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This paper empirically examines differences in how 50-year-olds imagine their future. It draws on answers to an open-ended survey question in a large British cohort study—the National Child Development Study. Over 6,700 written responses about respondents’ imagined future are examined using text mining methods. Results from a relative frequency analysis and a topic model reveal differences according to gender, occupational class, and educational qualification. The cohort members’ written texts reflect different lifestyles. Men are more likely to mention sport, like golf and football, whereas women are more prone to use words related to family and friends. Respondents with a degree are more likely to write about cultural activities, such as museum or theater visits. Overall, the findings reveal gendered and socially stratified patterns in individual future perceptions, contextualized in relation to leisure, health, and family.
Background: Efficacy of treatment after failure of check point inhibitors (ICI) therapy remains ill-defined in metastatic renal cell carcinoma (mRCC).
Objective: To evaluate the safety and effectiveness of cabozantinib after failure of ICI-based therapies.
Design, setting and participants: Patients with mRCC who concluded cabozantinib treatment directly after an ICI-based therapy were eligible. Data was collected retrospectively from participating sites in Germany.
Interventions: Cabozantinib was administered as a standard of care.
Outcome measurements and statistical analysis
Adverse events (AE) were reported according to CTCAE v5.0. Objective response rate according to RECIST 1.1 and Progression Free Survival (PFS) were collected from medical records. Descriptive statistics and Kaplan-Meyer-plots were utilized.
Results and limitations: About 56 eligible patients (71.4% male) with median age of 66 years and clear cell histology in 66.1% (n = 37) were analyzed. 87.5% (n = 49) had ≥ 2 previous lines. IMDC risk was intermediate or poor in 17 patients (30.4%) and missing in 66.1%. 20 patients (35.7%) started with 60 mg. 55.4% (n = 31) required dose reductions, 26.8% (n = 15) treatment delays and 1.8% (n = 1) treatment discontinuation. Partial response was reported in 10.7% (n = 6), stable and progressive disease were reported in 19.6% (n = 11) and in 12.5% (n = 7). 32 patients were not evaluable (57.1%). Median treatment duration was 6.1 months. Treatment related AE were reported in 76.8% (n = 43) and 19.6% (n = 11) had grade 3-5. Fatigue (26.8%), diarrhea (26.8%) and hand-foot-syndrome (25.0%) were the 3 most frequent AEs of any grade and causality. SAE were reported in 21.4% (n = 12), 2 were fatal. Major limitation was the retrospective data capture in our study.
Conclusions: Cabozantinib followed directly after ICI-based therapy was safe and feasible. No new safety signals were reported. A lower starting dose was frequently utilized in this real-world cohort, which was associated with a favorable tolerability profile. Our data supports the use of cabozantinib after ICI treatment.
Charge-dependent two- and three-particle correlations measured in Xe-Xe collisions at sNN−−−√=5.44 TeV are presented. Results are obtained for charged particles in the pseudorapidity range |η|<0.8 and transverse momentum interval 0.2≤pT<5.0 GeV/c for different collision centralities. The three-particle correlator γαβ≡⟨cos(φα+φβ−2Ψ2)⟩, calculated for different combinations of charge sign α and β, is expected to be sensitive to the presence of the Chiral Magnetic Effect (CME). Its magnitude is similar to the one observed in Pb-Pb collisions in contrast to a smaller CME signal in Xe-Xe collisions than in Pb-Pb collisions predicted by Monte Carlo (MC) calculations including a magnetic field induced by the spectator protons. These observations point to a large non-CME contribution to the correlator. Furthermore, the charge dependence of γαβ can be described by a blast wave model calculation that incorporates background effects and by the Anomalous Viscous Fluid Dynamics model with values of the CME signal consistent with zero. The Xe-Xe and Pb-Pb results are combined with the expected CME signal dependence on the system size from the MC calculations including a magnetic field to obtain the fraction of CME contribution in γαβ, fCME. The CME fraction is compatible with zero for the 30% most central events in both systems and then becomes positive; averaging over the 0-70% centrality interval yields an upper limit of 2% (3%) and 25% (32%) at 95% (99.7%) confidence level for the CME signal contribution to γαβ in Xe-Xe and Pb-Pb collisions, respectively.
