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Abstract Current semiconductor qubits rely either on the spin or on the charge degree of freedom to encode quantum information. By contrast, in bilayer graphene the valley degree of freedom, stemming from the crystal lattice symmetry, is a robust quantum number that can therefore be harnessed for this purpose. The simplest implementation of a valley qubit would rely on two states with opposite valleys as in the case of a single-carrier bilayer graphene quantum dot immersed in a small perpendicular magnetic field (B ⊥ ≲ 100 mT). However, the single-carrier quantum dot excited states spectrum has not been resolved to date in the relevant magnetic field range. Here, we fill this gap, by measuring the parallel and perpendicular magnetic field dependence of this spectrum with an unprecedented resolution of 4 μeV. We use a time-resolved charge detection technique that gives us access to individual tunnel events. Our results come as a direct verification of the predicted spectrum and establish a new upper-bound on inter-valley mixing, equal to our energy resolution. Our charge detection technique opens the door to measuring the relaxation time of a valley qubit in a single-carrier bilayer graphene quantum dot.

Abstract Van der Waals heterostructures provide a versatile platform for tailoring electronic properties through the integration of two-dimensional materials. Among these combinations, the interaction between bilayer graphene and transition metal dichalcogenides (TMDs) stands out due to its potential for inducing spin–orbit coupling (SOC) in graphene. Future devices concepts require the understanding of the precise nature of SOC in TMD/bilayer graphene heterostructures and its influence on electronic transport phenomena. Here, we experimentally confirm the presence of two distinct types of SOC – Ising (Δ I = 1.55 meV) and Rashba (Δ R = 2.5 meV) – in bilayer graphene when interfaced with molybdenum disulfide. Furthermore, we reveal a non-monotonic trend in conductivity with respect to the electric displacement field at charge neutrality. This phenomenon is ascribed to the existence of single-particle gaps induced by the Ising SOC, which can be closed by a critical displacement field. Our findings also unveil sharp peaks in the magnetoconductivity around the critical displacement field, challenging existing theoretical models.

Abstract Modified vaccinia Ankara (MVA) virus does not replicate in human cells and is the vaccine deployed to curb the current outbreak of mpox. Here, we conduct a multiplexed proteomic analysis to quantify >9000 cellular and ~80% of viral proteins throughout MVA infection of human fibroblasts and macrophages. >690 human proteins are down-regulated >2-fold by MVA, revealing a substantial remodelling of the host proteome. >25% of these MVA targets are not shared with replication-competent vaccinia. Viral intermediate/late gene expression is necessary for MVA antagonism of innate immunity, and suppression of interferon effectors such as ISG20 potentiates virus gene expression. Proteomic changes specific to infection of macrophages indicate modulation of the inflammatory response, including inflammasome activation. Our approach thus provides a global view of the impact of MVA on the human proteome and identifies mechanisms that may underpin its abortive infection. These discoveries will prove vital to design future generations of vaccines.

In the published publication [...]

Hydrokinetic tidal energy is one of the few marine renewable energy resources with sufficiently mature technology for commercial exploitation. However, several parameters affect its exploitability, such as the minimum speed threshold, ambient turbulence levels, or tidal asymmetry, to name but a few. These parameters are particularly important in regions with lower mean speeds than those in first-generation sites, such as the North Sea. The Gulf of California is one of those regions. In this paper, a Delft3D Flexible Mesh Suite (Delft3D FM) model in barotropic configuration is set up over the Gulf of California using a flexible mesh with resolution varying from O (500 m) in the deep regions to O (10 m) in the coastal regions. A simulation is run over the year of 2020, with a tidal forcing of 75 components. The model is validated at four tidal gauge locations and four Acoustic Doppler Current profiler (ADCP) locations. The speed, U, and tidal power density (TPD) indicators used for the validation were the annual means, the annual means for speeds above the 0.5 m s−1 threshold, the annual means of the spring tide maxima, and the annual maxima. The contour maps of the annual means, that is, the annual means for speeds above the 0.5 m s−1 threshold, allow us to identify tidal energy hot spots throughout the Gulf of California, particularly in the Great Island region (GIR). In this region, these hot spots have higher U and TPD values, in agreement with previous studies. The patterns of circulation around Tiburón Island and San Esteban Island on the East, and Ángel de la Guarda Island and San Lorenzo Island on the West, the four islands in the region with the highest tidal energy potential, are also discussed while recognizing that Tiburón Channel, between Tiburón Island and San Esteban Island, has proved to be the best siting location, based on the technical results obtained so far. The hot spots sites are further characterized by computing the tidal asymmetry in these small regions, showing the locations of the sites with smallest asymmetry, which would be the best for tidal energy exploitation. The hot spots around San Esteban Island are particularly important because they have the largest TPD in the GIR, with the model predicting a TPD on the order of 500–1000 W m−2. Here, complementary field measurements obtained with two ADCPs, close to San Esteban Island, one at 15 m depth, SEs (shallow region), and the other at 60 m depth, SEd (deep region), produced TPDs of 1200 W m−2 and 400 W m−2, respectively. The analysis of the vertical profiles and the tidal asymmetry over the vertical shows the importance of developing 3D models in future investigations.

