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Background: The efficacy of oncolytic viruses (OV) in cancer treatment depends on their ability to successfully infect and destroy tumor cells. However, patients' tumors vary, and in the case of individual insensitivity to an OV, therapeutic efficacy is limited. Here, we present a protocol for rapid generation of tumor cell-specific adapted oncolytic coxsackievirus B3 (CVB3) with enhanced oncolytic potential and a satisfactory safety profile. This is achieved by combining directed viral evolution (DVE) with genetic modification of the viral genome and the use of a microRNA-dependent regulatory tool. Methods: The oncolytic CVB3 variant PD-H was adapted to the refractory colorectal carcinoma cell line Colo320 through serial passaging. XTT assays and virus plaque assays were used to determine virus cytotoxicity and virus replication in vitro. Recombinant PD-H variants were generated through virus mutagenesis. Apoptosis was detected by Western blots, Caspase 3/7 assays, and DAPI staining. The therapeutic efficacy and safety of the adapted recombinant OV PD-SK-375TS were assessed in vivo using a subcutaneous Colo320 xenograft mouse model. Results: PD-H was adapted to the colorectal cancer cell line Colo320 within 10 passages. Sequencing of passage 10 virus P-10 revealed a heterogenous virus population with five nucleotide mutations resulting in amino acid substitutions. The genotypically homogeneous OV PD-SK was generated by inserting the five detected mutations of P-10 into the genome of PD-H. PD-SK showed significantly stronger replication and cytotoxicity than PD-H in Colo320 cells, but not in other colorectal carcinoma cell lines. Increase of apoptosis induction was detected as key mechanisms of Colo320 cell-specific adaptation of PD-SK. For in vivo safety PD-SK was engineered with target sites of the miR-375 (miR-375TS) to exclude virus replication in normal tissues. PD-SK-375TS, unlike the PD-H-375TS not adapted homolog suppressed the growth of subcutaneous Colo320 tumors in nude mice without causing any side effects. Conclusion: Taken together, here we present an optimized protocol for the rapid generation of tumor cell-specific adapted oncolytic CVB3 based on the oncolytic CVB3 strain PD-H. The protocol is promising for the generation of personalized OV for tumor therapy and has the potential to be applied to other OV. [ABSTRACT FROM AUTHOR]

The finite physical source problem is usually studied with the concept of volume and time integrals over Green's functions (GFs), representing delta-impulse solutions to the governing partial differential field equations. In seismology, the use of realistic Earth models requires the calculation of numerical or synthetic GFs, as analytical solutions are rarely available. The computation of such synthetic GFs is computationally and operationally demanding. As a consequence, the on-the-fly recalculation of synthetic GFs in each iteration of an optimisation is time-consuming and impractical. Therefore, the pre-calculation and efficient storage of synthetic GFs on a dense grid of source to receiver combinations enables the efficient lookup and utilisation of GFs in time-critical scenarios. We present a Python-based framework and toolkit – Pyrocko-GF – that enables the pre-calculation of synthetic GF stores, which are independent of their numerical calculation method and GF transfer function. The framework aids in the creation of such GF stores by interfacing a suite of established numerical forward modelling codes in seismology (computational back ends). So far, interfaces to back ends for layered Earth model cases have been provided; however, the architecture of Pyrocko-GF is designed to cover back ends for other geometries (e.g. full 3-D heterogeneous media) and other physical quantities (e.g. gravity, pressure, tilt). Therefore, Pyrocko-GF defines an extensible GF storage format suitable for a wide range of GF types, especially handling elasticity and wave propagation problems. The framework assists with visualisations, quality control, and the exchange of GF stores, which is supported through an online platform that provides many pre-calculated GF stores for local, regional, and global studies. The Pyrocko-GF toolkit comes with a well-documented application programming interface (API) for the Python programming language to efficiently facilitate forward modelling of geophysical processes, e.g. synthetic waveforms or static displacements for a wide range of source models.

On 22 December 2018, the western flank of Anak Krakatau collapsed into the sea of the Sunda Strait triggering a tsunami which killed approximately 430 people and displaced 33,000. Here, the authors show that Anak Krakatau exhibited an elevated state of activity several months prior to the collapse, including precursory thermal anomalies, an increase in the island’s surface area, and a gradual seaward motion of the southwestern flank.

Sparse data coverage in the Arctic hampers our understanding of its carbon cycle dynamics and our predictions of the fate of its vast carbon reservoirs in a changing climate. In this paper, we present accurate measurements of atmospheric carbon dioxide (CO2) and methane (CH4) dry air mole fractions at the new atmospheric carbon observation station Ambarchik, which closes a large gap in the atmospheric trace gas monitoring network in northeastern Siberia. The site, which has been operational since August 2014, is located near the delta of the Kolyma River at the coast of the Arctic Ocean. Data quality control of CO2 and CH4 measurements includes frequent calibrations traced to World Meteorological Organization (WMO) scales, employment of a novel water vapor correction, an algorithm to detect the influence of local polluters, and meteorological measurements that enable data selection. The available CO2 and CH4 record was characterized in comparison with in situ data from Barrow, Alaska. A footprint analysis reveals that the station is sensitive to signals from the East Siberian Sea, as well as the northeast Siberian tundra and taiga regions. This makes data from Ambarchik highly valuable for inverse modeling studies aimed at constraining carbon budgets within the pan-Arctic domain, as well as for regional studies focusing on Siberia and the adjacent shelf areas of the Arctic Ocean.

