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Abstract Aims Diuretic resistance (i.e., insufficient diuretic and natriuretic response to an appropriate dose of intravenously administered loop diuretic) is a major cause of insufficient decongestion in acute heart failure (AHF). Early assessment of diuretic and natriuretic response already after the first administration of loop diuretic is currently recommended, but few data exist on the prevalence and characteristics of upfront diuretic resistance in AHF. The aim of this sub‐study of the P‐Value‐AHF randomized clinical trial was to investigate the prevalence and characteristics of upfront diuretic resistance in patients presenting with AHF in the emergency department (ED). Methods Consecutive patients presenting with a clinical diagnosis of AHF, ≥1 sign of congestion, and NT‐proBNP >1000 ng/L between February and June 2024 were prospectively screened. Loop diuretics were administered per protocol: 40 mg furosemide i.v. in diuretic‐naïve patients and those on oral torasemide

Objective: To examine social connection as a protective factor against exam stress. Participants: 55 undergraduate students at two universities. Methods: Students were evaluated on an exam day for their hardest class and at baseline, a day in a week where they had no exams. Social connection, salivary cortisol, perceived stress, and cognitive control (measured with the Stroop test) were assessed. Exam scores were later reported. Results: Higher social connection was associated with lower perceived stress on exam day. At a small liberal arts school, higher levels of social connection were associated with higher Stroop scores. This correlation with cognitive control was not significant at a large public university. Conclusions: These findings indicate that social connection may be a protective factor in mitigating perceived stress and cognitive control capabilities may help facilitate reduced exam stress in some school environments.

Abstract Particle‐fluid separation by settling is a ubiquitous process in Earth and Planetary Sciences. The settling velocity of particles is controlled by a balance between buoyancy and drag forces. Since the seminal work of George Gabriel Stokes, parameterizations for the reduction of particle velocities caused by viscous dissipation due to mutual interactions have been described by a non‐linear mapping between particle volume fraction and separation velocity. We argue that these parameterizations neglect important physical behavior at high particle volume fractions (>80% of the maximum packing) and are only appropriate when considering suspensions where the particle volume fraction does not evolve in space or time. We introduce a more general model that accounts for the energy dissipation caused by changes in local particle volume fraction, which introduces a new term similar to the compaction term at higher particle volume fraction. This term depends on a consolidation/compaction viscosity that measures the resistance to changes in solid volume fraction. We derive closure equations for this compaction viscosity under dilute and concentrated particle volume fraction limits. Numerical simulations show that the extended hindered settling model predicts two significant differences compared to traditional hindered settling. First, while the steepening of particle volume fraction fronts remains, a dynamic instability is also generated at the front. Second, the rate of growth and structure of a cumulate layer growing above a no‐flux boundary is affected by the compaction‐like term and predicts the trapping of a higher volume fraction of interstitial melt in a correspondingly thicker cumulate layer.

Abstract Volcanic activity has been shown to affect Earth's climate in a myriad of ways. One such example is that eruptions proximate to surface ice will promote ice melting. In turn, the crustal unloading associated with melting an ice sheet affects the internal dynamics of the underlying magma plumbing system. Geochronologic data from the Andes over the last two glacial cycles suggest that glaciation and volcanism may interact via a positive feedback loop. At present, accurate sea‐level predictions hinge on our ability to forecast the stability of the West Antarctic Ice Sheet, and thus require consideration of two‐way subglacial volcano‐deglaciation processes. The West Antarctic Ice Sheet is particularly vulnerable to collapse, yet its position atop an active volcanic rift is seldom considered. Ice unloading deepens the zone of melting and alters the crustal stress field, impacting conditions for dike initiation, propagation, and arrest. However, the consequences for internal magma chamber dynamics and long‐term eruption behavior remain elusive. Given that unloading‐triggered volcanism in West Antarctica may contribute to the uncertainty of ice loss projections, we adapt a previously published thermomechanical magma chamber model and simulate a shrinking ice load through a prescribed lithostatic pressure decrease. We investigate the impacts of varying unloading scenarios on magma volatile partitioning and eruptive trajectory. Considering the removal of km‐thick ice sheets, we demonstrate that the rate of unloading influences the cumulative mass erupted and consequently the heat released into the ice. These findings provide fundamental insights into the complex volcano‐ice interactions in West Antarctica and other subglacial volcanic settings.

Background/Objectives: Zika virus (ZIKV) infection is associated with life-threatening diseases in humans. To date, there are no available FDA-approved therapies or vaccines for the specific treatment or prevention of ZIKV infection. Variation in the ZIKV envelope protein (Env), along with its complex quaternary structure, presents challenges to synthetic approaches for developing an effective vaccine and broadly neutralizing antibodies (bnAbs). We hypothesized that beta-cyclodextrin (BCD) could be used to uniquely inactivate infectious ZIKV without disruption of Env. Methods: ZIKV was propagated in Vero cells and admixed with BCD. The BCD-treated ZIKV was evaluated for infectivity using immunofluorescence and quantitative RT-PCR (qRT-PCR) assays, for immunoreactivity in Western blots, structural integrity by electron microscopy, and immunogenicity in mice. Results: Here, we show that 200 mM BCD-treated ZIKV is non-infectious in cell culture, remains immunoreactive with an Env-specific antibody, retains its virion shape and size, and elicits the production of immunogen-specific antibodies in immunized mice. Conclusions: These results indicate that BCD can be used to safely inactivate ZIKV, and they provide insights for vaccine and antibody development.

