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Background: SARS-CoV-2 is one of the most threatening pandemics in human history. As of the date of this analysis, it had claimed about 2 million lives worldwide, and the number is rising sharply. Governments, societies, and scientists are equally challenged under this burden. Objective: This study aimed to map global coronavirus research in 2020 according to various influencing factors to highlight incentives or necessities for further research. Methods: The application of established and advanced bibliometric methods combined with the visualization technique of density-equalizing mapping provided a global picture of incentives and efforts on coronavirus research in 2020. Countries’ funding patterns and their epidemiological and socioeconomic characteristics as well as their publication performance data were included. Results: Research output exploded in 2020 with momentum, including citation and networking parameters. China and the United States were the countries with the highest publication performance. Globally, however, publication output correlated significantly with COVID-19 cases. Research funding has also increased immensely. Conclusions: Nonetheless, the abrupt decline in publication efforts following previous coronavirus epidemics should demonstrate to global researchers that they should not lose interest even after containment, as the next epidemiological challenge is certain to come. Validated reporting worldwide and the inclusion of low-income countries are additionally important for a successful future research strategy.
Following publication of the original article, the authors noticed an incorrect affiliation for Christine Stürken and Udo Schumacher. The correct affiliations are as follows: Christine Stürken: Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. Udo Schumacher: Institute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. The affiliations have been correctly published in this correction and the original article has been updated.
Morbus Parkinson ist die zweithäufigste neurodegenerativen Erkrankung, die durch Untergang der dopaminergen Neuronen im Mesenzephalon zu einer Störung des extrapyramidalen motorischen Systems führt. Daraus resultierende Bewegungsstörungen, zu denen Rigor, Tremor, Hypokinese und posturale Instabilität gehören, werden von nichtmotorischen Symptomen wie autonome Dysregulation, veränderte sensorische Wahrnehmung, sowie kognitive und psychische Störungen begleitet.
Mehrere Studien berichten über erhöhte Schmerzprävalenz bei Parkinson Patienten. Die genaue Pathogenese der gestörten Schmerzwahrnehmung bleibt unklar. Zusätzlich zu den zentralen Mechanismen entstehen die Schmerzen bei Morbus Parkinson wahrscheinlich durch eine Schädigung der peripheren somatosensorischen und autonomen Neuronen, die sich in sensorischen Defiziten, sowie in erhöhter Schmerzempfindlichkeit manifestieren. Als Korrelat dazu wurden abnormale somatosensorisch evozierte Potenziale, pathologische Ergebnisse in der quantitativen sensorischen Testung und eine Abnahme der Nervenfaserdichte beschrieben.
Ein Schwerpunkt unserer Untersuchungen lag auf der Erforschung von potentiellen Veränderungen von Lipidsignalmolekülen. Eine Reihe von Studien zeigen eine Schmerzlinderung durch Cannabis-Einnahme, sowie eine Tendenz zur Schmerzentwicklung bei Parkinson Patienten mit dem bekannten FAAHPolymorphismus. Die Ergebnisse deuten darauf hin, dass eine Störung im Endocannabinoid-System höchstwahrscheinlich zu erhöhter Schmerzprävalenz bei Morbus Parkinson beiträgt. Eine weitere wichtige Lipid-Gruppe sind Glycosylceramide. Ihr Abbau kann durch heterozygote Mutationen des lipidabbauenden Enzyms Glukocerebrosidase 1 (GBA1) gestört sein. GBA1 Mutationen sind mit der schnell progredienten sporadischen Verlaufsform der Parkinson-Krankheit assoziiert.
Im Rahmen der Studie wurden zwei Kohorten von Parkinson Patienten analysiert. Die 128 Patienten aus Israel wurden im ersten Teil mit 224 jungen gesunden deutschen Probanden verglichen. Im zweiten Teil wurden 50 deutschen Patienten und 50 gesunde altersgleiche Probanden untersucht. Die Schmerzevaluation erfolgte anhand der "Brief Pain Inventory“ und "Neuro Detect“ Fragebögen. Bei allen Probanden wurde quantitative sensorische Testung durchgeführt und die Plasmakonzentrationen der Lipidsignalmoleküle mittels quantitativer HPLC-Tandem-Massenspektrometrie analysiert.
