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AimAnalysis of data from bicycle accidents reveals that handlebar impacts are a significant cause of injury, particularly among children. Despite existing safety regulations, such as helmet requirements, little attention is given to abdominal injuries. The aim of this study is to investigate the influence of handlebar ends on abdominal loading during bicycle crashes.MethodsThis study delves into the impact of five different handlebar designs on abdominal injuries during bicycle crashes, using finite element simulations with detailed Human Body Models (HBMs) of a six-year-old child (PIPER child model, Version 0.99.0). Four impact locations were identified in the injury scenario, selected according to the anatomical location of the most commonly injured organs, liver, pancreas, spleen and abdomen.ResultsGrip design features, such as shape and rigidity, significantly influence injury outcomes. Grips designed specifically for children demonstrate superior performance in reducing abdominal loading and injury metrics compared to standard grips. The highest injury potential was seen in a damaged handlebar end.ConclusionThese findings underscore the importance of improved handlebar designs and standardized safety measures, especially for children. Implementation of such measures could mitigate the significant health and economic burden associated with handlebar-related injuries and enhance overall bicycle safety for children.

The European Larynx Organ Preservation Study (ELOS; NCT06137378) is a prospective, randomized, open-label, two-armed parallel group controlled, phase II multicenter larynx organ preservation (LOP) trial in locoregionally advanced (LA) stage III, IVA/B head and neck squamous cell carcinoma of the larynx or hypopharynx (LHSCC) amenable for total laryngectomy (TL) with PD-L1 expression within tumor tissue biopsy, calculated as CPS ≥ 1. Induction chemotherapy (IC) with docetaxel and cisplatin (TP) followed by radiation will be compared to TP plus PD-1 inhibition by pembrolizumab (MK-3475; 200 mg i.v. starting day 1 q3w for 17 cycles). After a short induction early response evaluation (ERE) 21 ± 3 days after the first cycle of IC (IC-1), responders achieving endoscopic estimated tumor surface shrinkage (ETSS) ≥30% will get an additional two cycles of IC followed by intensity-modulated radiotherapy 70–72 Gy (EQD2/α/β = 10) aiming at LOP. Nonresponders (ETSS < 30% or progressing disease) will receive TL and bilateral neck dissection followed by postoperative radiation or chemoradiation as recommended by the clinic’s multidisciplinary tumor board. Pembrolizumab treatment will be continued in the intervention arm regardless of ETSS status after IC-1 in both responders and laryngectomized nonresponders, independent of subsequent decisions on adjuvant therapy after TL.Clinical Trial Registrationclinicaltrials.gov, identifier NCT06137378.

BackgroundData on the use of the wearable cardioverter defibrillator in patients suffering from inherited and congenital heart disease are limited. Consequently, evidence for guideline recommendations in this patient population is lacking.MethodsIn total 1,675 patients were included in a multicenter registry of eight European centers. In the present cohort, we included 18 patients suffering from congenital and inherited heart disease.ResultsNine patients (50%) were male with a mean age of 41.3 ± 16.4 years. Four patients suffered from hypertrophic cardiomyopathy (HCM), four patients suffered from non-compaction cardiomyopathy (NCCM), two patients were diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC) and one patient suffered from muscular dystrophy of the limb-girdle type with cardiac involvement, secondary cardiomyopathy. Three patients presented with Brugada syndrome (BrS). One patient suffered from long-QT syndrome type 1 (LQTS1). Furthermore, two patients had congenital heart defects and one patient suffered from cardiac sarcoidosis (CS). There were no appropriate/inappropriate shocks with the WCD in this cohort. One patient had recurrent self-limiting sustained ventricular tachycardia during the wear time, but actively inhibited a shock and was hospitalized. The compliance rate in this cohort was 77.8% with a mean wear time of 45.3 ± 26.9 days with a mean follow-up time of 570 ± 734 days. 55.6% (10/18) of the patients received an ICD after WCD wear time.ConclusionsThis retrospective study of patients with inherited and congenital heart disease shows that WCD use is not beneficial in the majority of patients with inherited and congenital heart disease.

IntroductionLarynx organ preservation (LOP) in locoregional-advanced laryngeal and hypopharyngeal squamous cell carcinoma (LA-LHSCC) being only R0-resectable (clear margins > 5 mm) by total laryngectomy (TL) is desirable. Based on tumor-specific survival (TSS) and overall survival (OS) data from the RTOG 91-11 trial and meta-analyses of randomized clinical trials (RCTs), cisplatin-based concurrent radiochemotherapy (CRT) is discussed being superior to cisplatin-based induction chemotherapy followed by radiotherapy (IC+RT) and TL followed by postoperative RT (TL+PORT) or radiochemotherapy (TL+PORCT). Outside of RCTs, T4 LHSCC treated with TL+PORCT demonstrated improved OS and TSS compared to CRT alone; comparisons with docetaxel plus cisplatin (TP)-based IC+RT are unpublished. Head-to-head comparisons in RCTs of these four alternatives are missing.Materials and methodsWe utilized monocentric registry data to compare the outcome in the LOP trial DeLOS-II (NCT00508664) and propensity score (PS)–matched LHSCC patients. DeLOS-II utilized endoscopic tumor staging after one cycle of TP-based IC for selecting TL+R(C)T for non-responders versus IC+RT for responders. Main risk factors for survival (localization hypopharynx, T4, N+, tobacco smoking >30 pack years, alcohol consumption >60 g/day, age, sex) were used to calculate the individual PS for each DeLOS-II patient and 330 LHSCC patients suitable for DeLOS-II according to eligibility criteria in Leipzig by CRT (78), TL+PORT (148), and TL+PORCT (104). We performed PS matching with caliper width 0.2.ResultsThe 52 DeLOS-II patients (whole intent-to-treat cohort) and three PS-matched cohorts (52 LHSCC patients each) had equal distribution regarding risk factors including Charlson comorbidity score (CS; all p > 0.05) but differed in outcome. During 12,498.6 months of follow-up, 162 deaths (36/41/43/42 in DeLOS-II/TL+PORCT/TL+PORT/CRT, p = 0.356) occurred; DeLOS-II patients had superior OS and TSS. Compared to DeLOS-II, the HR (95% CI) observed in TL+PORCT, TL+PORT, and CRT for OS and TSS were 1.49 (0.92–2.43), 1.49 (1.15–3.18), and 1.81 (1.11–2.96) for OS; and 2.07 (0.944–4.58), 3.02 (1.32–6.89), and 3.40 (1.58–7.31) for TSS.ConclusionIn addition potential LOP, LA-LHSCC suitable for LOP according the DeLOS-II protocol may achieve improved survival.