Abstract Background Cricothyrotomy is an invasive and rare emergency intervention to secure the airway in a “cannot intubate, cannot ventilate” situation. This leads to lack of routine. Cricothyrotomy is performed only hesitantly. Therefore, we aim to improve teaching by including a virtual reality (VR) cricothyrotomy as a learning tool. Methods We programmed the VR cricothyrotomy in the C# programming language on the open-source Unity platform. We could include 149 students that we randomly assigned to either a study group (VR cricothyrotomy) or control group (educational video). We asked the study group to subjectively rate the VR cricothyrotomy. To evaluate our intervention (VR cricothyrotomy) we took the time participants needed to perform a cricothyrotomy on a plastic model of a trachea and evaluated the correct procedural steps. Results The majority of students that performed the VR simulation agreed that they improved in speed (81%) and procedural steps (92%). All participants completed the cricothyrotomy in 47s ± 16s and reached a total score of 8.7 ± 0.7 of 9 possible points. We saw no significant difference in time needed to perform a cricothyrotomy between study and control group (p > 0.05). However, the total score of correct procedural steps was significantly higher in the study group than in the control group (p

Aseptic abscess syndrome (AAS) is a medical rarity. The combination of multiple abscess collections in different organs, negative microbiological studies, and the association with an inflammatory bowel disease is highly suggestive for an AAS. The AAS is an acute neutrophilic dermatosis, so “generalized pyoderma gangraenosum” or “generalized bullous sweet syndrome” might be used synonymously. It is important to note that the diagnosis of an AAS can be made only after careful exclusion of an infectious disease. Of interest, despite the severity of the inflammation, patients with AAS are commonly hemodynamically stable. To date, no studies have investigated the optimal regimen, dose, and duration of therapy. Corticosteroids are the cornerstone of immunosuppression during the acute phase. After the induction phase, therapy might be switched to anakinra or infliximab.

ABSTRACTStreptococcus pyogenes (group A streptococcus; GAS) causes a variety of invasive diseases (iGAS) such as bacteremia, toxic shock syndrome, and pneumonia, which are associated with high mortality despite the susceptibility of the bacteria to penicillin ex vivo. Epidemiologic studies indicate that respiratory influenza virus infection is associated with an increase in the frequency of iGAS diseases, including those not directly involving the lung. We modified a murine model of influenza A (IAV)-GAS superinfection to determine if viral pneumonia increased the susceptibility of mice subsequently infected with GAS in the peritoneum. The results showed that respiratory IAV infection increased the morbidity (weight loss) of mice infected intraperitoneally (i.p.) with GAS 3, 5, and 10 d after the initial viral infection. Mortality was also significantly increased when mice were infected with GAS 3 and 5 d after pulmonary IAV infection. Increased mortality among mice infected with virus 5 d prior to bacterial infection correlated with increased dissemination of GAS from the peritoneum to the blood, spleen, and lungs. The interval was also associated with a significant increase in the pro-inflammatory cytokines IFN-γ, IL-12, TNF-α, MCP-1 and IL-27 in sera. We conclude, using a murine model, that respiratory influenza virus infection increases the likelihood and severity of systemic iGAS disease, even when GAS infection does not originate in the respiratory tract.

Introduction Approximately 30% of somatic hospital inpatients experience psychosocial distress, contributing to increased (re-)hospitalisation rates, treatment resistance, morbidity, and direct and indirect costs. However, such distress often remains unrecognised and unaddressed. We established ‘SomPsyNet’, a ‘stepped and collaborative care model’ (SCCM) for somatic hospital inpatients, aiming at alleviating this issue through early identification of distress and provision of appropriate care, providing problem-focused pathways and strengthening collaborative care. We report the protocol of the ‘SomPsyNet’ study, aiming to evaluate implementation and impact of the SCCM on distressed patients’ health-related quality of life. Secondary objectives include assessing efficacy of the screening procedures, influence of SCCM on other health outcomes and associated costs.Methods and analysis Our stepped wedge cluster randomised trial conducted at three tertiary hospitals comprises three conditions: treatment as usual (TAU) without screening for distress (phase 0), TAU with screening but without consequences (phase I, main comparator) and TAU with screening and psychosomatic-psychiatric consultations for those distressed (phase II). The time-of-transition between phases I and II was randomised. Sample size target is N=2200–2500 participants, with 6 month follow-up for distressed (anticipated n=640–700) and a subsample of non-distressed (anticipated n=200) patients. Primary outcome is mental health-related quality of life (SF-36 ‘Mental Health Component Summary score’); secondary outcomes include psychosocial distress, anxiety, depressive and somatic symptoms, symptom burden and distress, resilience, social support and qualitative of life, assessed by internationally accepted instruments, with good psychometric properties. Further, health claims data will be used to assess SCCM’s impact on direct and indirect costs.Ethics and dissemination SomPsyNet adheres to the Helsinki Declaration and is approved by the ‘Ethikkommission Nordwest- und Zentralschweiz’ (2019–01724). Findings will be published in peer-reviewed journals and communicated to participants, healthcare professionals and the public.Trial registration number Swiss National Clinical Trials Portal; ClinicalTrials.gov (NCT04269005, updated 19.09.2023).