Nach Auswertung der Schmerzevaluation konnte eine erhöhte Schmerzprävalenz bei Parkinson Patienten festgestellt werden. Die Prävalenz betrug 66% im ersten Teil der Studie und 74% in der deutschen Kohorte, im Vergleich zu 40% bei den altersgleichen gesunden Probanden. Ergebnisse der quantitativen sensorischen Testung zeigen einen Verlust der thermischen Empfindung (erhöhte Schwellen) bei der gleichzeitigen mechanischen Überempfindlichkeit (erniedrigte Schwellen). In der multivariaten LipidAnalyse konnten erniedrigte Konzentrationen von Anandamid und Lysophosphatidsäure 20:4 und eine Erhöhung der Glucosylceramide nachgewiesen werden. Diese Veränderungen waren bei Parkinson Patienten mit Schmerzen stärker ausgeprägt. Außerdem wurde eine lineare Korrelation zwischen Glucosylceramiden (GlcCer 18:1, GlcCer 24:1) und der Schmerzintensität, sowie sensorischem Defizit festgestellt.
Nach sorgfältiger Auswertung der Studienergebnisse kommen wir zu der Schlussfolgerung, dass eine Veränderung der Endocannabinoide und der Glucosylceramide zur Pathogenese der Schmerzen und der sensorischen Neuropathie bei Morbus Parkinson beitragen. Die Erkenntnisse könnten zukünftig zur Diagnosestellung durch frühzeitige Erkennung prämotorischer sensorischer Symptome beitragen. Darüber hinaus könnten unsere Ergebnisse zur Therapieoptimierung durch Wiederherstellung der Lipid-Homeostases beitragen.
Diese Dissertation soll die Frage beantworten, ob die Forderung der Krankenkassen, die Nabelhernie und die epigastrische Hernie als ambulante Operation zu realisieren, gerechtfertigt bzw. sinnvoll ist. Sie soll ferner Steuergrößen und Maßnahmen identifizieren, die die Überführung des Eingriffs in den ambulanten Rahmen begünstigen können.
Seit den achtziger Jahren des letzten Jahrhunderts wird versucht, durch die kurzstationäre und ambulante Operation verschiedener Krankheitsbilder der Forderung nach Kostenersparnis im Gesundheitswesen nachzukommen. Von den Krankenkassen wird gefordert, den Verschluss einer Hernia umbilicalis: Ohne Plastik: Mit Exstirpation einer Nabelzyste, den Verschluss einer Hernie epigastrica: Ohne Plastik sowie den Verschluss einer Hernia umbilicalis: Mit Plastik im Rahmen einer ambulanten Operation zu korrigieren. Entsprechend wurden diese Eingriffe 2005 in die Liste der ambulant zu erbringenden und stationsersetzenden Maßnahmen aufgenommen. Dennoch liegt die durchschnittliche stationäre Verweildauer nach diesem Eingriff weiterhin bei 3,5 Tagen.
Phylogenetisch ist die Entstehung von Nabelhernien durch anatomisch präformierte Schwachstellen der Bauchwand bedingt, an denen Muskulatur fehlt und nur Aponeurosen und Faszien vorhanden sind. Die Entstehung wird aber auch durch Begleiterkrankungen und Risikofaktoren begünstigt.
In die vorliegende Untersuchung wurden nach Anwendung verschiedener Ausschlusskriterien 95 Patienten aufgenommen, die im Zeitraum zwischen dem 24. August 2009 und dem 24. Juni 2012 mit der Hauptdiagnose einer Nabelhernie bzw. epigastrischen Hernie - Diagnose nach ICD10 - K42.0, K42.1, K42.9, K43.0, K43.1 und K43.9 in der Klinik für Allgemein- und Viszeralchirurgie der Hochtaunuskliniken Bad Homburg operiert wurden. Die selektierten Patienten, welche betrachtet wurden, teilten sich in 61 primäre Nabelhernien, fünf Rezidivnabelhernien, elf epigastrische Hernien, drei Rezidive epigastrischer Hernien und 15 Kombinationseingriffe mit simultaner Operation einer Nabelhernie und einer Leistenhernie auf.
Als Operationsverfahren kam entweder eine Naht Stoß-auf-Stoß (NSAS), die Technik nach Mayo mit einer Fasziendoppelung oder die Implantation von alloplastischem Fremdmaterial entweder mittels eines Ventralex™ Patch oder Proceed™ Patch in Sublay-Technik oder bei ausgedehnten Befunden eine retromuskuläre Mesh Plastik (RMMP) zum Einsatz. Als laparoskopisches Verfahren wurde das Intraperitoneale Onlay Mesh (IPOM) verwendet.