Ground-based atmospheric observations of CO2, δ(O2∕N2), N2O, and CH4 were used to make estimates of the air–sea fluxes of these species from the Lüderitz and Walvis Bay upwelling cells in the northern Benguela region, during upwelling events. Average flux densities (±1σ) were 0.65±0.4 µmol m−2 s−1 for CO2, -5.1±2.5 µmol m−2 s−1 for O2 (as APO), 0.61±0.5 nmol m−2 s−1 for N2O, and 4.8±6.3 nmol m−2 s−1 for CH4. A comparison of our top-down (i.e., inferred from atmospheric anomalies) flux estimates with shipboard-based measurements showed that the two approaches agreed within ±55 % on average, though the degree of agreement varied by species and was best for CO2. Since the top-down method overestimated the flux density relative to the shipboard-based approach for all species, we also present flux density estimates that have been tuned to best match the shipboard fluxes. During the study, upwelling events were sources of CO2, N2O, and CH4 to the atmosphere. N2O fluxes were fairly low, in accordance with previous work suggesting that the evasion of this gas from the Benguela is smaller than for other eastern boundary upwelling systems (EBUS). Conversely, CH4 release was quite high for the marine environment, a result that supports studies that indicated a large sedimentary source of CH4 in the Walvis Bay area. These results demonstrate the suitability of atmospheric time series for characterizing the temporal variability of upwelling events and their influence on the overall marine greenhouse gas (GHG) emissions from the northern Benguela region.

Abstract Background Treatment with anti-PD1 monoclonal antibodies improves the survival of metastatic melanoma patients but only a subgroup of patients benefits from durable disease control. Predictive biomarkers for durable benefit could improve the clinical management of patients. Methods Plasma samples were collected from patients receiving anti-PD1 therapy for ctDNA quantitative assessment of BRAF V600 and NRAS Q61/G12/G13 mutations. Results After a median follow-up of 84 weeks 457 samples from 85 patients were analyzed. Patients with undetectable ctDNA at baseline had a better PFS (Hazard ratio (HR) = 0.47, median 26 weeks versus 9 weeks, p = 0.01) and OS (HR = 0.37, median not reached versus 21.3 weeks, p = 0.005) than patients with detectable ctDNA. Additionally, the HR for death was lower after the ctDNA level became undetectable during follow-up (adjusted HR: 0.16 (95% CI 0.07–0.36), p-value 500 copies/ml at baseline or week 3 were associated with poor clinical outcome. Patients progressive exclusively in the central nervous system (CNS) had undetectable ctDNA at baseline and at subsequent assessments. In multivariate analysis adjusted for LDH, CRP, ECOG and number of metastatic sites, the ctDNA remained significant for PFS and OS. A positive correlation was observed between ctDNA levels and total metabolic tumor volume (TMTV), number of metastatic sites and total tumor burden. Conclusions Assessment of ctDNA baseline and during therapy was predictive for tumor response and clinical outcome in metastatic melanoma patients and reflected the tumor burden. ctDNA evaluation provided reliable complementary information during anti-PD1 antibody therapy.

We calibrated the JSBACH model with six different stomatal conductance formulations using measurements from 10 FLUXNET coniferous evergreen sites in the boreal zone. The parameter posterior distributions were generated by the adaptive population importance sampler (APIS); then the optimal values were estimated by a simple stochastic optimisation algorithm. The model was constrained with in situ observations of evapotranspiration (ET) and gross primary production (GPP). We identified the key parameters in the calibration process. These parameters control the soil moisture stress function and the overall rate of carbon fixation. The JSBACH model was also modified to use a delayed effect of temperature for photosynthetic activity in spring. This modification enabled the model to correctly reproduce the springtime increase in GPP for all conifer sites used in this study. Overall, the calibration and model modifications improved the coefficient of determination and the model bias for GPP with all stomatal conductance formulations. However, only the coefficient of determination was clearly improved for ET. The optimisation resulted in best performance by the Bethy, Ball–Berry, and the Friend and Kiang stomatal conductance models. We also optimised the model during a drought event at a Finnish Scots pine forest site. This optimisation improved the model behaviour but resulted in significant changes to the parameter values except for the unified stomatal optimisation model (USO). Interestingly, the USO demonstrated the best performance during this event.

During the last decade, carbon cycle data assimilation systems (CCDAS) have focused on improving the simulation of seasonal and mean global carbon fluxes over a few years by simultaneous assimilation of multiple data streams. However, the ability of a CCDAS to predict longer-term trends and variability of the global carbon cycle and the constraint provided by the observations have not yet been assessed. Here, we evaluate two near-decade-long assimilation experiments of the Max Planck Institute – Carbon Cycle Data Assimilation System (MPI-CCDAS v1) using spaceborne estimates of the fraction of absorbed photosynthetic active radiation (FAPAR) and atmospheric CO2 concentrations from the global network of flask measurement sites from either 1982 to 1990 or 1990 to 2000. We contrast these simulations with independent observations from the period 1982–2010, as well as a third MPI-CCDAS assimilation run using data from the full 1982–2010 period, and an atmospheric inversion covering the same data and time. With 30 years of data, MPI-CCDAS is capable of representing land uptake to a sufficient degree to make it compatible with the atmospheric CO2 record. The long-term trend and seasonal amplitude of atmospheric CO2 concentrations at station level over the period 1982 to 2010 is considerably improved after assimilating only the first decade (1982–1990) of observations. After 15–19 years of prognostic simulation, the simulated CO2 mixing ratio in 2007–2010 diverges by only 2±1.3 ppm from the observations, the atmospheric inversion, and the MPI-CCDAS assimilation run using observations from the full period. The long-term trend, phenological seasonality, and interannual variability (IAV) of FAPAR in the Northern Hemisphere over the last 1 to 2 decades after the assimilation were also improved. Despite imperfections in the representation of the IAV in atmospheric CO2, model–data fusion for a decade of data can already contribute to the prognostic capacity of land carbon cycle models at relevant timescales.

