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Focused lung ultrasound (FLUS) has high diagnostic accuracy in many common conditions seen in a variety of emergency settings. Competencies are essential for diagnostic success and patient safety but can be challenging to acquire in clinical environments. Immersive virtual reality (IVR) offers an interactive risk-free learning environment and is progressing as an educational tool. First, this study explored the educational impact of novice FLUS users participating in a gamified or non-gamified IVR training module in FLUS by comparing test scores using a test with proven validity evidence. Second, the learning effect was assessed by comparing scores of each group with known test scores of novices, intermediates and experienced users in FLUS. A total of 48 participants were included: 24 received gamified and 24 received non-gamified IVR training. No significant difference was found between gamified (mean = 15.5 points) and non-gamified (mean = 15.2 points), indicating that chosen gamification elements for our setup did not affect learning outcome (p = 0.66). The mean scores of both groups did not significantly differ from those of known intermediate users in FLUS (gamified p = 0.63, non-gamified p = 0.24), indicating that both IVR modules could be used as unsupervised out-of-hospital training for novice trainees in FLUS.

Purpose Our study analyzes the influence of minimally invasive vs. open surgery on the postoperative need for nursing care in patients with colorectal carcinoma. Colorectal cancer is an age-related disease, and oncologic surgery is increasingly performed in elderly patients. Long-term effects of the procedural choice on patients’ self-sufficiency and autonomy have not been scientifically addressed so far. Methods Multivariable logistic regression models based on claims data from a statutory health insurer (AOK, Baden-Württemberg, Germany) were applied to assess potential risk factors for assignment patients to a nursing care level, a German scale to categorize individual need for nursing care, at 12 and 36 months after colorectal cancer surgery. Results A total of 3996 patients were eligible to be included in the analysis. At 36 months postoperatively, 44 of 427 (10.3%) patients after minimally invasive colon cancer surgery and 231 of 1287 (17.9%) patients after open procedure were newly graded into a nursing care level (OR = 0.62, 95%CI = 0.44–0.90, p = 0.010). Thirty-four of 251 (13.5%) patients receiving minimally invasive rectal cancer surgery compared to 142 of 602 (23.6%) patients after open approach were newly assigned to a nursing care level (OR = 0.53, 95%CI = 0.34–0.81, p = 0.003). Conclusions Laparoscopically assisted resection of colorectal cancer seems to be superior in preserving physical autonomy of elderly patients with colorectal cancer.

BACKGROUND Whether ultrathin-strut stents are particularly beneficial for lesions requiring implantation of more than one stent is unknown. METHODS In a post-hoc lesion-level analysis of two randomized trials comparing ultrathin-strut biodegradable polymer Sirolimus-eluting stents (BP-SES) versus thin-strut durable polymer Everolimus-eluting stents (DP-EES), lesions were stratified into multi stent lesions (MSL) versus single-stent lesions (SSL). The primary endpoint was target lesion failure (TLF), a composite of lesion-related unclear/cardiac death, myocardial infarction (MI), or revascularization, at 24 months. RESULTS Among 5328 lesions in 3397 patients, 1492 (28%) were MSL (722 with BP-SES, 770 with DP-EES). At two years, TLF occurred in 63 lesions (8.9%) treated with BP-SES and 60 lesions (7.9%) treated with DP-EES in the MSL-group (subdistibution hazard ratio [SHR], 1.13; 95%CI, 0.77-1.64; p=0.53), and in 121 (6.4%) and 136 (7.4%) lesions treated with BP-SES and DP-EES respectively (SHR, 0.86; 95%CI, 0.62-1.18; p = 0.35) in the SSL-group (p for interaction = 0.241). While the rates of lesion-related MI or revascularization were significantly lower in SSL treated with BP-SES as compared to DP-EES (3.5% vs. 5.2%; SHR, 0.67; 95%CI 0.46-0.97; p=0.036), no significant difference was observed in MSL (7.1% vs. 5.4%; SHR, 1.31; 95%CI 0.85-2.03; p=0.216) with significant interaction between groups (p for interaction=0.014). CONCLUSIONS Rates of TLF are similar between ultrathin-strut BP-SES and thin-strut DP-EES in MSL and SSL. The use of ultrathin-strut BP-SES versus thin-strut DP-EES did not prove to be particularly beneficial for the treatment of multi-stent lesions. CONDENSED ABSTRACT Whether ultrathin-strut stents are particularly beneficial for lesions requiring implantation of more than one stent is unknown. In a post-hoc analysis of two randomized trials comparing ultrathin-strut biodegradable polymer Sirolimus-eluting stents (BP-SES) versus thin-strut durable polymer Everolimus-eluting stents (DP-EES), 5328 lesions in 3397 patients were stratified into multi-stent lesions (MSL) versus single-stent lesions (SSL). At 2 years, rates of target lesion failure were comparable between BP-SES and DP-EES in both MSL and SSL. In the SSL group, lesion-related myocardial infarction or revascularization were significantly lower in BP-SES as compared to DP-EES; in contrast, no significant difference between stents was observed in the MSL group (p for interaction = 0.014).

In mass spectrometry-based proteomics, heavy internal standards are used to validate target peptide detections and to calibrate peptide quantitation. Here, we report light contamination present in heavy labelled synthetic peptides of high isotopic enrichment. Application of such peptides as assay-internal standards potentially compromises the detection and quantitation especially of low abundant cellular peptides. Therefore, it is important to adopt guidelines to prevent false-positive identifications of endogenous light peptides as well as errors in their quantitation from biological samples.

While some have argued that abandoning religious belief is the only way to help religious individuals accept evolution, we strongly contend that highlighting faith-evolution compatibility is much more effective. This article describes a professional development event for science teachers and religious educators highlighting ways to teach human evolution using a science inquiry approach coupled with methods for helping students reconcile science and religion. Since many science teachers in our population face a highly religious student body, are religious themselves, and have religious education integrated into the school system, we asked them to invite the religious educators (i.e., seminary teachers) at their schools to join them at the event. In addition, a group of religious educator faculty members from the local university joined the event. We collected data both before and after intervention. Results showed that the event strengthened understanding of the intersection between evolution and religion for this particular faith group, decreased feelings of conflict in participants themselves, and increased their confidence and comfort level in offering reconciliation to students and designing lesson plans that include human examples of evolution. Differential impacts on each group of participants are discussed in terms of what we can apply to efforts like this going forward.