Die Auswertung für die deskriptive Statistik erfolgte mit Microsoft® Excel® 2013. Anschließend wurde die Auswertung der explorativen wie auch der mathematisch/induktiven Statistik mit Hilfe von BiAS. für Windows™ Version 11/2015 durchgeführt.
Nach Analyse des Patientengutes konnte anhand von Korrelationsanalysen herausgearbeitet werden, dass das Alter, die Anzahl der Begleiterkrankungen, die Anzahl der Risikofaktoren und die ASA-Klassifikation (American Society of Anesthesiologists), die Größe der Bruchlücke in Zentimetern und die Schmerzen am zweiten postoperativen Tag einen schwachen Zusammenhang rho (ρ) zwischen 0,23 und 0,39 mit der Liegedauer bei jedoch signifikanten p-Wert p ≤ 0,05 aufwiesen. Einen stärkeren Zusammenhang mit einem Korrelationskoeffizienten ρ von 0,42 und 0,40 im Hinblick auf die Liegedauer zeigten hierbei die Operationsdauer und die Schmerzen am ersten postoperativen Tag. Den stärksten signifikanten Zusammenhang mit einem ρ von 0,64 zeigten die Schmerzen am dritten postoperativen Tag.
Die Verweildauer wurde auch durch die Wahl des Operationsverfahrens beeinflusst. Hier ergab sich eine signifikante Verlängerung der Verweildauer durch unterschiedliche Operationsverfahren sowohl in der Begutachtung des Gesamtkollektivs als auch in der Subgruppe NSAS, Mayo und Patch.
Im Anschluss konnte anhand multivariater Analysen festgestellt werden, dass die Operationsdauer, das Operationsverfahren und die ASA-Klassifikation mit p-Werten ≤ 0,05 mit der Liegedauer signifikant korrelierten. Auch konnte mit Hilfe der multivariaten Analyse aufgezeigt werden, dass die Größe der Bruchlücke in Zentimetern und die Schmerzen am ersten und zweiten postoperativen Tag mit Signifikanzwerten ≤ 0,05 mit der Liegedauer korrelierten.
Nach der durchgeführten Analyse, wie auch nach Betrachtung der Literatur, ist die Grundlage zur Durchführbarkeit einer ambulanten Operation die Erfüllung der medizinischen Voraussetzungen, die Erfüllung der Kriterien für ambulante Operationen und die Erfüllung der Entlassungskriterien. Zudem sollten Patienten mit kardiovaskulären Erkrankungen, insbesondere bei Vorliegen einer Herzinsuffizienz, aber auch bei COPD, Asthma und Schlafapnoesyndrom und einem BMI größer 30 nicht für eine ambulante Operation in Betracht gezogen werden. Auch gelten ein ASA Status größer als 2, Nebenwirkungen der (Allgemein-)Narkose wie PONV, Schwindel, Schläfrigkeit und ein erhöhtes postoperatives Schmerzniveau sowie eine große Defektgröße als hinderlich für die ambulante Durchführung der Operationen.
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Conduct disorder (CD), a psychiatric disorder characterized by a repetitive pattern of antisocial behaviors, results from a complex interplay between genetic and environmental factors. The clinical presentation of CD varies both according to the individual’s sex and level of callous-unemotional (CU) traits, but it remains unclear how genetic and environmental factors interact at the molecular level to produce these differences. Emerging evidence in males implicates methylation of genes associated with socio-affective processes. Here, we combined an epigenome-wide association study with structural neuroimaging in 51 females with CD and 59 typically developing (TD) females to examine DNA methylation in relation to CD, CU traits, and gray matter volume (GMV). We demonstrate an inverse pattern of correlation between CU traits and methylation of a chromosome 1 region in CD females (positive) as compared to TD females (negative). The identified region spans exon 1 of the SLC25A24 gene, central to energy metabolism due to its role in mitochondrial function. Increased SLC25A24 methylation was also related to lower GMV in multiple brain regions in the overall cohort. These included the superior frontal gyrus, dorsolateral prefrontal cortex, supramarginal gyrus, secondary visual cortex and ventral posterior cingulate cortex, which are regions that have previously been implicated in CD and CU traits. While our findings are preliminary and need to be replicated in larger samples, they provide novel evidence that CU traits in females are associated with methylation levels in a fundamentally different way in CD and TD individuals, which in turn may relate to observable variations in GMV across the brain.