Objectives: Novel formulations (gastro-resistant tablet and intravenous solution) of posaconazole (POS) have been approved in prophylaxis and therapy of invasive fungal diseases (IFDs). Study aim was to analyze treatment strategies and clinical effectiveness. Methods: We set up a web-based registry on www.ClinicalSurveys.net for documentation of comprehensive data of patients who received novel POS formulations. Data analysis was split into two groups of patients who received novel POS formulations for antifungal prophylaxis (posaconazole prophylaxis group) and antifungal therapy (posaconazole therapy group), respectively. Results: Overall, 180 patients (151 in the posaconazole prophylaxis group and 29 in the posaconazole therapy group) from six German tertiary care centers and hospitalized between 05/2014 – 03/2016 were observed. Median age was 58 years (range: 19 – 77 years) and the most common risk factor for IFD was chemotherapy (n = 136; 76%). In the posaconazole prophylaxis group and posaconazole therapy group, median POS serum levels at steady-state were 1,068 μg/L (IQR 573–1,498 μg/L) and 904 μg/L (IQR 728–1,550 μg/L), respectively (P = 0.776). During antifungal prophylaxis with POS, nine (6%) probable/proven fungal breakthroughs were reported and overall survival rate of hospitalization was 86%. The median overall duration of POS therapy was 18 days (IQR: 7 – 23 days). Fourteen patients (48%) had progressive IFD under POS therapy, of these five patients (36%) died related to or likely related to IFD. Conclusions: Our study demonstrates clinical effectiveness of antifungal prophylaxis with novel POS formulations. In patients treated for possible/probable/proven IFD, we observed considerable mortality in patients receiving salvage treatment and with infections due to rare fungal species. Keywords: Invasive fungal infection, Neutropenia, Posaconazole serum level, Clinical effectiveness, High-risk patient

In the context of the so-called refugee crisis, political disputes about solidarity become a central issue with member states applying competing concepts. At the same time, European cities use transnational networks to implement a new form of solidarity among municipalities via city diplomacy (Acuto, Morissette, & Tsouros, 2017). Analyzing the deadlock between member states and the emerging activities of cities, we scrutinize the limits of existing approaches to political solidarity (e.g., Agustín & Jørgensen, 2019; Knodt, Tews, & Piefer, 2014; Sangiovanni, 2013) to explain this phenomenon. Based on expert interviews and document analysis from a study on transnational municipal networks, we identify an emerging concept of solidarity that challenges the nation states as core providers of solidarity from within: transmunicipal solidarity focuses on joint action of local governments to scale out and scale up.

The reduction of 2-naphtoyl-CoA to 5,6 dihydro-2-naphtoyl-CoA by 2-naphtoyl-CoA reductase is below the negative redox limit usually encountered in biological hydride transfer. Here, via X-ray crystallography and spectroscopic analysis, the authors elucidated the mechanism behind this.

Abstract Strain in magmatic rifts is accommodated by both faulting and dike intrusion, but little is known of the frequency of dike intrusions in early‐stage rifts. We use a new earthquake data set from a dense temporary seismic array (2013–2014) in the ~7‐Myr‐old Magadi‐Natron‐Manyara section of the East African Rift, which includes the carbonatitic Oldoinyo Lengai volcano that erupted explosively in 2007–2008. Full moment tensor analyses were performed on M > 3.4 earthquakes (0.03‐ to 0.10‐Hz band) that occurred during the intereruptive cycle. We find two opening crack‐type and various non‐double‐couple earthquake source mechanisms and interpret these as fluid‐involved fault rupture. From waveform analysis on the nearest permanent seismic station, we conclude that similar rupture processes probably occur over eruptive and intereruptive cycles. The repeated and dynamically similar fluid‐involved seismicity, along with intrabasinal localization of active deformation, suggests that significant and persistent strain is accommodated by magmatic processes, modulated by tectonic cycles.

Abstract Background Mesenchymal stem cells are used for different therapeutic approaches, e.g. for osteoarthritis, lesions of the tendon as well as for bone defects. Current research on the mechanism of stem cells on the repair of damaged tissue suggest an important role of a cell-to-cell communication through secreted extracellular vesicles, mainly represented by exosomes. To enhance the scarce knowledge on the functional role of exosomes we compared as a first step different techniques to isolate and identify exosomes from the supernatant of equine adipose derived mesenchymal stem cells for further characterization and usage in functional assays. Results It was possible to obtain exosomes secreted from equine adipose derived mesenchymal stem cells with three common techniques: a stepwise ultracentrifugation at 100.000 g, an ultrafiltration with 3 kDa exclusion membranes and a charge-based precipitation method. The mean sizes and amounts of exosomes isolated with the different techniques were measured by the nanoparticle tracking analysis. The diameter ranged between 116.2 nm (ultracentrifugation), 453.1 nm (precipitation) and 178.7 nm (ultrafiltration), the counts of particles / ml ranged between 9.6 × 108 (ultracentrifugation), 2.02 × 109 (precipitation) and 52.5 × 109 (ultrafiltration). Relevant marker for exosomes, tetraspanins CD9, CD63 and CD81 were detectable by immunofluorescence staining of the investigated exosomes secreting mesenchymal stem cells. In addition, transmission electron microscopy and immunogold labeling with CD9 and CD90 was performed to display the morphological shape of exosomes and existence of marker relevant for exosomes (CD9) and mesenchymal stem cells (CD90). Western blot analysis of CD9 and CD90 of exosomes ensured the specificity of the rare available respectively cross reacting antibodies against equine antigens. Conclusion Exosomes generated by equine mesenchymal stem cells can be obtained by ultrafiltration and ultracentrifugation in an equal quality for in vitro experiments. Especially for later therapeutic usage we recommend ultrafiltration due to a higher concentration without aggregation of extracellular vesicles in comparison to exosomes obtained by ultracentrifugation.