A Single-Event MicroKinetic (SEMK) model has been extended towards the simulation of Steady State Isotopic Transient Kinetic Analysis (SSITKA) data for Co catalyzed Fischer-Tropsch Synthesis (FTS). The extended model considers two types of sites and both direct and H-assisted CO dissociation. Regression of the model parameters to the data obtained from 17 steady state and 11 SSITKA experiments resulted in physicochemically meaningful estimates for the activation energies and atomic chemisorption enthalpies. The application of the phenomenological UBI-QEP method allows to physically interpret the nature of the two site types considered in the model, i.e., terrace and step sites. A reaction path analysis shows that over 80 percent of the CO reacts on the step sites. Furthermore, chain growth exclusively occurs on these sites. The terrace sites are less reactive for CO dissociation and are identified as responsible for methane production. A fraction of the alkenes, produced on the step sites, is hydrogenated to alkanes on the terrace sites. Based on model simulations, the metal particle size effect, i.e., a lower TOF, higher methane selectivity and increasing alkane to alkene ratio with decreasing metal particle size, is attributed to an increasing relative importance of the terrace sites on the reaction kinetics.

Aims Routine revascularization in patients with ST-segment elevation myocardial infarction (STEMI) presenting >48 h after symptom onset is not recommended. Methods and results We compared outcomes of STEMI patients undergoing percutaneous coronary intervention (PCI) according to total ischaemic time. Patients included in the Bern-PCI registry and the Multicenter Special Program University Medicine ACS (SPUM-ACS) between 2009 and 2019 were analysed. Based on symptom-to-balloon-time, patients were categorized as early (48 h). Co-primary endpoints were all-cause mortality and target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction, and target lesion revascularization at 1 year. Of 6589 STEMI patients undergoing PCI, 73.9% were early, 17.2% late, and 8.9% very late presenters. The mean age was 63.4 years, and 22% were female. At 1 year, all-cause mortality occurred more frequently in late vs. early [5.8 vs. 4.4%, hazard ratio (HR) 1.34, 95% confidence interval (CI) 1.01–1.78, P = 0.04] and very late (6.8%) vs. early presenters (HR 1.59, 95% CI 1.12–2.25, P < 0.01). There was no excess in mortality comparing very late and late presenters (HR 1.18, 95% CI 0.79–1.77, P = 0.42). Target lesion failure was more frequent in late vs. early (8.3 vs. 6.5%, HR 1.29, 95% CI 1.02–1.63, P = 0.04) and very late (9.4%) vs. early presenters (HR 1.47, 95% CI 1.09–1.97, P = 0.01), and similar between very late and late presenters (HR 1.14, 95% CI 0.81–1.60, P = 0.46). Following adjustment, heart failure, impaired renal function, and previous gastrointestinal bleeding, but not treatment delay, were the main drivers of outcomes. Conclusion PCI >12 h after symptom onset was associated with less favourable outcomes, but very late vs. late presenters did not have an excess in events. While benefits seem uncertain, (very) late PCI appeared safe.

The capacity of host cells to detect and restrict an infecting virus rests on an array of cell-autonomous antiviral effectors and innate immune receptors that can trigger inflammatory processes at tissue and organismal levels. Dynamic changes in protein abundance, subcellular localisation, post-translational modifications and interactions with other biomolecules govern these processes. Proteomics is therefore an ideal experimental tool to discover novel mechanisms of host antiviral immunity. Additional information can be gleaned both about host and virus by systematic analysis of viral immune evasion strategies. In this review, we summarise recent advances in proteomic technologies and their application to antiviral innate immunity.

The learners’ multiple intelligences (MI) are the key measures to be assessed by teachers to make the teaching and learning process meaningful. In today's scenario, teachers face different challenges in addressing the various learning needs of the learners in implementing learning objectives to enhance learners’ academic engagement and performance. Hence, the study is anchored in Gardner's Theory of Multiple intelligences, which emphasizes the holistic perspectives of the minds that every individual has a unique ability, and strengths that contribute to the community's success. The study aimed to determine the extent and the significant difference of learners’ multiple intelligences when grouped according to age, sex, and family monthly income. The study utilized the descriptive-comparative research design. The research locale of the study is the rural elementary school in a second-class northern municipality in one of the provinces in the Philippines with a population of 290 pupils and a sample of 165 Grades five and six respondents, and the researchers utilized a stratified random sampling technique. The study employed a self-made questionnaire based on William Spady’s twenty-five kinds of multiple intelligences, and the use of mean, standard deviation, and non-parametric tests of the Mann-Whitney U test and Kruskal Wallis Test were employed. The results show that students have a very high extent of visual and attentiveness intelligence, a high extent of humor and social skills, and a moderate extent of Gastronomic intelligence. Moreover, there is a significant difference in the Spatial, Kinesthetics, Conceptual, and Strategic Intelligences when grouped as to age. Verbal, Logical, Mathematical, Kinesthetics, Visual, and Visionary Intelligence were significant as to the sex, and empathetic, functional, and imaginative intelligence were significant to the family’s monthly income. Overall, intelligence is enhanced through creative strategies, appropriate instructional materials, and a stimulating and nurturing environment. The MI as a basis for preparing MI Module is one approach to improving teaching and learning processes in the Philippine context. Learners may be made aware of their intelligence even at an early age so that they may be able to use them in learning and apply it in real-life scenarios that would eventually develop a sense of compact readiness in facing the future.