BackgroundConestat alfa (ConA), a recombinant human C1 inhibitor, may prevent thromboinflammation.MethodsWe conducted a randomized, open-label, multi-national clinical trial in which hospitalized adults at risk for progression to severe COVID-19 were assigned in a 2:1 ratio to receive either 3 days of ConA plus standard of care (SOC) or SOC alone. Primary and secondary endpoints were day 7 disease severity on the WHO Ordinal Scale, time to clinical improvement within 14 days, and safety, respectively.ResultsThe trial was prematurely terminated because of futility after randomization of 84 patients, 56 in the ConA and 28 in the control arm. At baseline, higher WHO Ordinal Scale scores were more frequently observed in the ConA than in the control arm. On day 7, no relevant differences in the primary outcome were noted between the two arms (p = 0.11). The median time to defervescence was 3 days, and the median time to clinical improvement was 7 days in both arms (p = 0.22 and 0.56, respectively). Activation of plasma cascades and endothelial cells over time was similar in both groups. The incidence of adverse events (AEs) was higher in the intervention arm (any AE, 30% with ConA vs. 19% with SOC alone; serious AE, 27% vs. 15%; death, 11% vs. 0%). None of these were judged as being related to the study drug.ConclusionThe study results do not support the use of ConA to prevent COVID-19 progression.Clinical trial registrationhttps://clinicaltrials.gov, identifier NCT04414631.

The Viruses Editorial Office retracts the article, “Contribution of Host Immune Responses Against Influenza D Virus Infection Toward Secondary Bacterial Infection in a Mouse Model” [...]

Abstract Within this work, we demonstrate in-situ alignment of the easy axis single-crystal magnetic particles inside a polymer matrix using fused filament fabrication. Two different magnetic materials are investigated: (i) Strontium hexaferrite inside a PA6 matrix, fill grade: 49 vol% and (ii) Samarium iron nitride inside a PA12 matrix, fill grade: 44 vol%. In the presence of the external alignment field, the strontium hexaferrite particles inside the PA6 matrix can be well aligned with a ratio of remnant magnetization to saturation magnetization in an easy axis of 0.7. No significant alignment for samarium iron nitride could be achieved. The results show the feasibility to fabricate magnets with arbitrary and locally defined easy axis using fused filament fabrication since the permanent magnets (or alternatively an electromagnet) can be mounted on a rotatable platform.

Abstract Vascular graft surgeries are often conducted in trauma cases, which has increased the demand for scaffolds with good biocompatibility profiles. Biodegradable scaffolds resembling the extracellular matrix (ECM) of blood vessels are promising vascular graft materials. In the present study, polyurethane (PU) was blended with ECM proteins collagen and elastin (Col-El) and gelatin (Gel) to produce fibrous scaffolds by using the rotary jet spinning (RJS) technique, and their effects on in vitro properties were evaluated. Morphological and structural characterization of the scaffolds was performed using scanning electron microscopy (SEM) and atomic force microscopy (AFM). Micrometric fibers with nanometric rugosity were obtained. Col-El and Gel reduced the mechanical strength and increased the hydrophilicity and degradation rates of PU. No platelet adhesion or activation was observed. The addition of proteins to the PU blend increased the viability, adhesion, and proliferation of human umbilical vein endothelial cells (HUVECs). Therefore, PU-Col-El and PU-Gel scaffolds are promising biomaterials for vascular graft applications.

Studying a prospective cohort, the authors develop and validate a predictive score for post-acute COVID-19 syndrome, also known as long-COVID. This score relies on an immunoglobulin signature and is independent of timepoint of blood sampling.

Abstract Polyethylene (C2H4)n was compressed to pressures between 10 and 30 GPa in a diamond anvil cell (DAC) and laser heated above 2500 K for approximately one second. This resulted in the chemical decomposition of the polymer into carbon and hydrocarbon reaction products. After quenching to ambient temperature, the decomposition products were measured in the DAC at pressures ranging from ambient to 29 GPa using a combination of x-ray diffraction (XRD) and small angle x-ray scattering (SAXS). XRD identified cubic diamond and methane as the predominant product species with their pressure–volume relationships exhibiting strong correlations to the diamond and methane equations of state. Length scales associated with the diamond products, obtained from SAXS measurements, indicate the formation of nanodiamonds with a radius of gyration between 12 and 35 nm consistent with 32–90 nm diameter spherical particles. These results are in good agreement with the predicted product composition under thermodynamic and chemical equilibrium.

Abstract Background COVID-19 has a direct impact on the employment of older people. This adds to the challenge of ageism. The World Health Organization has started a worldwide campaign to combat ageism and has called for more research and evidence-based strategies that have the potential to be scaled up. This study specifically aims to identify solutions to combat the adverse effects of COVID-19 on the global ageing workforce. Methods We present 15 case studies from different countries and report on what those countries are doing or not doing to address the impact of COVID-19 on ageing workers. Results We provide examples of how COVID-19 influences older people’s ability to work and stay healthy, and offer case studies of what governments, organizations or individuals can do to help ensure older people can obtain, maintain and, potentially, expand their current work. Case studies come from Australia, Austria, Canada, China, Germany, Israel, Japan, Nigeria, Romania, Singapore, Sweden, South Korea, Thailand, United Kingdom (UK), and the United States (US). Across the countries, the impact of COVID-19 on older workers is shown as widening inequalities. A particular challenge has arisen because of a large proportion of older people, often with limited education and working in the informal sector within rural areas, e.g. in Nigeria, Thailand and China. Remedies to the particular disadvantage experienced by older workers in the context of COVID are presented. These range from funding support to encouraging business continuity, innovative product and service developments, community action, new business models and localized, national and international actions. The case studies can be seen as frequently fitting within strategies that have been proven to work in reducing ageism within the workplace. They include policy and laws that have increased benefits to workers during lockdowns (most countries); educational activities such as coaching seniorpreneurship (e,g, Australia); intergenerational contact interventions such as younger Thai people who moved back to rural areas and sharing their digital knowledge with older people and where older people reciprocate by teaching the younger people farming knowledge. Conclusion Global sharing of this knowledge among international, national and local governments and organizations, businesses, policy makers and health and human resources experts will further understanding of the issues that are faced by older workers. This will facilitate the replication or scalability of solutions as called for in the WHO call to combat ageism in 2021. We suggest that policy makers, business owners, researchers and international organisations build on the case studies by investing in evidence-based strategies to create inclusive workplaces. Such action will thus help to challenge ageism, reduce inequity, improve business continuity and add to the quality of life of older workers.

