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Bei einer Schaumsklerosierungstherapie von Varizen können als Nebenwirkungen sowohl tiefe (TVT) als auch oberflächliche Beinvenenthrombosen (OVT) auftreten. Noch weitgehend unklar sind die Risikofaktoren, welche die Entstehung einer OVT oder TVT nach Schaumsklerosierung begünstigen. Das Ziel dieser retrospektiven Analyse war, anhand eines größeren Kollektivs von Patienten mit thromboembolischen Komplikationen sowohl patienten- als auch eingriffsbezogene Risikofaktoren für thromboembolische Komplikationen durch eine Schaumsklerosierung herauszuarbeiten.Insgesamt wurden 170 Patienten untersucht, die eine Schaumsklerosierung erhielten. Vor dem Stichtag 17. März 2020 wurden die letzten 85 Patienten mit thromboembolischen Komplikationen als Studiengruppe A und die letzten 85 Patienten ohne thromboembolische Komplikationen als Kontrollgruppe B nach Sklerosierung mit aufgeschäumtem Sklerosierungsmittel erfasst und verglichen.Patienten mit thromboembolischen Komplikationen hatten häufiger eine Thrombophilie (11/85 vs. 3/85). Die mittleren BMI-Werte waren in Gruppe A (25,9 ± 5,1) signifikant niedriger als in Gruppe B (28,0 ± 7,2) (P = 0,034). Thromboembolische Komplikationen zeigen sich nach Schaumsklerosierung eher am Unterschenkel (61/105) als am Oberschenkel (1/13) (P 0,001) dabei häufiger nach dorsaler als nach ventraler Schaumsklerosierung (39 von 47 vs. 5 von 40, P 0,001). Von den 39 thromboembolischen Komplikationen am dorsalen Unterschenkel waren 23 Muskelvenenthrombosen.Das Risiko für Muskelvenenthrombosen nach Schaumsklerosierung ist vor allem bei schlanken Patienten, welche am dorsalen Unterschenkel sklerosiert werden, erhöht.

Coevolution is often considered a major driver of speciation, but evidence for this claim is not always found because diversity might be cryptic. When morphological divergence is low, molecular data are needed to uncover diversity. A taxon for which this holds true are the mites, which are known for their extensive and often cryptic diversity. We studied mites of the genus Poecilochirus that are phoretic on burying beetles (Silphidae: Nicrophorus). Poecilochirus taxonomy is poorly understood. Most studies on this genus focus on the evolutionary ecology of Poecilochirus carabi sensu lato, a complex of at least two biological species. Based on molecular data of 230 specimens from 43 locations worldwide, we identified 24 genetic clusters that may represent species. We estimate that these mites began to diversify during the Paleogene, when the clade containing P. subterraneus branched off and the remaining mites diverged into two further clades. One clade resembles P. monospinosus and P. austroasiaticus. The other clade contains 17 genetic clusters resembling P. carabi s.l.. Among these are P. carabi sensu stricto, P. necrophori, and potentially many additional cryptic species. Our analyses suggest that these clades were formed in the miocene by large-scale geographic separation. Diversification also seems to have happened on a smaller scale, potentially due to adaptation to specific hosts or local abiotic conditions, causing some clusters to specialize on certain beetle species. Our results suggest that biodiversity in this genus was generated by multiple interacting forces shaping the tangled webs of life.

Background It is unclear whether asthma and its allergic phenotype are risk factors for hospitalization or severe disease from SARS‐CoV‐2. Methods All patients over 28 days old testing positive for SARS‐CoV‐2 between March 1 and September 30, 2020, were retrospectively identified and characterized through electronic analysis at Stanford. A sub‐cohort was followed prospectively to evaluate long‐term COVID‐19 symptoms. Results 168,190 patients underwent SARS‐CoV‐2 testing, and 6,976 (4.15%) tested positive. In a multivariate analysis, asthma was not an independent risk factor for hospitalization (OR 1.12 [95% CI 0.86, 1.45], p = .40). Among SARS‐CoV‐2‐positive asthmatics, allergic asthma lowered the risk of hospitalization and had a protective effect compared with non‐allergic asthma (OR 0.52 [0.28, 0.91], p = .026); there was no association between baseline medication use as characterized by GINA and hospitalization risk. Patients with severe COVID‐19 disease had lower eosinophil levels during hospitalization compared with patients with mild or asymptomatic disease, independent of asthma status (p = .0014). In a patient sub‐cohort followed longitudinally, asthmatics and non‐asthmatics had similar time to resolution of COVID‐19 symptoms, particularly lower respiratory symptoms. Conclusions Asthma is not a risk factor for more severe COVID‐19 disease. Allergic asthmatics were half as likely to be hospitalized with COVID‐19 compared with non‐allergic asthmatics. Lower levels of eosinophil counts (allergic biomarkers) were associated with a more severe COVID‐19 disease trajectory. Recovery was similar among asthmatics and non‐asthmatics with over 50% of patients reporting ongoing lower respiratory symptoms 3 months post‐infection., Asthma is not a risk factor for more severe COVID‐19 disease. Allergic asthmatics are half as likely to be hospitalized compared with non‐allergic asthmatics and lower levels of eosinophil counts (allergic biomarkers) are associated with a more severe COVID‐19 disease trajectory. Recovery is similar among asthmatics and non‐asthmatics.