Work-Life Balance (WLB) profoundly impacts employees' job satisfaction in their working environment. Every worker envisions an excellent working climate, but there are some challenges in how an employee can cope with their personal life and work obligations; in this light, the employer shall create programs that will boost opportunities to strengthen their skills and character development. Hence, the study is anchored on the Motivation Hygiene Theory of Job Satisfaction, which includes many factors that contribute to an employee's job satisfaction (Herzberg,1954). The research study aimed to determine the extent of WLB and Job Satisfaction of personnel during the pandemic and their significant difference and relationship. The study employs the descriptive comparative and correlational research design. The locale of the study is the North Campus of State University in Negros Occidental; the respondents of the study were 49 personnel which includes the teaching personnel and 17 non-teaching personnel using a stratified random sampling technique. The researchers utilized a self-made questionnaire, and data were analyzed using mean, standard deviation, T-Test, Analysis of Variance, and Pearson Product Moment Correlation. Results show that there is a great extent on the WLB, which implies that personnel has balanced their work-life during the pandemic, and there is a great extent on Job Satisfaction which means they are highly satisfied with their work. However, there is a significant difference in the extent of job satisfaction when grouped according to sex, which means that male personnel were more satisfied than females. There is also a significant relationship between the WLB and Job Satisfaction. Therefore, the higher the work-life balance, the greater the personnel's job satisfaction. Thus, the employer shall ensure a therapeutic working environment that enables personnel to feel valued, appreciated, and supported in the tasks assigned to them, thereby promoting a more productive academic working environment to attain quality education in line with the strategic goals of a state university.

BACKGROUND Treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on top of statins leads to plaque regression and stabilisation. The effects of PCSK9 inhibitors on coronary physiology and angiographic diameter stenosis (DS%) are unknown. AIMS This study aimed to investigate the effects of the PCSK9 inhibitor alirocumab on coronary haemodynamics as assessed by quantitative flow ratio (QFR) and DS% by three-dimensional quantitative coronary angiography (3D-QCA) in non-infarct-related arteries (non-IRA) among acute myocardial infarction (AMI) patients. METHODS This was a prespecified substudy of the randomised controlled PACMAN-AMI trial, comparing alirocumab versus placebo on top of rosuvastatin. QFR and 3D-QCA were assessed at baseline and 1 year in any non-IRA ≥2.0 mm and 3D-QCA DS% >25%. The prespecified primary endpoint was the number of patients with a mean QFR increase at 1 year, and the secondary endpoint was the change in 3D-QCA DS%. RESULTS Of 300 enrolled patients, 265 had serial follow-up, of which 193 underwent serial QFR/3D-QCA analysis in 282 non-IRA. At 1 year, QFR increased in 50/94 (53.2%) patients with alirocumab versus 40/99 (40.4%) with placebo (Δ12.8%; odds ratio 1.7, 95% confidence interval [CI]: 0.9 to 3.0; p=0.076). DS% decreased by 1.03±7.28% with alirocumab and increased by 1.70±8.27% with placebo (Δ-2.50%, 95% CI: -4.43 to -0.57; p=0.011). CONCLUSIONS Treatment of AMI patients with alirocumab versus placebo for 1 year resulted in a significant regression in angiographic DS%, whereas no overall improvement of coronary haemodynamics was observed. CLINICALTRIALS gov: NCT03067844.

BACKGROUND Routine revascularisation in patients with ST-segment-elevation myocardial infarction (STEMI) presenting >48 hours after symptom onset is not recommended. METHODS We compared outcomes of STEMI patients undergoing percutaneous coronary intervention (PCI) according to total ischemic time. Patients included in the Bern-PCI registry and the Multicenter Special Program University Medicine ACS (SPUM-ACS) between 2009-2019 were analysed. Based on symptom-to-balloon-time, patients were categorised as early (48 h). Co-primary endpoints were all-cause mortality and target lesion failure (TLF), a composite of cardiac death, target-vessel myocardial infarction and target-lesion revascularisation at one year. RESULTS Of 6,589 STEMI patients undergoing PCI, 73.9% were early, 17.2% late and 8.9% very late presenters. Mean age was 63.4 years, 22% were female. At one year, all-cause mortality occurred more frequently in late vs. early (5.8% vs. 4.4%, HR 1.34,95%CI 1.01-1.78, p = 0.04) and very late (6.8%) vs. early presenters (HR 1.59, 95%CI 1.12-2.25, p 12 h after symptom onset was associated with less favourable outcomes, but very late vs. late presenters did not have an excess in events. While benefits seem uncertain, (very) late PCI appeared safe.

Citrullination is the conversion of peptidyl-arginine into the non-coded amino acid citrulline. Despite its importance in physiology and disease, global identification of citrullinated proteins and precise modification sites has remained challenging. Here, we employed quantitative mass spectrometry-based proteomics to generate a comprehensive atlas of citrullination sites in a physiologically relevant cell type. Collectively, we identified 14.056 citrullination sites within 4.008 proteins and quantified their regulation upon inhibition of the citrullinating enzyme PADI4. Using this rich dataset, we uncover general mechanistic and cell biological principles of citrullination function, while providing site-specific and quantitative information on thousands of PAD4 substrates within cells. Our findings include signature histone marks and numerous modifications on transcriptional regulators and chromatin-related signaling effectors. Additionally, we identify precise citrullination sites on an extensive list of known autoantigens. Collectively, we describe systems attributes of the human citrullinome and provide a resource framework for understanding citrullinaiton at the mechanistic level.

ADP-ribosylation is a posttranslational modification (PTM) that has crucial functions in a wide range of cellular processes. Although mass spectrometry (MS) in recent years has emerged as a valuable tool for profiling ADP-ribosylation on a system level, the use of conventional MS methods to profile ADP-ribosylation sites in an unbiased way remains a challenge. Here, we describe a protocol for identification of ADP-ribosylated proteins in vivo on a proteome-wide level, and localization of the amino acid side chains modified with this PTM. The method relies on the enrichment of ADP-ribosylated peptides using the Af1521 macrodomain (Karras GI, Kustatscher G, Buhecha HR, Allen MD, Pugieux C, Sait F, Bycroft M, Ladurner AG, EMBO J 24:1911-1920, 2005), followed by liquid chromatography-high-resolution tandem MS (LC-MS/MS) with electron transfer dissociation-based peptide fragmentation methods, resulting in accurate localization of ADP-ribosylation sites. This protocol explains the step-by-step enrichment and identification of ADP-ribosylated peptides from cell culture to data processing using the MaxQuant software suite.

