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Case Presentation: A 32-year-old male who recently immigrated from Kenya presented to the emergency department (ED) with a painful, enlarging, right-sided neck mass for eight weeks duration. Point-of-care ultrasound was used to reveal a large cystic mass with internal septations and numerous hypoechoic round lesions. Initial tuberculosis blood test ordered in the ED was positive with cultures ultimately growing Mycobaceterium tuberculosis.Discussion: Scrofula should be considered in the differential in patients presenting with enlarging neck masses who have epidemiological risk factors for tuberculosis.

Background: It can be challenging for people with intellectual disabilities to convey their thoughts and opinions because of cognitive, speech and language impairments. Consequently, facilitating their ability to communicate using augmentative and alternative communication methods is essential. The picture-based framework Talking Mats has been applied in many studies and has been shown to be successful in facilitating communication and soliciting views from individuals with intellectual disabilities and communication difficulties. The aim of this study was to describe the views of students with intellectual disabilities and communication difficulties on speech and reading activities and to examine whether valence scores (from negative to positive) on these views were associated with performance on tests of their corresponding abilities. Methods: This is a cross-sectional quantitative survey study. A group of 111 students with intellectual disabilities and communication difficulties aged 7-21 were interviewed about their speech and reading activities using the visual framework Talking Mats. Their answers were scored on a three-grade like-dislike continuum and were correlated with their results on adapted tests of the corresponding abilities. Findings: The students expressed their views on speech and reading activities. The scored views on speech were positively associated with speech production, and the scored views on reading activities were positively related to reading ability. This suggests that their opinions as expressed through Talking Mats were consistent and reliable. Conclusions: Most students with intellectual disabilities and communicative difficulties can reliably express their own opinions of their abilities when they are provided with a clear visual structure and pictorial support, such as Talking Mats. In this study, this was seen for students with a mild intellectual disability from age seven and onwards and for students with a more severe intellectual disability from 12 years of age and onwards.

Abstract Theories of embodied cognition suggest that a shared environment and ongoing sensorimotor interaction are central for interpersonal learning and engagement. To investigate the embodied, distributed and hence dynamically unfolding nature of social cognitive capacities, we present a novel laboratory-based coordination task: the BallGame. Our paradigm requires continuous sensing and acting between two players who jointly steer a virtual ball around obstacles towards as many targets as possible. By analysing highly resolved measures of movement coordination and gaming behaviour, game-concurrent experience ratings, semi-structured interviews, and personality questionnaires, we reveal contributions from different levels of observation on social experience. In particular, successful coordination (number of targets collected) and intermittent periods of high versus low movement coordination (variability of relation) emerged as prominent predictors of social experience. Importantly, having the same (but incomplete) view on the game environment strengthened interpersonal coordination, whereas complementary views enhanced engagement and tended to generate more complex interactive behaviour. Overall, we find evidence for a critical balance between similarity and synchrony on the one hand, and variability and difference on the other, for successful engagement in social interactions. Finally, following participant reports, we highlight how interpersonal experience emerges from specific histories of coordination that are closely related to the interaction context in both space and time.

Abstract Objectives To compare the prevalence of femoral head decentration (FHD) on different MR imaging planes in patients undergoing direct/indirect hip MR arthrography (MRA) with asymptomatic controls and to evaluate its association with osseous deformities. Methods IRB-approved retrospective single-center study of symptomatic hips undergoing direct or indirect hip MRA at 3 T. Asymptomatic participants underwent non-contrast hip MRI at 3 T. FHD was defined as a continuous fluid layer between the acetabulum and femoral head and assessed on axial, sagittal and radial images. The association of intra-articular/intra-venous contrast agents and the prevalence of FHD was evaluated. The association of FHD with osseous deformities and joint damage was assessed using multiple logistic regression analysis. Results Three-hundred ninety-four patients (447 hips, mean age 31 ± 9 years, 247 females) were included and compared to 43 asymptomatic controls (43 hips, mean age 31 ± 6 years, 26 females). FHD was most prevalent on radial images and more frequent in symptomatic hips (30% versus 2%, p