Biostimulants (Bio-effectors, BEs) comprise plant growth-promoting microorganisms and active natural substances that promote plant nutrient-acquisition, stress resilience, growth, crop quality and yield. Unfortunately, the effectiveness of BEs, particularly under field conditions, appears highly variable and poorly quantified. Using random model meta-analyses tools, we summarize the effects of 107 BE treatments on the performance of major crops, mainly conducted within the EU-funded project BIOFECTOR with a focus on phosphorus (P) nutrition, over five years. Our analyses comprised 94 controlled pot and 47 field experiments under different geoclimatic conditions, with variable stress levels across European countries and Israel. The results show an average growth/yield increase by 9.3% (n=945), with substantial differences between crops (tomato > maize > wheat) and growth conditions (controlled nursery + field (Seed germination and nursery under controlled conditions and young plants transplanted to the field) > controlled > field). Average crop growth responses were independent of BE type, P fertilizer type, soil pH and plant-available soil P (water-P, Olsen-P or Calcium acetate lactate-P). BE effectiveness profited from manure and other organic fertilizers, increasing soil pH and presence of abiotic stresses (cold, drought/heat or salinity). Systematic meta-studies based on published literature commonly face the inherent problem of publication bias where the most suspected form is the selective publication of statistically significant results. In this meta-analysis, however, the results obtained from all experiments within the project are included. Therefore, it is free of publication bias. In contrast to reviews of published literature, our unique study design is based on a common standardized protocol which applies to all experiments conducted within the project to reduce sources of variability. Based on data of crop growth, yield and P acquisition, we conclude that application of BEs can save fertilizer resources in the future, but the efficiency of BE application depends on cropping systems and environments.

Abstract Atomically thin layered van der Waals heterostructures feature exotic and emergent optoelectronic properties. With growing interest in these novel quantum materials, the microscopic understanding of fundamental interfacial coupling mechanisms is of capital importance. Here, using multidimensional photoemission spectroscopy, we provide a layer- and momentum-resolved view on ultrafast interlayer electron and energy transfer in a monolayer-WSe2/graphene heterostructure. Depending on the nature of the optically prepared state, we find the different dominating transfer mechanisms: while electron injection from graphene to WSe2 is observed after photoexcitation of quasi-free hot carriers in the graphene layer, we establish an interfacial Meitner-Auger energy transfer process following the excitation of excitons in WSe2. By analysing the time-energy-momentum distributions of excited-state carriers with a rate-equation model, we distinguish these two types of interfacial dynamics and identify the ultrafast conversion of excitons in WSe2 to valence band transitions in graphene. Microscopic calculations find interfacial dipole-monopole coupling underlying the Meitner-Auger energy transfer to dominate over conventional Förster- and Dexter-type interactions, in agreement with the experimental observations. The energy transfer mechanism revealed here might enable new hot-carrier-based device concepts with van der Waals heterostructures.

As renewable energies need to be extended massively, new concepts are necessary to prevent land conflicts with other uses. Such concepts should have a high generality to offer a swift expansion of renewables anywhere. Within the project, the Photovoltaic Road Roofing Concept (PV-SÜD), a concept for the roofing of roadways with solar panels, was investigated. Its effects on the road infrastructure were analyzed, and a demonstrator was built. The technical boundary conditions and requirements resulting from the specific application type were determined regarding the photovoltaic technology, the possible energy generation, and the supporting structure. The study was completed for a technical solution of 10 m length, 17 m width, and 6.8 m height, with the option of a pent roof (highways running east–west) or gable roofs (highways running north–south). The main target aim was to investigate the potential for widespread use at any site, in contrast to previous studies which mainly aimed at a singular site or demonstrator project. The final solution can support a 38.5 kWp photovoltaic system with a specific annual yield of between 37.5 MWh and 44.0 MWh. The yield variation in sites in Austria and Germany was 14.7% and 17.9%, respectively. One demonstrator roofing was realized as a steel-frame construction with active glass–glass photovoltaic technology at a highway in Hegau (GE).

Aims: To describe the incidence of type 1 diabetes (T1D), and incidence of comorbidities in addition to T1D, in adults over a 22-year period in Denmark and explore the associations between socioeconomic status (SES) and the development of comorbidities. Methods: We conducted a retrospective cohort study on nationwide registry data to describe incidences of T1D and comorbidities in adults (≥21 years) from 1996 to 2018. People were followed from T1D diagnosis until a first event of interest, death, or end of follow-up, whichever came first. Cox proportional hazards models were used to quantify the associations between SES and development of comorbidities. Results: We included 7877 adults with T1D. Overall, the incidence of T1D decreased (411 in 1996 to 191 in 2018) while it increased for comorbidities in addition to T1D (< 3 to 38 and 10 to 53). Low education and income, compared to higher counterparts, increased the risks of comorbidity by 55 % (HR 1.55, 95 % CI 1.36–1.77) and 82 % (HR 1.82, 95 % CI 1.60–2.06), respectively. Conclusions: Low SES increases the risk of comorbidities in adults with T1D. This indicates that SES is an important factor to consider when aiming to prevent or predict development of comorbidities in adults with T1D.

Aims of the studyPercutaneous coronary intervention (PCI) exposes operators to ionizing radiation. Robotic-assisted PCI (RA-PCI) is a novel technology that enables interventional cardiologists to operate coronary devices remotely from a radiation-shed cockpit. The aim of this study is to describe the experience and challenges during the initiation of a RA-PCI program and to report outcomes of the first 21 patients undergoing RA-PCI in Switzerland.MethodsAll patients undergoing RA-PCI using the CorPath GRX Vascular Robotic System between 06/2021 and 12/2021 at Inselspital, Bern University Hospital were included in this retrospective registry study. Baseline, procedural and clinical follow-up data were prospectively assessed as part of the Cardiobase Bern PCI registry (NCT02241291). The two endpoints of interest were clinical success [defined as

Here, the authors observe tightly bound, valley-polarized, UV-emissive trions in monolayer transition metal dichalcogenide transistors. These are 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.

