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In this prospective observational pilot study patients with the diagnosis of end-stage lung disease and listed for lung transplantation underwent a cognitive function test battery before and after lung transplantation to investigate postoperative cognitive function in three domains (visual and verbal memory, executive functioning, concentration/speed of processing). Additionally we investigated intraoperative risk factors for postoperative cognitive dysfunction. In total, 24 patients were included in this pilot study. The incidence of postoperative cognitive dysfunction was 58.3%. In the cognitive dysfunction group, the domains executive functioning and concentration/attention were significantly impaired whereas memory was not affected. Patients with cognitive impairment had a significantly longer ICU stay. The strongest independent risk factor for the development of cognitive dysfunction was operation time. No influence of cerebral oxygen desaturations on cognitive dysfunction was found. This might have important implications for early psychological rehabilitation strategies in this high-risk patient collective., (© 2021. The Author(s).)

BackgroundIn the SARS-CoV-2 pandemic, viral genomes are available at unprecedented speed, but spatio-temporal bias in genome sequence sampling precludes phylogeographical inference without additional contextual data.AimWe applied genomic epidemiology to trace SARS-CoV-2 spread on an international, national and local level, to illustrate how transmission chains can be resolved to the level of a single event and single person using integrated sequence data and spatio-temporal metadata.MethodsWe investigated 289 COVID-19 cases at a university hospital in Munich, Germany, between 29 February and 27 May 2020. Using the ARTIC protocol, we obtained near full-length viral genomes from 174 SARS-CoV-2-positive respiratory samples. Phylogenetic analyses using the Auspice software were employed in combination with anamnestic reporting of travel history, interpersonal interactions and perceived high-risk exposures among patients and healthcare workers to characterise cluster outbreaks and establish likely scenarios and timelines of transmission.ResultsWe identified multiple independent introductions in the Munich Metropolitan Region during the first weeks of the first pandemic wave, mainly by travellers returning from popular skiing areas in the Alps. In these early weeks, the rate of presumable hospital-acquired infections among patients and in particular healthcare workers was high (9.6% and 54%, respectively) and we illustrated how transmission chains can be dissected at high resolution combining virus sequences and spatio-temporal networks of human interactions.ConclusionsEarly spread of SARS-CoV-2 in Europe was catalysed by superspreading events and regional hotspots during the winter holiday season. Genomic epidemiology can be employed to trace viral spread and inform effective containment strategies.

Background: Inflammation is an important driver of malignant glioma disease. Inflammatory mediators are not only produced by immune cells in the tumor microenvironment, but also by glioblastoma (GBM) cells themselves creating a mutually reinforcing loop. We here aimed at identifying an "anti-inflammatory switch" that allows to dampen inflammation in GBM., Methods: We used human GBM specimens, primary cultures, and cell lines. The response of GBM cells toward inflammatory stimuli was tested by incubation with supernatant of stimulated human immune cells. Expression levels were measured by whole transcriptome microarrays and qRT-PCR, and protein was quantified by LUMINEX and SDS-PAGE. MicroRNA binding to 3'UTRs was analyzed by luciferase assays. Proliferation rates were determined by flow cytometry, and invasion and angiogenesis were studied using migration and endothelial tube formation assays., Results: We demonstrated GBM cells to secrete high amounts of proinflammatory mediators in an inflammatory microenvironment. We found miR-93 as a potential "anti-inflammatory tumor suppressor" dramatically downregulated in GBM. Concordantly, cytokine secretion dropped after miR-93 re-expression. Transfection of miR-93 in GBM cells led to down-regulation of hubs of the inflammatory networks, namely, HIF-1α and MAP3K2 as well as IL-6, G-CSF, IL-8, LIF, IL-1β, COX2, and CXCL5. We showed only COX2 and CXCL5 to be indirectly regulated by miR-93 while all other genes are true targets. Phenotypically, re-expression of miR-93 in GBM cells substantially suppressed proliferation, migration, and angiogenesis., Conclusions: Alleviating GBM-derived inflammation by re-expression of miR-93 may be a powerful tool to mitigate these tumors' aggressiveness and holds promise for new clinical approaches., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Early industrialization and the development of cheap production processes for paper have led to an exponential accumulation of paper-based documents during the last two centuries. Archives and libraries harbor vast amounts of ancient and modern documents and have to undertake extensive endeavors to protect them from abiotic and biotic deterioration. While services for mechanical preservation such as ex post de-acidification of historic documents are already commercially available, the possibilities for long-term protection of paper-based documents against fungal attack (apart from temperature and humidity control) are very limited. Novel processes for mechanical enhancement of damaged cellulosic documents use Ionic Liquids (IL) as essential process components. With some of these ILs having azole-functionalities similar to well-known fungicides such as Clotrimazole, the possibility of antifungal activities of these ILs was proposed but has not yet been experimentally confirmed. We evaluated the potency of four ILs with potential application in paper restoration for suppression of fungal growth on five relevant paper-infesting molds. The results revealed a general antifungal activity of all ILs, which increased with the size of the non-polar group. Physiological experiments and ultimate elemental analysis allowed to determine the minimal inhibitory concentration of each IL as well as the residual IL concentration in process-treated paper. These results provide valuable guidelines for IL-applications in paper restoration processes with antifungal activity as an added benefit. With azoles remaining in the paper after the process, simultaneous repair and biotic protection in treated documents could be facilitated., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Nitrochemie Aschau GmbH holds patents (LU93386B1; EP3339508A1) for the paper reinforcement process discussed in this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. CLM still is and KL was employed by Nitrochemie Aschau GmbH as this study was conducted. All other authors have declared that no competing interests exist.