Observations of the atmospheric sources and sinks of carbon dioxide (CO2) and methane (CH4) in the pan-Arctic domain are extremely scarce, limiting our knowledge of carbon turnover in this climatically sensitive environment and the fate of the enormous carbon reservoirs conserved in the permafrost. Especially critical are the gaps in the high latitudes of Siberia, covered by the vast permafrost underlain tundra, where only several atmospheric monitoring sites are operational. This paper presents the first two years (September 2018–January 2021) of accurate continuous observations of atmospheric CO2 and CH4 dry mole fractions at the recently deployed tower-based measurement station “DIAMIS” (73.5068° N, 80.5198° E) located on the southwestern coast of the Taimyr Peninsula, Siberia, at the Gulf of the Yenisei River that opens to the Kara Sea (Arctic Ocean). In this paper, we summarized the scientific rationale of the site, examined the seasonal footprint of the station with an analysis of terrestrial vegetation and maritime sector contributing to the captured atmospheric signal, and illustrated temporal patterns of CO2 and CH4 for the daytime mixed atmospheric layer over the continent–sea interface. Along with the temporal variations reflecting a signal caused pan-Arctic and not very much influenced by the local processes, we analyzed the spatiotemporal distribution of the synoptic anomalies representing the atmospheric signatures of regional sources and sinks of CO2 and CH4 for the studied high-arctic Siberian domain of ~625 thousand km2, with nearly equal capturing the land surface (54%) and the ocean (46%) throughout the year. Both for CO2 and CH4, we have observed a sea–continent declining trend, presuming a larger depletion of trace gases in the maritime air masses compared to the continental domain. So far, over the Kara Sea, we have not detected any prominent signals of CH4 that might have indicated processes of subsea permafrost degradation and occurrence of cold seeps–still mainly observed in the eastern Arctic Seas—The Laptev Sea and the East-Siberian Sea.

The effect of aerosol loading on solar radiation and the subsequent effect on photosynthesis is a relevant question for estimating climate feedback mechanisms. This effect is quantified in the present study using ground-based measurements from five remote sites in boreal and hemiboreal (coniferous and mixed) forests of Eurasia. The diffuse fraction of global radiation associated with the direct effect of aerosols, i.e. excluding the effect of clouds, increases with an increase in the aerosol loading. The increase in the diffuse fraction of global radiation from approximately 0.11 on days characterized by low aerosol loading to 0.2–0.27 on days with relatively high aerosol loading leads to an increase in gross primary production (GPP) between 6 % and 14 % at all sites. The largest increase in GPP (relative to days with low aerosol loading) is observed for two types of ecosystems: a coniferous forest at high latitudes and a mixed forest at the middle latitudes. For the former ecosystem the change in GPP due to the relatively large increase in the diffuse radiation is compensated for by the moderate increase in the light use efficiency. For the latter ecosystem, the increase in the diffuse radiation is smaller for the same aerosol loading, but the smaller change in GPP due to this relationship between radiation and aerosol loading is compensated for by the higher increase in the light use efficiency. The dependence of GPP on the diffuse fraction of solar radiation has a weakly pronounced maximum related to clouds.

Personality traits describe dispositions influencing individuals' behavior and performance at work. However, in the context of personnel selection, the use of personality measures has continuously been questioned. To date, research in selection settings has focused uniquely on predicting task performance, missing the opportunity to exploit the potential of personality traits to predict non-task performance. Further, personality is often measured with self-report inventories, which are susceptible to self-distortion. Addressing these gaps, the planned study seeks to design new personality measures to be used in the selection context to predict a wide range of performance criteria. Specifically, we will develop a situational judgment test and a behavior description interview, both assessing Big Five personality traits and Honesty-Humility to systematically compare these new measures with traditional self-report inventories regarding their criterion-related validity to predict four performance criteria: task performance, adaptive performance, organizational citizenship behavior, and counterproductive work behavior. Data will be collected in a simulated selection procedure. Based on power analyses, we aim for 200 employed study participants, who will allow us to contact their supervisors to gather criterion data. The results of this study will shed light on the suitability of different personality measures (i.e., situational judgment tests and behavior description interviews) to predict an expanded range of performance criteria.