Abstract Background Venous leg ulcers (VLU) have a prevalence of 1–2% in developed countries, and affected patients are severely and long-term impaired in daily activities, work, and social participation. Evidence-based outpatient treatment based on compression therapy is frequently not implemented. The “Ulcus Cruris Care” project was established to develop a disease management concept to improve outpatient treatment for patients with VLU in German primary care. For this purpose, a multifaceted intervention was conceived consisting of an online training for general practitioners and medical assistants, standardized treatment recommendations, e-learning and print-based information for patients, and a software support for case management. The main aims of the Ulcus Cruris Care intervention are to promote standardized treatment according to current scientific knowledge, to facilitate case management for VLU patients exerted by medical assistants, and to support patient education and participation in the treatment process. The UCC trial was designed to evaluate the effectiveness of the Ulcus Cruris Care intervention. Methods The UCC trial is a prospective cluster-randomized controlled multicenter trial. Fifty GP practices are intended to be recruited and randomized 1:1 to intervention or control arm. Patients with venous leg ulcers will be recruited by participating GP practices, to include a total of 63 patients in each arm. The primary outcome is time to ulcer healing. Secondary outcomes comprise number and sizes of ulcers, recurrence, pain intensity according to the visual analog scale, health-related quality of life according to EQ-5D-5L, depressiveness according to Patient Health Questionnaire (PHQ-9), patient satisfaction according to the Patient Assessment of Chronic Illness Care (PACIC-5A) query, and adherence to VLU treatment. The outcome analysis of the UCC trial is accompanied by a health economic analysis and a process evaluation. Discussion The UCC trial will evaluate whether the Ulcus Cruris Care intervention may lead to faster wound healing, higher health-related quality of life, and lower use of medical resources. If the intervention turns out to have a positive impact on assessed outcomes, comprehensive implementation in primary care may be considered. Trial registration The trial protocol (version 1 as of July 19, 2021) has been registered in the German Clinical Trials Register on August 30, 2021 ( DRKS00026126 ).

Abstract Atherosclerosis and its consequences cause considerable morbidity and mortality world-wide. We have previously shown that expression of the DNA glycosylase NEIL3 is regulated in human atherosclerotic plaques, and that NEIL3-deficiency enhances atherogenesis in Apoe −/− mice. Herein, we identified a time point prior to quantifiable differences in atherosclerosis between Apoe −/− Neil3 −/− mice and Apoe −/− mice. Mice at this age were selected to explore the metabolic and pathophysiological processes preceding extensive atherogenesis in NEIL3-deficient mice. Untargeted metabolomic analysis of young Apoe −/− Neil3 −/− mice revealed significant metabolic disturbances as compared to mice expressing NEIL3, particularly in metabolites dependent on the gut microbiota. 16S rRNA gene sequencing of fecal bacterial DNA indeed confirmed that the NEIL3-deficient mice had altered gut microbiota, as well as increased circulating levels of the bacterially derived molecule LPS. The mice were challenged with a FITC-conjugated dextran to explore gut permeability, which was significantly increased in the NEIL3-deficient mice. Further, immunohistochemistry showed increased levels of the proliferation marker Ki67 in the colonic epithelium of NEIL3-deficient mice, suggesting increased proliferation of intestinal cells and gut leakage. We suggest that these metabolic alterations serve as drivers of atherosclerosis in NEIL3-deficient mice.

ADP-ribosylation is regulated by HPF1 and ARH3, but the cellular target spectrum of these enzymes is not fully understood. Here, the authors use quantitative proteomics to define the HPF1- and ARH3-dependent ADP-ribosylome, providing evidence that mono-ADP-ribosylation of serine predominates in cells.

Here, the authors report on evidence of an excitonic species formed by electrons in high-energy conduction band states with a negative effective mass, explaining previous observations of quantum interference phenomena in two-dimensional semiconductors.

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.

Abstract Background A pan-European approach to evaluate policy impact on health behaviour requires the employment of a consensus set of established and relevant indicators. Methods As part of the Joint Programming Initiative on a Healthy Diet for a Healthy Life, the Policy Evaluation Network PEN identified key indicators of health behaviours and their determinants. These key indicators are already, or have the potential to be, adopted by large European Union surveillance systems for the assessment of policy impact. The iterative selection process included consultations in two rounds via email prior to a 2-days expert workshop. The experts collated a list of dietary behaviour, physical activity and sedentary behaviour indicators for European policy monitoring in young and adult populations based on existing frameworks and literature reviews. The expert panel was composed of researchers, policy makers and representatives of major European surveillance systems and related initiatives, as well as, representatives of organisations providing monitoring data, such as the European Commission and Eurostat. Results The process provided two lists of key indicators including 37 diet ‘policy’ indicators and 35 indicators for dietary behaviour and their ‘determinants’; as well as 32 physical activity ‘policy’ indicators and 35 indicators for physical activity, sedentary behaviour and their ‘determinants’. Conclusion A total of 139 key indicators related to the individual, the setting and the population level, and suitable for the assessment of dietary behaviour, physical activity and sedentary behaviour were prioritised by policy makers and researchers with the ultimate aim to embed policy evaluation measures in existing surveillance systems across the European Union. In a next step, data sources and suitable instruments will be identified to assess these key indicators.

Objectives We aimed to assess general practice (GP) trainees’ self-perception of surgical competencies and to explore longitudinal effects of a compact intervention.Design We 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.Setting In 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).Participants All enrolled GP trainees were offered participation. GP trainees who did not attend a seminar (non-attendees) were recruited for CG after the 13th intervention.Intervention Attendees 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.Results 326 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.Conclusions A 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.

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.