The onset of puberty in adolescents and whether it is related to obesity is an ongoing topic for debate. Epidemiological cross-sectional and longitudinal studies show a shift towards earlier onset of puberty in girls who are obese; however, the situation is less clear in boys. Boys who are overweight seem to mature earlier, and boys who are obese mature later, than boys at a healthy weight. The underlying mechanisms are not yet fully understood, and whether earlier onset of puberty in obese girls is based on the activation of the hypothalamic-pituitary-gonadal axis is unclear. The most promising link between obesity and puberty is the adipokine leptin and its interaction with the kisspeptin system, which is an important regulator of puberty. However, peripheral action of adipose tissue (eg, via other adipokines, aromatase activity) could also be involved in changes to the onset of puberty. In addition, nutritional factors, epigenetics, or endocrine disrupting chemicals are potential mediators linking the onset of puberty to obesity. This Review summarises our knowledge concerning the relationship between obesity and onset and tempo of puberty, and the consequences of early puberty on obesity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The second intron of Mitogen-Activated Protein Kinase Kinase 4 (MAP2K4), an important hub in the pro-invasive MAPK pathway, harbors miR-744. There is accumulating evidence that intronic micro-RNAs (miRNAs) are capable of either supporting or restraining functional pathways of their host genes, thereby creating intricate regulative networks. We thus hypothesized that miR-744 regulates glioma migration by interacting with its host's pathways., Methods: Patients' tumor specimens were obtained stereotactically. MiR-744 was overexpressed in U87, T98G, and primary glioblastoma (GBM) cell lines. Cell mobility was studied using migration and Boyden chamber assays. Protein and mRNA expression was quantified by SDS-PAGE and qRT-PCR. Interactions of miR-744 and 3'UTRs were analyzed by luciferase reporter assays, and SMAD2/3, p38, and beta-Catenin activities by TOP/FOPflash reporter gene assays., Results: As compared to a normal brain, miR-744 levels were dramatically decreased in GBM samples and in primary GBM cell lines. Astrocytoma WHO grade II/III exhibited intermediate expression levels. Re-expression of miR-744 in U87, T98G, and primary GBM cell lines induced focal growth and impaired cell mobility. Luciferase activity of 3'UTR reporter constructs revealed the pro-invasive factors TGFB1 and DVL2 as direct targets of miR-744. Re-expression of miR-744 reduced levels of TGFB1, DVL2, and the host MAP2K4, and mitigated activity of TGFB1 and DVL2 downstream targets SMAD2/3 and beta-Catenin. TGFB1 knock-down repressed MAP2K4 expression., Conclusion: MiR-744 acts as an intrinsic brake on its host. It impedes MAP2K4 functional pathways through simultaneously targeting SMAD-, beta-Catenin, and MAPK signaling networks, thereby strongly mitigating pro-migratory effects of MAP2K4. MiR-744 is strongly repressed in glioma, and its re-expression might attenuate tumor invasiveness.

Purpose of Review: Chronic inflammation, adipokines, and hepatokines have been identified as basis of insulin resistance and β cell failure in animal models. We present our current knowledge concerning the potential relationship between these cytokines, inflammation, metabolic syndrome (MetS), and type 2 diabetes mellitus (T2DM) in the pediatric population., Recent Findings: Pro-inflammatory cytokines related to insulin resistance and MetS in children are tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-1β, interferon gamma, pigment epithelium-derived factor, chemerin, vaspin, and fetuin A. Anti-inflammatory cytokines associated with insulin resistance and MetS in children are leptin, adiponectin, omentin, fibroblast growth factor (FGF)-21, osteocalcin, and irisin. These anti-inflammatory cytokines are decreased (adiponectin, omentin, and osteocalcin) or increased (leptin, FGF-21, and irisin) in obesity suggesting a resistance state. TNF-α, fetuin A, and FGF-21 are altered in obese children with T2DM suggesting an involvement in β cell failure. These cytokines, adipokines, and hepatokines may be able to predict development of MetS and T2DM and have a potential therapeutic target ameliorating insulin resistance.