Many practicing physicians struggle to properly evaluate clinical research studies – they either simply do not know them, regard the reported findings as ‘truth’ since they were reported in a ‘reputable’ journal and blindly implement these interventions, or they disregard them as having little pragmatic impact or relevance to their daily clinical work. Three aspects for the latter are highlighted: study populations rarely reflect their practice population, the absolute average benefits on specific outcomes in most controlled studies, while statistically significant, are so small that they are pragmatically irrelevant, and overall mortality between the intervention and control groups are unaffected. These observations underscore the need to rethink our research approaches in the clinical context – moving from the predominant reductionist to an eco-systemic research approach will lead to knowledge better suited to clinical decision-making for an individual patient as it takes into account the complex interplay of multi-level variables that impact health outcomes in the real-world setting.

The functionality of photoreceptors, rods, and cones is highly dependent on their outer segments (POS), a cellular compartment containing highly organized membranous structures that generate biochemical signals from incident light. While POS formation and degeneration are qualitatively assessed on microscopy images, reliable methodology for quantitative analyses is still limited. Here, we developed methods to quantify POS (QuaPOS) maturation and quality on retinal sections using automated image analyses. POS formation was examined during the development and in adulthood of wild-type mice via light microscopy (LM) and transmission electron microscopy (TEM). To quantify the number, size, shape, and fluorescence intensity of POS, retinal cryosections were immunostained for the cone POS marker S-opsin. Fluorescence images were used to train the robust classifier QuaPOS-LM based on supervised machine learning for automated image segmentation. Characteristic features of segmentation results were extracted to quantify the maturation of cone POS. Subsequently, this quantification method was applied to characterize POS degeneration in “cone photoreceptor function loss 1” mice. TEM images were used to establish the ultrastructural quantification method QuaPOS-TEM for the alignment of POS membranes. Images were analyzed using a custom-written MATLAB code to extract the orientation of membranes from the image gradient and their alignment (coherency). This analysis was used to quantify the POS morphology of wild-type and two inherited retinal degeneration (“retinal degeneration 19” and “rhodopsin knock-out”) mouse lines. Both automated analysis technologies provided robust characterization and quantification of POS based on LM or TEM images. Automated image segmentation by the classifier QuaPOS-LM and analysis of the orientation of membrane stacks by QuaPOS-TEM using fluorescent or TEM images allowed quantitative evaluation of POS formation and quality. The assessments showed an increase in POS number, volume, and membrane coherency during wild-type postnatal development, while a decrease in all three observables was detected in different retinal degeneration mouse models. All the code used for the presented analysis is open source, including example datasets to reproduce the findings. Hence, the QuaPOS quantification methods are useful for in-depth characterization of POS on retinal sections in developmental studies, for disease modeling, or after therapeutic interventions affecting photoreceptors.

Sialic acids are terminal sugars of the cellular glycocalyx and are highly abundant in the nervous tissue. Sialylation is sensed by the innate immune system and acts as an inhibitory immune checkpoint. Aminoglycoside antibiotics such as neomycin have been shown to activate tissue macrophages and induce ototoxicity. In this study, we investigated the systemic subcutaneous application of the human milk oligosaccharide 6’-sialyllactose (6SL) as a potential therapy for neomycin-induced ototoxicity in postnatal mice. Repeated systemic treatment of mice with 6SL ameliorated neomycin-induced hearing loss and attenuated neomycin-triggered macrophage activation in the cochlear spiral ganglion. In addition, 6SL reversed the neomycin-mediated increase in gene transcription of the pro-inflammatory cytokine interleukin-1β (Il-1b) and the apoptotic/inflammatory kinase Pik3cd in the inner ear. Interestingly, neomycin application also increased the transcription of desialylating enzyme neuraminidase 3 (Neu3) in the inner ear. In vitro, we confirmed that treatment with 6SL had anti-inflammatory, anti-phagocytic, and neuroprotective effects on cultured lipopolysaccharide-challenged human THP1-macrophages. Thus, our data demonstrated that treatment with 6SL has anti-inflammatory and protective effects against neomycin-mediated macrophage activation and ototoxicity.

BackgroundRandomized controlled trials have indicated reduced mortality rates in very preterm infants assigned to high compared to low oxygen saturation (SpO2) target levels, accompanied by higher rates of retinopathy of prematurity and bronchopulmonary dysplasia. However, the benefit-to-harm ratio may depend on the local background mortality risk. We therefore aimed to quantify the risk–benefit ratios of different SpO2 target ranges in 10 tertiary newborn intensive care units (NICUs) in East Germany.MethodsIn a retrospective multicenter study, 1,399 infants born between 2008 and 2012 at a gestational age between 24 0/7 and 27 6/7 weeks and with a birthweight below 1,250 g were grouped according to the hospital's target SpO2 range [high oxygen saturation group (HOSG) above 90%], low oxygen saturation group (LOSG) below 90%] and the compliance of units with their target SpO2 range. The association between neonatal morbidities, neurodevelopmental outcomes, selected treatment strategies, and target SpO2 ranges was calculated using chi-squared and Mann Whitney U tests.ResultsNine of the ten participating NICUs met their SpO2 target ranges. Five units were considered as HOSG, and five units were considered as LOSG. Necrotizing enterocolitis and intraventricular hemorrhage grade ≥ 2 occurred significantly more frequently in the HOSG than in the LOSG (8.4% vs. 5.1%, p = 0.02; and 26.6% vs. 17.7%, p

BackgroundAn increasing number of mHealth interventions aim to contribute to mental healthcare of which interventions that foster cognitive reappraisal may be particularly effective.ObjectivesTo evaluate the efficacy of mHealth interventions enhancing cognitive reappraisal to improve mental health in adult populations.MethodsThe literature search (four databases) yielded 30 eligible randomized controlled trials (comprising 3,904 participants). We performed a multi-level meta-analysis to examine differences between intervention and comparator conditions at post-intervention assessment. Moderator analyses were conducted for potential moderator variables (e.g., type of comparators).ResultsMost interventions were CBT-based with other training components in addition to cognitive reappraisal. We found preliminary evidence for a small to medium effect favouring mHealth interventions to enhance cognitive reappraisal over comparators, M(SMD) = 0.34, p = .002. When analysing single symptoms, there was evidence for a small to medium effect of mHealth interventions on anxiety and depressive symptoms, but not for psychological distress and well-being. All analyses showed substantial heterogeneity. Moderator analyses revealed evidence for more favourable effects in studies with passive comparators. There was an overall high risk of bias in most of the studies.ConclusionsWe found preliminary evidence for a small to medium effect of mHealth interventions including a cognitive reappraisal component to improve mental health. However, most of the interventions were complex (i.e., reappraisal was provided alongside other components), which prevents us from examining reappraisal-specific effects beyond general mental health promotion in mHealth. Dismantling studies examining the effects of single intervention components are warranted to corroborate these promising results.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=142149, identifier [CRD42019142149].