Abstract Background Mild cognitive impairment (MCI) involves cognitive decline beyond typical age-related changes, but without significant daily activity disruption. It can encompass various cognitive domains as the causes of MCI are diverse. MCI as well as frequent comorbid neuropsychiatric conditions like depression and anxiety affect individuals’ quality of life. Early interventions are essential, and computerized cognitive training (cCT) is an established treatment method. This paper presents the protocol for the NeuroNation MED Effectiveness Study, evaluating the self-administered mobile cCT intervention (“NeuroNation MED”) in individuals with MCI to assess training effects on cognitive domains, health competence, neuropsychiatric symptoms, psychological well-being, and the general application usability. Methods This study protocol presents a single-blinded multicenter randomized controlled trial that will be carried out in six study centers in Germany and Luxembourg. We included adults with MCI (existing F06.7 ICD-10-GM diagnosis and TICS ≥ 21 and ≤ 32). The intervention group will use a mobile, multi-domain cCT (“NeuroNation MED”) for 12 weeks. Meanwhile, the wait list control group will receive standard medical care or no care. The eligibility of volunteers will be determined through a telephone screening. After completion of the baseline examination, patients will be randomly assigned to one of the experimental conditions in a 2:1 ratio. In total, 286 participants will be included in this study. The primary outcome is the change of cognitive performance measured by the index score of the screening module of the Neuropsychological Assessment Battery. Secondary outcomes are changes in the Cognitive Failures Questionnaire, Hospital Anxiety and Depression Scale, Health-49, Health Literacy Questionnaire, among others. All of the primary and secondary outcomes will be assessed at baseline and after the 12-week post-allocation period. Furthermore, the intervention group will undergo an assessment of the System Usability Scale, and the training data of the NeuroNation MED application will be analyzed. Discussion This study aims to assess the effectiveness of a mobile self-administered cCT in enhancing cognitive abilities among individuals diagnosed with MCI. Should the findings confirm the effectiveness of the NeuroNation MED app, it may confer possible benefits for the care management of patients with MCI, owing to the accessibility, cost-effectiveness, and home-based setting it provides. Specifically, the cCT program could provide patients with personalized cognitive training, educational resources, and relaxation techniques, enabling participants to independently engage in cognitive training sessions at home without further supervision. Trial registration German Clinical Trials Register DRKS00025133. Registered on November 5, 2021.

Case Presentation: A 32-year-old male who recently immigrated from Kenya presented to the emergency department (ED) with a painful, enlarging, right-sided neck mass for eight weeks duration. Point-of-care ultrasound was used to reveal a large cystic mass with internal septations and numerous hypoechoic round lesions. Initial tuberculosis blood test ordered in the ED was positive with cultures ultimately growing Mycobaceterium tuberculosis. Discussion: Scrofula should be considered in the differential in patients presenting with enlarging neck masses who have epidemiological risk factors for tuberculosis.

Climate warming and associated accelerated permafrost thaw in the Arctic lead to a shift in landscape patterns, hydrologic conditions, and release of carbon. In this context, the lateral transport of carbon and shifts therein following thaw remain poorly understood. Crucial hydrologic factors affecting the lateral distribution of carbon include the depth of the saturated zone above the permafrost table with respect to changes in water table and thaw depth and the connectivity of water-saturated zones. Landscape conditions are expected to change in the future due to rising temperatures and polygonal or flat floodplain Arctic tundra areas in various states of degradation; hydrologic conditions will also change. This study is focused on an experimental site near Chersky, northeast Siberia, where a drainage ditch was constructed in 2004 to simulate landscape degradation features that result in drier soil conditions and channeled water flow. We compared water levels and thaw depths in the drained area (dry soil conditions) with those in an adjacent control area (wet soil conditions). We also identified the sources of water at the site via stable water isotope analysis. We found substantial spatiotemporal changes in the water conditions at the drained site: (i) lower water tables resulting in drier soil conditions, (ii) quicker water flow through drier areas, (iii) larger saturation zones in wetter areas, and (iv) a higher proportion of permafrost meltwater in the liquid phase towards the end of the growing season. These findings suggest decreased lateral connectivity throughout the drained area. Shifts in hydraulic connectivity in combination with a shift in vegetation abundance and water sources may impact carbon sources and sinks as well as transport pathways. Identifying lateral transport patterns in areas with degrading permafrost is therefore crucial.

Abstract The transforming growth factor (TGF)-β3 is a well-known inducer for tenogenic differentiation, signaling via the Smad2/3 pathway. Furthermore, other factors like extracellular matrix or mechanical force can induce tenogenic differentiation and possibly alter the response to TGF-β3 by signaling via the Rho/ROCK pathway. The aim of this study was to investigate the interplay of Rho/ROCK and TGF-β3/Smad signaling in tenogenic differentiation, with the Smad2/3 molecule hypothesized as a possible interface. Cultured as monolayers or on collagen I matrices, mesenchymal stromal cells (MSC) were treated with the ROCK inhibitor Y-27632 (10 µM), TGF-β3 (10 ng/ml) or both combined. Control cells were cultured accordingly, without Y-27632 and/or without TGF-β3. At different time points, MSC were analyzed by real-time RT-PCR, immunofluorescence, and Western blot. Cultivation of MSC on collagen matrices and ROCK inhibition supported tenogenic differentiation and fostered the effect of TGF-β3. The phosphorylation of the linker region of Smad2 was reduced by cultivation on collagen matrices, but not by ROCK inhibition. The latter, however, led to increased phosphorylation of the linker region of Smad3. In conclusion, collagen matrices and the Rho/ROCK signaling pathway influence the TGF-β3/Smad2/3 pathway by regulating different phosphorylation sites of the Smad linker region.