Background: Strategies for managing respiratory motion, specifically motion-encompassing methods, in radiation therapy typically assume reproducible breathing. In reality, respiratory motion variations occur and ultimately cause tumor motion variations, which can result in differences between the planned and delivered dose distributions. Therefore, breathing guidance techniques have been investigated to improve respiratory reproducibility. To our knowledge, bilevel positive airway pressure (BIPAP) ventilation assistance has not been previously investigated as a technique for improving respiratory reproducibility and is the focus of this work. Methods and Materials: Ten patients undergoing radiation therapy treatment for cancers affected by respiratory motion (eg, lung and esophagus) participated in sessions in which their breathing was recorded during their course of treatment; these sessions occurred either before or after radiation treatments. Both unassisted free-breathing (FB) and BIPAP ventilation-assisted respiratory volume data were collected from each patient using spirometry. Patients used 2 different BIPAP ventilators (fixed BIPAP and flexible BIPAP), each configured to deliver the same volume of air per breath (ie, tidal volume). The flexible BIPAP ventilator permitted patient triggering (ie, it permitted patients to initiate each breath), and the fixed BIPAP did not. Intrasession and intersession metrics quantifying tidal volume variations were calculated and compared between the specific breathing platforms (FB or BIPAP). In addition, patient tolerance of both BIPAP ventilators was qualitatively assessed through verbal feedback. Results: Both BIPAP ventilators were tolerated by patients, although the fixed BIPAP was not as well tolerated as the flexible BIPAP. Both BIPAP ventilators showed significant reductions (P < .05) in intrasession tidal volume variation compared with FB. However, only the fixed BIPAP significantly reduced the intersession tidal volume variation compared with FB. Conclusions: Based on the established correlation between tidal volume and tumor motion, any reduction of the tidal volume variation could result in reduced tumor motion variation. Fixed BIPAP ventilation was found to be tolerated by patients and was shown to significantly reduce intrasession and intersession tidal volume variations compared with FB. Therefore, future investigation into the potential of fixed BIPAP ventilation is warranted to define the possible clinical benefits.

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.

Head and neck squamous cell carcinomas (HNSCC) caused by infections with high-risk human papillomaviruses (HPV) are responsible for an increasing number of head and neck cancers, particularly in the oropharynx. Despite the significant biological differences between HPV-driven and HPV-negative HNSCC, treatment strategies are similar and not HPV targeted. HPV-driven HNSCC are known to be more sensitive to treatment, particularly to radiotherapy, which is at least partially due to HPV-induced immunogenicity. The development of novel therapeutic strategies that are specific for HPV-driven cancers requires tumor models that reflect as closely as possible the characteristics and complexity of human tumors and their response to treatment. Current HPV-positive cancer models lack one or more hallmarks of their human counterpart. This study presents the development of a new HPV16 oncoprotein-dependent tumor model in MHC-humanized mice, modeling the major biologic features of HPV-driven tumors and presenting HLA-A2-restricted HPV16 epitopes. Furthermore, this model was developed to be orthotopic (base of tongue). Thus, it also reflects the correct tumor microenvironment of HPV-driven HNSCC. The cancer cells are implanted in a manner that allows the exact control of the anatomical location of the developing tumor, thereby homogenizing tumor growth. In conclusion, the new model is suited to study HPV16-specific therapeutic vaccinations and other immunotherapies, as well as tumor-targeted interventions, such as surgery or radiotherapy, or a combination of all these modalities.

We report an experimental study of temperature-dependent spectral line shapes of phonon sideband emission stemming from dark excitons in monolayer and bilayer WSe_{2}. Using photoluminescence spectroscopy in the range from 4 to 100 K, we observe a pronounced asymmetry in the phonon-assisted luminescence from momentum-indirect exciton reservoirs. We demonstrate that the corresponding spectral profiles are distinct from those of bright excitons with direct radiative decay pathways. The line-shape asymmetry reflects thermal distribution of exciton states with finite center-of-mass momenta, characteristic for phonon sideband emission. The extracted temperature of the exciton reservoirs is found to generally follow that of the crystal lattice, with deviations reflecting overheated populations. The latter are most pronounced in the bilayer case and at lowest temperatures. Our results add to the understanding of phonon-assisted recombination of momentum-dark excitons and, more generally, establish means to access the thermal distribution of finite-momentum excitons in atomically thin semiconductors with indirect band gaps.

This article examines educational differences in the prevalence of behavioural risk factors among adults and compares the results for Germany with the average from the European Union (EU). Data were derived from the second wave of the European Health Interview Survey, which took place between 2013 and 2015 (EHIS 2). Analyses were conducted using a regression-based calculation of relative and absolute educational differences in the prevalence of behavioural risk factors, based on self-reported data from women and men aged between 25 and 69 (n=217,215). Current smoking, obesity, physical activity lasting less than 150 minutes per week, heavy episodic drinking and non-daily fruit or vegetable intake are more prevalent among people with a low education level than those with a high education level. This applies to Germany as well as the EU average. Overall, the relative educational differences identified for these risk factors place Germany in the mid-range compared to the EU average. However, relative educational differences in current smoking and heavy episodic drinking are more manifest among women in Germany than the EU average, with the same applying to low physical activity among men. In contrast, relative educational differences in non-daily fruit or vegetable intake are less pronounced among women and men in Germany than the average across the EU. Increased efforts are needed in various policy fields to improve the structural conditions underlying health behaviour, particularly for socially disadvantaged groups, and increase health equity.

The scientific assessment of health issues, the design and further development of political guidelines as well as the targeted planning of measures in the European Union (EU) require data on population health. For this reason, all EU Member States regularly collect data on the health status, provision of healthcare, health determinants and socioeconomic situation of their respective populations in the European Health Interview Survey (EHIS). Participants are at least 15 years old and live in private households. The second wave of EHIS (EHIS 2) was conducted between 2013 and 2015. For EHIS 2, each EU Member State drew a nationally representative population sample from population registers, censuses, dwelling registers or other statistical or administrative sources. Data collection modes within individual EU Member States were used, according to nationally established methods, including the use of mixed-mode surveys. Across all EU Member States, data collection took an average of eight months to complete. Member States made considerable efforts to achieve the highest possible response rates. The harmonised EHIS data collected are highly comparable and constitute an important information base for European health policy and health reporting.