The possible applications for human retinal organoids (HROs) derived from human induced pluripotent stem cells (hiPSC) rely on the robustness and transferability of the methodology for their generation. Standardized strategies and parameters to effectively assess, compare, and optimize organoid protocols are starting to be established, but are not yet complete. To advance this, we explored the efficiency and reliability of a differentiation method, called CYST protocol, that facilitates retina generation by forming neuroepithelial cysts from hiPSC clusters. Here, we tested seven different hiPSC lines which reproducibly generated HROs. Histological and ultrastructural analyses indicate that HRO differentiation and maturation are regulated. The different hiPSC lines appeared to be a larger source of variance than experimental rounds. Although previous reports have shown that HROs in several other protocols contain a rather low number of cones, HROs from the CYST protocol are consistently richer in cones and with a comparable ratio of cones, rods, and Müller glia. To provide further insight into HRO cell composition, we studied single cell RNA sequencing data and applied CaSTLe, a transfer learning approach. Additionally, we devised a potential strategy to systematically evaluate different organoid protocols side-by-side through parallel differentiation from the same hiPSC batches: In an explorative study, the CYST protocol was compared to a conceptually different protocol based on the formation of cell aggregates from single hiPSCs. Comparing four hiPSC lines showed that both protocols reproduced key characteristics of retinal epithelial structure and cell composition, but the CYST protocol provided a higher HRO yield. So far, our data suggest that CYST-derived HROs remained stable up to at least day 200, while single hiPSC-derived HROs showed spontaneous pathologic changes by day 200. Overall, our data provide insights into the efficiency, reproducibility, and stability of the CYST protocol for generating HROs, which will be useful for further optimizing organoid systems, as well as for basic and translational research applications.

Spermatogenesis is a crucial biological process that enables the production of functional sperm, allowing for successful reproduction. Proper germ cell differentiation and maturation require tight regulation of hormonal signals, cellular signaling pathways, and cell biological processes. The acrosome is a lysosome-related organelle at the anterior of the sperm head that contains enzymes and receptors essential for egg-sperm recognition and fusion. Even though several factors crucial for acrosome biogenesis have been discovered, the precise molecular mechanism of pro-acrosomal vesicle formation and fusion is not yet known. In this study, we investigated the role of the insulin inhibitory receptor (inceptor) in acrosome formation. Inceptor is a single-pass transmembrane protein with similarities to mannose-6-phosphate receptors (M6PR). Inceptor knockout male mice are infertile due to malformations in the acrosome and defects in the nuclear shape of spermatozoa. We show that inceptor is expressed in early spermatids and mainly localizes to vesicles between the Golgi apparatus and acrosome. Here we show that inceptor is an essential factor in the intracellular transport of trans-Golgi network-derived vesicles which deliver acrosomal cargo in maturing spermatids. The absence of inceptor results in vesicle-fusion defects, acrosomal malformation, and male infertility. These findings support our hypothesis of inceptor as a universal lysosomal or lysosome-related organelle sorting receptor expressed in several secretory tissues.

BackgroundSedentary behavior (SB) is highly prevalent among university students and has increased during COVID-19 pandemic. As SB is associated with negative health outcomes, appropriate prevention measures in the university setting are needed.ObjectiveThis pilot study aimed at investigating the effects of videos using different message strategies to interrupt SB in the collective of university students during online lectures.MethodsDuring online lectures, university students (N = 96) were shown one of three videos on the interruption of SB. The videos differed in their message strategies with regard to evidence type (statistical vs. narrative) and vividness (static vs. animated images). Demographics, health variables (SB intentions, SB attitudes) and selected media reception variables (identification, homophily, counterarguing) were examined as possible influence factors on the interruption of SB evoked by watching the video.ResultsApproximately half of the students interrupted sedentary behavior during watching the videos and students of the older age group (cut-off: median = 22 years) interrupted SB significantly more often (p = 0.046). The interruption of SB was predicted by SB intentions (p

Neurodegenerative diseases remain incompletely understood and therapies are needed. Stem cell-derived organoid models facilitate fundamental and translational medicine research. However, to which extent differential neuronal and glial pathologic processes can be reproduced in current systems is still unclear. Here, we tested 16 different chemical, physical, and cell functional manipulations in mouse retina organoids to further explore this. Some of the treatments induce differential phenotypes, indicating that organoids are competent to reproduce distinct pathologic processes. Notably, mouse retina organoids even reproduce a complex pathology phenotype with combined photoreceptor neurodegeneration and glial pathologies upon combined (not single) application of HBEGF and TNF, two factors previously associated with neurodegenerative diseases. Pharmacological inhibitors for MAPK signaling completely prevent photoreceptor and glial pathologies, while inhibitors for Rho/ROCK, NFkB, and CDK4 differentially affect them. In conclusion, mouse retina organoids facilitate reproduction of distinct and complex pathologies, mechanistic access, insights for further organoid optimization, and modeling of differential phenotypes for future applications in fundamental and translational medicine research.

Metastatic BRAFV600E mutated colorectal cancer is associated with poor overall survival and modest effectiveness to standard therapies. Furthermore, survival is influenced by the microsatellite status. Patients with microsatellite-stable and BRAFV600E mutated colorectal cancer have the worst prognosis under the wide range of genetic subgroups in colorectal cancer. Herein, we present a patient case of an impressive therapeutic efficacy of dabrafenib, trametinib, and cetuximab as later-line therapy in a 52-year-old woman with advanced BRAFV600E mutated, microsatellite-stable colon cancer. This patient achieved a complete response after 1 year of triple therapy. Due to skin toxicity grade 3 and recurrent urinary tract infections due to mucosal toxicity, a therapy de-escalation to dabrafenib and trametinib was performed, and the double therapy was administered for further 41 months with ongoing complete response. For 1 year, the patient was off therapy and is still in complete remission.

