutation. We collected imaging characteristics, performed volumetric analysis of tumor size and peritumoral edema (PTBE), and calculated the edema index (EI, i.e., ratio of PTBE to tumor volume). Receiver operating characteristic curve analysis was performed to identify cut-off EI values to predict the mutational status of KLF4. Results Eighteen (10.6%) of the meningiomas carried the KLF4K409Q mutation; these were significantly associated with a secretory subtype (P Conclusions The KLF4K409Q mutation is associated with a distinct small tumor subtype, prone to substantial PTBE. EI is a reliable parameter to predict the KLF4K409Q mutation in meningioma, thus providing a tool for improvement of pre- and perioperative medical management.

Fear conditioning and generalization are well-known mechanisms in the pathogenesis of anxiety disorders. Extinction of conditioned fear responses is crucial for the psychotherapeutic treatment of these diseases. Anxious depression as a subtype of major depression shares characteristics with anxiety disorders. We therefore aimed to compare fear learning mechanisms in patients with anxious versus non-anxious depression. Fear learning mechanisms in patients with major depression (n = 79; for subgroup analyses n = 41 patients with anxious depression and n = 38 patients with non-anxious depression) were compared to 48 healthy participants. We used a well-established differential fear conditioning paradigm investigating acquisition, generalization, and extinction. Ratings of valence, arousal and probability of expected threat were assessed as well as skin conductance response as an objective psychophysiological measure. Patients with major depression showed impaired acquisition of conditioned fear. In addition, depressed patients showed impaired extinction of conditioned fear responses after successful fear conditioning. Generalization was not affected. However, there was no difference between patients with anxious and non-anxious depression. Results differed between objective and subjective measures. Our findings show altered fear acquisition and extinction in major depression as compared to healthy controls, but they do not favor differential fear learning and extinction mechanisms in the pathogenesis of anxious versus non-anxious depression. The results of impaired extinction warrant future studies addressing extinction learning elements in the treatment of depression.

Background In 2016, the American Statistical Association stated that the use of statistical significance leads to distortion of the scientific process. The principal alternative to significance or null hypothesis testing (NHT) is estimation with point estimates and confidence intervals (CIs). Objectives The aim of this study was to determine the time trend of statistical inference and statistical reporting style in abstracts in major cardiovascular journals. Methods A total of 84,250 abstracts published from 1975 to 2019 in 9 high-ranking cardiovascular journals (Circulation, Circulation Research, European Heart Journal, European Heart Journal: Cardiovascular Imaging, European Journal of Heart Failure, Journal of the American College of Cardiology, JACC: Cardiovascular Imaging, JACC: Cardiovascular Interventions, and JAMA Cardiology) were reviewed; in particular, proportions of abstracts containing statistical inference and its major variants (NHT, significance testing) were compared over time and among journals. Results Overall, 49,924 abstracts (59%) contained statistical inference. Among these abstracts, NHT was the most frequent reporting style of statistical inference (79% among all journals). Journals differed considerably in the prevalence of CI reporting (1% to 78% in 2017–2019). With the exception of 2 journals, the proportion of abstracts containing CIs was higher in the more recent period. From 2013–2015 to 2017–2019, the proportion of abstracts containing only CIs increased by 5 (95% CI: 0 to 10), 18 (95% CI: 15 to 21), and 9 (95% CI: 3 to 15) percentage points in the European Heart Journal, the Journal of the American College of Cardiology, and JACC: Cardiovascular Imaging, respectively. Conclusions NHT is still the prevailing reporting style of statistical inference in major cardiovascular journals. Reporting of CIs in abstracts of major cardiovascular journals appears to be growing more popular.

Childhood trauma as well as severe events occurring later in life have been associated with the development of major depressive disorder (MDD). However, the interaction of early and later occurring adverse events in patients with MDD is understudied. This study aims to disentangle this interaction by investigating the effects on two of the main stress-response systems of the body, the hypothalamic–pituitaryadrenal (HPA-) axis and the immune system in depressed patients. The function of the HPA-axis was assessed by measuring FKBP5, SGK1 and NR3C1 mRNA-expression in peripheral blood after an in vivo glucocorticoid receptor (GR) challenge with 1.5 mg dexamethasone in 150 depressed in-patients (47.4% females). Childhood trauma was evaluated using the Childhood Trauma Questionnaire (CTQ), severe life events occurring one year prior to hospital admission were assessed with the List of Threatening Experiences (LTE). Multiple childhood traumata, i.e. ≥ 3, were present in 68 (45.5%) patients, 59 (39.3%) experienced ≥ 3 severe recent life events. The history of ≥ 3 severe recent life events was associated with an impaired GR-induction of SGK1 (F = 10.455; df = 1; p = 0.002) and FKBP5 mRNA expression (F = 8.720; df = 1; p = 0.004), and with elevated measures of the immune system such as CRP and lymphocyte count. In addition, severe recent life events were associated with a substantially impaired treatment response to antidepressants (F = 7.456; df = 1; p = 0.008). These effects could not be observed in relation to childhood trauma. Severe life events occurring prior to MDD development substantially impaired the stress-response systems and the response to treatment with antidepressants. This finding may indicate the need to employ additional treatment options such as psychotherapy right at the beginning of treatment or immune-modulating approaches.