Shock-wave driven reactions of organic molecules may have played a key role in prebiotic chemistry, but their mechanisms are difficult to investigate. The authors, using time-resolved x-ray diffraction and small-angle x-ray scattering experiments, observe the transformation of liquid benzene during a shock, identifying carbon and hydrocarbon solid products.

BackgroundCOVID-19 has caused nearly 1 million deaths in the United States, not to mention job losses, business and school closures, stay-at-home orders, and mask mandates. Many people have suffered increased anxiety and depression since the pandemic began. Not only have mental health symptoms become more prevalent, but alcohol consumption has also increased during this time. Helplines offer important insight into both physical and mental wellness of a population by offering immediate, anonymous, cheap, and accessible resources for health and substance use disorders (SUD) that was unobstructed by many of the mandates of the pandemic. Further, the pandemic also launched the use of wastewater surveillance, which has the potential for tracking not only population infections but also consumption of substances such as alcohol. ObjectiveThis study assessed the feasibility of using multiple public surveillance metrics, such as helpline calls, COVID-19 cases, and alcohol metabolites in wastewater, to better understand the need for interventions or public health programs in the time of a public health emergency. MethodsEthanol metabolites were analyzed from wastewater collected twice weekly from September 29 to December 4, 2020, in a Midwestern state. Calls made to the helpline regarding housing, health care, and mental health/SUD were correlated with ethanol metabolites analyzed from wastewater samples, as well as the number of COVID-19 cases during the sampling period. ResultsCorrelations were observed between COVID-19 cases and helpline calls regarding housing and health care needs. No correlation was observed between the number of COVID-19 cases and mental health/SUD calls. COVID-19 cases on Tuesdays were correlated with the alcohol metabolite ethyl glucuronide (EtG). Finally, EtG levels were negatively associated with mental health/SUD helpline calls. ConclusionsAlthough helpline calls provided critical services for health care and housing-related concerns early in the pandemic, evidence suggests helpline calls for mental health/SUD-related concerns were unrelated to COVID-19 metrics. Instead, COVID metrics were associated with alcohol metabolites in wastewater. Although this research was formative, with continued and expanded monitoring of population metrics, such as helpline usage, COVID-19 metrics, and wastewater, strategies can be implemented to create precision programs to address the needs of the population.

Abstract To investigate the COVID-19 pandemic related alteration of health promoting behaviour during lockdown among medical students compared to other students. In this cross-sectional study, we enrolled 1940 Bavarian students. Participants were asked to complete an online questionnaire 3 weeks after lockdown implementation, evaluating their lifestyle behaviour focusing on self-reported and objectively assessed physical activity. 1154 medical (59.5%) and 786 non-medical (40.5%) students were included (median age 22.0 [IQR, 20.0–25.0], 71.5% female). Physical activity decreased in both groups after lockdown implementation. During lockdown, medical students reported higher physical activity levels compared to non-medical students. This was corroborated by daily step count data assessed by wearables (median steps per day [IQR], 6979 [5218–9348] versus 6581 [4497–8491], p = 0.02). Smoking behaviour during lockdown did not differ between medical and non-medical students (increased in 11.8% vs 13.6%, decreased in 31.9% versus 36.9%). During the COVID-19 pandemic, alteration of lifestyle behaviour among medical students was significantly different compared to non-medical students. This result suggests that medical students are more concerned about health promoting behaviour even in crisis situations.

Abstract Background Since the onset of the COVID-19 pandemic in December 2019, many countries around the world have imposed lockdown measures in order to reduce virus spread. Social isolation is known to have a significant psychological impact, potentially triggering alcohol misuse in adults. In our study, we aimed to investigate the effect of COVID-19 lockdown measures on alcohol consumption in adults in Bavaria. Methods In this cross-sectional study, we enrolled 2067 participants, with 1961 young adults (mean age 23.3 ± 4.1) and 106 mature adults (mean age 66.7 ± 9.7). Participants were asked to complete a standardized questionnaire, semi-quantitatively evaluating the alcohol drinking behaviour before and during the pandemic lockdown. Results After implementation of lockdown, the alteration of alcohol consumption was significantly different between young and mature adults (p 0 to

