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Abstract Adaptive sampling and situational awareness are key features of modern autonomous underwater vehicles (AUVs) since data quality can be improved while operation time and cost can be reduced. An example for adaptive sampling in the marine environmental context is thermocline detection and tracking. The thermocline as horizontal ocean layer separates warm and cold water and is a key feature in many marine disciplines. For example, it influences the distribution and exchange of nutrients and is a habitat for many organisms. In this paper we use an unscented Kalman Filter (UKF) based extremum seeking control (ESC) to find and follow ocean layers such as the thermocline. Computer simulations and real-world tests show that the method is able to find and track non-trivial real-world ocean layers with sensors subject to hysteresis and delay effects.

Abstract Predictors of rebound after correction of coronal plane deformities using temporary hemiepiphysiodesis (TH) are not well defined. The following research questions were tested: (1) Is the dynamic knee joint load useful to improve rebound prediction accuracy? (2) Does a large initial deformity play a critical role in rebound development? (3) Are BMI and a young age risk factors for rebound? Fifty children and adolescents with idiopathic knee valgus malalignment were included. A deviation of the mechanical femorotibial angle (MFA) of ≥ 3° into valgus between explantation and the one-year follow-up period was chosen to classify a rebound. A rebound was detected in 22 of the 50 patients (44%). Two predictors of rebound were identified: 1. reduced peak lateral knee joint contact force in the first half of the stance phase at the time of explantation (72.7% prediction); 2. minor initial deformity according to the MFA (70.5% prediction). The best prediction (75%) was obtained by including both parameters in the binary logistic regression method. A TH should not be advised in patients with a minor initial deformity of the leg axis. Dynamic knee joint loading using gait analysis and musculoskeletal modeling can be used to determine the optimum time to remove the plates.

Abstract The COVID-19 pandemic has had a major impact on society, causing significant disruptions to everyday life. Risk communication strategies can play an important role in risk management as they allow individuals to prepare for and respond to public health emergencies appropriately. The aim of this study is to investigate public risk behaviors, perceptions of risk and risk communication, and experiences with COVID-19 to better understand the impact of COVID-19 on our community and to better inform public health decisions about communicating and reducing personal risk. Nine virtual focus groups were conducted with 79 residents of Milwaukee County. Audio transcripts of focus group recordings were qualitatively analyzed using MAXQDA. Predominant themes identified include public risk protective behaviors, the emotional toll associated with lockdown measures, and risk communication. Our findings provide a better understanding of how adults, African American and Hispanic groups in particular, viewed the risk communications and protective behaviors associated with COVID-19, how their lives were impacted by the pandemic, and how to effectively communicate public information about personal risk. These findings can help guide risk communication efforts and public health policy interventions for potential infection outbreaks in the future.

Background: Gestational diabetes mellitus (GDM) is the main cause of hyperglycemia in pregnancy and is related to complications throughout the gestational and post-partum period. Objectives: To analyze the pregnancy outcomes related to the occurrence of GDM in women and their offspring. Methods: Third-trimester pregnant women were interviewed and monitored until childbirth. The diagnosis of GDM, blood glucose ≥ 92 mg/dL, was defined by the criteria of the International Association of the Diabetes and Pregnancy Study Groups (IADPSG). Results: A total of 138 women participated, and there were 136 births (due to 2 fetal losses); 23 (16.7%) were diagnosed with GDM. The risk of complications during childbirth was higher among pregnant women with GDM (RR 3.40; 95%CI 1.65–7.00), as was the occurrence of cesarean birth (RR 1.9; 95%CI 1.46–2.59). The occurrence of preterm birth did not show a significant difference between GDM/non-GDM groups. There was a non-significant association in adjusted analyses of macrosomia (birth weight ≥ 4000 g) among newborns born to mothers with GDM (RR 1.27; 95%CI 0.67–2.38). For newborns born to pregnant women with GDM, there was a higher risk for the following outcomes: large for gestational age (LGA) (3.29 95%CI 1.62–6.64), low Apgar (4.98 95%CI 2.32–10.69), and birth asphyxia (9.51 95%CI 3.42–26.48). Conclusions: The findings reinforce that GDM is an important risk factor for adverse pregnancy outcomes for women and their offspring.