Objective: Despite extensive study of the obesity epidemic, research on whether obesity has risen faster in lower or in higher socioeconomic groups is inconsistent. This study examined secular trends in obesity prevalence by socioeconomic position and the resulting obesity inequalities in the German adult population. Methods: Data were drawn from three national examination surveys conducted in 1990–1992, 1997–1999 and 2008–2011 (n = 18,541; age range: 25–69 years). Obesity was defined by a body mass index ≥30 kg/m2 using standardised measurements of body height and weight. Education and equivalised household disposable income were used as indicators of socioeconomic position. Time trends in socioeconomic inequalities in obesity were examined using linear probability and log-binomial regression models. Results: In each survey period, the highest socioeconomic groups had the lowest prevalence of obesity. The low and medium socioeconomic groups showed increases in obesity prevalence, whereas no such trend was observed in the high socioeconomic groups. Absolute inequalities in obesity by income increased by an average of 0.53 percentage points per year (95% confidence interval [CI] 0.01–1.05, p = 0.047) among men and 0.47 percentage points per year (95% CI 0.05–0.90, p = 0.029) among women. Absolute inequalities in obesity by education increased on average by 0.64 percentage points per year (95% CI 0.19–1.08, p = 0.005) among women but not among men (0.33 percentage points, 95% CI –0.27 to 0.92, p = 0.283). Conclusions: These findings suggest a widening obesity gap between the top and the bottom of the socioeconomic spectrum. This has the potential to have adverse consequences for population health and health inequalities in coming decades. Interventions that are effective in preventing and reducing obesity in socially disadvantaged groups are needed.

Abstract Introduction Sublingual microcirculation monitoring is suitable for bedside use in critically ill patients. We present a case in which severely impaired sublingual microcirculation was the first alarming sign of an early deterioration of the patient’s medical situation. Case presentation This is the case of a 58-year-old white woman admitted to our intensive care unit after the removal of parts of her small intestine due to a volvulus. Her microcirculation was checked the day after surgery in terms of an ongoing study and predicted a massive deterioration of her clinical situation. Conclusions This case highlights the potential value of monitoring the microcirculation in critically ill patients. Two full hours could have been saved for diagnostic workup and earlier treatment had we considered the impaired microcirculation alone as a warning sign. Regardless of the supposed cause, impaired microcirculation should alert the responsible physician and should be followed by a diagnostic workup. Sublingual microcirculation monitoring can be useful in intensive care units to detect a deteriorated microcirculation earlier than with standard monitoring.

This study examines the extent to which health inequalities among children and adolescents in Germany have developed over the past decade. The analyses are based on data from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS), which are representative of the 0- to 17-year-old population in Germany. The KiGGS data were collected in three waves: the KiGGS baseline study (2003-2006), KiGGS Wave 1 (2009-2012) and KiGGS Wave 2 (2014-2017). Prevalences of five health outcomes are considered: general health, mental health problems, physical activity, the consumption of sugary soft drinks, and smoking. Moreover, it defines health inequalities in relation to differences in the socioeconomic status of the family (SES), an index derived from the parents’ level of education, occupation and income, and considers both absolute and relative health inequalities. In order to do so, the Slope Index of Inequality (SII) and the Relative Index of Inequality (RII) were calculated using linear probability or log-binomial models. Significant inequalities were identified to the detriment of young people from families with a low SES. These inequalities were particularly pronounced in the KiGGS Wave 2 data with regard to general health and the consumption of sugary soft drinks. Additionally, evidence from trend analyses for these two outcomes suggests that relative inequalities have increased. However, absolute inequalities decreased during the same period, and this also applies to smoking. The persistently high and, in some cases, widened levels of health inequalities indicate that adolescents from families with a low SES do not benefit to the same extent from disease prevention and health promotion measures for children and adolescents as young people from families with a higher SES.

The objective of this study was to identify odorous gases “fingerprint” and quantify odor throughout the production process of an oil refinery located in Rio Grande do Sul State, Brazil. The NH3 (ammonia), H2S/CH4S (hydrogen sulphide/methylmercaptan), SO2 (sulfur dioxide) and VOCs (volatile organic compounds) gases were measured during 14 consecutive days around emission sources and throughout the company's production process. The monitoring was performed on main stacks, tanks vent, production process and wastewater treatment station. To measure over the stacks, it was used a Drone DJI to suspend a set of integrated electrochemical sensors that analyze the air continuously. This system made it possible to record the emission from stacks at heights of up to 120 meters above ground level, which was previously impossible to accomplish. Cairpol’s electrochemical sensors were used to provide automatic and continuous measurement. This equipment records the measurements in ppb (part per billion) every minute and stores them in an internal data logger. The odorous gas analysis results showed that the largest sources of emissions are the industrial effluent treatment, which is responsible for the emission H2S/CH4S and VOCs and the emission from the oil-water separator is only of VOCs. The flare stack and the Sulfur Recovery Unit’s stack are the main emitters of H2S/CH4S and SO2. However, the coverage radius for the effluent treatment station and the oil-water separator is small due to the emission characteristics, as the emissions at ground level. The main sources of odor emission that can spread and annoy the neighborhood are the stacks as they presented the higher concentrations, henceforth their odor emission can be perceived from kilometers of distance.