Cellular proteins often have multiple and diverse functions. This is illustrated with protein Spir-1 that is an actin nucleator, but, as shown here, also functions to enhance innate immune signalling downstream of RNA sensing by RIG-I/MDA-5. In human and mouse cells lacking Spir-1, IRF3 and NF-κB-dependent gene activation is impaired, whereas Spir-1 overexpression enhanced IRF3 activation. Furthermore, the infectious virus titres and sizes of plaques formed by two viruses that are sensed by RIG-I, vaccinia virus (VACV) and Zika virus, are increased in Spir-1 KO cells. These observations demonstrate the biological importance of Spir-1 in the response to virus infection. Like cellular proteins, viral proteins also have multiple and diverse functions. Here, we also show that VACV virulence factor K7 binds directly to Spir-1 and that a diphenylalanine motif of Spir-1 is needed for this interaction and for Spir-1-mediated enhancement of IRF3 activation. Thus, Spir-1 is a new virus restriction factor and is targeted directly by an immunomodulatory viral protein that enhances virus virulence and diminishes the host antiviral responses.

Human–swarm interaction is a frontier in the realms of swarm robotics and human-factors engineering. However, no holistic theory has been explicitly formulated that can inform how humans and robot swarms should interact through an interface while considering real-world demands, the relative capabilities of the components, as well as the desired joint-system behaviours. In this article, we apply a holistic perspective that we refer to as joint human–swarm loops, that is, a cybernetic system made of human, swarm and interface. We argue that a solution for human–swarm interaction should make the joint human–swarm loop an intelligent system that balances between centralized and decentralized control. The swarm-amplified human is suggested as a possible design that combines perspectives from swarm robotics, human-factors engineering and theoretical neuroscience to produce such a joint human–swarm loop. Essentially, it states that the robot swarm should be integrated into the human’s low-level nervous system function. This requires modelling both the robot swarm and the biological nervous system as self-organizing systems. We discuss multiple design implications that follow from the swarm-amplified human, including a computational experiment that shows how the robot swarm itself can be a self-organizing interface based on minimal computational logic.

Highlights • First longitudinal data analyses on sports activity patterns and health. • Long-standing sports activity engagement improves cardio-metabolic health. • Starting regular sports activity reduces cardio-metabolic risk factor occurrence. • Relapse from regular sports activity increases cardio-metabolic disease incidence., Background Physical activity is favorable for health, and vigorous sports activity is particularly beneficial. This study investigates the association between changes in sports participation patterns over time and cardio-metabolic and self-perceived health outcomes. Methods Data from 3752 adults (18–79 years of age) who participated in 2 national health interview and examination surveys in 1997–1999 and 2008–2011 were included, with a mean follow-up time of about 12 years. A change in self-reported sports activity was analyzed with respect to the incidence of type 2 diabetes, coronary heart disease (CHD), hypertension, obesity, dyslipidemia, metabolic syndrome, and poor self-perceived health. Participants with pre-existing disease or risk factor of interest at baseline were excluded from the analysis. Being sufficiently active in sports was specified as doing sports for at least 1–2 h per week, and 4 activity categories were defined: 1) inactive at both time points (inactive–inactive), 2) inactive at baseline and active at follow-up (inactive–active), 3) active at baseline and inactive at follow-up (active–inactive), and 4) active at both time points (active–active). Associations between sports activity engagement and health outcomes were estimated by logistic regression models with different stages of adjustments. Results Not engaging in any regular sports activity at both time points (inactive–inactive) was associated with higher rates of type 2 diabetes (odds ratio (OR) = 1.82, 95% confidence interval (95%CI): 1.08–3.08), CHD (OR = 1.82, 95%CI: 1.16–2.84), hypertension (OR = 1.36, 95%CI: 1.03–1.81), metabolic syndrome (OR = 1.58, 95%CI: 1.08–2.32), and poor self-perceived health (OR = 2.54, 95%CI: 1.83–3.53) compared to doing regular sports for a minimum of 1–2 h per week over time (active–active). In case of change from inactivity to any regular sports activity (inactive–active), the rate of risk factor occurrence was not statistically different from the active–active reference group except for poor self-perceived health, but it was higher for type 2 diabetes (OR = 2.15, 95%CI: 1.12–4.14) and CHD (OR = 1.77, 95%CI: 1.03–3.03). Being active at baseline but inactive at follow-up (active–inactive) was not associated with higher disease incidence of type 2 diabetes (OR = 0.70, 95%CI: 0.25–1.97) or CHD (OR = 1.20, 95%CI: 0.49–2.99), but was associated with higher rates of hypertension (OR = 1.61, 95%CI: 1.11–2.34), obesity (OR = 2.34, 95%CI: 1.53–3.57), metabolic syndrome (OR = 1.70, 95%CI: 1.11–2.63), and poor self-perceived health (OR = 2.16, 95%CI: 1.53–3.07) at follow-up. Conclusion Even a low weekly quantity (1–2 h) of regular sports activity is partly associated with health benefits. Being formerly but not currently active was not associated with an increased disease incidence, but was associated with a higher risk-factor development compared to the reference group (active–active). Becoming active was preventive for risk-factor development but was not preventive for disease incidence, which probably means that the health benefits from sports activity are not sustainable and disease incidence is only shifted to a later period in life. For this reason, the promotion of and commitment to regular sports activity should be addressed as early as possible over the lifespan to achieve the best health benefits., Graphical Abstract Image, graphical abstract

Previous literature has shown general trade-offs between plan complexity and resulting quality assurance (QA) outcomes. However, existing solutions for controlling this trade-off do not guarantee corresponding improvements in deliverability. Therefore, this work explored the feasibility of an optimization framework for directly maximizing predicted QA outcomes of plans without compromising the dosimetric quality of plans designed with an established knowledge-based planning (KBP) technique.A support vector machine (SVM) was developed - using a database of 500 previous VMAT plans - to predict gamma passing rates (GPRs; 3%/3mm percent dose-difference/distance-to-agreement with local normalization) based on selected complexity features. A heuristic, QA-based optimization (QAO) framework was devised by utilizing the SVM model to iteratively modify mechanical treatment features most commonly associated with suboptimal GPRs. Specifically, leaf gaps (LGs)50 mm were widened by random amounts, which impacts all aperture-based complexity features. 13 prostate KBP-guided VMAT plans were optimized via QAO using user-specified maximum LG displacements before corresponding changes in predicted GPRs and dose were assessed.Predicted GPRs increased by an average of 1.14 ± 1.25% (p = 0.006) with QAO using a 3 mm maximum random LG displacement. There were small differences in dose, resulting in similarly small changes in tumor control probability (maximum increase = 0.05%) and normal tissue complication probabilities in the bladder, rectum, and femoral heads (maximum decrease = 0.2% in the rectum).This study explored the feasibility of QAO and warrants future investigations of further incorporating QA endpoints into plan optimization.