BackgroundHypertension is a prevalent cardiovascular risk factor disproportionately affecting Black Americans, who also experience a higher incidence of Alzheimer disease and Alzheimer disease–related dementias. Monitoring blood pressure (BP) and cognition may be important strategies in reducing these disparities. ObjectiveThe objective of the Reach Out Cognition study was to explore the feasibility and acceptability of remote cognitive and BP assessments in a predominantly Black, low-income population. MethodsReach Out was a randomized, controlled, mobile health–based clinical trial to reduce BP among patients with hypertension at an emergency department in a safety-net hospital (ie, a US hospital in which 25% of the patients are Medicaid recipients). Upon conclusion of Reach Out, participants were given the option of continuing into an extension phase, Reach Out Cognition, that included Bluetooth-enabled BP monitoring and digital cognitive assessments for 6 months. Digital cognitive assessments were text message–linked online surveys of the Self-Administered Gerocognitive Exam and Quality of Life in Neurological Disorders scale. BP assessments were measured with Bluetooth-enabled BP cuffs paired with an app and the data were manually sent to the research team. Outcomes were feasibility (ie, enrollment and 3- and 6-month completion of digital cognitive and BP assessments) and acceptability of assessments using a 4-item validated survey, ranging from 1 (not acceptable) to 5 (completely acceptable). ResultsOf the 211 Reach Out participants, 107 (50.7%) consented and 71 (33.6%) completed enrollment in Reach Out Cognition. Participants had a mean age of 49.9 years; 70.4% were female and 57.8% identified as Black. Among the 71 participants, 51 (72%) completed cognitive assessments at 3 months and 34 (48%) completed these assessments at 6 months. BP assessments were completed by 37 (52%) and 20 (28%) of the 71 participants at 3 and 6 months, respectively. Participants were neutral on the acceptability of the digital cognitive assessments (mean 3.7) and Bluetooth self-measured BP (SMBP) monitoring (mean 3.9). Participants noted challenges syncing the BP cuff to the app, internet connection, and transmitting the data to the research team. ConclusionsEnrollment and assessment completion were low, while acceptability was moderate. Technological advances will eliminate some of the Bluetooth SMBP barriers and offer new strategies for cognitive assessments. Subsequent studies could benefit from offering more comprehensive support to overcome Bluetooth-related hurdles, such as personalized training materials, video conferencing, or in-person research team support. Alternatively, strategies that do not require pairing with an app and passive transmission of data could be considered. Overall, further research is warranted to optimize participant engagement and overcome technological challenges. Trial RegistrationClinicalTrials.gov NCT03422718; https://clinicaltrials.gov/study/NCT03422718

Abstract Pseudarthrosis following transforaminal interbody fusion (TLIF) is not infrequent. Although cage migration and subsidence are commonly regarded as evidence of the absence of solid fusion, there is still no evidence of the influence of cage migration and subsidence on fusion. This study aimed to evaluate cage migration and subsidence using computed tomography (CT) DICOM data following lumbar interbody fusion. The effects of cage migration and subsidence on fusion and clinical outcomes were also assessed. A postoperative CT data set of 67 patients treated with monosegmental TLIF was analyzed in terms of cage position. To assess the effects of cage migration and subsidence on fusion, 12-month postoperative CT scans were used to assess fusion status. Clinical evaluation included the visual analog scale for pain and the Oswestry Disability Index. Postoperative cage migration occurred in 85.1% of all patients, and cage subsidence was observed in 58.2%. Radiological signs of pseudarthrosis was observed in 7.5% of the patients Neither cage migration nor subsidence affected the clinical or radiographic outcomes. No correlation was found between clinical and radiographic outcomes. The incidence of cage migration was considerable. However, as cage migration and subsidence were not associated with bony fusion, their clinical significance was considered limited.

COVID-19 mortality rates increase rapidly with age, are higher among men than women, and vary across racial/ethnic groups, but this is also true for other natural causes of death. Prior research on COVID-19 mortality rates and racial/ethnic disparities in those rates has not considered to what extent disparities reflect COVID-19-specific factors, versus preexisting health differences. This study examines both questions. We study the COVID-19-related increase in mortality risk and racial/ethnic disparities in COVID-19 mortality, and how both vary with age, gender, and time period. We use a novel measure validated in prior work, the COVID Excess Mortality Percentage (CEMP), defined as the COVID-19 mortality rate (Covid-MR), divided by the non-COVID natural mortality rate during the same time period (non-Covid NMR), converted to a percentage. The CEMP denominator uses Non-COVID NMR to adjust COVID-19 mortality risk for underlying population health. The CEMP measure generates insights which differ from those using two common measures-the COVID-MR and the all-cause excess mortality rate. By studying both CEMP and COVID-MRMR, we can separate the effects of background health from Covid-specific factors affecting COVID-19 mortality. We study how CEMP and COVID-MR vary by age, gender, race/ethnicity, and time period, using data on all adult decedents from natural causes in Indiana and Wisconsin over April 2020-June 2022 and Illinois over April 2020-December 2021. CEMP levels for racial and ethnic minority groups can be very high relative to White levels, especially for Hispanics in 2020 and the first-half of 2021. For example, during 2020, CEMP for Hispanics aged 18-59 was 68.9% versus 7.2% for non-Hispanic Whites; a ratio of 9.57:1. CEMP disparities are substantial but less extreme for other demographic groups. Disparities were generally lower after age 60 and declined over our sample period. Differences in socio-economic status and education explain only a small part of these disparities.