Most of the patients with head and neck squamous cell carcinoma (HNSCC) are diagnosed with locally advanced disease. Standards of care for curative-intent treatment of this patient group are either surgery and adjuvant radio(chemo)therapy (aRCT) or definitive chemoradiation. Despite these treatments, especially pathologically intermediate and high-risk HNSCC often recur. The ADRISK trial investigates in locally advanced HNSCC and intermediate and high risk after up-front surgery if the addition of pembrolizumab to aRCT with cisplatin improves event-free sur-vival compared to aRCT alone. ADRISK is a prospective, randomized controlled investiga-tor-initiated (IIT)-phase II multicenter trial within the German Interdisciplinary Study Group of German Cancer Society (IAG-KHT). Patients with primary resectable stage III and IV HNSCC of the oral cavity, oropharynx, hypopharynx and larynx with pathologic high (R1, extracapsular nodal extension) or intermediate risk (R0

IntroductionThe objective of this study was to determine whether postoperative additive systemic steroid administration in chronic rhinosinusitis with nasal polyps (CRSwNP) impacted selected endoscopic, subjective and objective outcome measures.MethodsThis was a prospective, randomized, double-blind, placebo-controlled, noninferiority multicenter trial of n=106 patients with CRSwNP. All patients underwent primary functional endoscopic sinus surgery (FESS) followed by topical nasal steroids. Patients were randomized to a systemic steroid or placebo for 1 month. Patients were followed up for 2 years over 9 time points. The primary outcome measures were the differences between groups with respect to the nasal polyp score (NPS) and sinonasal quality of life (SNQoL). Secondary outcome measures included interactions with respect to the Lund-Kennedy score (LKS), sinonasal symptoms, general quality of life (GQoL), 16-item odor identification test scores, recurrence rates, need for revision surgery and mucus biomarker levels.Results106 patients were randomized to either the placebo or the systemic steroid group (n=53 per group). Postoperative systemic steroids were not superior to placebo with respect to all primary (p= 0.077) and secondary outcome measures (p>0.05 for all). Reported adverse events were similar between the two groups.ConclusionIn conclusion, the addition of postoperative systemic steroids after primary FESS did not confer a benefit over topical steroid nasal spray alone with respect to NPS, SNQOL, LKS, GQOL, sinonasal symptoms, smell scores, recurrence rates, the need for revision surgery or biomarkers over a short-term follow-up of up to 9 months and a long-term follow-up of up to 24 months in CRSwNP patients. Functional endoscopic surgery did, however, show a strong effect on all outcome measures, which remained relatively stable up to the endpoint at 2 years.

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is a rare, autoimmune disease of the central nervous system that produces acute, unpredictable relapses causing cumulative neurological disability. Satralizumab, a humanized, monoclonal recycling antibody that targets the interleukin-6 receptor, reduced NMOSD relapse risk vs. placebo in two Phase 3 trials: SAkuraSky (satralizumab ± immunosuppressive therapy; NCT02028884) and SAkuraStar (satralizumab monotherapy; NCT02073279). Satralizumab is approved to treat aquaporin-4 IgG-seropositive (AQP4-IgG+) NMOSD. SAkuraBONSAI (NCT05269667) will explore fluid and imaging biomarkers to better understand the mechanism of action of satralizumab and the neuronal and immunological changes following treatment in AQP4-IgG+ NMOSD.ObjectivesSAkuraBONSAI will evaluate clinical disease activity measures, patient-reported outcomes (PROs), pharmacokinetics, and safety of satralizumab in AQP4-IgG+ NMOSD. Correlations between imaging markers (magnetic resonance imaging [MRI] and optical coherence tomography [OCT]) and blood and cerebrospinal fluid (CSF) biomarkers will be investigated.Study designSAkuraBONSAI is a prospective, open-label, multicenter, international, Phase 4 study that will enroll approximately 100 adults (18–74 years) with AQP4-IgG+ NMOSD. This study includes two patient cohorts: newly diagnosed, treatment-naïve patients (Cohort 1; n = 60); and inadequate responders to recent (

Perceptual performance, anticipating opponents' strategies, and judging chess positions especially in subliminal processing is related to expertise level and dependent on chunking processes. It becomes obvious that chess expertise is a multidimensional phenomenon related predominantly to experience. Under consideration of chess expertise categorization, we conducted two priming experiments expanding existing designs by gradually increasing the target and task complexity. The main aim was the evaluation of potential visuocognitive limitations. The results reveal experts' perceptual superiority manifested by their faster reaction times in settings with increased stimulus and task complexity. Further, experts' priming effects seem to be affected by the target content and/ or priming duration. For short prime duration, experts show priming effects only for less complex prime-target content. Interestingly, for longer prime duration and more complex prime-target content, all participants reveal priming effects. In summary, we argue that experts' visuocognitive processing (i.e., detecting or anticipating potential threats to the king) is rooted in a more efficient visuocognition due to stored chunks of checking and mating constellations. We suggest that visuocognitive limitations are related also to the prime-target complexity as well as to the task. Further investigations must be conducted in order to elucidate the factors with an increased impact on chess players' performance.

Meat species of raw meat and processed meat products were investigated by 1H NMR spectroscopy with subsequent multivariate data analysis. Sample preparation was based on aqueous extraction combined with ultrafiltration in order to reduce macromolecular components in the extracts. 1H NMR data was analyzed by using a non—targeted approach followed by principal component analysis (PCA), linear discrimination analysis (LDA), and cross-validation (CV) embedded in a Monte Carlo (MC) resampling approach. A total of 379 raw meat samples (pork, beef, poultry, and lamb) and 81 processed meat samples (pork, beef, poultry) were collected between the years 2018 and 2021. A 99% correct prediction rate was achieved if the raw meat samples were classified according to meat species. Predicting processed meat products was slightly less successful (93 %) with this approach. Furthermore, identification of spectral regions that are relevant for the classification via polar chemical markers was performed. Finally, data on polar metabolites were fused with previously published 1H NMR data on non-polar metabolites in order to build a broader classification model and to improve prediction accuracy.

In order to foster pro-environmental behavior in the midst of a global ecological crisis, current research in environmental psychology is often limited to individual-related factors and theories about conscious processing. However, in recent years, we observe a certain discontentment with the limitations of this approach within the community as well as increasing efforts toward broadening the scope (e.g., promotions of collective and social identity processes). In our work, we aim for a closer investigation of the relations between individuals, societal factors, and pro-environmental actions while considering the role of the unconscious. We hereby draw on the work of critical social psychology (CSP). From a life course perspective, we emphasize the important role of socialization, institutional and cultural contexts for mindsets and related perceptions, decisions and actions. This link between the individual and the society enables us to understand biographical trajectories and related ideologies dominant within a society. We seek to show that the approach of CSP is helpful for understanding why efforts of establishing pro-environmental actions on a large scale are still failing. In this article, we discuss the theoretical links between environmental psychology and CSP as well as possible implications, paving the way for a comprehensive future research agenda.