Zusammenfassung Hintergrund Empfehlungen aus S3-Leitlinien (S3-LL) stellen eine wichtige Grundlage fur die Entwicklung von Qualitatsindikatoren (QI) dar. Ein einheitliches methodisches Vorgehen zur Entwicklung von QI im Kontext von S3-LL existiert in Deutschland bisher nicht. Aus diesem Grund wurde ein methodischer Standard fur die leitlinienbasierte Entwicklung von QI (QI-Standard) anhand eines strukturierten Konsensprozesses unter Einbezug der relevanten Experten- und Interessengruppen erarbeitet. Methoden Die Inhalte des QI-Standards wurden evidenzgeleitet zusammengestellt, basierend auf den Ergebnissen von Ubersichtsarbeiten und qualitativen Studien sowie unter Berucksichtigung der bereits existierenden Manuale zur leitlinienbasierten QI-Entwicklung. Fur die Abstimmung des QI-Standards wurde ein multiperspektivisches Panel mit breiter Reprasentanz von Experten- und Interessengruppen aus dem deutschen Gesundheitssystem und Expertise in Leitlinienarbeit und/oder Qualitatsmanagement nominiert. Das iterative, strukturierte Konsensverfahren beinhaltete eine zweistufige Onlinebefragung angelehnt an das Delphi-Verfahren („vorlaufige Abstimmung“) sowie eine moderierte Abschlusskonferenz, bei der diejenigen Empfehlungen in den QI-Standard aufgenommen wurden, die eine Zustimmung von >75% (Konsens-Kriterium) des Expertenpanels erhielten. Ergebnisse Der erarbeitete QI-Standard sieht als QI-Entwicklungsschritte zuerst die kriteriengestutzte Auswahl „potenzieller QI“ vor, die nach ihrer Verabschiedung als „vorlaufige QI“ in der S3-LL veroffentlicht werden und schlieslich nach erfolgreicher Testung den Status „finale QI“ erlangen. Der QI-Standard setzt sich aus insgesamt 30 Empfehlungen zusammen, die sich auf sechs Bereiche verteilen: A) Vorbereitende Arbeitsschritte fur die leitlinienbasierte Empfehlung von QI, B) Zusammensetzung der QI-Entwicklergruppe und Zusammenarbeit mit der LL-Gruppe, C) Entwicklung der potenziellen QI, D) Bewertung der potenziellen QI, E) Verabschiedung und Publikation sowie F) Pilotierung/Testung der vorlaufigen und Uberfuhrung in finale QI. Diskussion Bevor der QI-Standard bei kunftigen S3-LL-Erstellungen oder Aktualisierungen zur Implementierung empfohlen werden kann, sollte dieser in ausgewahlten S3-Leitlinienprojekten erfolgreich erprobt worden sein. Neben methodischen Anforderungen an die QI-Entwicklung muss sichergestellt sein, dass den LL-Gruppen adaquate Ressourcen fur die Umsetzung des QI-Standards zur Verfugung stehen. Schlussfolgerung Vom Einsatz des QI-Standards durch Leitliniengruppen konnen wissenschaftlich fundierte und fur die Versorgung relevante QI erwartet werden.

In newly diagnosed systemic diffuse large B-cell lymphoma, next-generation sequencing of plasma-derived cell-free DNA (cfDNA) detects somatic mutations as accurate as genotyping of the tumor biopsy. A distinct diffuse large B-cell lymphoma entity confined to the central nervous system is primary central nervous system lymphoma (PCNSL), which requires intracerebral biopsy and neuropathologic analysis to establish the diagnosis. So far, a biomarker for diagnosis and follow-up of PCNSL that can be investigated in blood has not been identified. This article addresses the question whether somatic mutations of the CD79B and MYD88 driver genes of PCNSL can be detected in cfDNA at disease diagnosis. Stereotactic biopsies and cfDNA of 27 PCNSL patients were analyzed for CD79B and MYD88 mutations. As control, cfDNA derived from six healthy volunteers was used. CD79B and MYD88 hot spot mutations were identified in 16 of 27 (59%) and 23 of 27 (85%) PCNSL biopsies, respectively, but only in 0 of 27 (0%) and 1 of 27 (4%) corresponding cfDNA samples, respectively. In cfDNA of one of four patients with Waldenstrom disease, as a further control, the MYD88 L265P mutation was readily detected, despite complete clinical remission. These data suggest that in PCNSL even if they carry such mutations, alterations of CD79B and MYD88 cannot be reliably detected in blood-derived cfDNA obtained before intracerebral biopsy.