The use of sol-gel materials can simplify the industrial fabrication of high-efficiency silicon solar cells if a suitable deposition method is established. In this work, we investigate the possibilities to adapt a borosilicate glass sol-gel to provide a stable screen printing process. This material has previously been used as a boron dopant source for silicon solar cells. We now use an adjusted synthesis process, with an increased gelling time and different additives. This changes the rheological properties (i.e., the elastic and viscous moduli G′ and G″) in a way that avoids the dripping of paste through the screen and that stabilizes the material transfer in subsequent printing steps. Using this synthesis process, we were able to show a printing process with long-term stability of more than 500 prints. When comparing the adjusted to the initial paste, we show that, after thermal treatment, the obtained thin films are very similar in terms of their constitution, with a refractive index between n = 1.47 (initial) and n = 1.55 (adjusted). We also show that they provide the same amount of doping under the tested conditions (950 °C, 30 min), resulting in sheet resistances of R□ = (42.5 ± 2.6) Ω/□ (initial) and R□ = (46.4 ± 3.6) Ω/□ (adjusted).

The world is currently dealing with a devastating pandemic. Although growing COVID-19 case numbers, deaths, and hospitalizations are concerning, this spread is particularly alarming in the United States where polarizing opinions, changing policies, and misinformation abound. In particular, American college campuses have been a venue of rampant transmission, with concerning spillover into surrounding, more vulnerable, communities. We surveyed over 600 college students from across the United States and modeled predictors of compliance with non-pharmaceutical interventions. We identified concern with severity, constitutionalism, news exposure, and religiosity as significant positive correlates with compliance, and general trust in science as a significant negative correlate. To determine how applicable nationwide modeling might be to individual local campuses we also administered this same survey to nearly 600 students at two large universities in Utah County. In this population, concern with severity was the only significant positive correlate with compliance; Additionally, feelings of inconvenience were negatively correlated. The effects of feelings of inconvenience, and news exposure were significantly different between populations. These results suggest that we should focus our efforts on increasing knowledge about the pandemic's effects on our society and informing about constitutionality amongst college students. However, we also show that nationwide surveys and modeling are informative, but if campuses are to efficiently curb the spread of COVID-19 this coming semester, they would be best served to utilize data collected from their student populations as these might significantly differ from general consensus data.

Prosthetic joint infection (PJI) is a devastating complication after a joint replacement. PJI and its treatment have a high monetary cost, morbidity, and mortality. The lack of success treating PJI with conventional antibiotics alone is related to the presence of bacterial biofilm on medical implants. Consequently, surgical removal of the implant and prolonged intravenous antibiotics to eradicate the infection are necessary prior to re-implanting a new prosthetic joint. Growing clinical data shows that bacterial predators, called bacteriophages (phages), could be an alternative treatment strategy or prophylactic approach for PJI. Phages could further be exploited to degrade biofilms, making bacteria more susceptible to antibiotics and enabling potential combinatorial therapies. Emerging research suggests that phages may also directly interact with the innate immune response. Phage therapy may play an important, and currently understudied, role in the clearance of PJI, and has the potential to treat thousands of patients who would either have to undergo revision surgery to attempt to clear an infections, take antibiotics for a prolonged period to try and suppress the re-emerging infection, or potentially risk losing a limb.

Objectives This study aimed to investigate associations between occupational physical activity patterns (physical work demands linked to job title) and leisure time physical activity (assessed by questionnaire) with cardiorespiratory fitness (assessed by exercise test) among men and women in the German working population.Design Population-based cross-sectional study.Setting Two-stage cluster-randomised general population sample selected from population registries of 180 nationally distributed sample points. Information was collected from 2008 to 2011.Participants 1296 women and 1199 men aged 18–64 from the resident working population.Outcome measure Estimated low maximal oxygen consumption (V˙O2max), defined as first and second sex-specific quintile, assessed by a standardised, submaximal cycle ergometer test.Results Low estimated V˙O2max was strongly linked to low leisure time physical activity, but not occupational physical activity. The association of domain-specific physical activity patterns with low V˙O2max varied by sex: women doing no leisure time physical activity with high occupational physical activity levels were more likely to have low V˙O2max (OR 6.54; 95% CI 2.98 to 14.3) compared with women with ≥2 hours of leisure time physical activity and high occupational physical activity. Men with no leisure time physical activity and low occupational physical activity had the highest odds of low V˙O2max (OR 4.37; 95% CI 2.02 to 9.47).Conclusion There was a strong association between patterns of leisure time and occupational physical activity and cardiorespiratory fitness within the adult working population in Germany. Women doing no leisure time physical activity were likely to have poor cardiorespiratory fitness, especially if they worked in physically demanding jobs. However, further investigation is needed to understand the relationships between activity and fitness in different domains. Current guidelines do not distinguish between activity during work and leisure time, so specifying leisure time recommendations by occupational physical activity level should be considered.

Abstract Background This review aims to (1) consolidate evidence regarding the association between socioeconomic status (SES) and cardiorespiratory fitness (CRF), (2) conduct a meta-analysis of the association between SES and CRF using methodologically comparable data, stratified by sex, and (3) test whether the association varies after adjustment for physical activity (PA). Methods A systematic review of studies from MEDLINE, EMBASE, Latin American and Caribbean Health Sciences (LILACS), Scientific Electronic Library Online (ScIELO), and Cochrane Library without time or language restrictions, which investigated associations between SES and CRF. Risk of bias within studies was assessed using a customized quality assessment tool. Results were summarized in table format and methodologically similar studies were synthesized using meta-analysis of Hedges’ g effect sizes. Synthesized results were appraised for cross-study bias. Results were tested for the impact of PA adjustment using meta-regression. Results Compared to individuals with low education, both men and women showed higher CRF among individuals with high education (men 0.12 [0.04–0.20], women 0.19 [0.02–0.36]), while participants with medium education showed no significant difference in CRF (men 0.03 [− 0.04–0.11], women 0.09 [− 0.03–0.21]). Adjustment for PA did not significantly impact the association between education and CRF. Conclusions There is fair evidence for an association between high levels of education and increased CRF. This could have implications for monitoring, of health target compliance and of chronic disease risk among higher risk populations, to detect and prevent non-communicable diseases (NCDs) and to diminish social health inequalities. Trial Registration PROSPERO, CRD42017055456

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.