IntroductionOver the last decade, the use of New/Novel Synthetic Opioids (NSO) has emerged as an increasing problem, and especially so in the USA. However, only little is known about the prevalence and history of NSO use in European heroin dependents.MethodA cross-sectional multicenter study, carried out with the means of both standardized interviews and urine toxicology enhanced screening, in a sample of opioid addicted patients referred for an in-patient detoxification treatment.ResultsSample size included here n = 256 patients; prior to admission, 63.7% were prescribed with an opioid maintenance treatment. Lifetime use of heroin and opioid analgesics was reported by 99.2 and 30.4%, respectively. Lifetime NSO/fentanyl use was reported by 8.7% (n = 22); a regular use was reported by 1.6% (n = 4), and ingestion over the 30 days prior to admission by 0.8% (n = 2). Most typically, patients had started with a regular consumption of heroin, followed by maintenance opioids; opioid analgesics; and by NSO. Self-reported data were corroborated by the toxicology screenings carried out; no evidence was here identified for the presence of heroin being contaminated by fentanyl/derivatives.DiscussionNSO and also opioid analgesics did not play a relevant role in the development and the course of opioid/opioid use disorders in German patients referred for an inpatient detoxification treatment.

Suicide prevention is an important public mental health issue that can be significantly brought forward by recent advances in psychological research methods and assessment. The project “TempRes” aims to harness the power of Ecological Momentary Assessment (EMA) to investigate the transdiagnostic risk and resilience factors associated with suicidal ideation drawn from the most recent research in suicide prevention and personality assessment. Participants will comprise the general population (planned: N = 100) and a risk group (patients currently in psychosomatic or psychiatric treatment) (planned: N = 50). After a comprehensive baseline assessment, they will complete up to ten short assessments per day over the course of 10 days at roughly equidistant intervals. In detail, the project examines the interplay of biography (previous suicidal behavior, experiences of childhood maltreatment), individual differences (level of personality functioning), and time-varying factors (entrapment, loneliness, mood) with respect to the emergence and fluctuation of suicidal ideation. There are two main research foci: First, the project will provide an operationalization and empirical verification of a core assumption of the integrated motivational-volitional model of suicide (IMV model). It will test whether the interaction of the time-varying predictors entrapment with loneliness (as a motivational moderator) explains reports of suicidal ideation over time. Second, it will be the first to examine personality functioning (a transdiagnostic, psychodynamically grounded conceptualization of vulnerability to psychological crises over the life span) as a time-invariant predictor of suicidal ideation assessed within an intensive longitudinal study design. The main analyses will be built on linear mixed models. The overarching aim of the project is to gain a better understanding of the psychological dynamics underlying suicidal ideation in different populations by bringing together concepts from different theoretical traditions. This will inform prevention efforts geared toward the general public as well as intervention in clinical populations.

Temporal correlation has been exploited for accelerated dynamic MRI reconstruction. Some methods have modeled inter-frame motion into the reconstruction process to produce temporally aligned image series and higher reconstruction quality. However, traditional motion-compensated approaches requiring iterative optimization of registration and reconstruction are time-consuming, while most deep learning-based methods neglect motion in the reconstruction process. We propose an unrolled deep learning framework with each iteration consisting of a groupwise diffeomorphic registration network (GRN) and a motion-augmented reconstruction network. Specifically, the whole dynamic sequence is registered at once to an implicit template which is used to generate a new set of dynamic images to efficiently exploit the full temporal information of the acquired data via the GRN. The generated dynamic sequence is then incorporated into the reconstruction network to augment the reconstruction performance. The registration and reconstruction networks are optimized in an end-to-end fashion for simultaneous motion estimation and reconstruction of dynamic images. The effectiveness of the proposed method is validated in highly accelerated cardiac cine MRI by comparing with other state-of-the-art approaches.

Appearance properties of vegetables can affect consumers' acceptance toward them as well as purchase intent. Hence, appearance is highly associated with quality of edamame (Glycine max (L.) Merr.), a protein-rich vegetable that is experiencing increased sales in the USA. Edamame is a high-value specialty crop and its production has been promoted in Virginia and other states in the USA where the tobacco production has decreased in the last decade. To support current efforts to develop the edamame industry in the USA, consumer and color data of 10 edamame genotypes grown in Virginia were analyzed in this follow-up study to understand the role of overall appearance and color characteristics in consumers' acceptability of edamame beans. In two consecutive years, untrained adult volunteers used 9-point hedonic scales (1 = “dislike extremely”, 9 = “like extremely”) to evaluate appearance and overall liking of edamame samples (cooked and shelled edamame beans) and our researchers measured the reflective color of the samples with a chroma meter. In the first year, sensory panelists also completed a choice-based conjoint analysis to determine their willingness-to-pay (WTP) for dark vs. light green edamame beans in a salad. Edamame genotypes were significantly different in appearance and overall liking (p < 0.05) and the genotype R14-16195 was the most liked overall. Hedonic scores and color were significantly affected by “year” (p < 0.05), so intentional changes between years (e.g., sample preparation) should be avoided in future studies. Consumers showed higher WTP for dark green edamame beans. Additionally, green intensity (color index) and a* color coordinate were correlated to appearance liking scores (p < 0.05), which suggests color data can support breeding selection criteria and possibly predict consumer acceptability. Employing color measurement as quality control method can help improve harvest procedures, post-harvest handling, and define edamame quality standards for the USA market.

Cardiovascular disease (CVD) is the leading single cause of morbidity and mortality, causing over 17. 9 million deaths worldwide per year with associated costs of over $800 billion. Improving prevention, diagnosis, and treatment of CVD is therefore a global priority. Cardiovascular magnetic resonance (CMR) has emerged as a clinically important technique for the assessment of cardiovascular anatomy, function, perfusion, and viability. However, diversity and complexity of imaging, reconstruction and analysis methods pose some limitations to the widespread use of CMR. Especially in view of recent developments in the field of machine learning that provide novel solutions to address existing problems, it is necessary to bridge the gap between the clinical and scientific communities. This review covers five essential aspects of CMR to provide a comprehensive overview ranging from CVDs to CMR pulse sequence design, acquisition protocols, motion handling, image reconstruction and quantitative analysis of the obtained data. (1) The basic MR physics of CMR is introduced. Basic pulse sequence building blocks that are commonly used in CMR imaging are presented. Sequences containing these building blocks are formed for parametric mapping and functional imaging techniques. Commonly perceived artifacts and potential countermeasures are discussed for these methods. (2) CMR methods for identifying CVDs are illustrated. Basic anatomy and functional processes are described to understand the cardiac pathologies and how they can be captured by CMR imaging. (3) The planning and conduct of a complete CMR exam which is targeted for the respective pathology is shown. Building blocks are illustrated to create an efficient and patient-centered workflow. Further strategies to cope with challenging patients are discussed. (4) Imaging acceleration and reconstruction techniques are presented that enable acquisition of spatial, temporal, and parametric dynamics of the cardiac cycle. The handling of respiratory and cardiac motion strategies as well as their integration into the reconstruction processes is showcased. (5) Recent advances on deep learning-based reconstructions for this purpose are summarized. Furthermore, an overview of novel deep learning image segmentation and analysis methods is provided with a focus on automatic, fast and reliable extraction of biomarkers and parameters of clinical relevance.