Background: Glucagon-like peptide-1 receptor agonists may be a treatment option in patients with non-alcoholic fatty liver disease (NAFLD). Aims: To investigate the effects of semaglutide on liver stiffness and liver fat in subjects with NAFLD using non-invasive magnetic resonance imaging (MRI) methods. Methods: This randomised, double-blind, placebo-controlled trial enrolled subjects with liver stiffness 2.50-4.63 kPa by magnetic resonance elastography (MRE) and liver steatosis ≥10% by MRI proton density fat fraction (MRI-PDFF). The primary endpoint was change from baseline to week 48 in liver stiffness assessed by MRE. Results: Sixty-seven subjects were randomised to once-daily subcutaneous semaglutide 0.4 mg (n = 34) or placebo (n = 33). Change from baseline in liver stiffness was not significantly different between semaglutide and placebo at week 48 (estimated treatment ratio 0.96 (95% CI 0.89, 1.03; P = 0.2798); significant differences in liver stiffness were not observed at weeks 24 or 72. Reductions in liver steatosis were significantly greater with semaglutide (estimated treatment ratios: 0.70 [0.59, 0.84], P = 0.0002; 0.47 [0.36, 0.60], P < 0.0001; and 0.50 [0.39, 0.66], P < 0.0001) and more subjects achieved a ≥ 30% reduction in liver fat content with semaglutide at weeks 24, 48 and 72, (all P < 0.001). Decreases in liver enzymes, body weight and HbA1c were also observed with semaglutide. Conclusions: The change in liver stiffness in subjects with NAFLD was not significantly different between semaglutide and placebo. However, semaglutide significantly reduced liver steatosis compared with placebo which, together with improvements in liver enzymes and metabolic parameters, suggests a positive impact on disease activity and metabolic profile. ClinicalTrials.gov identifier: NCT03357380
Aim: Comparison of the clinical efficacy (digitally volumetric, aesthetic, patient-centred outcomes) of tunnel technique (TUN) with subepithelial connective tissue graft (CTG) versus coronally advanced flap (CAF) with enamel matrix derivate (EMD) 5 years after gingival recession therapy. Materials and methods: In 18 patients contributing 36 RT1 recessions, study models were collected at baseline and follow-ups. Optical scans assessed recessions computer-assisted [recession depth, recession reduction (RECred), complete root coverage (CRC), percentage of root coverage (RC), pointwise (pTHK) and mean areal (aTHK) marginal soft tissue thickness]. Root coverage aesthetic Score (RES) was used for aesthetic evaluation and visual analogue scales for patient-centred data collection applied. Results: Sixty months after surgery, 50.0% (TUN+CTG) and 0.0% (CAF+EMD) of sites showed CRC (p = 0.0118), 82.2% (TUN+CTG) and 32.0% (CAF+EMD) achieved RC, respectively (p = 0.0023). CTG achieved significantly better RECred (TUN+CTG: 1.75±0.74 mm; CAF+EMD: 0.50 ± 0.39 mm; p = 0.0009) and aTHK (TUN+CTG: 0.95 ± 0.41 mm; CAF+EMD: 0.26 ± 0.28 mm; p = 0.0013). RES showed superior outcomes (p = 0.0533) for TUN+CTG (6.86 ± 2.31) compared to CAF+EMD (4.63 ± 1.99). The study failed to find significant differences related to patient-centred outcomes (TUN+CTG: 8.30 ± 2.21; CAF+EMD: 7.50 ± 1.51; p = 0.1136). Conclusions: Five years after treatment, CTG resulted in better clinical and aesthetic outcomes than CAF+EMD. Increased THK was associated with improved outcomes for RECred and RC.