To track blood pressure (BP) and resting heart rate (RHR) in children and adolescents is important due to its associations with cardiovascular outcomes in the adulthood. Therefore, the aim of this study was to examine BP and RHR over a decade among children and adolescents living in Germany using national examination data. Cross-sectional data from 3- to 17-year-old national survey participants (KiGGS 2003–06, n = 14,701; KiGGS 2014–17, n = 3509) including standardized oscillometric BP and RHR were used for age- and sex-standardized analysis. Measurement protocols were identical with the exception of the cuff selection rule, which was accounted for in the analyses. Different BP and RHR trends were observed according to age-groups. In 3- to 6-year-olds adjusted mean SBP and DBP were significantly higher in 2014–2017 compared to 2003–2006 (+2.4 and +1.9 mm Hg, respectively), while RHR was statistically significantly lower by −3.8 bpm. No significant changes in BP or in RHR were observed in 7- to 10-year-olds over time. In 11- to 13-year-olds as well as in 14- to 17-year-olds lower BP has been observed (SBP −2.4 and −3.2 mm Hg, respectively, and DBP −1.8 and −1.7 mm Hg), while RHR was significantly higher (+2.7 and +3.7 bpm). BP trends did not parallel RHR trends. The downward BP trend in adolescents seemed to follow decreasing adult BP trends in middle and high-income countries. The increase in BP in younger children needs confirmation from other studies as well as further investigation. In school-aged children and adolescents, the increased RHR trend may indicate decreased physical fitness.

Bacteriophages have attracted extensive interest in vaccine design. This includes the use of phage display technology to select antigens, the use of engineered phages displaying target antigens in vaccine formulations, and phage DNA vaccines. However, the development of these approaches is limited in part by uncertainty regarding the underlying mechanisms by which phages elicit immunity. This has stymied the clinical development of this technology. Here we review the immunology of phage vaccines and highlight the gaps in our knowledge regarding the underlying mechanisms. First, we review the basic biology of phages and their use in vaccines. Next we discuss what is known about the mechanisms of immunity against engineered phages and phage DNA. Finally, we highlight the gaps in our understanding regarding the immunogenicity of these preparations. We argue that mechanistic insight into the immunology of phage vaccines is essential for the further development and clinical utility of these technologies.

We study theoretically effects of an anisotropic elastic strain on the exciton energy spectrum fine structure and optical selection rules in atom-thin crystals based on transition-metal dichalcogenides. The presence of strain breaks the chiral selection rules at the $\bm K$-points of the Brillouin zone and makes optical transitions linearly polarized. The orientation of the induced linear polarization is related to the main axes of the strain tensor. Elastic strain provides an additive contribution to the exciton fine structure splitting in agreement with experimental evidence obtained from uniaxially strained WSe$_2$ monolayer. The applied strain also induces momentum-dependent Zeeman splitting. Depending on the strain orientation and magnitude, Dirac points with a linear dispersion can be formed in the exciton energy spectrum. We provide a symmetry analysis of the strain effects and develop a microscopic theory for all relevant strain-induced contributions to the exciton fine structure Hamiltonian., Comment: 12 pages, 5 figures

ObjectivesWe aimed to assess general practice (GP) trainees’ self-perception of surgical competencies and to explore longitudinal effects of a compact intervention.DesignWe performed a mixed-methods study including a before and after comparison in the intervention group (IG), a comparison of attendees and non-attendees (control group (CG)) and a qualitative evaluation of the intervention. Competencies were self-assessed through surveys. Semi-structured interviews were performed after 9 months.SettingIn 2019, a 2-day voluntary seminar focussing on minor surgery/injuries was offered on 13 occasions by educators from KWBW Verbundweiterbildungplus (Competence Centre for Postgraduate Medical Education Baden-Württemberg).ParticipantsAll enrolled GP trainees were offered participation. GP trainees who did not attend a seminar (non-attendees) were recruited for CG after the 13th intervention.InterventionAttendees took part in an interactive, GP-oriented short course incorporating 270 min of focused minor surgery/injuries training (compact intervention) on the second day of the 2-day seminar.Results326 GP trainees (IG: n=257; CG: n=69) participated in the study. 17 attendees were interviewed. CG had more often experienced a surgical rotation (p=0.03) and reported higher interest in performing minor surgery in future practice (p=0.03). GP trainees self-rated their all-round competency in minor surgery as average (IG: 3.0±1.0, CG: 3.2±0.9, IG:CG p=0.06). After the intervention, attendees felt that surgical skills should be a core component of GP vocational training (p=0.05). After 9 months, attendees remembered a variety of content and valued the interactive, case-oriented, peer-to-peer approach in a mixed learning group. Some attendees reported they had started to overcome competency gaps in minor surgery.ConclusionsA compact intervention in minor surgery provides an ‘intense’ stimulus which could foster positive attitudes towards minor surgery and promote longitudinal personal development of related competencies in GP trainees, including those with little interest in surgery. Such measures appear crucial to support individual progress of GP trainees to provide comprehensive primary care.