In T cells, processes such as migration and immunological synapse formation are accompanied by the dynamic reorganization of the actin cytoskeleton, which has been suggested to be mediated by regulators of RhoGTPases and by F-actin bundlers. SWAP-70 controls F-actin dynamics in various immune cells, but its role in T cell development and function has remained incompletely understood. CD4+ regulatory T (Treg) cells expressing the transcription factor Foxp3 employ diverse mechanisms to suppress innate and adaptive immunity, which is critical for maintaining immune homeostasis and self-tolerance. Here, we propose Swap-70 as a novel member of the Foxp3-dependent canonical Treg cell signature. We show that Swap-70-/- mice have increased numbers of Foxp3+ Treg cells with an effector/memory-like phenotype that exhibit impaired suppressor function in vitro, but maintain overall immune homeostasis in vivo. Upon formation of an immunological synapse with antigen presenting cells in vitro, cytosolic SWAP-70 protein is selectively recruited to the interface in Treg cells. In this context, Swap-70-/- Treg cells fail to downregulate CD80/CD86 on osteoclast precursor cells by trans-endocytosis and to efficiently suppress osteoclastogenesis and osteoclast function. These data provide first evidence for a crucial role of SWAP-70 in Treg cell biology and further highlight the important non-immune function of Foxp3+ Treg cells in bone homeostasis mediated through direct SWAP-70-dependent mechanisms.

Currently, no treatments available for Parkinson’s disease (PD) can slow PD progression. At the early stage of the disease, only a subset of individuals with PD progress quickly, while the majority have a slowly progressive form of the disease. In developing treatments that aim to slow PD progression, clinical trials aim to include individuals who are likely to progress faster, such that a treatment effect, if one exists, can be identified easier and earlier. The aim of the present study was to identify baseline predictors of clinical progression in early PD. We analyzed 12-month data acquired from the PASADENA trial Part 1 (NCT03100149, n = 76 participants who were allocated to the placebo arm and did not start symptomatic therapy) and the Parkinson’s Progression Markers Initiative (PPMI) study (n = 139 demographically and clinically matched participants). By using ridge regression models including clinical characteristics, imaging, and non-imaging biomarkers, we found that Hoehn and Yahr stage and dopamine transporter single-photon emission computed tomography specific binding ratios (Dat-SPECT SBR) in putamen ipsilateral to the side of motor symptom onset predicted PD progression at the early stage of the disease. Further studies are needed to confirm the validity of these predictors to identify with high accuracy individuals with early PD with a faster progression phenotype.

BackgroundStandardized staging procedures and presentation of oral squamous cell carcinoma (OSCC) patients in multidisciplinary tumor boards (MDTB) before treatment and utilization of elective neck dissection (ND) are expected to improve the outcome, especially in local advanced LAOSCC (UICC stages III–IVB). As standardized diagnostics but also increased heterogeneity in treatment applied so far have not been demonstrated to improve outcome in LAOSCC, a retrospective study was initiated.MethodsAs MDTB was introduced into clinical routine in 2007, 316 LAOSCC patients treated during 1991-2017 in our hospital were stratified into cohort 1 treated before (n=104) and cohort 2 since 2007 (n=212). Clinical characteristics, diagnostic procedures and treatment modality of patients were compared using Chi-square tests and outcome analyzed applying Kaplan-Meier plots and log-rank tests as well as Cox proportional hazard regression. Propensity scores (PS) were used to elucidate predictors for impaired distant metastasis-free survival (DMFS) in PS-matched patients.ResultsMost patient characteristics and treatment modalities applied showed insignificant alteration. Surgical treatment included significantly more often resection of the primary tumor plus neck dissection, tracheostomy and percutaneous endoscopic gastrostomy tube use. Cisplatin-based chemo-radiotherapy was the most frequent. Only insignificant improved disease- (DFS), progression- (PFS) and event-free (EFS) as well as tumor-specific (TSS) and overall survival (OS) were found after 2006 as local (LC) and loco-regional control (LRC) were significantly improved but DMFS significantly impaired. Cox regression applied to PS-matched patients elucidated N3, belonging to cohort 2 and cisplatin-based chemo-radiotherapy as independent predictors for shortened DMFS. The along chemo-radiotherapy increased dexamethasone use in cohort 2 correlates with increased DM.ConclusionsDespite standardized diagnostic procedures, decision-making considering clear indications and improved therapy algorithms leading to improved LC and LRC, shortened DMFS hypothetically linked to increased dexamethasone use had a detrimental effect on TSS and OS.

Recent measurements of pore-water oxygen profiles in ridge flank sediments of the East Pacific Rise revealed an upward-directed diffusive oxygen flux from the hydrothermally active crust into the overlying sediment. This double-sided oxygenation from above and below results in a dual redox transition from an oxic sedimentary environment near the seabed through suboxic conditions at sediment mid-depth back to oxic conditions in the deeper basal sediment. The potential impact of this redox reversal on the paleo- and rock magnetic record was analyzed for three sediment cores from the Clarion-Clipperton-Zone (low-latitude eastern North Pacific). We found that the upward-directed crustal oxygen flux does not impede high quality reversal-based and relative paleointensity-refined magnetostratigraphic dating. Despite low and variable sedimentation rates of 0.1–0.8 cm/kyr, robust magnetostratigraphic core chronologies comprising the past 3.4 resp. 5.2 million years could be established. These age-models support previous findings of significant local sedimentation rate variations that are probably related to the bottom current interactions with the topographic roughness of the young ridge flanks. However, we observed some obvious paleomagnetic irregularities localized at the lower oxic/suboxic redox boundaries of the investigated sediments. When analyzing these apparently remagnetized sections in detail, we found no evidence of physical disturbance or chemical alteration. A sharp increase in single-domain magnetite concentration just below the present lower oxic/suboxic redox boundary suggests secondary magnetite biomineralization by microaerophilic magnetotactic bacteria living as a separate community in the lower, upward oxygenated part of the sediment column. We therefore postulate a two-phased post-depositional remanent magnetization of ridge flank sediments, first by a shallow and later by a deep-living community of magnetotactic bacteria. These findings are the first evidence of a second, deep population of probably inversely oriented magnetotactic bacteria residing in the inverse oxygen gradient zone of ridge flank sediments.