Therapeutic management of patients with leptomeningeal carcinomatosis (LC) may require treatment of concomitant hydrocephalus (HC) in addition to intrathecal chemotherapy (ITC). Ventriculoperitoneal shunts (VPS) equipped with a valve for manual deactivation of shunt function and a concomitant reservoir for application of ITC pose an elegant solution to both problems. The present study evaluates indication, feasibility, and safety of such a modified shunt/reservoir design (mS/R). All patients with LC aged ≥ 18 years who had undergone mS/R implantation between 2013 and 2020 at the authors’ institution were further analyzed. ITC was indicated following the recommendation of the neuro-oncological tumor board and performed according to a standardized protocol. Sixteen patients with LC underwent mS/R implantation for subsequent ITC and concomitant treatment of HC. Regarding HC-related clinical symptoms, 69% of patients preoperatively exhibited lethargy, 38% cognitive impairment, and 38% (additional) visual disturbances. Postoperatively, 86% of patients achieved subjective improvement of HC-related symptoms. Overall, postoperative complications occurred in three patients (19%). No patient encountered cancer treatment-related complications. The present study describes a combination procedure consisting of a standard VPS-system and a standard reservoir for patients suffering from LC and HC. No cancer treatment-related complications occurred, indicating straightforward handling and thus safety.

Abstract Background The efficacy of oncolytic viruses (OV) in cancer treatment depends on their ability to successfully infect and destroy tumor cells. However, patients’ tumors vary, and in the case of individual insensitivity to an OV, therapeutic efficacy is limited. Here, we present a protocol for rapid generation of tumor cell-specific adapted oncolytic coxsackievirus B3 (CVB3) with enhanced oncolytic potential and a satisfactory safety profile. This is achieved by combining directed viral evolution (DVE) with genetic modification of the viral genome and the use of a microRNA-dependent regulatory tool. Methods The oncolytic CVB3 variant PD-H was adapted to the refractory colorectal carcinoma cell line Colo320 through serial passaging. XTT assays and virus plaque assays were used to determine virus cytotoxicity and virus replication in vitro. Recombinant PD-H variants were generated through virus mutagenesis. Apoptosis was detected by Western blots, Caspase 3/7 assays, and DAPI staining. The therapeutic efficacy and safety of the adapted recombinant OV PD-SK-375TS were assessed in vivo using a subcutaneous Colo320 xenograft mouse model. Results PD-H was adapted to the colorectal cancer cell line Colo320 within 10 passages. Sequencing of passage 10 virus P-10 revealed a heterogenous virus population with five nucleotide mutations resulting in amino acid substitutions. The genotypically homogeneous OV PD-SK was generated by inserting the five detected mutations of P-10 into the genome of PD-H. PD-SK showed significantly stronger replication and cytotoxicity than PD-H in Colo320 cells, but not in other colorectal carcinoma cell lines. Increase of apoptosis induction was detected as key mechanisms of Colo320 cell-specific adaptation of PD-SK. For in vivo safety PD-SK was engineered with target sites of the miR-375 (miR-375TS) to exclude virus replication in normal tissues. PD-SK-375TS, unlike the PD-H-375TS not adapted homolog suppressed the growth of subcutaneous Colo320 tumors in nude mice without causing any side effects. Conclusion Taken together, here we present an optimized protocol for the rapid generation of tumor cell-specific adapted oncolytic CVB3 based on the oncolytic CVB3 strain PD-H. The protocol is promising for the generation of personalized OV for tumor therapy and has the potential to be applied to other OV.

We live in times of humanitarian and environmental crises. The effects of climate change add to the economic, physical, and mental suffering caused by social discrimination, in the form of gender, class, and race inequalities. Encounters with and creation of arts have been suggested as a potential remedy, allowing to stay with the trouble rather than running from it, and imagining a different future rather than manifesting the past. But what are the concrete chances that all this really happens? Similar questions can be raised in relation to immersive media. The latter have been claimed to possess an unprecedented prosocial potential. However, what are the appropriate strategies to ensure that such potential is actually expressed? For this issue of AN-ICON. Studies in Environmental Images, we selected diverse contributions investigating the role of the arts and media in rethinking (and acting upon) societal and environmental problems, focussing on immersive experiences in particular.