Background: To test for rates of other cause mortality (OCM) and cancer-specific mortality (CSM) in elderly prostate cancer (PCa) patients treated with the combination of radical prostatectomy (RP) and external beam radiation therapy (EBRT) versus RP alone, since elderly PCa patients may be over-treated. Methods: Within the Surveillance, Epidemiology and End Results database (2004–2016), cumulative incidence plots, after propensity score matching for cT-stage, cN-stage, prostate specific antigen, age and biopsy Gleason score, and multivariable competing risks regression models (socioeconomic status, pathological Gleason score) addressed OCM and CSM in patients (70–79, 70–74, and 75–79 years) treated with RP and EBRT versus RP alone. Results: Of 18,126 eligible patients aged 70–79 years, 2520 (13.9%) underwent RP and EBRT versus 15,606 (86.1%) RP alone. After propensity score matching, 10-year OCM rates were respectively 27.9 versus 20.3% for RP and EBRT versus RP alone (p < .001), which resulted in a multivariable HR of 1.4 (p < .001). Moreover, 10-year CSM rates were respectively 13.4 versus 5.5% for RP and EBRT versus RP alone. In subgroup analyses separately addressing 70–74 year old and 75–79 years old PCa patients, 10-year OCM rates were 22.8 versus 16.2% and 39.5 versus 24.0% for respectively RP and EBRT versus RP alone patients (all p < .001). Conclusion: Elderly patients treated with RP and EBRT exhibited worrisome rates of OCM. These higher than expected OCM rates question the need for combination therapy (RP and EBRT) in elderly PCa patients and indicate the need for better patient selection, when combination therapy is contemplated.
Aims: Parkinson's disease (PD) is frequently associated with a prodromal sensory neuropathy manifesting with sensory loss and chronic pain. We have recently shown that PD-associated sensory neuropathy in patients is associated with high levels of glucosylceramides. Here, we assessed the underlying pathology and mechanisms in Pink1−/−SNCAA53T double mutant mice. Methods: We studied nociceptive and olfactory behaviour and the neuropathology of dorsal root ganglia (DRGs), including ultrastructure, mitochondrial respiration, transcriptomes, outgrowth and calcium currents of primary neurons, and tissue ceramides and sphingolipids before the onset of a PD-like disease that spontaneously develops in Pink1−/−SNCAA53T double mutant mice beyond 15 months of age. Results: Similar to PD patients, Pink1−/−SNCAA53T mice developed a progressive prodromal sensory neuropathy with a loss of thermal sensitivity starting as early as 4 months of age. In analogy to human plasma, lipid analyses revealed an accumulation of glucosylceramides (GlcCer) in the DRGs and sciatic nerves, which was associated with pathological mitochondria, impairment of mitochondrial respiration, and deregulation of transient receptor potential channels (TRPV and TRPA) at mRNA, protein and functional levels in DRGs. Direct exposure of DRG neurons to GlcCer caused transient hyperexcitability, followed by a premature decline of the viability of sensory neurons cultures upon repeated GlcCer application. Conclusions: The results suggest that pathological GlcCer contribute to prodromal sensory disease in PD mice via mitochondrial damage and calcium channel hyperexcitability. GlcCer-associated sensory neuron pathology might be amenable to GlcCer lowering therapeutic strategies.
Amide proton transfer-chemical exchange saturation transfer (APT-CEST) imaging provides important information for the diagnosis and monitoring of tumors. For such analysis, complete coverage of the brain is advantageous, especially when registration is performed with other magnetic resonance (MR) modalities, such as MR spectroscopy (MRS). However, the acquisition of Z-spectra across several slices via multislice imaging may be time-consuming. Therefore, in this paper, we present a new approach for fast multislice imaging, allowing us to acquire 16 slices per frequency offset within 8 s. The proposed fast CEST-EPI sequence employs a presaturation module, which drives the magnetization into the steady-state equilibrium for the first frequency offset. A second module, consisting of a single CEST pulse (for maintaining the steady-state) followed by an EPI acquisition, passes through a loop to acquire multiple slices and adjacent frequency offsets. Thus, the whole Z-spectrum can be recorded much faster than the conventional saturation scheme, which employs a presaturation for each single frequency offset. The validation of the CEST sequence parameters was performed by using the conventional saturation scheme. Subsequently, the proposed and a modified version of the conventional CEST sequence were compared in vitro on a phantom with different T1 times and in vivo on a brain tumor patient. No significant differences between both sequences could be found in vitro. The in vivo data yielded almost identical MTRasym contrasts for the white and gray matter as well as for tumor tissue. Our results show that the proposed fast CEST-EPI sequence allows for rapid data acquisition and provides similar CEST contrasts as the modified conventional scheme while reducing the scanning time by approximately 50%.