This article focuses on selected indicators related to sports and dietary behaviour – two important factors that influence the development of obesity. The analyses are based on data collected for the second wave of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS Wave 2), which was conducted between 2014 and 2017. These data were collected, using a questionnaire, from 6,810 girls and 6,758 boys aged between 3 and 17. The analyses also compare the data collected for wave 2 with those from the KiGGS baseline study (2003-2006). More than 70% of 3- to 17-year-olds state that they participated in sports. However, boys do so significantly more often than girls, and 11- to 17-year-olds do so more frequently than 3- to 10-year-olds. In addition, there is a correlation between children’s and adolescents’ sports participation and those of their parents, and with an activity-friendly living environment. Younger children and girls have healthier diets than older children and boys. However, although the consumption of confectionery and sugary drinks by 3- to 17-year-olds has declined significantly since the KiGGS baseline study was conducted, 11- to 17-year-olds, in particular, eat significantly smaller amounts of vegetables than they did about ten years ago. Significantly more 3- to 10-year-olds currently eat at least five servings of fruit and vegetables per day than ten years ago, although the proportion of the children who reach this recommendation continues to remain very low at 14% overall. It is important to set an example by following a healthy lifestyle within families and other settings in early life. Furthermore, the living environments also need to be made more health-oriented to support children and adolescents in reaching the national recommendations on physical activity and healthy eating.

Self-reported data from wave 2 of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS Wave 2, 2014-2017) provides the basis for assessing whether the levels of physical activity of children and adolescents in Germany meet the levels recommended by the World Health Organization (WHO). Merely 22.4% of girls and 29.4% of boys in the 3-17 age group are physically active for at least 60 minutes per day and therefore meet the WHO recommendations. Prevalence of recommended levels of physical activity decreases continuously with age, both for girls and boys. In KiGGS Wave 2, girls in the 3-10 age group met the levels of physical activity recommended by the World Health Organization significantly less often than in KiGGS Wave 1. Low levels of physical activity were highest amongst adolescent age girls, as well as among boys and girls of low socioeconomic status. The results indicate a great potential to promote physical activity.

Abstract The ability of bacteriophages to kill bacteria is well known, as is their potential use as alternatives to antibiotics. As such, bacteriophages reach high doses locally through infection of their bacterial host in the human body. In this study we assessed the gene expression profile of peripheral blood monocytes from six donors for twelve immunity-related genes (i.e. CD14, CXCL1, CXCL5, IL1A, IL1B, IL1RN, IL6, IL10, LYZ, SOCS3, TGFBI and TNFA) induced by Staphylococcus aureus phage ISP and four Pseudomonas aeruginosa phages (i.e. PNM, LUZ19, 14-1 and GE-vB_Pae-Kakheti25). The phages were able to induce clear and reproducible immune responses. Moreover, the overall immune response was very comparable for all five phages: down-regulation of LYZ and TGFBI, and up-regulation of CXCL1, CXCL5, IL1A, IL1B, IL1RN, IL6, SOCS3 and TNFA. The observed immune response was shown to be endotoxin-independent and predominantly anti-inflammatory. Addition of endotoxins to the highly purified phages did not cause an immune response comparable to the one induced by the (endotoxin containing) phage lysate. In addition, the use of an intermediate level of endotoxins tipped the immune response to a more anti-inflammatory response, i.e. up-regulation of IL1RN and a strongly reduced expression of CXCL1 and CXCL5.

Abstract Background Social inequalities in health can be explained in part by the social patterning of leisure-time physical activity, such as non-participation in sports. This study is the first to explore whether absolute and relative educational inequalities in sporting inactivity among adults have changed in Germany since the early 2000s. Methods Data from four cross-sectional national health surveys conducted in 2003 (n = 6890), 2009 (n = 16,418), 2010 (n = 17,145) and 2012 (n = 13,744) were analysed. The study population was aged 25–69 years in each survey. Sporting inactivity was defined as no sports participation during the preceding 3 months. The regression-based Slope Index of Inequality (SII) and Relative Index of Inequality (RII) were calculated to estimate the extent of absolute and relative educational inequalities in sporting inactivity, respectively. Results Sporting inactivity was consistently more prevalent in less-educated groups. The overall prevalence of sporting inactivity declined significantly over time. However, the decline was observed only in the high and medium education groups, while no change was observed in the low education group. Both absolute and relative educational inequalities in sporting inactivity were found to have widened significantly between 2003 (SII = 0.30, 95% CI = 0.25–0.35; RII = 2.08, 95% CI = 1.83–2.38) and 2012 (SII = 0.41, 95% CI = 0.37–0.45; RII = 3.44, 95% CI = 3.03–3.91). Interaction analysis showed that these increases in inequalities were larger in the younger population under the age of 50 than among the elderly. Conclusions The findings suggest that the gap in sports participation between adults with high and low educational attainment has widened in both absolute and relative terms because of an increase in sports participation among the better educated. Health-enhancing physical activity interventions specifically targeted to less-educated younger adults are needed to prevent future increases in social inequalities in health.