BackgroundPreterm birth and fetal growth restriction are the main determinants of perinatal mortality. In the absence of therapeutic interventions, management is restricted to the observation of fetal growth and fetoplacental perfusion to determine the timing of delivery. Fetal circulatory redistribution, known as “brain sparing,” represents a sign of fetal hypoxia and has been implemented in algorithms for when to deliver. In the absence of any other option, the nitric oxide donor pentaerythrityl tetranitrate (PETN), which has been shown to improve fetoplacental flow and reduce preterm birth in high-risk patients, is offered to patients as a personal therapy attempt. The aim of this study was to evaluate determinants related to pregnancy, including PETN intake during pregnancy, on immediate neonatal outcomes in a cohort of growth-restricted infants born before 32 completed weeks of gestation.MethodsWe performed a retrospective cohort study of 98 infants born with a birth weight below the 10th percentile before 32 completed weeks of gestation at our tertiary care center between 2010 and 2019. PETN was offered to all mothers with a history of severe adverse pregnancy outcomes who were at high risk of developing fetal growth restriction as an individual therapy attempt.ResultsThe mean gestational age at birth was 188.5 days, and the mean birth weight was 549 g, corresponding to a median percentile of three. In 73 (79.3%) cases, brain sparing occurred during pregnancy. A total of 22 (22.4%) neonates were stillborn, 20 died postnatally, and 37.3% developed a severe complication. Multivariable analysis revealed birth weight percentile, gestational age at birth, and gestational age when brain sparing first occurred to be robust predictors of mortality or severe neonatal morbidity. In 39 neonates of mothers taking PETN, this impact of brain sparing was not observed.ConclusionOur study is the first to demonstrate a significant association between the early occurrence of brain-sparing and severe neonatal outcomes in a cohort of very early preterm, growth-restricted newborns. The data suggest that PETN intake may ameliorate the effect of brain sparing in the affected neonates.

Objectives To train, test and validate the performance of a convolutional neural network (CNN)-based approach for the automated assessment of bone erosions, osteitis and synovitis in hand MRI of patients with inflammatory arthritis.Methods Hand MRIs (coronal T1-weighted, T2-weighted fat-suppressed, T1-weighted fat-suppressed contrast-enhanced) of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients from the rheumatology department of the Erlangen University Hospital were assessed by two expert rheumatologists using the Outcome Measures in Rheumatology-validated RA MRI Scoring System and PsA MRI Scoring System scores and were used to train, validate and test CNNs to automatically score erosions, osteitis and synovitis. Scoring performance was compared with human annotations in terms of macro-area under the receiver operating characteristic curve (AUC) and balanced accuracy using fivefold cross-validation. Validation was performed on an independent dataset of MRIs from a second patient cohort.Results In total, 211 MRIs from 112 patients (14 906 region of interests (ROIs)) were included for training/internal validation using cross-validation and 220 MRIs from 75 patients (11 040 ROIs) for external validation of the networks. The networks achieved high mean (SD) macro-AUC of 92%±1% for erosions, 91%±2% for osteitis and 85%±2% for synovitis. Compared with human annotation, CNNs achieved a high mean Spearman correlation for erosions (90±2%), osteitis (78±8%) and synovitis (69±7%), which remained consistent in the validation dataset.Conclusions We developed a CNN-based automated scoring system that allowed a rapid grading of erosions, osteitis and synovitis with good diagnostic accuracy and using less MRI sequences compared with conventional scoring. This CNN-based approach may help develop standardised cost-efficient and time-efficient assessments of hand MRIs for patients with arthritis.

We utilize hybrid quantum deep reinforcement learning to learn navigation tasks for a simple, wheeled robot in simulated environments of increasing complexity. For this, we train parameterized quantum circuits (PQCs) with two different encoding strategies in a hybrid quantum-classical setup as well as a classical neural network baseline with the double deep Q network (DDQN) reinforcement learning algorithm. Quantum deep reinforcement learning (QDRL) has previously been studied in several relatively simple benchmark environments, mainly from the OpenAI gym suite. However, scaling behavior and applicability of QDRL to more demanding tasks closer to real-world problems e.g., from the robotics domain, have not been studied previously. Here, we show that quantum circuits in hybrid quantum-classic reinforcement learning setups are capable of learning optimal policies in multiple robotic navigation scenarios with notably fewer trainable parameters compared to a classical baseline. Across a large number of experimental configurations, we find that the employed quantum circuits outperform the classical neural network baselines when equating for the number of trainable parameters. Yet, the classical neural network consistently showed better results concerning training times and stability, with at least one order of magnitude of trainable parameters more than the best-performing quantum circuits. However, validating the robustness of the learning methods in a large and dynamic environment, we find that the classical baseline produces more stable and better performing policies overall. For the two encoding schemes, we observed better results for consecutively encoding the classical state vector on each qubit compared to encoding each component on a separate qubit. Our findings demonstrate that current hybrid quantum machine-learning approaches can be scaled to simple robotic problems while yielding sufficient results, at least in an idealized simulated setting, but there are yet open questions regarding the application to considerably more demanding tasks. We anticipate that our work will contribute to introducing quantum machine learning in general and quantum deep reinforcement learning in particular to more demanding problem domains and emphasize the importance of encoding techniques for classic data in hybrid quantum-classical settings.