In high--energy heavy--ion collisions, the correlations between the emitted particles can be used as a probe to gain insight into the charge creation mechanisms. In this Letter, we report the first results of such studies using the electric charge balance function in the relative pseudorapidity (Δη) and azimuthal angle (Δφ) in Pb--Pb collisions at sNN−−−−√=2.76 TeV with the ALICE detector at the Large Hadron Collider. The width of the balance function decreases with growing centrality (i.e. for more central collisions) in both projections. This centrality dependence is not reproduced by HIJING, while AMPT, a model which incorporates strings and parton rescattering, exhibits qualitative agreement with the measured correlations in Δφ but fails to describe the correlations in Δη. A thermal blast--wave model incorporating local charge conservation and tuned to describe the pmT spectra and v2 measurements reported by ALICE, is used to fit the centrality dependence of the width of the balance function and to extract the average separation of balancing charges at freeze--out. The comparison of our results with measurements at lower energies reveals an ordering with sNN−−−−√:the balance functions become narrower with increasing energy for all centralities. This is consistent with the effect of larger radial flow at the LHC energies but also with the late stage creation scenario of balancing charges. However, the relative decrease of the balance function widths in Δη and \dphi with centrality from the highest SPS to the LHC energy exhibits only small differences. This observation cannot be interpreted solely within the framework where the majority of the charge is produced at a later stage in the evolution of the heavy--ion collision.
Measurements of the sphericity of primary charged particles in minimum bias proton--proton collisions at s√=0.9, 2.76 and 7 TeV with the ALICE detector at the LHC are presented. The observable is linearized to be collinear safe and is measured in the plane perpendicular to the beam direction using primary charged tracks with pT≥0.5 GeV/c in |η|≤0.8. The mean sphericity as a function of the charged particle multiplicity at mid-rapidity (Nch) is reported for events with different pT scales ("soft" and "hard") defined by the transverse momentum of the leading particle. In addition, the mean charged particle transverse momentum versus multiplicity is presented for the different event classes, and the sphericity distributions in bins of multiplicity are presented. The data are compared with calculations of standard Monte Carlo event generators. The transverse sphericity is found to grow with multiplicity at all collision energies, with a steeper rise at low Nch, whereas the event generators show the opposite tendency. The combined study of the sphericity and the mean pT with multiplicity indicates that most of the tested event generators produce events with higher multiplicity by generating more back-to-back jets resulting in decreased sphericity (and isotropy). The PYTHIA6 generator with tune PERUGIA-2011 exhibits a noticeable improvement in describing the data, compared to the other tested generators.
n this paper measurements are presented of π+, π−, K+, K−, p and p¯¯¯ production at mid-rapidity < 0.5, in Pb-Pb collisions at sNN−−−√=2.76 TeV as a function of centrality. The measurement covers the transverse momentum (pT) range from 100, 200, 300 MeV/c up to 3, 3, 4.6 GeV/c, for π, K, and p respectively. The measured pT distributions and yields are compared to expectations based on hydrodynamic, thermal and recombination models. The spectral shapes of central collisions show a stronger radial flow than measured at lower energies, which can be described in hydrodynamic models. In peripheral collisions, the pT distributions are not well reproduced by hydrodynamic models. Ratios of integrated particle yields are found to be nearly independent of centrality. The yield of protons normalized to pions is a factor ~1.5 lower than the expectation from thermal models.
We present first measurements of the evolution of the differential transverse momentum correlation function, {\it C}, with collision centrality in Au+Au interactions at sNN−−−−√=200 GeV. {\it C} exhibits a strong dependence on collision centrality that is qualitatively similar to that of number correlations previously reported. We use the observed longitudinal broadening of the near-side peak of {\it C} with increasing centrality to estimate the ratio of the shear viscosity to entropy density, η/s, of the matter formed in central Au+Au interactions. We obtain an upper limit estimate of η/s that suggests that the produced medium has a small viscosity per unit entropy.