Purpose The purpose of this work is to create a decision support methodology to predict when patients undergoing radiotherapy treatment for locally advanced lung cancer would potentially benefit from adaptive radiotherapy. The proposed methodology seeks to eliminate the manual subjective review by developing an automated statistical learning model to predict when tumor regression would trigger implementation of adaptive radiotherapy based on quantified anatomic changes observed in individual patients on-treatment cone beam computed tomographies (CTs). This proposed process seeks to improve the efficacy and efficiency of both the existing manual and automated adaptive review processes for locally advanced stage III lung cancer. Methods A predictive algorithm was developed as a decision support tool to determine the potential utility of mid-treatment adaptive radiotherapy based on anatomic changes observed on 1158 daily CBCT images across 43 patients. The anatomic changes on each axial slice within specified regions-of-interest were quantified into a single value utilizing imaging similarity criteria comparing the daily CBCT to the initial simulation CT. The range of the quantified metrics for each fraction across all axial slices are reduced to specified quantiles, which are used as the predictive input to train a logistic regression algorithm. A "ground-truth" of the need for adaptive radiotherapy based on tumor regression was evaluated systematically on each of the daily CBCTs and used as the classifier in the logistic regression algorithm. Accuracy of the predictive model was assessed utilizing both a tenfold cross validation and an independent validation dataset, with the sensitivity, specificity, and fractional accuracy compared to the ground-truth. Results The sensitivity and specificity for the individual daily fractions ranged from 87.9%-94.3% and 91.9%-98.6% for a probability threshold of 0.2-0.5, respectively. The corresponding average treatment fraction difference between the model predictions and assessed ART "ground-truth" ranged from -2.25 to -0.07 fractions, with the model predictions consistently predicting the potential need for ART earlier in the treatment course. By initially utilizing a lower probability threshold, the higher sensitivity minimizes the chance of false negative by alerting the clinician to review a higher number of questionable cases. Conclusions The proposed methodology accurately predicted the first fraction at which individual patients may benefit from ART based on quantified anatomic changes observed in the on-treatment volumetric imaging. The generalizability of the proposed method has potential to expand to additional modes of adaptive radiotherapy for lung cancer patients with observed underlying anatomic changes.

Introduction Promoting physical activity (PA) is a key strategy to prevent noncommunicable diseases worldwide. In order to monitor physical activity levels in Germany, several large-scale studies have reported on prevalence rates and correlates. However, a comprehensive analysis of correlates of PA over time is currently lacking for Germany. Methods For the analysis, 13 national cross-sectional data sets were utilized. Data analysis was restricted to respondents aged 18 and older. In a first step, data sets were kept separate in order to explore social gradients of PA and sport. In the second step, data sets were pooled, demographic factors harmonized and binary logistic regressions were conducted. Results Regarding sports participation, different data sets indicate comparable social gradients. People with a higher age, lower income, lower levels of education, or a migrant background consistently have a higher risk of not engaging in sports. Compared to sports participation, social gradients are less pronounced for engaging in vigorous PA. Higher age, lower education, and lower income are also markers for an increased risk of not engaging in vigorous PA. Discussion The study confirms that factors of age, income, education and migrant background continue to contribute to differentials in sport and vigorous PA participation in Germany. For policy-making, this implies that PA promotion should focus on systems-based actions that might reduce population-wide inequalities. Future research might focus on pooling single studies with smaller samples in order to investigate PA and sports participation in specific disadvantaged target groups.

Introduction The numerous health benefits of physical activity (PA) for people with non-communicable diseases (NCDs) are well-documented. In Germany, there are limited data on whether adults with NCDs fulfill health-oriented PA recommendations. This study describes the prevalence of meeting PA recommendations among adults with select NCDs. Method Based on the national representative GEDA-2014/2015-EHIS (N = 24,016), the self-reported PA data of the European Health Interview Survey–Physical Activity Questionnaire (EHIS-PAQ) were classified with respect to fulfilling recommendations for health-enhancing aerobic activities (≥ 150 min per week with at least moderate intensity) and muscle strengthening (≥ 2 times per week). These binary indicators were used to analyze the association between the prevalence of sufficient PA and the self-reported presence of certain NCDs and multiple NCDs to reflect multimorbidity. Results Compared to the general adult population, sufficient aerobic PA was lower for most NCDs, with the lowest level among people with diabetes mellitus, obesity, stroke, chronic obstructive pulmonary disease (COPD), and depression. Compared to the general adult population, sufficient muscle strengthening was lower for some NCDs (diabetes mellitus, obesity, depression), but it was higher in people with musculoskeletal diseases (osteoarthritis, lower back pain). Multimorbidity was negatively associated with sufficient PA levels. Conclusion The study specifies the need to promote PA among adults with select NCDs to counteract insufficient levels of health-enhancing PA and to reduce the individual and societal burden of NCDs.

Contains fulltext : 238670.pdf (Publisher’s version ) (Open Access) BACKGROUND: Growing prevalence of chronic diseases is a rising challenge for healthcare systems. The Primary Care Practice-Based Care Management (PraCMan) programme is a comprehensive disease management intervention in primary care in Germany aiming to improve medical care and to reduce potentially avoidable hospitalisations for chronically ill patients. OBJECTIVES: This study aimed to assess the effect of PraCMan on hospitalisation rate and related costs. METHODS: A retrospective propensity-score matched cohort study was performed. Reimbursement data related to patients treated in general practices between 1st July 2013 and 31st December 2017 were supplied by a statutory health insurance company (AOK Baden-Wuerttemberg, Germany) to compare hospitalisation rate and direct healthcare costs between patients participating in the PraCMan intervention and propensity-score matched controls following usual care. Outcomes were determined for the one-year-periods before and 12 months after beginning of participation in the intervention. RESULTS: In total, 6148 patients participated in the PraCMan intervention during the observation period and were compared to a propensity-score matched control group of 6148 patients from a pool of 63,446 eligible patients. In the one-year period after the intervention, the per-patient hospitalisation rate was 8.3% lower in the intervention group compared to control (p = 0.0004). Per-patient hospitalisation costs were 9.4% lower in favour of the intervention group (p = 0.0002). CONCLUSION: This study showed that the PraCMan intervention may be associated with a lower rate of hospital admissions and hospitalisation costs than usual care. Further studies may assess long-term effects of PraCMan and its efficacy in preventing known complications of chronic diseases.