Organisms use color for camouflage, sexual signaling, or as a warning sign of danger. Primates are one of the most vibrantly colored Orders of mammals. However, the genetics underlying their coat color are poorly known, limiting our ability to study molecular aspects of its evolution. The role of the melanocortin 1 receptor (MC1R) in color evolution has been implicated in studies on rocket pocket mice (Chaetodipus intermediusi), toucans (Ramphastidae), and many domesticated animals. From these studies, we know that changes in MC1R result in a yellow/red or a brown/black morphology. Here, we investigate the evolution of MC1R in Lorisidae, a monophyletic nocturnal primate family, with some genera displaying high contrast variation in color patterns and other genera being monochromatic. Even more unique, the Lorisidae family has the only venomous primate: the slow loris (Nycticebus). Research has suggested that the contrasting coat patterns of slow lorises are aposematic signals for their venom. If so, we predict the MC1R in slow lorises will be under positive selection. In our study, we found that Lorisidae MC1R is under purifying selection (ω = 0.0912). In Lorisidae MC1R, there were a total of 75 variable nucleotides, 18 of which were nonsynonymous. Six of these nonsynonymous substitutions were found on the Perodicticus branch, which our reconstructions found to be the only member of Lorisidae that has predominantly lighter coat color; no substitutions were associated with Nycticebus. Our findings generate new insight into the genetics of pelage color and evolution among a unique group of nocturnal mammals and suggest putative underpinnings of monochromatic color evolution in the Perodicticus lineage., In primates, the most colorful of mammals, few have examined the influence the melanocortin 1 receptor (MC1R) has on color variation (light or dark) in primates. Here, we examined how MC1R impacts color variation in a cryptic primate family with high contrasting color variation. We found MC1R is under purifying selection, but there appears to be a link in nucleotide changes and light coat color.

Hydroxyurea and ruxolitinib are frequently used to treat myeloproliferative disorders, including polycythaemia vera, and chronic treatment is associated with many cutaneous adverse effects such as the development of aggressive non-melanoma skin cancer (NMSC). We report an 85-year-old man with a history of hydroxyurea- and ruxolitinib-treated polycythaemia vera who was referred for the management of progressively growing tumours on his scalp. Histopathology of the largest scalp lesion revealed a partly desmoplastic cutaneous squamous carcinoma with perineural invasion. Initial imaging revealed metastatic disease in cervical lymph nodes, bones and lungs. The scalp lesions were successfully treated with bleomycin-based electrochemotherapy. Under initial systemic therapy using four cycles of cetuximab, metastatic disease progressed. Following the approval by the health insurance, compassionate use of pembrolizumab monotherapy was initiated. After three cycles of pembrolizumab, however, metastatic disease further progressed and the patient finally died from global respiratory insufficiency. The present case exemplifies the cutaneous adverse effects of long-term hydroxyurea and ruxolitinib therapy, frequently resulting in highly aggressive NMSCs that are usually not responsive to systemic treatments even such as immune checkpoint inhibitors.

Dual combination therapy with a phosphodiesterase-5 inhibitor (PDE5i) and endothelin receptor antagonist is recommended for most patients with intermediate-risk pulmonary arterial hypertension (PAH). The RESPITE and REPLACE studies suggest that switching from a PDE5i to a soluble guanylate cyclase (sGC) activator may provide clinical improvement in this situation. The optimal approach to escalation or transition of therapy in this or other scenarios is not well defined. We developed an expert consensus statement on the transition to sGC and other treatment escalations and transitions in PAH using a modified Delphi process. The Delphi process used a panel of 20 physicians with expertise in PAH. Panelists answered three questionnaires on the management of treatment escalations and transitions in PAH. The initial questionnaire included open-ended questions. Later questionnaires consolidated the responses into statements that panelists rated on a Likert scale from -5 (