Objective: To assess the impact of weight changes on the onset of puberty in overweight children., Study Design: We evaluated the timing of puberty onset in 160 prepubertal overweight children (aged 11.2 ± 1.0 years) depending on the changes of their weight status in a 1-year lifestyle intervention. We determined body mass index (BMI), pubertal stage, luteinizing hormone (LH), follicle-stimulating hormone, insulin-like growth factor (IGF)-1, insulin-like growth factor binding protein-3, insulin resistance index homeostatic model assessment, and serum gonadotropins at baseline and 1 year later., Results: Puberty onset during the 1-year follow-up was significantly (P = .014) more frequent in girls without BMI-SDS reduction (75.0%) compared with girls with BMI-SDS reduction (45.7%). The start of puberty was significantly (P = .024) more frequent in boys with BMI-SDS reduction (76.9%) compared with boys without BMI-SDS reduction (53.6%). In logistic regression analyses adjusted for baseline age and BMI-SDS, BMI-SDS reduction was associated with a decreased likelihood for puberty onset in girls (OR 0.24; 95% CI 0.07-0.85) and an increased likelihood in boys (OR 3.77; 95% CI 1.34-10.52). Central onset of puberty was confirmed by an increase of LH concentration and LH/follicle-stimulating hormone ratio in both boys and girls. Homeostatic model assessment, IGF-1, and IGF-1/insulin-like growth factor binding protein-3 ratio as marker for free IGF-1 at baseline or their changes were not associated with the onset of puberty., Conclusions: BMI-SDS reduction in overweight children was associated with earlier gonadotropin-dependent onset of puberty in boys and later onset of puberty in girls, suggesting earlier puberty in obese girls and later puberty in obese boys. We found no evidence that insulin resistance or IGF-1 have an impact on the start of puberty in obese children., Trial Registration: ClinicalTrials.gov: NCT00435734., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Unlabelled: For patients with a craniopharyngioma (CP), treatment of hypothalamic obesity (HO) and hyperphagia following resection and/or radiotherapy is extremely difficult and few reports have been published on potential drug therapies. Psychomotor stimulant methylphenidate (MPH) has been reported to inhibit food intake (FI). In this paper, we report reduction of body mass index (BMI) and appetite in an adolescent CP patient suffering from HO. We then tested the ability of MPH to attenuate the FI and body weight (BW) gain in a rat model consistent with the neuroanatomical and metabolic disturbances commonly observed in obese CP patients. Specifically, we used a novel electrolytically generated combined medial hypothalamic lesion (CMHL) affecting the arcuate nucleus, ventromedial hypothalamic nucleus, and dorsomedial hypothalamic nucleus to induce hyperphagia, rapid weight gain, and adiposity. Both CMHL and control animals (n = 7 per group) were administered either methylphenidate HCl (MPH; 20 mg kg(-1) day(-1)) or saline for 4 days in a crossover design experiment 28 weeks post-surgery. A significant decrease in percent baseline FI (CMHL -23%, p = 0.008; control -20%, p = 0.002) and percent change in BW (CMHL -1.97%/4 days, p = 0.011; control -1.75%/4 days, p = 0.003) was observed during MPH treatment as compared to saline., Conclusion: This study shows MPH treatment of severely obese CMHL rats resulted in significantly reduced FI and BW loss.

Context: Little information is available on androgens in obese children, and it is unknown whether these hormones change after weight loss., Objective: The objective of this study was to compare androgens between obese and normal-weight children and to study the effect of weight loss on androgens., Design: The design was a cross-sectional comparison between obese and normal-weight children separated according to pubertal stage and longitudinal 1-yr follow-up study in obese children participating in a weight-loss intervention., Setting: The setting of this study was a primary care facility., Patients: A total of 273 obese and 79 lean children (aged 4-14 yr) were studied, including a subgroup of 155 obese children for the longitudinal study., Intervention: The intervention program was an outpatient 1-yr intervention program based on exercise, behavior, and nutrition therapy (high-carbohydrate low-fat diet)., Main Outcome Measures: The outcome measures included testosterone and dehydroepiandrosterone sulfate (DHEAS) at baseline and 1 yr later., Results: The obese prepubertal children and the obese pubertal girls showed significantly (P < 0.01) higher testosterone and DHEAS levels, whereas obese pubertal boys did not significantly differ in androgens from their lean counterparts. Significant correlations with body mass index were demonstrated in multivariate regression analyses for DHEAS in all children and for testosterone in prepubertal children and in pubertal girls. The obese prepubertal children and obese girls losing substantial weight showed a significant (P < 0.05) decrease in their testosterone concentrations., Conclusions: Moderately increased testosterone and DHEAS levels were found in obese prepubertal children and in obese pubertal girls, whereas androgen concentrations did not differ between obese and normal-weight pubertal boys. Weight loss induced a decrease in testosterone in obese prepubertal children and pubertal girls pointing to a reversible increase of androgens.