Interplay effects in highly modulated stereotactic body radiation therapy lung cases treated with volumetric modulated arc therapy. Purpose To evaluate the influence of tumor motion on dose delivery in highly modulated stereotactic body radiotherapy (SBRT) of lung cancer using volumetric modulated arc therapy (VMAT). Methods 4D‐CT imaging data of the quasar respiratory phantom were acquired, using a GE Lightspeed 16‐slice CT scanner, while the phantom reproduced patient specific respiratory traces. Flattening filter‐free (FFF) dual‐arc VMAT treatment plans were created on the acquired images in Pinnacle3 treatment planning system. Each plan was generated with varying levels of complexity characterized by the modulation complexity score. Static and dynamic measurements were delivered to GafChromic EBT3 film inside the respiratory phantom using an Elekta Versa HD linear accelerator. The treatment prescription was 10 Gy per fraction for 5 fractions. Comparisons of the planned and delivered dose distribution were performed using Radiological Imaging Technology (RIT) software. Results For the motion amplitudes and periods studied, the interplay effect is insignificant to the GTV coverage. The mean dose deviations between the planned and delivered dose distribution never went below −2.00% and a minimum dose difference of −5.05% was observed for a single fraction. However for amplitude of 2 cm, the dose error could be as large as 20.00% near the edges of the PTV at increased levels of complexity. Additionally, the modulation complexity score showed an ability to provide information related to dose delivery. A correlation value (R) of 0.65 was observed between the complexity score and the gamma passing rate for GTV coverage. Conclusions As expected, respiratory motion effects are most evident for large amplitude respirations, complex fields, and small field margins. However, under all tested conditions target coverage was maintained.

BackgroundProsthetic joint infection (PJI) is a potentially limb-threatening complication of total knee arthroplasty. Phage therapy is a promising strategy to manage such infections including those involving antibiotic-resistant microbes, and to target microbial biofilms. Experience with phage therapy for infections associated with retained hardware is limited. A 62-year-old diabetic man with a history of right total knee arthroplasty 11 years prior who had suffered multiple episodes of prosthetic knee infection despite numerous surgeries and prolonged courses of antibiotics, with progressive clinical worsening and development of severe allergies to antibiotics, had been offered limb amputation for persistent right prosthetic knee infection due to Klebsiella pneumoniae complex. Intravenous phage therapy was initiated as a limb-salvaging intervention.MethodsThe patient received 40 intravenous doses of a single phage (KpJH46Φ2) targeting his bacterial isolate, alongside continued minocycline (which he had been receiving when he developed increasing pain, swelling, and erythema prior to initiation of phage therapy). Serial cytokine and biomarker measurements were performed before, during, and after treatment. The in vitro anti-biofilm activity of KpJH46Φ2, minocycline and the combination thereof was evaluated against a preformed biofilm of the patient’s isolate and determined by safranin staining.ResultsPhage therapy resulted in resolution of local symptoms and signs of infection and recovery of function. The patient did not experience treatment-related adverse effects and remained asymptomatic 34 weeks after completing treatment while still receiving minocycline. A trend in biofilm biomass reduction was noted 22 hours after exposure to KpJH46Φ2 (P = .063). The addition of phage was associated with a satisfactory outcome in this case of intractable biofilm-associated prosthetic knee infection. Pending further studies to assess its efficacy and safety, phage therapy holds promise for treatment of device-associated infections.

To develop a methodology that can be used to measure the temporal latency of a respiratory gating system.The gating system was composed of an automatic gating interface (Response) and an in-house respiratory motion monitoring system featuring an optically tracked surface marker. Two approaches were used to measure gating latencies. A modular approach involved measuring separately the latency of the gating system's complementary metal-oxide-semiconductor tracking camera, tracking software, and a gating latency of the LINAC. Additionally, an end-to-end approach was used to measure the total latency of the gating system. End-to-end latencies were measured using the displacement of a radiographic target moving at known velocities during the gating process.Summing together the latencies of each of the modular components investigated yielded a total beam-on latency of 1.55 s and a total beam-off latency of 0.49 s. End-to-end beam-on and beam-off latency was found to be 1.49 and 0.34 s, respectively. In each case, no statistically significant differences were found between the end-to-end latency of the gating system and the summation of the individually measured components.Two distinct approaches to quantify gating latencies were presented. Measuring the end-to-end latency of the gating system provided an independent means of validating the modular approach. It is expected that the beam-on latencies reported in this work could be reduced by altering the control system configuration of the LINAC. The modular approach can be used to decouple the individual latencies of the gating system, but future improvements in the temporal resolution of the service graphing feature are needed to reduce the uncertainty of LINAC-related gating latencies measured using this approach. Both approaches are generalizable and can be used together when designing a quality assurance program for a respiratory gating system.

Poxvirus proteins remodel signaling throughout the cell by targeting host enzymes for inhibition and redirection. Recently, it was discovered that early in infection the vaccinia virus (VACV) B12 pseudokinase copurifies with the cellular kinase VRK1, a proviral factor, in the nucleus. Although the formation of this complex correlates with inhibition of cytoplasmic VACV DNA replication and likely has other downstream signaling consequences, the molecular mechanisms involved are poorly understood. Here, we further characterize how B12 and VRK1 regulate one another during poxvirus infection. First, we demonstrate that B12 is stabilized in the presence of VRK1 and that VRK1 and B12 coinfluence their respective solubility and subcellular localization. In this regard, we find that B12 promotes VRK1 colocalization with cellular DNA during mitosis and that B12 and VRK1 may be tethered cooperatively to chromatin. Next, we observe that the C-terminal tail of VRK1 is unnecessary for B12-VRK1 complex formation or its proviral activity. Interestingly, we identify a point mutation of B12 capable of abrogating interaction with VRK1 and which renders B12 nonrepressive during infection. Lastly, we investigated the influence of B12 on the host factor BAF and antiviral signaling pathways and find that B12 triggers redistribution of BAF from the cytoplasm to the nucleus. In addition, B12 increases DNA-induced innate immune signaling, revealing a new functional consequence of the B12 pseudokinase. Together, this study characterizes the multifaceted roles B12 plays during poxvirus infection that impact VRK1, BAF, and innate immune signaling. IMPORTANCE Protein pseudokinases comprise a considerable fraction of the human kinome, as well as other forms of life. Recent studies have demonstrated that their lack of key catalytic residues compared to their kinase counterparts does not negate their ability to intersect with molecular signal transduction. While the multifaceted roles pseudokinases can play are known, their contribution to virus infection remains understudied. Here, we further characterize the mechanism of how the VACV B12 pseudokinase and human VRK1 kinase regulate one another in the nucleus during poxvirus infection and inhibit VACV DNA replication. We find that B12 disrupts regulation of VRK1 and its downstream target BAF, while also enhancing DNA-dependent innate immune signaling. Combined with previous data, these studies contribute to the growing field of nuclear pathways targeted by poxviruses and provide evidence of unexplored roles of B12 in the activation of antiviral immunity.