Elastin-like proteins (ELPs) are polypeptides with potential applications as renewable bio-based high-performance polymers, which undergo a stimulus-responsive reversible phase transition. The ELP investigated in this manuscript—ELP[V2Y-45]—promises fascinating mechanical properties in biomaterial applications. Purification process scalability and purification performance are important factors for the evaluation of potential industrial-scale production of ELPs. Salt-induced precipitation, inverse transition cycling (ITC), and immobilized metal ion affinity chromatography (IMAC) were assessed as purification protocols for a polyhistidine-tagged hydrophobic ELP showing low-temperature transition behavior. IMAC achieved a purity of 86% and the lowest nucleic acid contamination of all processes. Metal ion leakage did not propagate chemical modifications and could be successfully removed through size-exclusion chromatography. The simplest approach using a high-salt precipitation resulted in a 60% higher target molecule yield compared to both other approaches, with the drawback of a lower purity of 60% and higher nucleic acid contamination. An additional ITC purification led to the highest purity of 88% and high nucleic acid removal. However, expensive temperature-dependent centrifugation steps are required and aggregation effects even at low temperatures have to be considered for the investigated ELP. Therefore, ITC and IMAC are promising downstream processes for biomedical applications with scale-dependent economical costs to be considered, while salt-induced precipitation may be a fast and simple alternative for large-scale bio-based polymer production.

Abstract Background Protein aggregates can be found in peripheral organs, such as the heart, kidney, and pancreas, but little is known about the impact of peripherally misfolded proteins on neuroinflammation and brain functional recovery following ischemic stroke. Methods Here, we studied the ischemia/reperfusion (I/R) induced brain injury in mice with cardiomyocyte-restricted overexpression of a missense (R120G) mutant small heat shock protein, αB-crystallin (CryABR120G), by examining neuroinflammation and brain functional recovery following I/R in comparison to their non-transgenic (Ntg) littermates. To understand how peripherally misfolded proteins influence brain functionality, exosomes were isolated from CryABR120G and Ntg mouse blood and were used to treat wild-type (WT) mice and primary cortical neuron-glia mix cultures. Additionally, isolated protein aggregates from the brain following I/R were isolated and subjected to mass-spectrometric analysis to assess whether the aggregates contained the mutant protein, CryABR120G. To determine whether the CryABR120G misfolding can self-propagate, a misfolded protein seeding assay was performed in cell cultures. Results Our results showed that CryABR120G mice exhibited dramatically increased infarct volume, delayed brain functional recovery, and enhanced neuroinflammation and protein aggregation in the brain following I/R when compared to the Ntg mice. Intriguingly, mass-spectrometric analysis of the protein aggregates isolated from CryABR120G mouse brains confirmed presence of the mutant CryABR120G protein in the brain. Importantly, intravenous administration of WT mice with the exosomes isolated from CryABR120G mouse blood exacerbated I/R-induced cerebral injury in WT mice. Moreover, incubation of the CryABR120G mouse exosomes with primary neuronal cultures induced pronounced protein aggregation. Transduction of CryABR120G aggregate seeds into cell cultures caused normal CryAB proteins to undergo dramatic aggregation and form large aggregates, suggesting self-propagation of CryABR120G misfolding in cells. Conclusions These results suggest that peripherally misfolded proteins in the heart remotely enhance neuroinflammation and exacerbate brain injury following I/R likely through exosomes, which may represent an underappreciated mechanism underlying heart-brain crosstalk.

The article examines how to adapt the global production network (GPN) approach to situations of natural resource extraction. Based on an integration of a political ecology perspective into GPN research, we exemplarily apply the GPN framework to the primary sector. Based on extensive qualitative fieldwork regarding Argentine lithium mining and Brazilian soy agribusiness we illustrate that particularly a political ecological environmental perspective allows for a more nuanced and critical analysis of ambiguous local development outcomes. While from a purely economic development perspective in both cases the economic activity (integrated into GPNs) is celebrated as an imperative economic growth driver, our framework helps identify the emergence of unilateral dependencies, a decline of social autonomy and an unequal distribution of environmental risks.

Purpose: To predict the global spread of SARS-CoV-2 Alpha Variant of Concern (VoC) from England via air travel and compare against observed importation. Methods & Materials: Risk models were used to estimate a country's likelihood of importing at least one traveller infected with the Alpha VoC from England by January 19, 2021.First, the prior 60-day incidence of Alpha VoC associated with each English airport was estimated using cumulative Alpha VoC cases reported by Public Health England between September 20, 2020 – January 4, 2021 proportionately allocated to each airport. Each airport's catchment population was derived from a probabilistic Huff model. Next, the prevalence of the Alpha VoC for each airport was derived from the estimated incidence to represent the probability that at least one departing traveller was infected with the Alpha VoC for each English airport. The prevalence and forecasted flight volumes were used to estimate the likelihood of each destination airport receiving at least one infected traveller from England. Forecasted flight volumes were based on historical passenger volumes data from the International Air Transport Association and prospective flight schedules from CIRIUM. All airport-level likelihoods were aggregated to the country-level.Each country's predicted likelihood was compared against observed cases of Alpha VoC by January 25, 2021, collected by cov-lineages.org and a manual search of online sources. Results: Among 211 countries, the median likelihood was 1.6% (interquartile range: 17.5%) and the mean was 13.9% (SD: 23.5%). In total, 28.9% (n=55) of countries had observed importation of the Alpha VoC by January 25th. Fifteen of 16 countries with a predicted likelihood of importation greater than 50% had reported at least one case (kappa = 0.88), while 31 of 39 countries with a predicted likelihood lower than 1% did not detect a case (kappa = 0.92). Conclusion: Risk models based on air travel to inform public health preparedness accurately identified most potential destinations at highest risk of importing the SARS-CoV-2 Alpha VoC.