Objective: To assess the effect of cesarean section (CS) timing, elective versus unplanned, on the residual myometrial thickness (RMT) and CS scars. Methods: This is a prospective single-blinded observational cohort study with 186 observations. Patients indicated to undergo first singleton CS were preoperatively recruited. Exclusion criteria were history of repeated CS, vertical hysterotomy, diabetes, and additional uterine surgeries. Sonographic examination was performed for assessing the RMT ratio, the presence of a niche, fibrosis, and the distance from the scar to the internal os (SO) 1 year after CS. Power analysis was performed with 0.05 α, 0.1 β, and all statistical analyses were conducted with Stata®. Results: Wilcoxon rank-sum test for the association between CS timing, RMT ratio and SO showed Z values of −0.59 and −4.94 (P = 0.553 and P < 0.001), respectively. There was no association between CS timing and niches and fibrosis (P > 0.99 and P = 0.268, respectively). Linear regression between SO and the extent of cervical dilatation showed a −0.45 β (95% confidence interval −0.68 to −0.21) and a 10.22-mm intercept (P < 0.001). Conclusion: RMT is independent of the timing of CS, but the SO distance shows a negative linear relationship with the cervical dilatation.
Aim: To evaluate preclinical education in Endodontology at Austrian, German and Swiss dental schools using an online survey. Methodology: An online survey divided into nine categories was sent using SurveyMonkey software to 37 dental schools, before the spread of the COVID-19 pandemic. The questionnaire included 50 questions to evaluate preclinical endodontic education, such as faculty-to-student ratios, topics taught and materials used, in preclinical phantom head courses. Seven and 14 days after the first e-mail contact, dental schools received a reminder e-mail. After four and six weeks, the dental schools were contacted by telephone and asked to participate in the online survey. The processing time was eight weeks in total. Results: The response rate was 89%. Preclinical endodontic education at the participating dental schools differs considerably. Theory classes ranged from 1 to 70 h (15 h mean), and practical classes ranged from 3 to 78 h (39 h mean). The faculty-to-student ratio varied between 1:4 and 1:38 (1:15 mean). Forty-five per cent of the dental schools had a specialist in endodontics teaching theory. Several dental microscopes were available for preclinical teaching purposes at 82% of the dental schools. The majority (82%) taught root canal preparation with rotary or reciprocating NiTi instruments. Overall, 85% of the dental schools taught lateral compaction, amongst other methods, for canal filling. Conclusion: A substantial divergence amongst the dental schools regarding the time dedicated to theory and practical instruction in Endodontology was reported. However, convergence in the use of root canal treatment techniques and materials was reported.
Background: Recently, an increase in the rates of high-risk prostate cancer (PCa) was reported. We tested whether the rates of and low, intermediate, high and very high-risk PCa changed over time. We also tested whether the number of prostate biopsy cores contributed to changes rates over time. Methods: Within the Surveillance, Epidemiology and End Results (SEER) database (2010–2015), annual rates of low, intermediate, high-risk according to traditional National Comprehensive Cancer Network (NCCN) and high versus very high-risk PCa according to Johns Hopkins classification were tabulated without and with adjustment for the number of prostate biopsy cores. Results: In 119,574 eligible prostate cancer patients, the rates of NCCN low, intermediate, and high-risk PCa were, respectively, 29.7%, 47.8%, and 22.5%. Of high-risk patients, 39.6% and 60.4% fulfilled high and very high-risk criteria. Without adjustment for number of prostate biopsy cores, the estimated annual percentage changes (EAPC) for low, intermediate, high and very high-risk were respectively −5.5% (32.4%–24.9%, p < .01), +0.5% (47.6%–48.4%, p = .09), +4.1% (8.2%–9.9%, p < .01), and +8.9% (11.8%–16.9%, p < .01), between 2010 and 2015. After adjustment for number of prostate biopsy cores, differences in rates over time disappeared and ranged from 29.8%–29.7% for low risk, 47.9%–47.9% for intermediate risk, 8.9%–9.0% for high-risk, and 13.6%–13.6% for very high-risk PCa (all p > .05). Conclusions: The rates of high and very high-risk PCa are strongly associated with the number of prostate biopsy cores, that in turn may be driven by broader use magnetic resonance imaging (MRI).