In steroid-responsive meningitis-arteritis (SRMA), inflammatory dysregulation is driven by neutrophilic granulocytes resulting in purulent leptomeningitis. Neutrophils can generate neutrophil extracellular traps (NET). Uncontrolled NET-formation or impaired NET-clearance evidently cause tissue and organ damage resulting in immune-mediated diseases. The aim of the study was to verify that NET-formation is detectable in ex vivo samples of acute diseased dogs with SRMA by visualizing and measuring NET-markers in serum and cerebrospinal fluid (CSF) samples. CSF-samples of dogs with acute SRMA (n = 5) and in remission (n = 4) were examined using immunofluorescence (IF)-staining of DNA-histone-1-complexes, myeloperoxidase and citrullinated Histone H3 (H3Cit). Immunogold-labeling of H3Cit and neutrophil elastase followed by transmission electron microscopy (TEM) were used to determine ultrastructural NET-formation in the CSF of one exemplary dog. H3Cit-levels and DNase-activity were measured in CSF and serum samples using an H3Cit-ELISA and a DNase-activity-assay, respectively in patients with the following diseases: acute SRMA (n = 34), SRMA in remission (n = 4), bacterial encephalitis (n = 3), meningioma with neutrophilic inflammation (n = 4), healthy dogs (n = 6). NET-formation was detectable with IF-staining in n = 3/5 CSF samples of dogs with acute SRMA but were not detectable during remission. Vesicular NET-formation was detectable in one exemplary dog using TEM. DNase-activity was significantly reduced in dogs suffering from acute SRMA compared to healthy control group (p < 0.0001). There were no statistical differences of H3Cit levels in CSF or serum samples of acute diseased dogs compared to dogs under treatment, dogs suffering from meningioma or bacterial encephalitis or the healthy control group. Our findings demonstrate that NET-formation and insufficient NET-clearance possibly drive the immunologic dysregulation and complement the pathogenesis of SRMA. The detection of NETs in SRMA offers many possibilities to explore the aetiopathogenetic influence of this defence mechanism of the innate immune system in infectious and non-infectious canine neuropathies.

Abstract Homeostasis comprises one of the main features of living organisms that enables their robust functioning by adapting to environmental changes. In particular, thermoregulation, as an instance of homeostatic behavior, allows mammals to maintain stable internal temperature with tightly controlled self-regulation independent of external temperatures. This is made by a proper reaction of the thermoeffectors (like skin blood vessels, brown adipose tissue (BAT), etc.) on a wide range of temperature perturbations that reflect themselves in the thermosensitive neurons’ activity. This activity is being delivered to the respective actuation points and translated into thermoeffectors’ actions, which bring the temperature of the organism to the desired level, called a set-point. However, it is still an open question whether these mechanisms can be implemented in an analog electronic device: both on a system theoretical and a hardware level. In this paper, we transfer this control loop into a real electric circuit by designing an analog electronic device for temperature regulation that works following bio-inspired principles. In particular, we construct a simplified single-effector regulation system and show how spiking trains of thermosensitive artificial neurons can be processed to realize an efficient feedback mechanism for the stabilization of the a priori unknown but system-inherent set-point. We also demonstrate that particular values of the set-point and its stability properties result from the interplay between the feedback control gain and activity patterns of thermosensitive artificial neurons, for which, on the one hand, the neuronal interconnections are generally not necessary. On the other hand, we show that such connections can be beneficial for the set-point regulation and hypothesize that the synaptic plasticity in real thermosensitive neuronal ensembles can play a role of an additional control layer empowering the robustness of thermoregulation. The electronic realization of temperature regulation proposed in this paper might be of interest for neuromorphic circuits which are bioinspired by taking the basal principle of homeostasis on board. In this way, a fundamental building block of life would be transferred to electronics and become a milestone for the future of neuromorphic engineering.

Abstract Compressive knee joint contact force during walking is thought to be related to initiation and progression of knee osteoarthritis. However, joint loading is often evaluated with surrogate measures, like the external knee adduction moment, due to the complexity of computing joint contact forces. Statistical models have shown promising correlations between medial knee joint contact forces and knee adduction moments in particularly in individuals with knee osteoarthritis or after total knee replacements (R 2 = 0.44–0.60). The purpose of this study was to evaluate how accurately model-based predictions of peak medial and lateral knee joint contact forces during walking could be estimated by linear mixed-effects models including joint moments for children and adolescents with and without valgus malalignment. Peak knee joint moments were strongly correlated (R 2 > 0.85, p

Abstract Oscillator networks rapidly become one of the promising vehicles for energy-efficient computing due to their intrinsic parallelism of execution. The criticality property of the oscillator-based networks is regarded to be essential for performing complex tasks. There are numerous bio-inspired synaptic and structural plasticity mechanisms available, especially for spiking neural networks, which can drive the network towards the criticality. However, there is no solid connection between these self-adaption mechanisms and the task performance, and it is not clear how and why particular self-adaptation mechanisms contribute to the solution of the task, although their relation to criticality is understood. Here we propose an evolutionary approach for the structural plasticity that relies solely on the task performance and does not contain any task-independent adaptation mechanisms, which usually contribute towards the criticality of the network. As a driver for the structural plasticity, we use a direct binary search guided by the performance of the classification task that can be interpreted as an interaction of the network with the environment. Remarkably, such interaction with the environment brings the network to criticality, although this property was not a part of the objectives of the employed structural plasticity mechanism. This observation confirms a duality of criticality and task performance, and legitimizes internal activity-dependent plasticity mechanisms from the viewpoint of evolution as mechanisms contributing to the task performance, but following the dual route. Finally, we analyze the trained network against task-independent information-theoretic measures and identify the interconnection graph’s entropy to be an essential ingredient for the classification task performance and network’s criticality.