While it is well appreciated that maternal immunity can provide neonatal protection, the contribution of maternal vaccination toward generating such immunity is not well characterized. In our previous work, we created a candidate influenza vaccine using our chimeric hemagglutinin (HA) construct, HA-129. The HA-129 was expressed as part of a whole-virus vaccine that was built on the A/swine/Texas/4199-2/98-H3N2 backbone to generate the recombinant virus TX98-129. The TX98-129 candidate vaccine has the ability to induce broadly protective immune responses against genetically diversified influenza viruses in both mice and nursery pigs. In the current study, we established a pregnant sow–neonate model to evaluate the maternal immunity induced by this candidate vaccine to protect pregnant sows and their neonatal piglets against influenza virus infection. In pregnant sows, the results consistently show that TX98-129 induced a robust immune response against the TX98-129 virus and the parental viruses that were used to construct HA-129. After challenge with a field strain of influenza A virus, a significant increase in antibody titers was observed in vaccinated sows at both 5 and 22 days post challenge (dpc). The challenge virus was detected at a low level in the nasal swab of only one vaccinated sow at 5 dpc. Evaluation of cytokine responses in blood and lung tissue showed that levels of IFN-α and IL-1β were increased in the lung of vaccinated sows at 5 dpc, when compared to unvaccinated pigs. Further analysis of the T-cell subpopulation in PBMCs showed a higher ratio of IFN-γ-secreting CD4+CD8+ and CD8+ cytotoxic T cells in vaccinated sows at 22 dpc after stimulation with either challenge virus or vaccine virus. Finally, we used a neonatal challenge model to demonstrate that vaccine-induced maternal immunity can be passively transferred to newborn piglets. This was observed in the form of both increased antibody titers and deceased viral loads in neonates born from immunized sows. In summary, this study provides a swine model system to evaluate the impact of vaccination on maternal immunity and fetal/neonatal development.

As the most common form of dementia and a progressive neurodegenerative disorder, Alzheimer’s disease (AD) affects over 10% world population with age 65 and older. The disease is neuropathologically associated with progressive loss of neurons and synapses in specific brain regions, deposition of amyloid plaques and neurofibrillary tangles, neuroinflammation, blood–brain barrier (BBB) breakdown, mitochondrial dysfunction, and oxidative stress. Despite the intensive effort, there is still no cure for the disorder. Stem cell-derived exosomes hold great promise in treating various diseases, including AD, as they contain a variety of anti-apoptotic, anti-inflammatory, and antioxidant components. Moreover, stem cell-derived exosomes also promote neurogenesis and angiogenesis and can repair damaged BBB. In this review, we will first outline the major neuropathological features associated with AD; subsequently, a discussion of stem cells, stem cell-secreted exosomes, and the major exosome isolation methods will follow. We will then summarize the recent data involving the use of mesenchymal stem cell- or neural stem cell-derived exosomes in treating AD. Finally, we will briefly discuss the challenges, perspectives, and clinical trials using stem cell-derived exosomes for AD therapy.

The purpose of the current study was to determine the influence of parenting style on body mass index (BMI) percentile, physical activity (PA), and sedentary time (ST) in children. Accelerometers were used to assess PA and ST in 152 fifth-grade children. Parenting style was assessed by the child participants’ responses to modified questions from the Parenting Style Inventory II and dichotomized as authoritative or non-authoritative. Multiple linear regression analyses were utilized to identify significant predictors of outcomes of interest. Parenting style did not predict ST or any intensity of PA; however, BMI percentile and gender were significant predictors of moderate-intensity PA, vigorous-intensity PA, and moderate-to-vigorous intensity PA ( P