Childhood and adolescence are key determining stages for health behaviour in the life course. Frequently, health-related attitudes and patterns of behaviour that develop at young age are also maintained at adult age. As studies show, already during childhood and adolescence, patterns of health risk behaviour are more common in certain population groups. KiGGS Wave 2 results confirm that 3- to 17-year-old children and adolescents from families with low socioeconomic status (SES) eat a less healthy diet, do fewer sports and are more often overweight or obese than their peers from more affluent backgrounds. Whereas socioeconomic differences appear to have little effect on levels of alcohol consumption among 11- to 17 year-olds, girls and boys with low SES smoke more frequently than their peers with high SES. Prevention and health promotion encourage children and adolescents to adopt healthy lifestyles, and aim to drive structural changes to stimulate behaviour which promotes good health. Combining measures that target individual behaviour and a settings-based approach appears to be the most promising preventative approach to reduce health inequalities among young people. Due to the clear impacts of socioeconomic differences on health behaviour already at young age measures for disadvantaged children and adolescents and their living conditions should be given an even stronger focus in the future.

Background: Strict monitoring of blood glucose during pregnancy is essential for ensuring optimal maternal and neonatal outcomes. Telemedicine could be a promising solution for supporting diabetes management; however, an updated meta-analysis is warranted. This study assesses the effects of telemedicine solutions for managing gestational and pregestational diabetes. Methods: PubMed, EMBASE, Cochrane Library Central Register of Controlled Trials, and CINAHL were searched up to October 14, 2020. All randomized trials assessing the effects of telemedicine in managing diabetes in pregnancy relative to any comparator without the use of telemedicine were included. The primary outcome was infant birth weight. A meta-analysis comparing the mean difference (MD) in birth weight across studies was applied, and subgroup and sensitivity analyses were performed. The revised Cochrane tool was applied to assess the risk of bias, and the certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Results: From a total of 18 studies, ten (totaling 899 participants) were used to calculate the effect on infant birth weight. The results nonsignificantly favored the control (MD of 19.34 g; [95% confidence interval, CI −47.8; 86.47]), with moderate effect certainty. Heterogeneity was moderate ( I2 = 37.39%). Statistically significant secondary outcomes included differences in two-hour glucose tolerance postpartum (gestational diabetes; two studies: standardized mean difference 9.62 mg/dL [95% CI: 1.95; 17.28]) that favored the control (GRADE level, very low) and risk of shoulder dystocia (four studies: log odds −1.34 [95% CI: −2.61; −0.08]) that favored telemedicine (GRADE, low). Conclusions: No evidence was found to support telemedicine as an alternative to usual care when considering maternal and fetal outcomes. However, further research is needed, including economic evaluations.

Optoelectronic functionalities of monolayer transition-metal dichalcogenide (TMDC) semiconductors are characterized by the emergence of externally tunable, correlated many-body complexes arising from strong Coulomb interactions. However, the vast majority of such states susceptible to manipulation has been limited to the region in energy around the fundamental bandgap. We report the observation of tightly bound, valley-polarized, UV-emissive trions in monolayer TMDC transistors: quasiparticles composed of an electron from a high-lying conduction band with negative effective mass, a hole from the first valence band, and an additional charge from a band-edge state. These high-lying trions have markedly different optical selection rules compared to band-edge trions and show helicity opposite to that of the excitation. An electrical gate controls both the oscillator strength and the detuning of the excitonic transitions, and therefore the Rabi frequency of the strongly driven three-level system, enabling excitonic quantum interference to be switched on and off in a deterministic fashion.

Attempts to develop a therapeutic vaccine against human papillomavirus (HPV)-induced malignancies have mostly not been clinically successful to date. One reason may be the hypoxic microenvironment present in most tumors, including cervical cancer. Hypoxia dysregulates the levels of human leukocyte antigen (HLA) class I molecules in different tumor entities, impacts the function of cytotoxic T cells, and leads to decreased protein levels of the oncoproteins E6 and E7 in HPV-transformed cells. Therefore, we investigated the effect of hypoxia on the presentation of HPV16 E6- and E7-derived epitopes in cervical cancer cells and its effect on epitope-specific T cell cytotoxicity. Hypoxia induced downregulation of E7 protein levels in all analyzed cell lines, as assessed by Western blotting. However, contrary to previous reports, no perturbation of antigen processing and presentation machinery (APM) components and HLA-A2 surface expression upon hypoxia treatment was detected by mass spectrometry and flow cytometry, respectively. Cytotoxicity assays performed in hypoxic conditions showed differential effects on the specific killing of HPV16-positive cervical cancer cells by epitope-specific CD8+ T cell lines in a donor- and peptide-specific manner. Effects of hypoxia on the expression of PD-L1 were ruled out by flow cytometry analysis. Altogether, our results under hypoxia show a decreased expression of E6 and E7, but an intact APM, and epitope- and donor-dependent effects on T cell cytotoxicity towards HPV16-positive target cells. This suggests that successful immunotherapies can be developed for hypoxic HPV-induced cervical cancer, with careful choice of target epitopes, and ideally in combination with hypoxia-alleviating measures.

SUMMARYA multitude of histone chaperones are required to protect histones after their biosynthesis until DNA deposition. They cooperate through the formation of co-chaperone complexes, but the crosstalk between nucleosome assembly pathways remains enigmatic. Using explorative interactomics approaches, we characterize the organization of the histone H3–H4 chaperones network and define the interplay between histone chaperone systems. We identify and validate several novel histone dependent complexes and predict the structure of the ASF1 and SPT2 co-chaperone complex, expanding the role of ASF1 in histone dynamics. We show that DAXX acts separately from the rest of the network, recruiting heterochromatin factors and promoting lysine 9 tri-methylation of new histone H3.3 prior to deposition onto DNA. With its functionality, DAXX provides a molecular mechanism for de novo heterochromatin assembly. Collectively, our findings provide a new framework for understanding how cells orchestrate histone supply and comply with chromatin dynamics throughout the cell cycle.

Additional file 2. SPIRIT figure of the UCC trial.docx

Additional file 4. Translation of the original funding documentation.pdf

Additional file 1. SPIRIT checklist of the UCC trial.docx

Additional file 3. English confirmation ethics approval UCC trial.pdf