Abstract Monoclonal antibodies (abs) targeting the programmed cell death 1 (PD-1) immune checkpoint pathway have revolutionized tumor therapy. Because T-cell-directed PD-1 blockade boosts tumor immunity, anti-PD-1 abs have been developed for examining T-cell-PD-1 functions. More recently, PD-1 expression has also been reported directly on cancer cells of various etiology, including in melanoma. Nevertheless, there is a paucity of studies validating anti-PD-1 ab clone utility in specific assay types for characterizing tumor cell-intrinsic PD-1. Here, we demonstrate reactivity of several anti-murine PD-1 ab clones and recombinant PD-L1 with live B16-F10 melanoma cells and YUMM lines using multiple independent methodologies, positive and negative PD-1-specific controls, including PD-1-overexpressing and PD-1 knockout cells. Flow cytometric analyses with two separate anti-PD-1 ab clones, 29F.1A12 and RMP1-30, revealed PD-1 surface protein expression on live murine melanoma cells, which was corroborated by marked enrichment in PD-1 gene (Pdcd1) expression. Immunoblotting, immunoprecipitation, and mass spectrometric sequencing confirmed PD-1 protein expression by B16-F10 cells. Recombinant PD-L1 also recognized melanoma cell-expressed PD-1, the blockade of which by 29F.1A12 fully abrogated PD-1:PD-L1 binding. Together, our data provides multiple lines of evidence establishing PD-1 expression by live murine melanoma cells and validates ab clones and assay systems for tumor cell-directed PD-1 pathway investigations.

Although team science has expanded with far-reaching benefits, universities generally have not established criteria to recognize its value in faculty promotion and tenure. This paper recommends how institutions might weigh a faculty member’s engagement in team science in the promotion and tenure process. Seventeen team science promotion and tenure criteria are recommended based on four sources – an evaluation framework, effectiveness metrics, collaborative influences, and authorship criteria. Suggestions are made for adaptation of the 17 criteria to committee guidelines, faculty team science portfolios, and the roles of individuals and institutions participating in large, cross-disciplinary research projects. Future research recommendations are advanced.

Abstract Grating-based X-ray dark-field imaging is a novel imaging modality with enormous technical progress during the last years. It enables the detection of microstructure impairment as in the healthy lung a strong dark-field signal is present due to the high number of air-tissue interfaces. Using the experience from setups for animal imaging, first studies with a human cadaver could be performed recently. Subsequently, the first dark-field scanner for in-vivo chest imaging of humans was developed. In the current study, the optimal tube voltage for dark-field radiography of the thorax in this setup was examined using an anthropomorphic chest phantom. Tube voltages of 50–125 kVp were used while maintaining a constant dose-area-product. The resulting dark-field and attenuation radiographs were evaluated in a reader study as well as objectively in terms of contrast-to-noise ratio and signal strength. We found that the optimum tube voltage for dark-field imaging is 70 kVp as here the most favorable combination of image quality, signal strength, and sharpness is present. At this voltage, a high image quality was perceived in the reader study also for attenuation radiographs, which should be sufficient for routine imaging. The results of this study are fundamental for upcoming patient studies with living humans.

Prior research generally finds that the Pfizer-BioNTech (BNT162b2) and Moderna (mRNA1273) COVID-19 vaccines provide similar protection against mortality, sometimes with a Moderna advantage due to slower waning. However, most comparisons do not address selection effects for those who are vaccinated and with which vaccine. We report evidence on large selection effects, and use a novel method to control for these effects. Instead of directly studying COVID-19 mortality, we study the COVID-19 excess mortality percentage (CEMP), defined as the COVID-19 deaths divided by non-COVID-19 natural deaths for the same population, converted to a percentage. The CEMP measure uses non-COVID-19 natural deaths to proxy for population health and control for selection effects. We report the relative mortality risk (RMR) for each vaccine relative to the unvaccinated population and to the other vaccine, using linked mortality and vaccination records for all adults in Milwaukee County, Wisconsin, from 1 April 2021 through 30 June 2022. For two-dose vaccinees aged 60+, RMRs for Pfizer vaccinees were consistently over twice those for Moderna, and averaged 248% of Moderna (95% CI = 175%,353%). In the Omicron period, Pfizer RMR was 57% versus 23% for Moderna. Both vaccines demonstrated waning of two-dose effectiveness over time, especially for ages 60+. For booster recipients, the Pfizer–Moderna gap is much smaller and statistically insignificant. A possible explanation for the Moderna advantage for older persons is the higher Moderna dose of 100 μg, versus 30 μg for Pfizer. Younger persons (aged 18–59) were well-protected against death by two doses of either vaccine, and highly protected by three doses (no deaths among over 100,000 vaccinees). These results support the importance of a booster dose for ages 60+, especially for Pfizer recipients. They suggest, but do not prove, that a larger vaccine dose may be appropriate for older persons than for younger persons.