Background: Currently available treatments for Parkinson's disease (PD) do not slow clinical progression nor target alpha-synuclein, a key protein associated with the disease.Objective: The study objective was to evaluate the efficacy and safety of prasinezumab, a humanized monoclonal antibody that binds aggregated alpha-synuclein, in individuals with early PD.Methods: The PASADENA study is a multicenter, randomized, double-blind, placebo-controlled treatment study. Individuals with early PD, recruited across the US and Europe, received monthly intravenous doses of prasinezumab (1,500 or 4,500 mg) or placebo for a 52-week period (Part 1), followed by a 52-week extension (Part 2) in which all participants received active treatment. Key inclusion criteria were: aged 40–80 years; Hoehn & Yahr (H&Y) Stage I or II; time from diagnosis ≤2 years; having bradykinesia plus one other cardinal sign of PD (e.g., resting tremor, rigidity); DAT-SPECT imaging consistent with PD; and either treatment naïve or on a stable monoamine oxidase B (MAO-B) inhibitor dose. Study design assumptions for sample size and study duration were built using a patient cohort from the Parkinson's Progression Marker Initiative (PPMI). In this report, baseline characteristics are compared between the treatment-naïve and MAO-B inhibitor-treated PASADENA cohorts and between the PASADENA and PPMI populations.Results: Of the 443 patients screened, 316 were enrolled into the PASADENA study between June 2017 and November 2018, with an average age of 59.9 years and 67.4% being male. Mean time from diagnosis at baseline was 10.11 months, with 75.3% in H&Y Stage II. Baseline motor and non-motor symptoms (assessed using Movement Disorder Society—Unified Parkinson's Disease Rating Scale [MDS-UPDRS]) were similar in severity between the MAO-B inhibitor-treated and treatment-naïve PASADENA cohorts (MDS-UPDRS sum of Parts I + II + III [standard deviation (SD)]; 30.21 [11.96], 32.10 [13.20], respectively). The overall PASADENA population (63.6% treatment naïve and 36.4% on MAO-B inhibitor) showed a similar severity in MDS-UPDRS scores (e.g., MDS-UPDRS sum of Parts I + II + III [SD]; 31.41 [12.78], 32.63 [13.04], respectively) to the PPMI cohort (all treatment naïve).Conclusions: The PASADENA study population is suitable to investigate the potential of prasinezumab to slow disease progression in individuals with early PD.Trial Registration: NCT03100149.

The development of super-resolution microscopy (SRM) has widened our understanding of biomolecular structure and function in biological materials. Imaging multiple targets within a single area would elucidate their spatial localization relative to the cell matrix and neighboring biomolecules, revealing multi-protein macromolecular structures and their functional co-dependencies. SRM methods are, however, limited to the number of suitable fluorophores that can be imaged during a single acquisition as well as the loss of antigens during antibody washing and restaining for organic dye multiplexing. We report the visualization of multiple protein targets within the pre- and postsynapse in 350–400 nm thick neuronal tissue sections using DNA-assisted single-molecule localization microscopy (SMLM). In a single labeling step, antibodies conjugated with short DNA oligonucleotides visualized multiple targets by sequential exchange of fluorophore-labeled complementary oligonucleotides present in the imaging buffer. This approach avoids potential effects on structural integrity when using multiple rounds of immunolabeling and eliminates chromatic aberration, because all targets are imaged using a single excitation laser wavelength. This method proved robust for multi-target imaging in semi-thin tissue sections with a lateral resolution better than 25 nm, paving the way toward structural cell biology with single-molecule SRM.

The pathogenesis of immune thrombocytopenia (ITP) is increasingly being elucidated, and its etiology is becoming more frequently identified, leading to a diagnostic shift from primary to secondary ITP. The overlap between autoimmunity, immunodeficiency, and cancer is evident, implying more interdisciplinarity in daily care. This mini-review is based on an expert meeting on ITP organized by the Intercontinental Cooperative ITP Study Group and presents the challenges of hematologists in understanding and investigating “out of the box” concepts associated with ITP.

BackgroundAbout five to 10% of cancers in the head and neck region are neck squamous cell carcinoma of unknown primary (NSCCUP). Their diagnosis and treatment are challenging given the risk of missing occult tumors and potential relapse. Recently, we described human papillomavirus (HPV)-related NSCCUP-patients (NSCCUP-P) as a subgroup with superior survival. However, standardized diagnostic workup, novel diagnostic procedures, decision-making in the multidisciplinary tumor board (MDTB) and multimodal therapy including surgery and post-operative radio-chemotherapy (PORCT) may also improve survival.MethodsFor assessing the impact of standardized diagnostic processes simultaneously established with the MDTB on outcome, we split our sample of 115 NSCCUP-P into two cohorts treated with curative intent from 1988 to 2006 (cohort 1; n = 53) and 2007 to 2018 (cohort 2; n = 62). We compared diagnostic processes and utilized treatment modalities applying Chi-square tests, and outcome by Kaplan–Meier plots and Cox regression.ResultsIn cohort 2, the standardized processes (regular use of [18F]-FDG-PET-CT imaging followed by examination under anesthesia, EUA, bilateral tonsillectomy and neck dissection, ND, at least of the affected site) improved detection of primaries (P = 0.026) mostly located in the oropharynx (P = 0.001). From 66.0 to 87.1% increased ND frequency (P = 0.007) increased the detection of extracapsular extension of neck nodes (ECE+) forcing risk factor-adapted treatment by increased utilization of cisplatin-based PORCT that improved 5-years progression-free and overall survival from 60.4 and 45.3 to 67.7% (P = 0.411) and 66.1% (P = 0.025).ConclusionsStandardized diagnostic workup followed by ND and risk-factor adapted therapy improves survival of NSCCUP-P.

Using retinal organoid systems, organ-like 3D tissues, relies implicitly on their robustness. However, essential key parameters, particularly retinal growth and longer-term culture, are still insufficiently defined. Here, we hypothesize that a previously optimized protocol for high yield of evenly-sized mouse retinal organoids with low variability facilitates assessment of such parameters. We demonstrate that these organoids reliably complete retinogenesis, and can be maintained at least up to 60 days in culture. During this time, the organoids continue to mature on a molecular and (ultra)structural level: They develop photoreceptor outer segments and synapses, transiently maintain its cell composition for about 5–10 days after completing retinogenesis, and subsequently develop pathologic changes – mainly of the inner but also outer retina and reactive gliosis. To test whether this organoid system provides experimental access to the retina during and upon completion of development, we defined and stimulated organoid growth by activating sonic hedgehog signaling, which in patients and mice in vivo with a congenital defect leads to enlarged eyes. Here, a sonic hedgehog signaling activator increased retinal epithelia length in the organoid system when applied during but not after completion of development. This experimentally supports organoid maturation, stability, and experimental reproducibility in this organoid system, and provides a potential enlarged retina pathology model, as well as a protocol for producing larger organoids. Together, our study advances the understanding of retinal growth, maturation, and maintenance, and further optimizes the organoid system for future utilization.