BAG3 is a negative regulator of ciliogenesis in glioblastoma and triple-negative breast cancer cells
(2021)
By regulating several hallmarks of cancer, BAG3 exerts oncogenic functions in a wide variety of malignant diseases including glioblastoma (GBM) and triple-negative breast cancer (TNBC). Here we performed global proteomic/phosphoproteomic analyses of CRISPR/Cas9-mediated isogenic BAG3 knockouts of the two GBM lines U343 and U251 in comparison to parental controls. Depletion of BAG3 evoked major effects on proteins involved in ciliogenesis/ciliary function and the activity of the related kinases aurora-kinase A and CDK1. Cilia formation was significantly enhanced in BAG3 KO cells, a finding that could be confirmed in BAG3-deficient versus -proficient BT-549 TNBC cells, thus identifying a completely novel function of BAG3 as a negative regulator of ciliogenesis. Furthermore, we demonstrate that enhanced ciliogenesis and reduced expression of SNAI1 and ZEB1, two key transcription factors regulating epithelial to mesenchymal transition (EMT) are correlated to decreased cell migration, both in the GBM and TNBC BAG3 knockout cells. Our data obtained in two different tumor entities identify suppression of EMT and ciliogenesis as putative synergizing mechanisms of BAG3-driven tumor aggressiveness in therapy-resistant cancers.
Rationale: Postinfectious bronchiolitis obliterans (PIBO) is a rare, chronic respiratory condition, which follows an acute insult due to a severe infection of the lower airways. Objectives: The objective of this study was to investigate the long-term course of bronchial inflammation and pulmonary function testing in children with PIBO. Methods: Medical charts of 21 children with PIBO were analyzed retrospectively at the Children's University Hospital Frankfurt/Main Germany. Pulmonary function tests (PFTs) with an interval of at least 1 month were studied between 2002 and 2019. A total of 382 PFTs were analyzed retrospectively and per year, the two best PFTs, in total 217, were evaluated. Additionally, 56 sputum analysis were assessed and the sputum neutrophils were evaluated. Results: The evaluation of the 217 PFTs showed a decrease in FEV1 with a loss of 1.07% and a loss in z score of −0.075 per year. FEV1/FVC decreased by 1.44 per year. FVC remained stable, showing a nonsignificant increase by 0.006 in z score per year. However, FEV1 and FVC in L increased significantly with FEV1 0.032 L per cm and FVC 0.048 L/cm in height. Sputum neutrophils showed a significant increase of 2.12% per year. Conclusion: Our results demonstrated that in patients with PIBO pulmonary function decreased significantly showing persistent obstruction over an average follow-up period of 8 years. However, persistent lung growth was revealed. In addition, pulmonary inflammation persisted clearly showing an increasing amount of neutrophils in induced sputum. Patients did not present with a general susceptibility to respiratory infections.
Objective: To assess tooth loss (TL) in initially periodontally healthy/gingivitis (PHG) and periodontally compromised (PC) individuals during a 15- to 25-year follow-up in a specialist practice and to identify the factors influencing TL. Materials and methods: Patients were re-examined 240 ± 60 months after active periodontal therapy (PC) or initial examination (PHG). PHG patients were periodontally healthy or had gingivitis, and PC patients exhibited at least stage II periodontitis. TL, patient-related outcomes, and risk factors for TL were assessed at the patient level (group-relation, gender, age, smoking, bleeding on probing, educational status, mean number of visits/year). Results: Fifty-six PC patients receiving regular supportive periodontal care (12 female, mean age 49.1 ± 10.9 years, stage II: 10, stage III/IV: 46) lost 38 teeth (0.03 ± 0.05 teeth/year). Fifty-one PHG patients (23 female, mean age 34.5 ± 12.4 years) following regular oral prevention lost 39 teeth (0.04 ± 0.05 teeth/year) (p = .631). Both PC and PHG groups did not show any significant differences regarding visual analogue scale measurements [aesthetics (p = .309), chewing function (p = .362), hygiene (p = .989)] and overall Oral Health Impact Profile (p = .484). Age at the start of follow-up was identified as a risk factor for TL (p < .0001). Conclusion: PC and PHG patients exhibited similarly small TL rates over 240 ± 60 months, which should, however, be interpreted with caution in view of the group heterogeneity. Clinical trial number: DRKS00018840 (URL: https://drks.de).
Degradation of the endoplasmic reticulum (ER) via selective autophagy (ER-phagy) is vital for cellular homeostasis. We identify FAM134A/RETREG2 and FAM134C/RETREG3 as ER-phagy receptors, which predominantly exist in an inactive state under basal conditions. Upon autophagy induction and ER stress signal, they can induce significant ER fragmentation and subsequent lysosomal degradation. FAM134A, FAM134B/RETREG1, and FAM134C are essential for maintaining ER morphology in a LC3-interacting region (LIR)-dependent manner. Overexpression of any FAM134 paralogue has the capacity to significantly augment the general ER-phagy flux upon starvation or ER-stress. Global proteomic analysis of FAM134 overexpressing and knockout cell lines reveals several protein clusters that are distinctly regulated by each of the FAM134 paralogues as well as a cluster of commonly regulated ER-resident proteins. Utilizing pro-Collagen I, as a shared ER-phagy substrate, we observe that FAM134A acts in a LIR-independent manner and compensates for the loss of FAM134B and FAM134C, respectively. FAM134C instead is unable to compensate for the loss of its paralogues. Taken together, our data show that FAM134 paralogues contribute to common and unique ER-phagy pathways.