O presente artigo apresenta e discute o caso de um paciente masculino, de 2 meses de idade, que foi encaminhado para o Hospital de Clínicas de Porto Alegre com história de icterícia persistente há 45 dias, apresentando-se em regular estado geral, afebril, com icterícia importante, desproporção peso/altura, abdômen distendido e fígado e baço palpáveis. Ecografia abdominal e cintilografia das vias biliares eram normais. O paciente permaneceu 26 dias no hospital para investigação, onde apresentou quadro respiratório diagnosticado como pneumonia, recebendo alta hospitalar em bom estado. Foi encaminhado para o ambulatório para prosseguir a investigação. Uma semana após a alta, apresentou febre, disfunção respiratória, sangramento difuso, ascite e falência de múltiplos órgãos, evoluindo para o óbito.

COVID-19 vaccines have saved millions of lives; however, understanding the long-term effectiveness of these vaccines is imperative to developing recommendations for booster doses and other precautions. Comparisons of mortality rates between more and less vaccinated groups may be misleading due to selection bias, as these groups may differ in underlying health status. We studied all adult deaths during the period of 1 April 2021–30 June 2022 in Milwaukee County, Wisconsin, linked to vaccination records, and we used mortality from other natural causes to proxy for underlying health. We report relative COVID-19 mortality risk (RMR) for those vaccinated with two and three doses versus the unvaccinated, using a novel outcome measure that controls for selection effects. This measure, COVID Excess Mortality Percentage (CEMP), uses the non-COVID natural mortality rate (Non-COVID-NMR) as a measure of population risk of COVID mortality without vaccination. We validate this measure during the pre-vaccine period (Pearson correlation coefficient = 0.97) and demonstrate that selection effects are large, with non-COVID-NMRs for two-dose vaccinees often less than half those for the unvaccinated, and non-COVID NMRs often still lower for three-dose (booster) recipients. Progressive waning of two-dose effectiveness is observed, with an RMR of 10.6% for two-dose vaccinees aged 60+ versus the unvaccinated during April–June 2021, rising steadily to 36.2% during the Omicron period (January–June, 2022). A booster dose reduced RMR to 9.5% and 10.8% for ages 60+ during the two periods when boosters were available (October–December, 2021; January–June, 2022). Boosters thus provide important additional protection against mortality.

Abstract Grating-based X-ray dark-field imaging is a novel imaging modality which has been refined during the last decade. It exploits the wave-like behaviour of X-radiation and can nowadays be implemented with existing X-ray tubes used in clinical applications. The method is based on the detection of small-angle X-ray scattering, which occurs e.g. at air-tissue-interfaces in the lung or bone-fat interfaces in spongy bone. In contrast to attenuation-based chest X-ray imaging, the optimal tube voltage for dark-field imaging of the thorax has not yet been examined. In this work, dark-field scans with tube voltages ranging from 60 to 120 kVp were performed on a deceased human body. We analyzed the resulting images with respect to subjective and objective image quality, and found that the optimum tube voltage for dark-field thorax imaging at the used setup is at rather low energies of around 60 to 70 kVp. Furthermore, we found that at these tube voltages, the transmission radiographs still exhibit sufficient image quality to correlate dark-field information. Therefore, this study may serve as an important guideline for the development of clinical dark-field chest X-ray imaging devices for future routine use.

Abstract Introduction Low exposure of the larynx can make laryngeal microsurgery difficult or even impossible. The application of rigid and contact endoscopy enabled oblique and retrograde angled visualization, allowing transoperative staging with greater reach of the anatomical areas. However, there is difficulty or even impossibility of performing the surgical act, due to the incompatibility of the angled path with the straight surgical tools. Objective To demonstrate the efficiency of the variant of the technique for laryngeal microsurgery in cases of difficult laryngoscopy and to analyze the new surgical instruments specific to the endoscopic procedure. Methods This is a cross-sectional retrospective study, based on the analysis of 30 medical records of patients treated surgically at a philanthropic hospital in the state of Sergipe, Brazil, between the years of 2014 and 2015. Results The technical variant used 30- and 70-degree endoscopes that provided complete oblique view of the endolarynx. The association of angled instruments (forceps, suction pumps, retractors and scissors) enabled the execution of the surgical procedures. Conclusion The association of rigid endoscopy with angled instruments promoted full visualization of the surgical lesion and operative resolution.