Abstract Background Foot lesions in suckling piglets have been associated with poor flooring in several studies and were recently proposed to be indicative of swine inflammatory and necrosis syndrome. However, identical findings are also the typical outcome of various non-infectious causes; thus, further risk analysis is needed. The objective of this study was to describe the development of heel bruising, coronary band lesions and forelimb skin abrasion in suckling pigs up to 5 days of age. Furthermore, the effects of various intrinsic and extrinsic factors were examined. On each of four commercial piglet-producing farms, piglets from two or three batches of eight sows were studied. The piglets were included within 18 h after birth. Each piglet was individually scored four times. The score for the heels differentiated six (0–5) and for the coronary band and forelimb skin abrasion three stages (0–2). The body weight was measured two times. The effect of the floor was estimated by allocating the sows randomly to farrowing pens equipped with either soft rubber mats covered with litter or fully slatted plastic floors. Results The final analysis comprised data from 1045 piglets. Foot lesions were not found at birth but started to develop on day 1. On day 5, heel bruising was found in 94%, main claw coronary band lesions in 49% and forelimb skin abrasion in 73% of the piglets. In a multifactorial logistic regression analysis, it was shown that a slatted plastic floor significantly increased the odds of heel bruising and coronary band lesions, while a rubber floor with litter increased the odds of forelimb skin abrasions. Conclusion Foot and forelimb lesions in new-born piglets are mainly induced by the floor. The effect of slatted plastic floors on heel bruising showed an overwhelming OR of 52.89 (CI 26.29–106.43). Notably, coronary band lesions in young suckling piglets occur on slatted as well as non-slatted floors, indicating that the piglets incur these injuries not only from the wedging of their feet into the gaps between slats but also from contact with the floor while suckling. Based on these findings, preventive measures should be redirected to the improvement of the floor in the farrowing pen, particularly in the area under the sow’s udder.

Abstract Background Intervertebral disk (IVD) degeneration affects both humans and canines and is a major cause of low back pain (LBP). Mast cell (MC) and macrophage (MØ) infiltration has been identified in the pathogenesis of IVD degeneration (IVDD) in the human and rodent model but remains understudied in the canine. MC degranulation in the IVD leads to a pro‐inflammatory cascade and activates protease activated receptor 2 (PAR2) on IVD cells. The objectives of the present study are to: (1) highlight the pathophysiological changes observed in the degenerate canine IVD, (2) further characterize the inflammatory effect of MCs co‐cultured with canine nucleus pulposus (NP) cells, (3) evaluate the effect of construct stiffness on NP and MCs, and (4) identify potential therapeutics to mitigate pathologic changes in the IVD microenvironment. Methods Canine IVD tissue was isolated from healthy autopsy research dogs (beagle) and pet dogs undergoing laminectomy for IVD herniation. Morphology, protein content, and inflammatory markers were assessed. NP cells isolated from healthy autopsy (Mongrel hounds) tissue were co‐cultured with canine MCs within agarose constructs and treated with cromolyn sodium (CS) and PAR2 antagonist (PAR2A). Gene expression, sulfated glycosaminoglycan content, and stiffness of constructs were assessed. Results CD 31+ blood vessels, mast cell tryptase, and macrophage CD 163+ were increased in the degenerate surgical canine tissue compared to healthy autopsy. Pro‐inflammatory genes were upregulated when canine NP cells were co‐cultured with MCs and the stiffer microenvironment enhanced these effects. Treatment with CS and PAR2 inhibitors mediated key pro‐inflammatory markers in canine NP cells. Conclusion There is increased MC, MØs, and vascular ingrowth in the degenerate canine IVD tissue, similar to observations in the clinical population with IVDD and LBP. MCs co‐cultured with canine NP cells drive inflammation, and CS and PAR2A are potential therapeutics that may mitigate the pathophysiology of IVDD in vitro.