Inhaled treprostinil is an approved therapy for pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease in the United States. Studies have confirmed the robust benefits and safety of nebulized inhaled treprostinil, but it requires a time investment for nebulizer preparation, maintenance, and treatment. A small, portable treprostinil dry powder inhaler has been developed for the treatment of PAH. The primary objective of this study was to evaluate the safety and tolerability of treprostinil inhalation powder (TreT) in patients currently treated with treprostinil inhalation solution. Fifty-one patients on a stable dose of treprostinil inhalation solution enrolled and transitioned to TreT at a corresponding dose. Six-minute walk distance (6MWD), device preference and satisfaction (Preference Questionnaire for Inhaled Treprostinil Devices [PQ-ITD]), PAH Symptoms and Impact (PAH-SYMPACT®) questionnaire, and systemic exposure and pharmacokinetics for up to 5 h were assessed at baseline for treprostinil inhalation solution and at Week 3 for TreT. Adverse events (AEs) were consistent with studies of inhaled treprostinil in patients with PAH, and there were no study drug-related serious AEs. Statistically significant improvements occurred in 6MWD, PQ-ITD, and PAH-SYMPACT. Forty-nine patients completed the 3-week treatment phase and all elected to participate in an optional extension phase. These results demonstrate that, in patients with PAH, transition from treprostinil inhalation solution to TreT is safe, well-tolerated, and accompanied by statistically significant improvements in key clinical assessments and patient-reported outcomes with comparable systemic exposure between the two formulations at evaluated doses (trial registration: clinicaltrials.gov identifier: NCT03950739).

The relevance of Hedgehog signaling in Merkel cell carcinoma has only been addressed by a few studies with conflicting results. Thus, we aimed to establish the expression of Hedgehog signaling molecules in Merkel cell carcinoma to characterize causes of aberrant expression and to correlate these findings with the clinical course of the patients. Immunohistochemistry was performed for Sonic, Indian, Patched 1 (PTCH1) and Smoothened on patients' tumor tissue. Respective mRNA expression was analyzed in 10 Merkel cell carcinoma cell lines using quantitative real-time polymerase chain reaction. PTCH1 sequencing and DNA methylation microarray analyses were carried out on tumor tissues as well as cell lines. PTCH1 immunoreactivity in Merkel cell carcinoma was similar to that of basal cell carcinomas, which both significantly differed from PTCH1 immunoreactivity in healthy skin. Most PTCH1 mutations found were synonymous or without known functional impact. However, on average, the promoter regions of both PTCH1 were hypomethylated independently from PTCH1 gene expression or Merkel cell polyomavirus status. PTCH1 and GLI1/2/3 genes were differently expressed in different cell lines; notably, there was a significant correlation between GLI2 and PTCH1 mRNA expression. Similar to PTCH1 protein expression in patient tissues, PTCH1 gene expression in Merkel cell carcinoma cell lines is highly variable, but due to the similar methylation pattern across Merkel cell carcinoma cell lines, effects other than methylation seem to be the reason for the differential expression and PTCH1 appears to be upregulated by GLI as a classical Hedgehog target gene.

Background In a small number of kindreds with familial hidradenitis suppurativa (HS) different mutations of NCSTN (nicastrin) have been identified. Blocking of NCSTN leads to impairment of the Notch and PI3K/AKT signalling pathway, which is assumed to play a pathogenic role in HS. However, very limited data are available concerning expression levels of these pathway components in HS skin. Objectives To analyse the mRNA and protein expression of NCSTN, Notch1-3, PIK3R3 and AKT3 in HS. Methods Skin samples from healthy controls, lesional and perilesional skin of HS patients with and without a positive family history were analysed by quantitative real-time RT-PCR and immunohistochemistry. Univariate statistical analyses were conducted regarding association between expression levels and patient's characteristics. Results Expression levels of all investigated genes showed significantly higher levels in lesional HS skin compared with healthy controls. Univariate analysis showed no association between a positive family history and mRNA expression levels. Perilesional HS skin of patients with mild disease severity (Hurley I) showed significant higher mRNA expression levels of the investigated pathway components compared to moderate (Hurley II) and severe disease (Hurley III). Conclusion We found no evidence for diminished expression levels of the Notch signalling. In contrast, the NCSTN, Notch and PI3K/AKT signalling components are overexpressed in HS. Future research is needed to investigate a possible pathogenetic role or to reveal a coactivation of these overexpressed components during inflammatory response in HS.