The present study examines for the first time the emission patterns and olfactory signatures of 9 complete human corpses of different stages of decomposition. Air sampling was performed inside the body bags with solid sorbents and analysed by coupled gas chromatography-mass spectrometry after thermal desorption (TD-GC-MS). Furthermore, odour-related substances were detected by gas chromatography-olfactometry (GC-O). Sulfurous compounds (mainly dimethyl di- and trisulfide) were identified as most important to the odour perception. Around 350 individual organic substances were detected by TD-GC-MS, notably sulfurous and nitrogenous substances as well as branched alkanes, aldehydes, ketones, alcohols, carboxylic acids, carboxylic acid esters and ethers. A range of terpenes was detected for the first time in a characteristic emission pattern over all decomposition stages. Concentrations of the substances varied greatly, and no correlation between the emission patterns, the stage of decomposition and the cause of death could be found. While previous studies often analysed pig cadavers or only parts of human tissue, the present study shows the importance of analysing complete human corpses over a range of decomposition stages. Moreover, it is shown that using body bags as a kind of “emission test chamber” is a very promising approach, also because it is a realistic application considering the usual transport and store of a body before autopsy.
Background: Transfusion of red blood cell concentrate can be life-saving, but requires accurate dose calculations in children. Aims: We tested the hypothesis that cognitive aids would improve identification of the correct recommended volumes and products, according to the German National Transfusion guidelines, in pediatric transfusion scenarios. Methods: Four online questionnaire-based scenarios, two with hemodynamically stable and two with hemodynamically unstable children, were sent to German and international pediatric anesthetists for completion. In the two stable scenarios, participants were given pre-filled tables that contained all required information. For the two emergency scenarios, existing algorithms were used and required calculation by the user. The results were classified into three categories of deviations from the recommended values (DRV): DRV120 (<80% or >120%), as the acceptable variation; DRV 300 (<33% or >300%), the deviation of concern for potential harm; and DRV 1000 (<10% or >1000%), the excessive deviation with a high probability of harm. Results: A total of 1.458 pediatric anesthetists accessed this simulation questionnaire, and 402 completed questionnaires were available for analysis. A pre-filled tabular aid, avoiding calculations, led to a reduction in deviation rates in the category of DRV120 by 60% for each and of DRV300 by 17% and 20%, respectively. The use of algorithms as aids for unstable emergencies led to a reduction in the deviation rate only for DRV120 (20% and 15% respectively). In contrast, the deviation rates for DRV300 and DRV1000 rose by 37% and 16%, respectively. Participants used higher transfusion thresholds for the emergency case of a 2-year-old compromised child than for the stable case with a patient of the same age (on average, 8.6 g/dL, 95% CI 8.5–8.8 versus 7.1 g/dL, 95% CI 7.0–7.2, p < 0.001) if not supported by our aids. Participants also used a higher transfusion threshold for unstable children aged 3 months than for stable children of the same age (on average, 8.9 g/dL, 95% CI 8.7–9.0 versus 7.9 g/dL, 95% CI 7.7–8.0, p < 0.001). Conclusions: The use of cognitive aids with precalculated transfusion volumes for determining transfusion doses in children may lead to improved adherence to published recommendations, and could potentially reduce dosing deviations outside those recommended by the German national transfusion guidelines.
Distinct immune patterns of hepatocellular carcinoma (HCC) may have prognostic implications in the response to transarterial chemoembolization (TACE). Thus, we aimed to exploratively analyze tumor tissue of HCC patients who do or do not respond to TACE, and to identify novel prognostic biomarkers predictive of response to TACE. We retrospectively included 15 HCC patients who had three consecutive TACE between January 2019 and November 2019. Eight patients had a response while seven patients had no response to TACE. All patients had measurable disease according to mRECIST. Corresponding tumor tissue samples were processed for differential expression profiling using NanoString nCounter® PanCancer immune profiling panel. Immune-related pathways were broadly upregulated in TACE responders. The top differentially regulated genes were the upregulated CXCL1 (log2fc 4.98, Benjamini–Hochberg (BH)-p < 0.001), CXCL6 (log2fc 4.43, BH-p = 0.016) and the downregulated MME (log2fc −4.33, BH-p 0.001). CD8/T-regs was highly increased in responders, whereas the relative number of T-regs to tumor-infiltrating lymphocytes (TIL) was highly decreased. We preliminary identified CXCL1 and CXCL6 as candidate genes that might have the potential to serve as therapeutically relevant biomarkers in HCC patients. This might pave the way to improve patient selection for TACE in HCC patients beyond expert consensus.