Abstract Bee declines pose a serious risk to agricultural sustainability, wild plant diversity, and the commercial bee industry, generating local and global concerns about bee health. Parasites, including micro‐parasites and macro‐parasites, negatively impact bee population dynamics. Management of parasites requires an understanding of the cyclic trends in prevalence and the factors impacting these patterns. In this study, we advance understanding of parasite epidemiology and transmission among members of the bee community toward the goal of improving predictability of parasite prevalence seasonally. Honey bees and bumble bees were collected throughout an active season and across multiple overwintering periods. These bees were molecularly tested for two common bee viruses—deformed wing virus (DWV) and black queen cell virus (BQCV)—and morphologically screened for Vairimorpha spp., nematodes, and parasitic flies to determine whether these parasites exhibit unique seasonal trends, if overwintering behavior impacts parasite survival, and how these patterns differ between honey bees and bumble bees. The results suggest consistent seasonal trends between honey bees and bumble bees; however, these trends are parasite‐specific. Honey bees consistently exhibited a higher magnitude of viral prevalence compared with bumble bees. Both honey bees and bumble bees reduced viral prevalence over the winter; however, only in bumble bees did this drop to negligible prevalence each spring. These data suggest that honey bees may have a larger impact on parasite transmission, as they pose to reinfect bees which otherwise would have very low prevalence each spring and sustain high levels of infection in communities year‐round.

Recent advances in sensor technology for air pollution monitoring open new possibilities in the field of environmental epidemiology. The low spatial resolution of fixed outdoor measurement stations and modelling uncertainties currently limit the understanding of personal exposure. In this context, air quality sensor systems (AQSSs) offer significant potential to enhance personal exposure assessment. A pilot study was conducted to investigate the feasibility of the NO2 sensor model B43F and the particulate matter (PM) sensor model OPC-R1, both from Alphasense (UK), for use in epidemiological studies. Seven patients with chronic obstructive pulmonary disease (COPD) or asthma had built-for-purpose sensor systems placed inside and outside of their homes at fixed locations for one month. Participants documented their indoor activities, presence in the house, window status, and symptom severity and performed a peak expiratory flow test. The potential inhaled doses of PM2.5 and NO2 were calculated using different data sources such as outdoor data from air quality monitoring stations, indoor data from AQSSs, and generic inhalation rates (IR) or activity-specific IR. Moreover, the relation between indoor and outdoor air quality obtained with AQSSs, an indoor source apportionment study, and an evaluation of the suitability of the AQSS data for studying the relationship between air quality and health were investigated. The results highlight the value of the sensor data and the importance of monitoring indoor air quality and activity patterns to avoid exposure misclassification. The use of AQSSs at fixed locations shows promise for larger-scale and/or long-term epidemiological studies.

IntroductionModic changes (MC) are signs of vertebral pathology visible on magnetic resonance (MR) images that have been associated with low back pain (LBP) and disc degeneration in people. Multiple breeds of dogs also develop MCs and coincident back pain. However, the association between breed, MC, and spinal pathologies has yet to be fully elucidated. This study aimed to identify the prevalence of MC that occur spontaneously in the lumbar vertebral column of dogs diagnosed with intervertebral disc disease (IVDD) and examine their association with demographic criteria and the disc width index (DWI).MethodsMedical records and lumbar vertebral column MR images were examined from 104 dogs (831 intervertebral disc spaces and adjacent vertebrae), which were divided into three groups: chondrodystrophic dogs (CD; n =54) and non-chondrodystrophic dogs (NCD; n =30) with IVDD as the primary diagnosis, and control dogs (n =20) with other spinal diseases as their primary diagnosis.ResultsIncreasing age and a diagnosis of IVDD were significantly associated with MC in dogs (p

Introduction: In addition to age-related changes in language, hemispheric lateralization of language functions steadily declines with age. Also, performance on word fluency tasks declines and is sensitive to the expression of dementia-related changes. The aim of this study is to evaluate the effect of anodal tDCS combined with a word fluency training on language lateralization and word fluency performance in healthy elderly subjects and in persons with mild cognitive impairment (MCI).Methods: The effect of anodal tDCS over the left inferio frontal gyrus (IFG) was measured in a group of healthy elderly up to the age of 67 years (YG, Ø = 63.9 ± 3.02), a group of healthy elderly aged 68 years and older (OG, Ø = 78.1, ± 4.85), and a group of patients with MCI (Ø = 81.18, ± 7.35) by comparing performance in phonological and semantic word fluency tasks before and after 3 days of tDCS. Half of the experimental participants received sham stimulation. In addition, language lateralization was determined using a lateralization index (LI) measured with functional transcranial Doppler sonography (fTCD) before and after the stimulation period.Results: Anodal tDCS was associated with significantly higher scores in phonological but not semantic word fluency in both YG and OG. In MCI patients, no difference was measured between the tDCS and sham groups in either word fluency task. fTCD showed significantly increased left lateralization in all three groups after the training phase. However, this effect was independent of tDCS and the degree of lateralization could not be predicted by word fluency performance in any of the groups.Discussion: Phonological word fluency can be increased with atDCS in healthy elderly people by stimulating the IFG in a 3-day training. When cognitive decline has reached a certain stage, as is the case with MCI, this paradigm does not seem to be effective enough.