The β2-adrenergic receptor (β2AR) is relevant for surfactant formation in alveolar type 2 cells and reduction of intracellular calcium concentration in bronchial muscle cells and thus for secretolytic and bronchospasmolytic effects. Herbal medicinal products that affect the β2AR system are used to treat common cold and bronchitis accompanied with mucus covered and narrowed airways. The present work compares the influence of an ivy preparation and an ivy/thyme combination on the β2-adrenergic signal transduction. For receptor binding studies and characterization of the lateral mobility of β2AR we have used single molecule detection by fluorescence correlation spectroscopy and single particle tracking. For the determination of both the second messenger cAMP and the internalization of β2AR we have generated luciferase based reporter cell lines, which produce a cAMP-dependent luciferase in the cytosol and express β2AR with extracellular luciferase moiety in the plasma membrane. While both preparations increased the β2AR binding, a significant increase of the cAMP level was observed only for the ivy preparation, which can be explained by the inhibited internalization of HiBiT-tagged β2AR under stimulating conditions. In contrast, isoprenaline-mediated internalization of HiBiT-tagged β2AR of ivy/thyme combination pre-treated cells was not inhibited. Cells comparatively pre-treated with a thyme preparation did not show inhibition of ß2AR internalization either. Furthermore, SNAP-tagged β2AR of ivy preparation pre-treated cells, which were not internalized after isoprenaline stimulation, showed a redistribution from fast-to-slowly diffusing β2AR. A corresponding redistribution of these receptors was not observed after pre-treatment with both the ivy/thyme combination and the thyme preparation. Comparable to the ivy/thyme combination, no decrease in the intratrack transitioning probability ratio (p23/p32) for fast and slow diffusing β2AR was found for the thyme preparation, which, however, significantly decreased for control cells and for pre-treatment with the ivy preparation under stimulating conditions. It can therefore be concluded that the thyme fluid extract fraction in the ivy/thyme combination may have in part a negative effect on the β2-adrenergic signal transduction.

Abstract Background Pancreatic injuries are rare in cases of blunt abdominal trauma and therefore easily misdiagnosed at time of hospital admission. They are associated with a significantly elevated morbidity and lethality. Bicycle handlebar injuries are the most common cause of pancreatic trauma in children and adolescents. Case presentation We report two cases of a 23-year-old Caucasian woman and a 15-year-old Caucasian boy who presented to our clinic with a similar history of a bicycle accident on 2 consecutive days. Both suffered from a fall from a bicycle with bicycle handlebar injury 4 and 6 days prior to admission in our clinic. Emergency distal pancreatectomies were performed in both cases. Conclusions Pancreatic injuries must be highly suspected in bicycle handlebar injuries, even if amylase/lipase levels or ultrasound findings seem unremarkable. The best initial strategies are early computed tomography and a quick referral to a level 1 trauma center. Distal pancreatectomy is the treatment of choice in cases of complete rupture of the pancreatic body.

High mobility group box (HMGB)1 action contributes to late phases of sepsis, but the effects of increased endogenous plasma HMGB1 levels on brain cells during inflammation are unclear. Here, we aimed to further investigate the role of HMGB1 in the brain during septic-like lipopolysaccharide-induced inflammation in rats (LPS, 10 mg/kg, i.p.). HMGB-1 mRNA expression and release were measured in the periphery/brain by RT-PCR, immunohistochemistry and ELISA. In vitro experiments with disulfide-HMGB1 in primary neuro-glial cell cultures of the area postrema (AP), a circumventricular organ with a leaky blood–brain barrier and direct access to circulating mediators like HMGB1 and LPS, were performed to determine the direct influence of HMGB1 on this pivotal brain structure for immune-to-brain communication. Indeed, HMGB1 plasma levels stayed elevated after LPS injection. Immunohistochemistry of brains and AP cultures confirmed LPS-stimulated cytoplasmatic translocation of HMGB1 indicative of local HMGB1 release. Moreover, disulfide-HMGB1 stimulation induced nuclear factor (NF)-κB activation and a significant release of interleukin-6, but not tumor necrosis factor α, into AP culture supernatants. However, only a few AP cells directly responded to HMGB1 with increased intracellular calcium concentration. Interestingly, priming with LPS induced a seven-fold higher percentage of responsive cells to HMGB1. We conclude that, as a humoral and local mediator, HMGB1 enhances brain inflammatory responses, after LPS priming, linked to sustained sepsis symptoms.