Abstract Objectives Conestat alfa, a recombinant human C1 esterase inhibitor, is a multi-target inhibitor of inflammatory cascades including the complement, the kinin-kallikrein and the contact activation system. The study objective is to investigate the efficacy and safety of conestat alfa in improving disease severity and short-term outcome in COVID-19 patients with pulmonary disease. Trial design This study is an investigator-initiated, randomized (2:1 ratio), open-label, parallel-group, controlled, multi-center, phase 2a clinical trial. Participants This trial is conducted in 3 hospitals in Switzerland, 1 hospital in Brazil and 1 hospital in Mexico (academic and non-academic). All patients with confirmed SARS-CoV-2 infection requiring hospitalization for at least 3 calendar days for severe COVID-19 will be screened for study eligibility. Inclusion criteria: - Signed informed consent - Age 18-85 years - Evidence of pulmonary involvement on CT scan or X-ray of the chest - Duration of symptoms associated with COVID-19 ≤ 10 days - At least one of the following risk factors for progression to mechanical ventilation on the day of enrolment: 1) Arterial hypertension 2) ≥ 50 years 3) Obesity (BMI ≥ 30 kg/m2) 4) History of cardiovascular disease 5) Chronic pulmonary disease 6) Chronic renal disease 7) C-reactive protein > 35mg/L 8) Oxygen saturation at rest of ≤ 94% when breathing ambient air Exclusion criteria: - Incapacity or inability to provide informed consent - Contraindications to the class of drugs under investigation (C1 esterase inhibitor) - Treatment with tocilizumab or another IL-6R or IL-6 inhibitor before enrolment - History or suspicion of allergy to rabbits - Pregnancy or breast feeding - Active or anticipated treatment with any other complement inhibitor - Liver cirrhosis (any Child-Pugh score) - Admission to an ICU on the day or anticipated within the next 24 hours of enrolment - Invasive or non-invasive ventilation - Participation in another study with any investigational drug within the 30 days prior to enrolment - Enrolment of the study investigators, their family members, employees and other closely related or dependent persons Intervention and comparator Patients randomized to the experimental arm will receive conestat alfa in addition to standard of care (SOC). Conestat alfa (8400 U followed by 4200 U every 8 hours) will be administered as a slow intravenous injection (5-10 minutes) over a 72-hour period (i.e. 9 administrations in total). The first conestat alfa treatment will be administered on the day of enrolment. The control group will receive SOC only. SOC treatment will be administered according to local institutional guidelines, including supplemental oxygen, antibiotics, corticosteroids, remdesivir, and anticoagulation. Main outcomes The primary endpoint of this trial is disease severity on day 7 after enrolment assessed by an adapted WHO Ordinal Scale for Clinical Improvement (score 0 will be omitted and score 6 and 7 will be combined) from 1 (no limitation of activities) to 7 (death). Secondary outcomes include (i) the time to clinical improvement (time from randomization to an improvement of two points on the WHO ordinal scale or discharge from hospital) within 14 days after enrolment, (ii) the proportion of participants alive and not having required invasive or non-invasive ventilation at 14 days after enrolment and (iii) the proportion of subjects without an acute lung injury (defined by PaO2/FiO2 ratio of ≤300mmHg) within 14 days after enrolment. Exploratory outcomes include virological clearance, C1 esterase inhibitor pharmacokinetics and changes in routine laboratory parameters and inflammatory proteins. Randomisation Subjects will be randomised in a 2:1 ratio to treatment with conestat alfa in addition to SOC or SOC only. Randomization is performed via an interactive web response system (SecuTrial®). Blinding (masking) In this open-label trial, participants, caregivers and outcome assessors are not blinded to group assignment. Numbers to be randomised (sample size) We will randomise approximately 120 individuals (80 in the active treatment arm, 40 in the SOC group). Two interim analyses after 40 and 80 patients are planned according to the Pocock adjusted levels αp = 0.0221. The results of the interim analysis will allow adjustment of the sample size (Lehmacher, Wassmer, 1999). Trial Status PROTECT-COVID-19 protocol version 3.0 (July 07 2020). Participant recruitment started on July 30 2020 in one center (Basel, Switzerland, first participant included on August 06 2020). In four of five study centers patients are actively recruited. Participation of the fifth study center (Mexico) is anticipated by mid December 2020. Completion of trial recruitment depends on the development of the SARS-CoV-2 pandemic. Trial registration Clinicaltrials.gov, number: NCT04414631 , registered on 4 June 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Purpose: To compare the rates of embolic debris (ED) generation during lower extremity arterial interventions and evaluate the safety and efficacy of the using an embolic protection device (EPD). Methods: This was a single-center retrospective review of 111 patients (114 vessels) having undergone peripheral arterial intervention with the use of an EPD (Emboshield NAV-6 device). A database was created through review of the electronic health record and images in PACS. The presence of ED was determined through visual inspection after retrieval of the device or from filling defects identified during digital subtraction angiography with the device deployed. Descriptive statistics were used to report the demographic and clinical information. Relative frequencies of debris generation were determined for vessel type, trans-atlantic inter-society consensus (TASC) classification, and type of intervention. Differences in frequencies between groups weer evaluated with the Chi-square test, and associations were examined using the logistic regression analysis. Results: Of the 114 vessels treated, 16 (14%) demonstrated true distal embolization (DE) past the filter basket and 58 (51%) demonstrated generation of ED as determined by filling of the filter basket. This was significantly higher in patients undergoing atherectomy (70%) compared with those undergoing thrombolysis (38%) or angioplasty with or without stenting (29%) (P < 0.001). Of those patients undergoing atherectomy, laser atherectomy had the lowest rate of DE (26%) compared with either orbital (67%) or directional atherectomy (57%) (P < 0.05). In regression analysis, atherectomy was the only factor with significant association with detection of ED (odds ratio: 4.52, P < 0.0001). There was no statistically significant difference in the frequency of debris generated based on vessel type or TASC classification. Conclusion: The frequency of ED is higher in patients undergoing atherectomy versus patients undergoing lysis or percutaneous transluminal balloon angioplasty with or without stenting. Laser atherectomy has a lower frequency of debris generation when compared to either orbital or directional atherectomy.

Detonation of high explosives can produce many nanocarbon allotropes and morphologies, but the mechanism of formation is challenging to explore. Here the authors observe, by time-resolved small-angle X-ray scattering, a transient liquid phase that precedes the formation of carbon onions.

In 2018, the Swiss Academy of Medical Sciences (SAMW) published a new guideline on physician-assisted dying (PAD). In line with the SAMW guideline published in 2004, the patients’ ability to judge, their self-determination, careful consideration and permanence of their wish to die as well as the lack of therapeutic options were set as necessary conditions. However, while the previous wording considered assisted suicide to be ethically justifiable if the patient’s condition is terminal, the new guideline requires that it is unbearable. This difference has been the subject of intense discussion in Swiss healthcare professionals and the population alike. This controversy is particularly important for those affected by mental illness who have a persistent desire to die. This is because mental disorders cannot usually be classified as terminal illnesses, but they can certainly lead to suffering that is perceived as unbearable. Furthermore, it is known that persons with mental illness are subject to stigmatization. It is therefore likely that there is a connection between the stigmatization of mentally ill people and the position on PAD for this group. This talk provides theoretical background on this discusion and proposes a study protocol to investigate the acceptance of PAD in relation to the type of illness as well as the factors of unbearable suffering and terminality. It will furthermore look into the criteria of the 2004 and 2018 guidelines and will explore if there is a connection between stigmatization and the assessment of whether a person should be granted access to assisted suicide.