Introduction: Targeting the tumor microenvironment may enhance response to immunotherapy (immune checkpoint inhibitors) and improve outcomes for patients. This study tested the safety and efficacy of vorolanib, a novel tyrosine kinase inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and c-KIT, in combination with programmed cell death protein 1 blockade using nivolumab for refractory thoracic malignancies. Methods: This single-arm multicenter study enrolled patients with extensive-stage SCLC, thymic carcinoma, and NSCLC, either naive or had progressed on previous chemotherapy or immune checkpoint inhibitors (either primary or acquired resistance). The primary objective of phase 1 was to determine the maximum tolerated dose, and the primary end point for each dose-expansion cohort was the objective response rate. Results: A total of 88 patients were enrolled in phase 1 (n = 11) and dose expansion (n = 77) cohorts. Transaminitis was dose-limiting and expansion proceeded with oral vorolanib 200 mg daily combined with intravenous nivolumab 240 mg every 2 weeks. The objective response rate per cohort were as follows: NSCLC naive 33% (five of 15, 95% confidence interval [CI]: 13%–60%), NSCLC primary refractory 5.9% (one of 17, 95% CI: 0%–17.6%), NSCLC acquired resistance 11.1% (two of 18, 95% CI: 0%–27.8%); SCLC 0% (zero of 18), and thymic carcinoma 11% (one of nine, 95% CI: 0%–33%). Disease control rate ranged from 11.1% in SCLC (two of 18, 0%–27.8%) to 66.7 % in thymic carcinoma (six of nine, 95% CI: 33.3%–100%). The most common adverse events were fatigue (32%), aspartate transaminase (27%) and alanine transaminase elevation (25%), and diarrhea (19%). Transaminitis was more common in patients with thymic carcinoma than other tumors. Conclusions: Vorolanib plus nivolumab had a manageable safety profile and may have clinical benefits in various thoracic malignancies. The disease control rate in thymic malignancies warrants further assessment.

Abstract The Renewable Energy Directive (RED II) by the European Union (EU) provides an updated framework for the use of renewable energy in the EU transport sector until 2030, and bans the use of biofuels with a high risk of causing indirect land‐use change in high carbon stock areas (high ILUC‐risk criteria). The only biofuel feedstock affected by this criterion is palm oil. We employ the computable general equilibrium (CGE) model DART‐BIO for a scenario‐based policy analysis and evaluate a phase‐out of palm oil‐based biodiesel, and an additional phase‐out of soy oil‐based biodiesel in the EU. Our results show that the palm phase‐out has only a relatively small impact on global palm fruit production and total crop land use in tropical and subtropical regions, while the soy phase‐out leads to a comparable stronger decrease in global soy production, and a reduction in total cropland use in soy‐producing regions. Both policies lead to increased oilseed production in the EU. Therefore, farmer in Malaysia and Indonesia face a significantly reduced income. While European farmers profit the most, EU firms and households are confronted with higher expenditures. Finally, this study indicates that unilateral demand‐side regulations for a single good in a single sector is not sufficient for effective environmental protection. Enhanced binding sustainability criteria and certification schemes for the use of all vegetable oils in every sector and industry as well as improved protection schemes for sensible forest areas are necessary.

Summary: Platform trials bring the promise of making clinical research more efficient and more patient centric. While their use has become more widespread, including their prominent role during the COVID-19 pandemic response, broader adoption of platform trials has been limited by the lack of experience and tools to navigate the critical upfront planning required to launch such collaborative studies. The European Union-Patient-cEntric clinicAl tRial pLatform (EU-PEARL) initiative has produced new methodologies to expand the use of platform trials with an overarching infrastructure and services embedded into Integrated Research Platforms (IRPs), in collaboration with patient representatives and through consultation with U.S. Food and Drug Administration and European Medicines Agency stakeholders. In this narrative review, we discuss the outlook for platform trials in Europe, including challenges related to infrastructure, design, adaptations, data sharing and regulation. Documents derived from the EU-PEARL project, alongside a literature search including PubMed and relevant grey literature (e.g., guidance from regulatory agencies and health technology agencies) were used as sources for a multi-stage collaborative process through which the 10 more important points based on lessons drawn from the EU-PEARL project were developed and summarised as guidance for the setup of platform trials. We conclude that early involvement of critical stakeholder such as regulatory agencies or patients are critical steps in the implementation and later acceptance of platform trials. Addressing these gaps will be critical for attaining the full potential of platform trials for patients. Funding: Innovative Medicines Initiative 2 Joint Undertaking with support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