For acute and chronic soft tissue infections, radical surgical debridement is required and is considered the gold standard, along with its immediate systemic antibiotic therapy. Treatment with local antibiotics and/or antibiotic-containing materials is commonly used as an additional tool in clinical practice. Spraying with fibrin and antibiotics is a newer technique that has been studied for some antibiotics. However, for gentamicin, data are not yet available on absorption, optimal application, antibiotic fate at the site and transfer of antibiotic into the blood. In an animal study involving 29 Sprague Dawley rats, 116 back wounds were sprayed with gentamicin using either gentamicin alone or one of two possible spray combinations of gentamicin and fibrin. Simultaneous application of gentamicin and fibrin via a spray system to soft tissue wounds resulted in significant antibiotic concentration over a long period of time. The technique is easy and cost-effective. The systemic crossover was significantly minimized in our study, which may have led to fewer side effects in patients. These results could lead to an improvement in local antibiotic therapy.
Background: The Rapid Upper Limb Assessment (RULA) is used for the risk assessment of workplace-related activities. Thus far, the paper and pen method (RULA-PP) has been predominantly used for this purpose. In the present study, this method was compared with an RULA evaluation based on kinematic data using inertial measurement units (RULA-IMU). The aim of this study was, on the one hand, to work out the differences between these two measurement methods and, on the other, to make recommendations for the future use of the respective method on the basis of the available findings. Methods: For this purpose, 130 (dentists + dental assistants, paired as teams) subjects from the dental profession were photographed in an initial situation of dental treatment and simultaneously recorded with the IMU system (Xsens). In order to compare both methods statistically, the median value of the difference of both methods, the weighted Cohen’s Kappa, and the agreement chart (mosaic plot) were applied. Results: In Arm and Wrist Analysis—area A—here were differences in risk scores; here, the median difference was 1, and the agreement in the weighted Cohen’s kappa test also remained between 0.07 and 0.16 (no agreement to poor agreement). In area B—Neck, Trunk, and Leg Analysis—the median difference was 0, with at least one poor agreement in the Cohen’s Kappa test of 0.23–0.39. The final score has a median of 0 and a Cohen’s Kappa value of 0.21–0.28. In the mosaic plot, it can be seen that RULA-IMU had a higher discriminatory power overall and more often reached a value of 7 than RULA-PP. Conclusion: The results indicate a systematic difference between the methods. Thus, in the RULA risk assessment, RULA-IMU is mostly one assessment point above RULA-PP. Therefore, future study results of RULA by RULA-IMU can be compared with literature results obtained by RULA-PP to further improve the risk assessment of musculoskeletal diseases.
Purpose: To evaluate the efficacy and safety of microwave ablation (MWA) as a treatment for recurrent hepatocellular carcinoma (HCC) after initial successful surgical resection. Methods: This retrospective study included 40 patients (11 women and 29 men; mean age: 62.3 ± 11.7 years) with 48 recurrent lesions of HCC after initial surgical resection that were treated by percutaneous MWA. Several parameters including complications, technical success, local tumor progression (LTP), intrahepatic distant recurrence (IDR), overall survival (OS), and progression-free survival (PFS) were evaluated in order to investigate the safety and efficacy of MWA for these recurrent HCC lesions after surgical treatment. Results: All MWA treatments were performed without complications or procedure-related deaths. Technical success was achieved in all cases. Two cases developed LTP at a rate of 5%, and IDR occurred in 23 cases at a rate of 57.5% (23/40). The 1-, 2-, 3-, 4-, and 6-year OS rates were 97%, 89.2%, 80.3%, 70.2%, and 60.2%, respectively. The 1- and 3-year PFS rates were 50.2% and 34.6%, respectively. Conclusion: MWA is effective and safe as a local treatment for recurrent HCC after initial surgical resection.
This study investigates the socio-economic characteristics, behavioral preferences, and consumption of individuals who own crypto-assets. Our empirical analysis utilizes data from a German personal finance management app where users connect their bank accounts and depots. We conducted a survey and elicited behavioral factors for financial decision-making. By combining survey with account and security account data, we identify crypto investors’ preferences for financial decision-making and financial advice. Our results suggest that, in particular, students or self-employed, young, and male individuals who are risk-seeking and impatient are more likely to have invested in crypto-assets. Most crypto owners have less experience with financial advisory. They see it as too time-consuming and qualitatively poor, and instead, they prefer to decide on their own as they have self-reported high financial literacy. Investigating their consumption in more detail we conclude that crypto investors more often spend on travelling, electronics, and food delivery and less on health. Our findings suggest policymakers in identifying high-risk consumers and investors, and help financial institutions develop appropriate products.