Scientists typically use physical indicators, such as average crustal abundance, and energy requirements in production, as measures of the availability of mineral resources. Economists, on the other hand, typically rely on measures such as prices, and extraction costs. This study investigates the role of crustal abundance, energy requirements, and other physical indicators in determining relative metal prices. The relationship between prices, and physical indicators is estimated statistically for a sample of 22 chemical elements over the period 1970–2013 using an economic market model. The results suggest that energy requirements in production explain 43% of observed variation in metal prices, crustal abundance 21%, and other physical indicators (toxicity, native metal status, and melting point) combine to explain 12% of the observed differences in metal prices.

Background: Biventricular (BiV) pacing increases transmural repolarization heterogeneity due to epicardial to endocardial conduction from the left ventricular (LV) lead. However, limited evidence is available on concomitant changes in ventricular depolarization and repolarization and long-term outcomes of BiV pacing. Therefore, we investigated associations of BiV pacing-induced concomitant changes in ventricular depolarization and repolarization with mortality (i.e., LV assist device, heart transplantation, or all-cause mortality) and sustained ventricular arrhythmia endpoints. Methods: Consecutive BiV-defibrillator recipients with digital preimplantation and postimplantation electrocardiograms recorded between 2006 and 2015 at Duke University Medical Center were included. We calculated changes in QRS duration and corrected JT (JTc) interval and split them by median values. For simplicity, these variables were named QRS decreased (≤ −12 ms), QRS increased (> –12 ms), JTc decreased (≤22 ms), and JTc increased (> 22 ms) and subsequently used to construct four mutually exclusive groups. Results: We included 528 patients (median age, 68 years; male, 69%). No correlation between changes in QRS duration and JTc interval was observed (P =.295). Compared to QRS decreased/JTc increased, increased risk of the composite mortality endpoint was associated with QRS decreased/JTc decreased (hazard ratio [HR] = 1.62; 95% confidence interval [CI] = 1.09-2.43), QRS increased/JTc decreased (HR = 1.86; 95% CI = 1.27-2.71), and QRS increased/JTc increased (HR = 2.25; 95% CI = 1.52-3.35). No QRS/JTc group was associated with excess sustained ventricular arrhythmia risk (P =.400). Conclusion: Among BiV-defibrillator recipients, QRS decreased/JTc increased was associated with the most favorable long-term survival free of LV assist device, heart transplantation, and sustained ventricular arrhythmias. Our findings suggest that improved electrical resynchronization may be achieved by assessing concomitant changes in ventricular depolarization and repolarization.

Strigolactones (SLs) are a group of plant hormones involved in many aspects of plant development and stress adaptation. Here, we investigated the drought response of a barley (Hordeum vulgare L.) mutant carrying a missense mutation in the gene encoding the SL-specific receptor HvD14. Our results clearly showed that hvd14.d mutant is hyper-sensitive to drought stress. This was illustrated by a lower leaf relative water content (RWC), impaired photosynthesis, disorganization of chloroplast structure, altered stomatal density and slower closure of stomata in response to drought in the mutant compared to the wild type parent cultivar Sebastian. Although the content of abscisic acid (ABA) and its derivatives remained unchanged in the mutant, significant differences in expression of genes related to ABA biosynthesis were observed. Moreover, hvd14.d was insensitive to ABA during seed germination. Analysis of Arabidopsis thaliana mutant atd14-1 also demonstrated that mutation in the SL receptor resulted in increased sensitivity to drought. Our results indicate that the drought-sensitive phenotype of barley SL mutant might be caused by a disturbed ABA metabolism and/or signalling pathways. These results together uncovered a link between SL signalling and ABA-dependent drought stress response in barley.

Background: Lefty and Nodal are transforming growth factor β‐related proteins, which, beside their role in determination of laterality during embryogenesis, have also been linked with cancer progression. Objectives: Prompted by the observed significant left‐sided laterality of Merkel cell carcinoma (MCC), we addressed whether Lefty and Nodal are expressed in MCC and correlated expression patterns with clinical parameters such as MCC laterality and patient outcome. Methods: Expression of Lefty and Nodal in primary MCC was assessed in 29 patients by immunohistochemistry. The histology (H‐)score was calculated and correlated with clinical parameters. Results: The median (range) H‐score of Lefty and Nodal was 17.6 (0–291) and 74.9 (0.7–272), respectively. There was a significant correlation between Lefty expression and Nodal expression (correlation coefficient of 0.60, P = 0.0006). There was no significant correlation between Lefty expression and Nodal expression with either tumour laterality, gender, age, Merkel cell polyomavirus status, disease stage, anatomical localization of primary tumours or disease relapse. On univariate analysis, low Lefty expression and Nodal expression were significantly associated with MCC‐specific death (P = 0.010 and P = 0.019, respectively). On univariate analysis, low Lefty expression was the only significant independent predictor for MCC‐specific death (P = 0.025) as indicated by an odds ratio of 14 (95% CI: 1.43–137.33). Conclusions: Lefty and Nodal are frequently expressed in MCC, but not correlated with tumour laterality. Importantly, our data suggest that a low level of Lefty expression in primary MCC is a strong predictor of MCC‐specific death.