ObjectiveSurgical resection represents a common treatment modality in patients with brain metastasis (BM). Postoperative prolonged mechanical ventilation (PMV) might have an enormous impact on the overall survival (OS) of these patients suffering from advanced cancer disease. We therefore have analyzed our institutional database with regard to a potential impact of PMV on OS of patients who had undergone surgery for brain metastases.Methods360 patients with surgically treated brain metastases were included. The definition of PMV consisted of postoperative mechanical ventilation lasting for more than 48 hours. Analysis of survival incorporating established prognostic factors such as age, location of BM, and preoperative physical status was performed.Results14 of 360 patients with BM (4%) suffered from postoperative PMV after surgical treatment of BM. Patients with PMV presented in a significantly more impaired neurological condition preoperatively than patients without (p

Digital media (DM), such as cellphones and tablets, are a common part of our daily lives and their usage has changed the communication structure within families. Thus, there is a risk that the use of DM might result in fewer opportunities for interactions between children and their parents leading to fewer language learning moments for young children. The current study examined the associations between children’s language development and early DM exposure.Participants: Ninety-two parents of 25months olds (50 boys/42 girls) recorded their home sound environment during a typical day [Language ENvironment Analysis (LENA)] and participated in an online questionnaire consisting of questions pertaining to daily DM use and media mediation strategies, as well as a Swedish online version of the MacArthur Communicative Development Inventory, which includes a vocabulary scale as well as a grammar and pragmatics scale.Results: Through correlations and stepwise regressions three aspects of language were analyzed. The child’s vocabulary was positively associated with interactional turn-taking. The child’s vocabulary and grammar were negatively associated with the likelihood of parent’s device use during everyday child routines and the amount of TV watched by the child. The child’s pragmatic development was also positively associated with the parent’s device use in child routines but also with the parent’s joint media engagement (JME), as well as the child’s gender (where girls perform better).Conclusion: Our study confirms that specific aspects of the 2-year old’s DM environment are associated with the child’s language development. More TV content, whether it is viewed on a big screen or tablet, is negatively associated with language development. The likelihood of parents’ use of DM during everyday child routines is also negatively associated with the child’s language development. Positive linguistic parental strategies such as interactional turn-taking with the child, JME, and book reading, on the other hand, are positively associated with the child’s language development.

The study investigates to what degree two different joint media engagement (JME) strategies affect children’s learning from two-dimensional (2D)-media. More specifically, we expected an instructed JME strategy to be more effective than a spontaneous, non-instructed, JME strategy. Thirty-five 2-year old children saw a short video on a tablet demonstrating memory tasks together with a parent. The parents were randomized into two groups: One group (N = 17) was instructed to help their child by describing the actions they saw on the video while the other group (N = 18) received no specific instruction besides “do as you usually do.” The parents in the instructed group used significantly more words and verbs when supporting their child but both groups of children did equally well on the memory test. In a second step, we compared the performance of the two JME groups with an opportunistic comparison group (N = 95) tested with half of the memory tasks live and half of the tasks on 2D without any JME support. Results showed that the JME intervention groups received significantly higher recall scores than the no JME 2D comparison group. In contrast, the three-dimensional (3D) comparison group outperformed both JME groups. In sum, our findings suggest that JME as implemented here is more effective in promoting learning than a no JME 2D demonstration but less so than the standard 3D presentation of the tasks.

We designed a marking stand for the DermojetⓇ, which substantially improves fish marking via needleless subcutaneous injection of dye. The marking stand allows to increase the nozzle-to-fish distance, adjust this position and to keep the jet injector fixed during operation as well as dye refilling. A laser pointer enables a precise and small-scale aiming. Using this marking stand we marked the caudal fin of small fish with Alcian blue for a flume experiment. In total we marked 204 gudgeon (Gobio gobio) and spirlin (Alburnoides bipunctatus) of 9–14 cm length with up to two dots per fish. Weighing, measuring and marking one sedated fish took 30 to 60 s. Immediate marking success was 100%. Fish were kept indoors in tanks for 7–12 days post-marking and the colour mark remained visible for the complete study period. During our flume experiment the colour marks at the caudal fin were detectable on all fish regardless of swimming position. With this easy and fast method fish can be marked gently, reliably and efficiently. • Application of a high-pressure jet injector for needleless and accurate colour marking of fish. • Manual for marking the caudal fin of small fish with Alcian blue.

Strengthening the connections between sign language and written language may improve reading skills in deaf and hard-of-hearing (DHH) signing children. The main aim of the present study was to investigate whether computerized sign language-based literacy training improves reading skills in DHH signing children who are learning to read. Further, longitudinal associations between sign language skills and developing reading skills were investigated. Participants were recruited from Swedish state special schools for DHH children, where pupils are taught in both sign language and spoken language. Reading skills were assessed at five occasions and the intervention was implemented in a cross-over design. Results indicated that reading skills improved over time and that development of word reading was predicted by the ability to imitate unfamiliar lexical signs, but there was only weak evidence that it was supported by the intervention. These results demonstrate for the first time a longitudinal link between sign-based abilities and word reading in DHH signing children who are learning to read. We suggest that the active construction of novel lexical forms may be a supramodal mechanism underlying word reading development.

Saccade latency is widely used across infant psychology to investigate infants' understanding of events. Interpreting particular latency values requires knowledge of standard saccadic RTs, but there is no consensus as to typical values. This study provides standard estimates of infants' (n = 194, ages 9 to 15 months) saccadic RTs under a range of different spatiotemporal conditions. To investigate the reliability of such standard estimates, data is collected at 4 laboratories in 3 countries. Results indicate that reactions to the appearance of a new object are much faster than reactions to the deflection of a currently fixated moving object; upward saccades are slower than downward or horizontal saccades; reactions to more peripheral stimuli are much slower; and this slowdown is greater for boys than girls. There was little decrease in saccadic RTs between 9 and 15 months, indicating that the period of slow development which is protracted into adolescence begins in late infancy. Except for appearance and deflection differences, infant effects were weak or absent in adults (n = 40). Latency estimates and spatiotemporal effects on latency were generally consistent across laboratories, but a number of lab differences in factors such as individual variation were found. Some but not all differences were attributed to minor procedural differences, highlighting the importance of replication. Confidence intervals (95%) for infants' median reaction latencies for appearance stimuli were 242 to 250 ms and for deflection stimuli 350 to 367 ms.