Marine environments are visual domains restricted regarding light characteristics. Overall, blue monochromatic spectrum prevails in offshore areas especially below 15m depth, since long wavelengths are quickly attenuated. Light intensity is even more constrained in coastal waters, particularly those of tropical estuaries and bays, because further scattering through dissolved and suspended materials. Biofluorescence, which is the ability of organisms to absorb light and reflect it in a different wavelength, has been reported for many marine fish. In this paper, biofluorescence was recorded for the first time for the longsnout seahorse Hippocampus reidi, under natural conditions at Ilha Grande bay, Brazil, and both adult, juvenile and fry individuals kept in captivity. Although displaying the same colour emissions, seahorses differed in relation to body lighting, colour patterns, and age wherein fluorescence occurs. Newborn seahorses exhibit green biofluorescence only in the eyes and stomach. Further experiments are necessary to address whether H. reidi can change the patterns of biofluorescence emission for sensorial and social purposes.

In chronic kidney disease both renal insufficiency and chronic inflammation trigger elevated hepcidin levels, which impairs iron uptake, availability. and erythropoiesis. Here we report the two first-in-human phase 1 trials of PRS-080#22, a novel, rationally engineered Anticalin protein that targets and antagonizes hepcidin. A single intravenous infusion of placebo or PRS-080#22 was administered to 48 healthy volunteers (phase 1a) and 24 patients with end stage chronic kidney disease (CKD) on hemodialysis (phase 1b) at different doses (0.08-16mg/kg for the phase 1a study and 2-8mg/kg for the phase 1b study) in successive dosing cohorts. The primary endpoint for both randomized, double-blind, phase 1 trials was safety and tolerability. Following treatment, all subjects were evaluable, with none experiencing dose limiting toxicities. Most adverse events were mild. One serious adverse event occurred in the phase 1b (CKD patient) study. There were no clinically significant changes in safety laboratory values or vital signs. PRS-080#22 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately three days in healthy volunteers and 10 to 12 days in CKD patients. Serum hepcidin levels were suppressed in a dose dependent manner and remained low for up to 48 hours after dosing. PRS-080#22 dose-dependently mobilized serum iron with increases in both serum iron concentration and transferrin saturation. No consistent changes were observed with regard to ferritin, reticulocytes, hemoglobin, and reticulocyte hemoglobin. Low titer anti-drug-antibodies were detected in five healthy volunteers but in none of the CKD patients. PRS-080#22, a novel Anticalin protein with picomolar affinity for hepcidin, was safe and well-tolerated when administered to healthy volunteers and CKD patients at all doses tested. The drug exhibited linear pharmacokinetics, longer half-life in CKD patients in comparison to healthy volunteers as well as expected pharmacodynamic effects which hold promise for further clinical studies.

PurposeModern non-invasive evaluation of Coronary Artery Disease (CAD) requires non-contrast low dose Computed Tomography (CT) imaging for determination of Calcium Scoring (CACS) and contrast-enhanced imaging for evaluation of vascular stenosis. Several methods for calculation of CACS from contrast-enhanced images have been proposed before. The main principle for that is generation of virtual non-contrast images by iodine subtraction from a contrast-enhanced spectral CT dataset. However, those techniques have some limitations: Dual-Source CT imaging can lead to increased radiation exposure, and switching of the tube voltage (rapid kVp switching) can be associated with slower rotation speed of the gantry and is thus prone to motion artefacts that are especially critical in cardiac imaging. Both techniques cannot simultaneously acquire spectral data. A novel technique to overcome these difficulties is spectral imaging with a dual-layer detector. After absorption of the lower energetic photons in the first layer, the second layer detects a hardened spectrum of the emitted radiation resulting in registration of two different energy spectra at the same time. The objective of the present investigation was to evaluate the accuracy of virtual non-contrast CACS computed from spectral data in comparison to standard non-contrast imaging.MethodsWe consecutively investigated 20 patients referred to Coronary Computed Tomography Angiography (CCTA) with suspicion of CAD using a Dual-Layer spectral CT system (IQon; Philips Healthcare, The Netherlands). CACS was calculated from both, real- and virtual non-contrast images by certified software for medical use. Correlation analyses for real- and virtual non-contrast images and agreement evaluation with Bland-Altman-Plots were performed.ResultsMean patient age was 57.7 ± 14 years (n = 20). 13 patients (65%) were male. Inter-quartile-range of clinical CACS was 0-448, the mean was 334. Correlation of CACS from real- and virtual non-contrast images was very high (0.94); p < 0.0001. The slope was 2.3 indicating that values from virtual non-contrast images are approximately half of the results obtained from real non-contrast data. Visual analysis of Bland-Altman-Plot shows good accordance of both methods when results from virtual non-contrast data are multiplied by the slope of the logistic regression model (2.3). The acquired power of this results is 0.99.ConclusionDetermination of Calcium Score from contrast enhanced CCTA using spectral imaging with a dual-layer detector is feasible and shows good agreement with the conventional technique when a proportionality factor is applied. The observed difference between both methods is due to an underestimation of plaque volume, and-to an even greater extend -an underestimation of plaque density with the virtual non-contrast approach. Our data suggest that radiation exposure can be reduced through omitting additional native scans for patients referred to CCTA when using a dual-layer spectral system without the usual limitations of dual energy analysis.