Stroke induces complex pathological cascades in the affected brain area, leading to brain injury and functional disability. To fight against cerebral ischemia/reperfusion-induced neuronal death, numerous neuroprotective strategies and reagents have been studied. However, translation of these neuroprotective drugs to clinical trials has been unsuccessful. To date, the tissue plasminogen activator is still the only FDA-approved drug for treating ischemic stroke. Thus, it is obligatory to identify and validate additional therapeutic strategies for stroke. A stroke rarely occurs without any other pathophysiological condition; but instead, it often has multi-morbidity conditions, one of which is cardiac disease. Indeed, up to half of the stroke cases are associated with cardiac and large artery diseases. As an adequate blood supply is essential for the brain to maintain its normal function, any pathophysiological alterations in the heart are frequently implicated in stroke outcomes. In this review, we summarize some of the cardiovascular factors that influence stroke outcomes and propose that considering these factors in designing stroke therapies should enhance success in clinical trials. We also highlight the recent advances regarding the potential effect of protein aggregates in a peripheral organ, such as in the heart, on ischemic stroke-caused brain injury and functional recovery. Including these and other comorbidity factors in the future therapeutic strategy designs should facilitate translational success toward developing effective combinational therapies for the disorder.

Abstract Objectives The upper respiratory tract is the major entry site for Streptococcus pyogenes and influenza virus. Vaccine strategies that activate mucosal immunity could significantly reduce morbidity and mortality because of these pathogens. The severity of influenza is significantly greater if a streptococcal infection occurs during the viraemic period and generally viral infections complicated by a subsequent bacterial infection are known as super‐infections. We describe an innovative vaccine strategy against influenza virus:S. pyogenes super‐infection. Moreover, we provide the first description of a liposomal multi‐pathogen‐based platform that enables the incorporation of both viral and bacterial antigens into a vaccine and constitutes a transformative development. Methods Specifically, we have explored a vaccination strategy with biocompatible liposomes that express conserved streptococcal and influenza A virus B‐cell epitopes on their surface and contain encapsulated diphtheria toxoid as a source of T‐cell help. The vaccine is adjuvanted by inclusion of the synthetic analogue of monophosphoryl lipid A, 3D‐PHAD. Results We observe that this vaccine construct induces an Immunoglobulin A (IgA) response in both mice and ferrets. Vaccination reduces viral load in ferrets from influenza challenge and protects mice from both pathogens. Notably, vaccination significantly reduces both mortality and morbidity associated with a super‐infection. Conclusion The vaccine design is modular and could be adapted to include B‐cell epitopes from other mucosal pathogens where an IgA response is required for protection.

The newest type of influenza virus, influenza D virus (IDV), was isolated in 2011. IDV circulates in several animal species worldwide, causing mild respiratory illness in its natural hosts. Importantly, IDV does not cause clinical disease in humans and does not spread easily from person to person. Here, we review what is known about the host–pathogen interactions that may limit IDV illness. We focus on early immune interactions between the virus and infected host cells in our summary of what is known about IDV pathogenesis. This work establishes a foundation for future research into IDV infection and immunity in mammalian hosts.

Image-guided percutaneous ablation methods have been further developed during the recent two decades and have transformed the minimally invasive and precision features of treatment options targeting primary and metastatic tumors. They work by percutaneously introducing applicators to precisely destroy a tumor and offer much lower risks than conventional methods. There are usually shorter recovery periods, less bleeding, and more preservation of organ parenchyma, expanding the treatment options of patients with cancer who may not be eligible for resection. Image-guided ablation techniques are currently utilized for the treatment of primary and metastatic tumors in various organs including the liver, pancreas, kidneys, thyroid and parathyroid, prostate, lung, bone, and soft tissue. This article provides a brief review of the various imaging modalities and available ablation techniques and discusses their applications and associated complications in various organs.

Among people infected with SARS-CoV-2, the determination of clinical features associated with poor outcome is essential to identify those at high risk of deterioration. Here, we aimed to investigate clinical phenotypes of patients hospitalized due to COVID-19 and to examine the predictive value of the neutrophil-to-lymphocyte ratio (NLR) in a representative patient collective of the Swiss population. We conducted a retrospective monocentriccohort study with patients hospitalized due to COVID-19 between 27 February and 31 December 2020. Data were analyzed descriptively, using the binary logistic regression model, proportional odds logistic regression model, competing risk analysis, and summary measure analysis. A total of 454 patients were included in our study. Dyspnea, elevated respiratory rate, low oxygen saturation at baseline, age, and presence of multiple comorbidities were associated with a more severe course of the disease. A high NLR at baseline was significantly associated with disease severity, unfavorable outcome, and mortality. In non-survivors, NLR further increased during hospital stay, whereas in survivors, NLR decreased. In conclusion, our data emphasize the importance of accurate history taking and clinical examination upon admission and confirm the role of baseline NLR as a surrogate marker for increased disease severity, unfavorable outcome, and mortality in patients hospitalized due to infection with SARS-CoV-2.