ObjectiveAlthough the treatment of glioblastoma patients is well established in neuro-oncological surgery, precious scarce data is available on patients with glioblastoma requiring postoperative prolonged mechanical ventilation (PMV). Therefore, the aim of the present study was to determine the influence of PMV on overall survival (OS) in patients with glioblastoma.MethodsPatients with newly diagnosed glioblastoma who had undergone surgical therapy and complete subsequent neuro-oncological treatment at the authors’ neuro-oncological center from January 2013 to December 2018 were selected and included in the further analysis. PMV was defined as mechanical ventilation for more than 24 h after surgery. Survival analyses were performed, including established prognostic factors such as age, Karnofsky performance score, MGMT-promoter methylation status and extent of resection.ResultsA total of 240 patients with newly diagnosed glioblastoma and subsequent surgical treatment were identified. 13 patients (5%) suffered from PMV during the treatment course of glioblastoma. All but one patient were successfully weaned from mechanical ventilation. Patients suffering from PMV achieved significantly less often favorable functional outcome after 3, 6, 9, and 12 months compared to patients without PMV. Multivariate analysis revealed PMV to constitute a significant prognostic factor for OS, independent of other prognostic factors (p

Purpose: Sarcoidosis is a chronic idiopathic granulomatous inflammatory disease that can affect many major organ systems, primarily the lungs, and hence has remarkable clinical heterogeneity. At least 50% of patients with systemic sarcoidosis develop inflammatory eye disease, and in approximately 21% of cases, it may be the first clinical manifestation. Neuro-ocular involvement occurs in

BackgroundExpensive optoelectronic systems, considered the gold standard, require a laboratory environment and the attachment of markers, and they are therefore rarely used in everyday clinical practice. Two-dimensional (2D) human pose estimations for clinical purposes allow kinematic analyses to be carried out via a camera-based smartphone app. Since clinical specialists highly depend on the validity of information, there is a need to evaluate the accuracy of 2D pose estimation apps. ObjectiveThe aim of the study was to investigate the accuracy of the 2D pose estimation of a mobility analysis app (Lindera-v2), using the PanopticStudio Toolbox data set as a reference standard. The study aimed to assess the differences in joint angles obtained by 2D video information generated with the Lindera-v2 algorithm and the reference standard. The results can provide an important assessment of the adequacy of the app for clinical use. MethodsTo evaluate the accuracy of the Lindera-v2 algorithm, 10 video sequences were analyzed. Accuracy was evaluated by assessing a total of 30,000 data pairs for each joint (10 joints in total), comparing the angle data obtained from the Lindera-v2 algorithm with those of the reference standard. The mean differences of the angles were calculated for each joint, and a comparison was made between the estimated values and the reference standard values. Furthermore, the mean absolute error (MAE), root mean square error, and symmetric mean absolute percentage error of the 2D angles were calculated. Agreement between the 2 measurement methods was calculated using the intraclass correlation coefficient (ICC[A,2]). A cross-correlation was calculated for the time series to verify whether there was a temporal shift in the data. ResultsThe mean difference of the Lindera-v2 data in the right hip was the closest to the reference standard, with a mean value difference of –0.05° (SD 6.06°). The greatest difference in comparison with the baseline was found in the neck, with a measurement of –3.07° (SD 6.43°). The MAE of the angle measurement closest to the baseline was observed in the pelvis (1.40°, SD 1.48°). In contrast, the largest MAE was observed in the right shoulder (6.48°, SD 8.43°). The medians of all acquired joints ranged in difference from 0.19° to 3.17° compared with the reference standard. The ICC values ranged from 0.951 (95% CI 0.914-0.969) in the neck to 0.997 (95% CI 0.997-0.997) in the left elbow joint. The cross-correlation showed that the Lindera-v2 algorithm had no temporal lag. ConclusionsThe results of the study indicate that a 2D pose estimation by means of a smartphone app can have excellent agreement compared with a validated reference standard. An assessment of kinematic variables can be performed with the analyzed algorithm, showing only minimal deviations compared with data from a massive multiview system.

Peptide DIIADDEPLT (Pep19) has been previously suggested to improve metabolic parameters, without adverse central nervous system effects, in a murine model of diet-induced obesity. Here, we aimed to further evaluate whether Pep19 oral administration has anti-obesogenic effects, in a well-established high-fat diet-induced obesity model. Male Swiss mice, fed either a standard diet (SD) or high-fat diet (HFD), were orally administrated for 30 consecutive days, once a day, with saline vehicle or Pep19 (1 mg/kg). Next, several metabolic, morphological, and behavioral parameters were evaluated. Oral administration of Pep19 attenuated HFD body-weight gain, reduced in approximately 40% the absolute mass of the endocrine pancreas, and improved the relationship between circulating insulin and peripheral insulin sensitivity. Pep19 treatment of HFD-fed mice attenuated liver inflammation, hepatic fat distribution and accumulation, and lowered plasma alanine aminotransferase activity. The inguinal fat depot from the SD group treated with Pep19 showed multilocular brown-fat-like cells and increased mRNA expression of uncoupling protein 1 (UCP1), suggesting browning on inguinal white adipose cells. Morphological analysis of brown adipose tissue (BAT) from HFD mice showed the presence of larger white-like unilocular cells, compared to BAT from SD, Pep19-treated SD or HFD mice. Pep19 treatment produced no alterations in mice behavior. Oral administration of Pep19 ameliorates some metabolic traits altered by diet-induced obesity in a Swiss mice model.