Long-term survival of high-risk neuroblastoma (NB) patients still remains under 50%. Here, we report the generation, in vitro characterization and anti-tumor effectivity of a new bicistronic xenogenic DNA vaccine encoding tyrosine hydroxylase (TH) that is highly expressed in NB tumors, and the immune stimulating cytokine interleukin 15 (IL-15) that induces cytotoxic but not regulatory T cells. The DNA sequences of TH linked to ubiquitin and of IL-15 were integrated into the bicistronic expression vector pIRES. Successful production and bioactivity of the vaccine-derived IL-15- and TH protein were shown by ELISA, bioactivity assay and western blot analysis. Further, DNA vaccine-driven gene transfer to the antigen presenting cells of Peyer's patches using attenuated Salmonella typhimurium that served as oral delivery system was shown by immunofluorescence analysis. The anti-tumor effect of the generated vaccine was evaluated in a syngeneic mouse model (A/J mice, n = 12) after immunization with S. typhimurium (3× prior and 3× after tumor implantation). Importantly, TH-/IL-15-based DNA vaccination resulted in an enhanced tumor remission in 45.5% of mice compared to controls (TH (16.7%), IL-15 (0%)) and reduced spontaneous metastasis (30.0%) compared to controls (TH (63.6%), IL-15 (70.0%)). Interestingly, similar levels of tumor infiltrating CD8+ T cells were observed among all experimental groups. Finally, co-expression of IL-15 did not result in elevated regulatory T cell levels in tumor environment measured by flow cytometry. In conclusion, co-expression of the stimulatory cytokine IL-15 enhanced the NB-specific anti-tumor effectivity of a TH-directed vaccination in mice and may provide a novel immunological approach for NB patients.

Introduction: Diet and activity counseling is recommended during all well child visits to promote optimal health and prevent childhood obesity. The objective of this study was to determine the effectiveness of a novel Wellness Action Plan aimed at: 1) improving parent recall of diet and activity plans made during routine well child visits 2) increasing adherence with plans, and 3) enhancing parents' identification of their child's weight category. Methods: Parents of children 2.5 to 14 years (n = 181) seen at a pediatric primary care clinic in Milwaukee, Wisconsin between March and August of 2013 received standard diet and activity counseling from their physician (both control and intervention groups). In addition, parents randomized to the intervention group were asked to complete a Wellness Action Plan, where established diet and activity goals were documented. Parents completed surveys about BMI identification, plan creation, and plan adherence pre visit, post visit, and at 1 and 3 months. Results: Intervention parents were significantly more likely to recall diet (p = 0.003) and activity (p = 0.03) plans at 3 months and were also more likely to report adherence with diet (p = 0.006) and activity (p = 0.08) plans at three months. There was no difference between groups in their ability to correctly identify children's weight categories (p > 0.05). Conclusion: The Wellness Action Plan was associated with higher parent diet and activity plan recall and self-reported adherence. The Wellness Action Plan is a potentially important counseling tool that can be used to help parents make lifestyle modifications for their children. Clinical Trial Registration: ClinicalTrials.gov, Identifier NCT02185248.

BACKGROUND:Implementation of evidence-based treatment for pre-hospital status epilepticus can improve outcomes. We hypothesized that publication of a pivotal pre-hospital clinical trial (RAMPART), demonstrating superiority of intramuscular midazolam over intravenous lorazepam, altered the national utilization rates of midazolam for pre-hospital benzodiazepine-treated seizures, while upholding its safety and efficacy outside the trial setting. METHODS AND FINDINGS:This is a retrospective, observational cohort study of pre-hospital patient encounters throughout the United States in the National Emergency Medicine Services Information System database, from January 2010 through December 2014. We compared the rates and odds of midazolam use as first-line treatment among all adult and pediatric benzodiazepine-treated seizures before and after RAMPART publication (February 2012). Secondary analyses were conducted for rates of airway interventions and rescue therapy, as proxies for safety and efficacy of seizure termination. 156,539 benzodiazepine-treated seizures were identified. Midazolam use increased from 26.1% in January 2010 to 61.7% in December 2014 (difference +35.6%, 95% CI, 32.7%-38.4%). The annual rate of midazolam adoption increased significantly from 5.9% per year to 8.9% per year after the publication of RAMPART (difference +3.0% per year; 95%CI, 1.6%-4.5% per year; adjusted OR 1.24; 95%CI, 1.17-1.32). Overall frequency of rescue therapy and airway interventions changed little after the publication of RAMPART. CONCLUSIONS:These data are consistent with effective, ongoing, but incomplete clinical translation of the RAMPART results. The effects of the trial, however, cannot be isolated. The study was limited by broad inclusion of all benzodiazepine-treated seizures as well as a lack of information on route of drug of administration. The safety and effectiveness of midazolam for benzodiazepine-treated seizures in prehospital clinical practice appear consistent with trial data, which should encourage continuing increases in utilization.