Background and Purpose: To investigate the effect of topical non-invasive physical plasma (NIPP), a volatile mix generated out of ambient air, on prevention of acute radiation dermatitis (RD) during and after whole-breast irradiation (WBI). Materials and Methods: Lateral and medial breast halves were randomised within each patient to receive either 120 s of NIPP or sham treatment daily during WBI. Standard skin care with urea lotion was applied to the whole breast. Blinded acute skin toxicity was assessed weekly for each breast half separately and included clinician- (CTCAE) and patient-reported (modified RISRAS), and objective (spectrophotometry) assessments. As an additional external control, a comparable standard of care (SoC) patient collective from a previous prospective trial was used. Results: Sixty-four patients were included. There were no significant differences between breast halves. Post-hoc comparison with a similar SoC control collective revealed OR = 0.28 (95% CI 0.11–0.76; p = 0.014) for grade ≥ 2 RD upon WBI completion, along with less hyperpigmentation (p

Background: We estimated metastatic-death risk when the treatment of small choroidal melanomas is deferred until growth is observed. Methods: In 24 patients with choroidal melanoma (median diameter 5.85 mm), the exponential growth rate estimated by a mixed-effects model was 4.3% per year. Using the Liverpool Uveal Melanoma Prognosticator Online v.3 (LUMPO3), we measured changes in 15-year metastatic and non-metastatic death risks according to whether the tumor is treated immediately or after observing growth 4 or 12 months later, considering age, sex, and metastasis predictors. Results: In 40-year-old females with 10 mm, disomy 3 and monosomy 3 choroidal melanomas (prevalence 16%), the 15-year absolute risks of metastatic death are 4.2% and 76.6%, respectively, increasing after a 4-month delay by 0.0% and 0.2% and by 3.0% and 2.3% with tumor growth rates of 5.0% and 20.0%, respectively. With 12-month delays, these risks increase by 0.0% and 0.5% and by 1.0% and 7.1%, respectively. Increases in metastatic-death risk are less with smaller tumors and with a higher risk of non-metastatic death. Conclusions: Deferring treatment of choroidal melanomas until documentation of growth may delay iatrogenic visual loss by months or years and is associated with minimal increase in metastatic mortality, at least with small tumors with usual growth rates of up to 40% per year.

Bottlenose dolphins (Tursiops truncatus) rely on frequency- and amplitude-modulated whistles to communicate, and noise exposure can inhibit the success of acoustic communication through masking or causing behavioral changes in the animal. At the US Navy Marine Mammal Program (MMP) in San Diego, CA, dolphins are housed in netted enclosures in the San Diego Bay and exposed to noise from vessels, unmanned underwater vehicles, and other remote sensing devices. The acoustic behavior of 20 dolphins was monitored and whistle rates during noise events were quantified. Whistle rates during the onset of the event (i.e., the first 5 min) did not significantly differ from the pre-onset (5 min immediately preceding). Whistle rates were also not significantly different for the entire duration of the event compared to a matched control period. The noise’s frequency range (i.e., control, mid-frequency (0–20 kHz) or high-frequency (21–80 kHz)), signal-to-noise ratio, and sound pressure level were not significantly related to the dolphins’ whistle rate. Considering this is a location of frequent and moderate noise output, these results lend support to established guidelines on anthropogenic noise exposure for cetaceans, suggesting that moderate noise exposure levels may not impact communication efforts in bottlenose dolphins.

Glioblastoma, the most common and lethal primary adult brain tumor, cannot be successfully removed surgically due to its highly invasive nature. Therapeutically, approaches must be aimed at a systemic brain disease and not merely at a tumor located within the brain, unless a successful containment strategy can be found. Reelin, an extracellular matrix glycoprotein, plays an important role in neuronal migration and serves here as a natural stop signal. Interestingly, the expression of reelin is negatively associated with tumor grade and, within glioblastoma, correlates with increased overall survival. To further elucidate a potential biological reason for these findings, we looked at the cellular behavior of glioblastoma cell lines grown on a pure fibronectin matrix or a matrix with reelin inserts. While reelin had no significant effects on cellular metabolism, proliferation, or resistance to chemotherapeutic agents, it did significantly affect the cells’ interaction with fibronectin. Both matrix attachment and detachment were modulated by reelin, and thus, the invasion and motility of cells interacting with a reelin-containing matrix were altered. The data presented in this work strongly suggest that reelin might be a potential modulator of underlying molecular mechanisms that contribute to glioblastoma invasion.