We present herein a novel nitroxide spin label‐containing RNA triphosphate TPT3NO and its application for site‐specific spin‐labeling of RNA through in vitro transcription using an expanded genetic alphabet. Our strategy allows the facile preparation of spin‐labeled RNAs with sizes ranging from short RNA oligonucleotides to large, complex RNA molecules with over 370 nucleotides by standard in vitro transcription. As a proof of concept, inter‐spin distance distributions are measured by pulsed electron paramagnetic resonance (EPR) spectroscopy in short self‐complementary RNA sequences and in a well‐studied 185 nucleotide non‐coding RNA, the B. subtilis glmS ribozyme. The approach is then applied to probe for the first time the folding of the 377 nucleotide A‐region of the long non‐coding RNA Xist, by PELDOR., UBPs meet EPR: Unnatural base pairs (UBPs) allow facile site‐specific introduction of nitroxide spin labels into long RNAs by in vitro transcription. Distances are determined in the glmS ribozyme and the 377 nt A‐region of the long non‐coding RNA Xist.

Numerical models are a suitable tool to quantify impacts of predicted climate change on complex ecosystems but are rarely used to study effects on benthic macroalgal communities. Fucus vesiculosus L. is a habitat-forming macroalga in the Baltic Sea and alarming shifts from the perennial Fucus community to annual filamentous algae are reported. We developed a box model able to simulate the seasonal growth of the Baltic Fucus-grazer-epiphyte system. This required the implementation of two state variables for Fucus biomass in units of carbon (C) and nitrogen (N). Model equations describe relevant physiological and ecological processes, such as storage of C and N assimilates by Fucus, shading effects of epiphytes or grazing by herbivores on both Fucus and epiphytes, but with species-specific rates and preferences. Parametrizations of the model equations and required initial conditions were based on measured parameters and process rates in the near-natural Kiel Outdoor Benthocosm (KOB) experiments during the Biological Impacts of Ocean Acidification project. To validate the model, we compared simulation results with observations in the KOB experiment that lasted from April 2013 until March 2014 under ambient and climate-change scenarios, that is, increased atmospheric temperature and partial pressure of carbon dioxide. The model reproduced the magnitude and seasonal cycles of Fucus growth and other processes in the KOBs over 1 yr under different scenarios. Now having established the Fucus model, it will be possible to better highlight the actual threat of climate change to the Fucus community in the shallow nearshore waters of the Baltic Sea.

This study examined saccade adaptation induced by intrasaccadic target steps (ITS). By manipulating the ITS, we investigated potential effects of the consistency of the feedback error on saccade adaptation, which would provide evidence against the linearity of standard models of visuomotor adaptation. Previous studies addressing saccade adaptation arrived at different interpretations, but in these experiments only a single saccade amplitude was trained rather than a variety of saccade amplitudes in random order (mixed training). We extend previous studies by testing for effects of error consistency under additional control conditions described by the factors training protocol (single-amplitude/mixed), ITS direction (onward/backward), and adaptation phase (training/washout). Adaptation dynamics were assessed using a model of "multi-gainfield adaptation" developed by tailoring an existing linear model for visuomotor adaptation of movements with multiple target positions to gain adaptation of saccades with multiple amplitudes. The total adaptive change did not depend on the consistency of the ITS in either mixed or single-amplitude training. The initial adaptation speed was lower with inconsistent ITS. However, the effect on adaptation speed occurred only during amplitude reduction and not during enlargement or washout. These results corroborate the linearity of saccade adaptation in that the mean error is the main factor determining the total adaptive change, independent of error consistency. The multi-gainfield adaptation model was confirmed in that the retention rate and error sensitivity did not depend on the training protocol. The absence of effects of error consistency on saccade adaptation is relevant in the context of adaptive deficits in movement disorders.