Functional transcranial Doppler sonography (fTCD) is a time- and cost-effective, non-invasive approach to determining real time hemispheric lateralization and is well-suited for repetitive study designs comprising multiple days. To date, no study has examined the reproducibility of the direction and degree (strength) of lateralization during word fluency (WF) over multiple, consecutive sessions within a single person, although there are many studies of lateralization during language processing. Moreover, there is conflicting evidence as to whether there is a relationship between the degree of laterality and the word fluency performance. In this study, one right-handed male (aged 24 years) completed a total of seven examination sessions in the time span of 10 days. Each session comprised multiple phonological and semantic WF tasks. The maximum difference of relative cerebral blood flow velocity (CBFV) changes between the left and right middle cerebral artery (MCA) during WF was defined as the Lateralization Index (LI). The word-fluency performance and the LIs were used in a linear regression model to detect relative changes in the direction and degree of lateralization during repetitive WF tasks. The reproducibility of the direction of language-related lateralization is very stable over multiple sessions within this single person and the processed LIs were left-lateralized in every session for both WF tasks. In addition, performance during phonological WF could significantly predict the variability in the degree of lateralization. This result could not be confirmed for the semantic WF task. The results of this pilot study support the usage of fTCD as a reliable method for examining lateralization patterns, especially in longitudinal study designs. They also provide evidence for the notion that performance in WF tasks can be related to the degree of lateralization, at least intra-individually.

Children’s and adolescents’ lives drastically changed during COVID lockdowns worldwide. To compare accident- and injury-related admissions to pediatric intensive care units (PICU) during the first German COVID lockdown with previous years, we conducted a retrospective multicenter study among 37 PICUs (21.5% of German PICU capacities). A total of 1444 admissions after accidents or injuries during the first lockdown period and matched periods of 2017–2019 were reported and standardized morbidity ratios (SMR) were calculated. Total PICU admissions due to accidents/injuries declined from an average of 366 to 346 (SMR 0.95 (CI 0.85–1.05)). Admissions with trauma increased from 196 to 212 (1.07 (0.93–1.23). Traffic accidents and school/kindergarten accidents decreased (0.77 (0.57–1.02 and 0.26 (0.05–0.75)), whereas household and leisure accidents increased (1.33 (1.06–1.66) and 1.34 (1.06–1.67)). Less neurosurgeries and more visceral surgeries were performed (0.69 (0.38–1.16) and 2.09 (1.19–3.39)). Non-accidental non-suicidal injuries declined (0.73 (0.42–1.17)). Suicide attempts increased in adolescent boys (1.38 (0.51–3.02)), but decreased in adolescent girls (0.56 (0.32–0.79)). In summary, changed trauma mechanisms entailed different surgeries compared to previous years. We found no evidence for an increase in child abuse cases requiring intensive care. The increase in suicide attempts among boys demands investigation.

Background: The aim of this prospective study was to assess the diagnostic value of nuclear imaging with 18F-FDG PET/CT (FDG PET/CT), combined 111In-WBC/99mTc-Nanocoll, and 99mTc-HDP SPECT/CT (dual-isotope WBC/bone marrow scan) for patients with chronic problems related to knee or hip prostheses (TKA or THA) scheduled by a structured multidisciplinary algorithm. Materials and Methods: Fifty-five patients underwent imaging with 99mTc–HDP SPECT/CT (bone scan), dual-isotope WBC/bone marrow scan, and FDG PET/CT. The final diagnosis of prosthetic joint infection (PJI) and/or loosening was based on the intraoperative findings and microbiological culture results and the clinical follow-up. Results: The diagnostic performance of dual-isotope WBC/bone marrow SPECT/CT for PJI showed a sensitivity of 100% (CI 0.74–1.00), a specificity of 97% (CI 0.82–1.00), and an accuracy of 98% (CI 0.88–1.00); for PET/CT, the sensitivity, specificity, and accuracy were 100% (CI 0.74–1.00), 71% (CI 0.56–0.90), and 79% (CI 0.68–0.93), respectively. Conclusions: In a standardized prospectively scheduled patient group, the results showed highly specific performance of combined dual-isotope WBC/bone marrow SPECT/CT in confirming chronic PJI. FDG PET/CT has an appropriate accuracy, but the utility of its use in the clinical diagnostic algorithm of suspected PJI needs further evidence.

Methane is an important greenhouse gas, responsible for about 20% of the warming induced by long-lived greenhouse gases since pre-industrial times. By reacting with hydroxyl radicals, methane reduces the oxidizing capacity of the atmosphere and generates ozone in the troposphere. Although most sources and sinks of methane have been identified, their relative contributions to atmospheric methane levels are highly uncertain. As such, the factors responsible for the observed stabilization of atmospheric methane levels in the early 2000s, and the renewed rise after 2006, remain unclear. Here, we construct decadal budgets for methane sources and sinks between 1980 and 2010, using a combination of atmospheric measurements and results from chemical transport models, ecosystem models, climate chemistry models and inventories of anthropogenic emissions. The resultant budgets suggest that data-driven approaches and ecosystem models overestimate total natural emissions. We build three contrasting emission scenarios-which differ in fossil fuel and microbial emissions-to explain the decadal variability in atmospheric methane levels detected, here and in previous studies, since 1985. Although uncertainties in emission trends do not allow definitive conclusions to be drawn, we show that the observed stabilization of methane levels between 1999 and 2006 can potentially be explained by decreasing-to-stable fossil fuel emissions, combined with stable-to-increasing microbial emissions. We show that a rise in natural wetland emissions and fossil fuel emissions probably accounts for the renewed increase in global methane levels after 2006, although the relative contribution of these two sources remains uncertain. © 2013 Macmillan Publishers Limited.