Introduction: Adeno-associated virus (AAV)-based gene therapy for haemophilia presents a challenge to the existing structure of haemophilia centres and requires a rethink of current collaboration and information exchange with the aim of ensuring a system that is fit-for-purpose for advanced therapies to maximise benefits and minimise risks. In Europe, a certification process based on the number of patients and facilities is offered to the haemophilia centres by European Haemophilia Network (EUHANET). Aim and methods: This joint European Association for Haemophilia and Allied Disorders (EAHAD) and European Haemophilia Consortium (EHC) publication describes criteria for centres participating in gene therapy care that require a reassessment of the infrastructure of comprehensive care and provides an outlook on how these criteria can be implemented in the future work of haemophilia centres. Results: The core definition of a haemophilia treatment centre remains, but additional roles could be implemented. A modifiable ‘hub-and-spoke’ model addresses all aspects associated with gene therapy, including preparation and administration of the gene therapy product, determination of coagulation and immunological parameters, joint score and function, and liver health. This will also include the strategy on how to follow-up patients for a long-term safety and efficacy surveillance. Conclusion: We propose a modifiable, networked ‘hub and spoke’ model with a long term safety and efficacy surveillance system. This approach will be progressively developed with the goal of making haemophilia centres better qualified to deliver gene therapy and to make gene therapy accessible to all persons with haemophilia, irrespective of their country or centre of origin.
Aim: It can be challenging to distinguish COVID-19 in children from other common infections. We set out to determine the rate at which children consulting a primary care paediatrician with an acute infection are infected with SARS-CoV-2 and to compare distinct findings. Method: In seven out-patient clinics, children aged 0–13 years with any new respiratory or gastrointestinal symptoms and presumed infection were invited to be tested for SARS-CoV-2. Factors that were correlated with testing positive were determined. Samples were collected from 25 January 2021 to 01 April 2021. Results: Seven hundred and eighty-three children participated in the study (median age 3 years and 0 months, range 1 month to 12 years and 11 months). Three hundred and fifty-eight were female (45.7%). SARS-CoV-2 RNA was detected in 19 (2.4%). The most common symptoms in children with as well as without detectable SARS-CoV-2 RNA were rhinitis, fever and cough. Known recent exposure to a case of COVID-19 was significantly correlated with testing positive, but symptoms or clinical findings were not. Conclusion: COVID-19 among the children with symptoms of an acute infection was uncommon, and the clinical presentation did not differ significantly between children with and without evidence of an infection with SARS-CoV-2.
The majority of excitatory synapses terminating on cortical neurons are found on dendritic spines. The geometry of spines, in particular the size of the spine head, tightly correlates with the strength of the excitatory synapse formed with the spine. Under conditions of synaptic plasticity, spine geometry may change, reflecting functional adaptations. Since the cytokine tumor necrosis factor (TNF) has been shown to influence synaptic transmission as well as Hebbian and homeostatic forms of synaptic plasticity, we speculated that TNF-deficiency may cause concomitant structural changes at the level of dendritic spines. To address this question, we analyzed spine density and spine head area of Alexa568-filled granule cells in the dentate gyrus of adult C57BL/6J and TNF-deficient (TNF-KO) mice. Tissue sections were double-stained for the actin-modulating and plasticity-related protein synaptopodin (SP), a molecular marker for strong and stable spines. Dendritic segments of TNF-deficient granule cells exhibited ∼20% fewer spines in the outer molecular layer of the dentate gyrus compared to controls, indicating a reduced afferent innervation. Of note, these segments also had larger spines containing larger SP-clusters. This pattern of changes is strikingly similar to the one seen after denervation-associated spine loss following experimental entorhinal denervation of granule cells: Denervated granule cells increase the SP-content and strength of their remaining spines to homeostatically compensate for those that were lost. Our data suggest a similar compensatory mechanism in TNF-deficient granule cells in response to a reduction in their afferent innervation.