CEND-1 (iRGD) is a bifunctional cyclic peptide that can modulate the solid tumour microenvironment, enhancing the delivery and therapeutic index of co-administered anti-cancer agents. This study explored CEND-1’s pharmacokinetic (PK) properties pre-clinically and clinically, and assessed CEND-1 distribution, tumour selectivity and duration of action in pre-clinical tumour models. Its PK properties were assessed after intravenous infusion of CEND-1 at various doses in animals (mice, rats, dogs and monkeys) and patients with metastatic pancreatic cancer. To assess tissue disposition, [3H]-CEND-1 radioligand was administered intravenously to mice bearing orthotopic 4T1 mammary carcinoma, followed by tissue measurement using quantitative whole-body autoradiography or quantitative radioactivity analysis. The duration of the tumour-penetrating effect of CEND-1 was evaluated by assessing tumour accumulation of Evans blue and gadolinium-based contrast agents in hepatocellular carcinoma (HCC) mouse models. The plasma half-life was approximately 25 min in mice and 2 h in patients following intravenous administration of CEND-1. [3H]-CEND-1 localised to the tumour and several healthy tissues shortly after administration but was cleared from most healthy tissues by 3 h. Despite the rapid systemic clearance, tumours retained significant [3H]-CEND-1 several hours post-administration. In mice with HCC, the tumour penetration activity remained elevated for at least 24 h after the injection of a single dose of CEND-1. These results indicate a favourable in vivo PK profile of CEND-1 and a specific and sustained tumour homing and tumour penetrability. Taken together, these data suggest that even single injections of CEND-1 may elicit long-lasting tumour PK improvements for co-administered anti-cancer agents.
Background:
There is growing evidence that Internet-based cognitive behavioral therapy (ICBT) is as effective as a stand-alone treatment and helps facilitating access to treatment. Given the complexity of the treatment, we argue that the effect of ICBT could be even greater if guided by a therapist, as this could increase treatment adherence. We modified an established and well-evaluated treatment approach and developed a mobile application for treating social anxiety disorder (SAD). In the present study, we compare the efficacy of app use alone (APP) with video-based, therapist-guided app use (TG-APP) and with a wait-list control group (WLC) in terms of symptom reduction, and various secondary outcomes such as increase in quality of life or decrease of general psychological distress.
Methods/design:
A within-between interaction design with randomization to one of three conditions will be used. In the APP condition, patients receive only the app without any additional contact with therapists, while in the TG-APP condition, therapists provide 8 sessions of video-based treatment in addition to using the app. The study will be conducted in two university outpatient treatment centers with reliably diagnosed SAD patients. The primary outcome will be defined as change in SAD symptoms, as measured by the Liebowitz Social Anxiety Scale (expert rating). Furthermore, a wide range of self-reports and clinician ratings for other symptoms (depression, general psychopathology) or quality of life will be used. A simulation-based power analysis for a 3 × 2 interaction effect (group × time) on the primary outcome in a linear mixed model resulted in a total sample size of N = 165.
Discussion:
The present study will be one of the first to examine the additional benefit of therapist-guided video sessions regarding the use of an app treating SAD. Study results are pivotal to future treatment application in SAD.
Highlights
• Different NADPH supply strategies are compared in Saccharomyces cerevisiae.
• Example products are d-xylitol and l-galactonate.
• ZWF1 overexpression is the most robust strategy in the diauxic batch fermentation.
• Carbon source dependencies and interferences of different strategies are explored.