Demographic change, new health threats, but also inequalities in health and health care provision in and between European Union (EU) member states pose major albeit similar challenges to European health systems. Regular information on health and health-related behaviour is essential if member states’ health systems are to respond and develop appropriately to these challenges. The ‘European Health Interview Survey’ (EHIS) is a vital source of data for indicators of health status and health-related behaviour in the EU. This article presents a comparative review of health-related behaviour at the European level. Health-related behaviour is of particular relevance because an unhealthy diet, physical inactivity, obesity, smoking, and harmful use of alcohol are among the most important determinants associated with non-communicable chronic diseases. Eurostat has used data from EHIS Wave 2 to publish details about the current prevalence of obesity, daily fruit and vegetable intake, health-enhancing aerobic physical activity, smoking and heavy episodic drinking for the EU’s member states. In the following, the figures for Germany are compared to the European average. A wide range of prevalences exists between the various EU member states, in some cases stretching to more than 50 percentage points. In Germany, the prevalence of obesity and smoking remains relatively close to the EU average. Moreover, the results on physical activity are especially welcome. In particular, the proportion of women and men who undertake adequate levels of physical activity decreases more slowly with increasing age compared to the EU average. Nevertheless, the low fruit and vegetable intake, especially among younger generations, and the high proportion of women and men who drink six or more alcoholic beverages on one occasion (heavy episodic drinking) at least once a month pose problems for Germany. In summary, the results provided by EHIS offer a basis for sharing experiences between EU member states regarding effective measures in health promotion and disease prevention.

Self-reported data from the GEDA 2014/2015-EHIS study was used to calculate the level of compliance among adults in Germany with the World Health Organization’s (WHO) recommendations on physical activity. The WHO’s recommendations distinguish between ‘aerobic activity’ and ‘muscle-strengthening activity’. In Germany, 42.6% of women and 48.0% of men reported that they conduct at least 2.5 hours of aerobic physical activity per week, and therefore meet the WHO’s recommendation on this form of activity. A higher level of education among women and men of all ages is associated with a higher frequency of meeting the WHO’s recommendations on aerobic activity. In addition, 27.6% of women and 31.2% of men conduct muscle-strengthening activity at least twice a week, thereby meeting the WHO’s recommendations on this form of activity. About one fifth of women (20.5%) and one quarter of men in Germany (24.7%) meet both of these recommendations. In summary, the results point to the value of encouraging people to conduct more physical activity during their leisure time. In fact, inactive people who begin to follow the WHO’s recommendations can significantly reduce their long-term risk of premature mortality.

In GEDA 2014/2015-EHIS the prevalence of work-related physical activity was estimated based on respondents’ self-reported data. 47.5% of women and 47.2% of men mostly sit or stand during work. The highest proportion of people who mostly sit or stand during work is found among 18- to 29-year-old women (55.5%) and men aged 30 to 44 (50.2%). A significantly higher proportion of men (14.8%) than women (3.2%) have jobs involving mostly heavy manual labour. For both genders, the higher a person’s level of education, the more likely it is that physical activity during work is limited to sitting or standing. The results highlight great potential to promote physical activity.

GEDA 2014/2015-EHIS is an up-to-date health survey of the adult population undertaken within the framework of the Robert Koch Institute’s (RKI) health monitoring system. It uses the EHIS (European Health Interview Survey) Wave 2 questionnaire and includes four modules covering health status, health care, health determinants, and socio-economic variables. Data on nationally relevant issues is also collected. The study employs a mixed-mode design, using both online and paper-based questionnaires to gather data from 24,016 people aged 18 and above: the response rate was 26.9%. The Statistical Office of the European Union (Eurostat) provides prepared data from 28 European Union (EU) member states (plus Norway and Iceland) on the Eurostat website. National analyses for Germany are published as Fact sheets on health reporting in the Journal of Health Monitoring.

Pf bacteriophage are temperate phages that infect the bacterium Pseudomonas aeruginosa, a major cause of chronic lung infections in cystic fibrosis (CF) and other settings. Pf and other temperate phages have evolved complex, mutualistic relationships with their bacterial hosts that impact both bacterial phenotypes and chronic infection. We and others have reported that Pf phages are a virulence factor that promote the pathogenesis of P. aeruginosa infections in animal models and are associated with worse skin and lung infections in humans. Here we review the biology of Pf phage and what is known about its contributions to pathogenesis and clinical disease. First, we review the structure, genetics, and epidemiology of Pf phage. Next, we address the diverse and surprising ways that Pf phages contribute to P. aeruginosa phenotypes including effects on biofilm formation, antibiotic resistance, and motility. Then, we cover data indicating that Pf phages suppress mammalian immunity at sites of bacterial infection. Finally, we discuss recent literature implicating Pf in chronic P. aeruginosa infections in CF and other settings. Together, these reports suggest that Pf bacteriophage have direct effects on P. aeruginosa infections and that temperate phages are an exciting frontier in microbiology, immunology, and human health.

The heparan sulfate mimetic PG545 (pixatimod) is under evaluation as an inhibitor of angiogenesis and metastasis including in human clinical trials. We have examined the effects of PG545 on lymphocyte phenotypes and function. We report that PG545 treatment suppresses effector T cell activation and polarizes T cells away from Th17 and Th1 and toward Foxp3+ regulatory T cell subsets in vitro and in vivo. Mechanistically, PG545 inhibits Erk1/2 signaling, a pathway known to affect both T cell activation and subset polarization. Interestingly, these effects are also observed in heparanase-deficient T cells, indicating that PG545 has effects that are independent of its role in heparanase inhibition. Consistent with these findings, administration of PG545 in a Th1/Th17-dependent mouse model of a delayed-type hypersensitivity led to reduced footpad inflammation, reduced Th17 memory cells, and an increase in FoxP3+ Treg proliferation. PG545 also promoted Foxp3+ Treg induction by human T cells. Finally, we examined the effects of other heparan sulfate mimetics PI-88 and PG562 on lymphocyte polarization and found that these likewise induced Foxp3+ Treg in vitro but did not reduce Th17 numbers or improve delayed-type hypersensitivity in this model. Together, these data indicate that PG545 is a potent inhibitor of Th1/Th17 effector functions and inducer of FoxP3+ Treg. These findings may inform the adaptation of PG545 for clinical applications including in inflammatory pathologies associated with type IV hypersensitivity responses.