Proton beam radiotherapy of uveal melanoma can be administered as primary treatment, as salvage therapy for recurrent tumor, and as neoadjuvant therapy prior to surgical resection. The physical properties of proton beams make it possible to deliver high-doses of radiation to the tumor with relative sparing of adjacent tissues. This form of therapy is effective for a wider range of uveal melanoma than any other modality, providing exceptionally-high rates of local tumor control. This is particularly the case with diffuse iris melanomas, many of which are unresectable. The chances of survival, ocular conservation, visual preservation and avoidance of iatrogenic morbidity depend greatly on the tumor size, location and extent. When treating any side-effects and/or complications, it is helpful to consider whether these are the result of collateral damage or persistence of the irradiated tumor ('toxic tumor syndrome').

The most common intraocular vascular tumours are choroidal haemangiomas, vasoproliferative tumours, and retinal haemangioblastomas. Rarer conditions include cavernous retinal angioma and arteriovenous malformations. Options for ablating the tumour include photodynamic therapy, argon laser photocoagulation, trans-scleral diathermy, cryotherapy, anti-angiogenic agents, plaque radiotherapy, and proton beam radiotherapy. Secondary effects are common and include retinal exudates, macular oedema, epiretinal membranes, retinal fibrosis, as well as serous and tractional retinal detachment, which are treated using standard methods (ie, intravitreal anti-angiogenic agents or steroids as well as vitreoretinal procedures, such as epiretinal membrane peeling and release of retinal traction). The detection, diagnosis, and monitoring of vascular tumours and their complications have improved considerably thanks to advances in imaging. These include spectral domain and enhanced depth imaging optical coherence tomography (SD-OCT and EDI-OCT, respectively), wide-angle photography and angiography as well as wide-angle fundus autofluorescence. Such novel imaging has provided new diagnostic clues and has profoundly influenced therapeutic strategies so that vascular tumours and secondary effects are now treated concurrently instead of sequentially, enhancing any opportunities for conserving vision and the eye. In this review, we describe how SD-OCT, EDI-OCT, autofluorescence, wide-angle photography and wide-angle angiography have facilitated the evaluation of eyes with the more common vascular tumours, that is, choroidal haemangioma, retinal vasoproliferative tumours, and retinal haemangioblastoma.

Personalized treatment of uveal melanoma involves the tailoring of all aspects of care to the condition, needs, wishes, and fears of the patient, taking account of the individual's circumstances. When selecting between radiotherapy, surgical resection, and phototherapy, or when deciding how best to combine these different therapeutic modalities, it is necessary to understand the patients utilities, with respect to tumour control, visual conservation, and preservation of the eye, so as to prioritize outcomes accordingly. For example, such considerations would influence the width of the safety margins when administering radiotherapy, according to whether the patient considers it more important to conserve vision or to guarantee tumour control. With 'suspicious naevi', the choice between observation, immediate treatment, and biopsy is complicated by the lack of adequate survival data on which to base rational decisions, making it necessary for both patient and doctor to accept uncertainty. Personalized care should involve close relatives, as appropriate. It must also adapt to changes in the patient's needs over time. Such personalized care demands the ability to respond to such needs and the sensitivity to identify these requirements in the first place. Personalized treatment enhances not only the patient's satisfaction but also the 'job satisfaction' of all members of the multidisciplinary team, improving quality of care.

Background/Aim: Older patients are considered to bear a higher perioperative risk. Since idiopathic normal pressure hydrocephalus (NPH) predominantly concerns older patients, identifying risk factors for early shunt failure for preoperative risk/benefit assessment is indispensable for indication and/or consultation of patients for ventriculoperitoneal shunting (VPS).Methods: We performed a retrospective study design, including data acquired from two university hospital neurosurgical institutions between 2012 and 2019. Overall, 211 consecutive patients with clinical/radiological signs for NPH who additionally showed alleviation of symptoms after lumbar cerebrospinal fluid (CSF) drainage, received VPS and were included for further analysis. Frailty was measured using the Clinical Frailty Scale (CFS). Main outcome was early shunt failure or post-operative complications within 30 days after initial VPS surgery.Results: The overall complication rate was 14%. Patient-related complications were observed in 13 patients (6%) and procedure-related complications in 16 patients (8%). Early post-operative complications resulted in a significantly prolonged length of hospital stay 6.9 ± 6.8 vs. 10.8 ± 11.8 days (p = 0.03). Diabetes mellitus with end-organ damage (OR 35.4, 95% CI 6.6 – 189.4, p < 0.0001) as well as preexisting Parkinson's disease were associated with early patient-related post-surgical complications after VPS for NPH.Conclusions: Patients comorbidities but not frailty were associated with early post-operative patient-related complications in patients suffering NPH. While frailty may deter patients from other (neurosurgical) procedures, VPS surgery might contribute to treating NPH in these patients at a tolerable risk.