Abstract
Enhancing the supply of the redox cofactor NADPH in metabolically engineered cells is a critical target for optimizing the synthesis of many product classes, such as fatty acids or terpenoids. In S. cerevisiae, several successful approaches have been developed in different experimental contexts. However, their systematic comparison has not been reported. Here, we established the reduction of xylose to xylitol by an NADPH-dependent xylose reductase as a model reaction to compare the efficacy of different NADPH supply strategies in the course of a batch fermentation, in which glucose and ethanol are sequentially used as carbon sources and redox donors. We show that strains overexpressing the glucose-6-phosphate dehydrogenase Zwf1 perform best, producing up to 16.9 g L−1 xylitol from 20 g L−1 xylose in stirred tank bioreactors. The beneficial effect of increased Zwf1 activity is especially pronounced during the ethanol consumption phase. The same notion applies to the deletion of the aldehyde dehydrogenase ALD6 gene, albeit at a quantitatively lower level. Reduced expression of the phosphoglucose isomerase Pgi1 and heterologous expression of the NADP+-dependent glyceraldehyde-3-phosphate dehydrogenase Gdp1 from Kluyveromyces lactis acted synergistically with ZWF1 overexpression in the presence of glucose, but had a detrimental effect after the diauxic shift. Expression of the mitochondrial NADH kinase Pos5 in the cytosol likewise improved the production of xylitol only on glucose, but not in combination with enhanced Zwf1 activity. To demonstrate the generalizability of our observations, we show that the most promising strategies – ZWF1 overexpression and deletion of ALD6 - also improve the production of l-galactonate from d-galacturonic acid. Therefore, we expect that these findings will provide valuable guidelines for engineering not only the production of xylitol but also of diverse other pathways that require NADPH.
Cycling as a form of active transportation provides many health benefits through increased physical activity. These benefits can be compromised in urban environments due to the intensified respiration while cycling and the proximity to vehicular traffic with associated exposure to traffic-related air pollution from particulate matter. This review provides an overview of the current literature with data on mobile measurements of particulate matter exposure of cyclists in urban areas. Also, the factors influencing particulate matter concentrations from meteorology, traffic, architecture, and the temporal conditions presented in the literature are described. In this respect, cycling represents an efficient method for characterizing individual particulate matter exposure with a high spatiotemporal resolution. Taking the background concentrations into consideration, statements on the relative exposure to pollutants and the associated health risk can be made with knowledge in favor of environmentally compatible inner city traffic planning.
Background and objectives: In light of the late stage of COVID-19 pandemic, the occurrence of persistent symptoms after COVID-19 infection has become more frequent. To date, there are no standardized treatments. Underlying mechanisms, risk and protective factors for severe persisting symptoms should be investigated to develop effective interventions.
Methods: An online questionnaire was used to assess gender, presence of prior mental disorder, severity of COVID-19 infection, and social connectedness (SCS-R) to determine their influence on symptom severity of persisting symptoms. The sample used to examine risk and protective factors consisted of 693 participants.
Results: The analysis revealed no significant gender differences for severity of persisting symptoms. However, prior mental health condition was associated with severity of persisting symptoms. Moreover, there was a positive association between symptom severity during COVID-19 infection and Post COVID 19. Social connectedness was found to be negatively associated with Post COVID 19 symptoms. Social connectedness was shown to be negatively associated with depressive symptoms and disordered self-organization. The symptoms of energy loss and concentration had the highest centrality.
Conclusion: The results of the study indicate that severity of post-covid symptoms is associated with higher levels of psychopathological symptoms and a lower level of social connectedness. In conclusion, social connectedness may be an important factor in the development of post-COVID symptoms and should be considered for future interventions. The results from the network analyses provide a first step for a more granular syndrome profile.
The process e+e−→D∗+sD∗−s is studied with a semi-inclusive method using data samples at center-of-mass energies from threshold to 4.95 GeV collected with the BESIII detector operating at the Beijing Electron Positron Collider. The Born cross sections of the process are measured for the first time with high precision in this energy region. Two resonance structures are observed in the energy-dependent cross sections around 4.2 and 4.4 GeV. By fitting the cross sections with a coherent sum of three Breit-Wigner amplitudes and one phase-space amplitude, the two significant structures are assigned masses of (4186.5±9.0±30) MeV/c2 and (4414.5±3.2±6.0) MeV/c2, widths of (55±17±53) MeV and (122.6±7.0±8.2) MeV, where the first errors are statistical and the second ones are systematic. The inclusion of a third Breit-Wigner amplitude is necessary to describe a structure around 4.79 GeV.