The consumption of edamame [Glycine max (L.) Merr.] in the US has rapidly increased due to its nutritional value and potential health benefits. In this study, 10 edamame genotypes were planted in duplicates in three different locations in the US—Whitethorne, Virginia (VA), Little Rock, Arkansas (AR), and Painter, VA. Edamame samples were harvested at the R6 stage of the bean development when beans filled 80–90% of the pod cavity. Afterward, comprehensive chemical composition analysis, including sugars, alanine, protein, oil, neutral detergent fiber (NDF), starch, ash, and moisture contents, were conducted on powdered samples using standard methods and the total sweetness was calculated based on the measured sugars and alanine contents. Significant effects of the location were observed on all chemical constituents of edamame (p < 0.05). The average performance of the genotypes was higher in Whitethorne for the contents of free sucrose (59.29 mg/g), fructose (11.42 mg/g), glucose (5.38 mg/g), raffinose (5.32 mg/g), stachyose (2.34 mg/g), total sweetness (78.63 mg/g), and starch (15.14%) when compared to Little Rock and Painter. The highest soluble alanine (2.67 mg/g), NDF (9.00%), ash (5.60%), and moisture (70.36%) contents were found on edamame planted in Little Rock while edamame planted in Painter had the highest crude protein (43.11%) and oil (20.33%) contents. Significant effects of genotype were observed on most of the chemical constituents (p < 0.05) except NDF and raffinose. Among the 10 genotypes, R13-5029 consistently had high sucrose content and total sweetness across the three locations, meanwhile it had relatively high protein and fiber contents. Overall, the results indicate that to breed better edamame genotypes in the US, both genotype and planting location should be taken into considerations.

Consumption of edamame (vegetable soybeans) has increased significantly in the U.S. over the last 20 years. Although market demand has been increasing, most edamame is still imported from Asian countries. A team of multistate plant-breeding programs in the mid-Atlantic and Southeast U.S. has focused on developing new breeding lines that grow well in the U.S. and deliver what domestic growers, processors and consumers need and expect from their edamame. In our study, sensory evaluation was used to identify edamame genotypes and sensory attributes preferred by consumers to support breeding selection criteria. In the first year (reported as our “screening study”), 20 edamame genotypes were grown in three locations: Newport, AR, and Blacksburg and Painter, VA. In the second year (reported as our “validation study”), 10 edamame genotypes selected after our screening study were grown in Blacksburg and Painter, VA, Portageville, MO, and Stoneville, MS. In both years of research, untrained participants (adults; vegetable consumers not allergic to soy; N ≥ 50) used a traditional 9-point acceptability (hedonic) scale (1 = “dislike extremely”; 9 = “like extremely”) to evaluate overall-liking, aroma, appearance, taste, and texture, and a 5-point scale (1 = “not sweet,” 5 = “extremely sweet”) to evaluate sweetness intensity. Next, participants used a check-all-that-apply (CATA) list of selected sensory terms to describe the sensory characteristics of each edamame sample. Overall acceptability of edamame genotypes was significantly different among all genotypes (p < 0.05). Samples described as “bitter,” “sour” (flavor) or “starchy” (texture) were associated with lower acceptability scores while “salty” and “sweet” (flavor) were correlated with higher acceptability. Sensory data from the screening study were used to select the best genotypes by use of a defined decision process based on the consumer data. The validation study tested the selection decisions and further supported the genotype choices. Sensory evaluation is a powerful tool to direct breeders to improve market acceptability and develop new edamame genotypes. Both screening and validation studies illustrate the significant role of consumer sensory data in support of genotypes targeted for domestic (U.S.) production.

Ultrafine particles (UFP; diameter less than 100 nm) are ubiquitous in urban air, and an acknowledged risk to human health. At the same time, little is known about the immission situation at typical urban sites such as high-traffic roads, residential areas with a high amount of solid fuels for home heating or commercial and industrial areas due to missing legal requirements for measurements of UFP. Therefore, UFP were measured and evaluated in the (sub-)urban background as well as on spots influenced by these various anthropogenic local sources in the city of Augsburg, Germany, for the year 2017. In particular, the spatial and temporal correlations of the UFP concentrations between the seven measurement sites, the quantification and valuation of the contribution of local emitters with regard to their diurnal, weekly and seasonal variations and the influence of meteorological conditions on the formation and dispersion of UFP were investigated. Our analysis results demonstrate that urban UFP concentrations show a pronounced temporal and spatial variability. The mean concentration level of UFP varies between below 8,000 ultrafine particles/cm3 at the suburban background site and above 16,700 ultrafine particles/cm3 at the measurement station located next to a busy street canyon. At this particularly traffic-exposed measurement station, maximum concentrations of over 50,000 ultrafine particles/cm3 were measured. The additional UFP load caused by intensive traffic volume during evening rush hour in connection with the unfavourable exchange processes in the street canyon can be quantified to concentrations of 14,000 ultrafine particles/cm3 on average (compared to the immission situation of the urban background). An aggravating effect is brought about by inversion weather conditions in connection with air-polluted easterly winds, low wind speeds, lack of precipitation and very low mixing layer heights, such as over Augsburg at the end of January 2017, and cause peak concentrations of UFP.

Scientific understanding about the psychological impact of the COVID-19 global pandemic is in its nascent stage. Prior research suggests that demographic factors, such as gender and age, are associated with greater distress during a global health crisis. Less is known about how emotion regulation impacts levels of distress during a pandemic. The present study aimed to identify predictors of psychological distress during the COVID-19 pandemic. Participants (N = 2,787) provided demographics, history of adverse childhood experiences, current coping strategies (use of implicit and explicit emotion regulation), and current psychological distress. The overall prevalence of clinical levels of anxiety, depression, and post-traumatic stress was higher than the prevalence outside a pandemic and was higher than rates reported among healthcare workers and survivors of severe acute respiratory syndrome. Younger participants (

Background: Over the past 15 years, comparative assessments of psychoactive substance harms to both users and others have been compiled by addiction experts. None of these rankings however have included synthetic cannabinoids or non-opioid prescription analgesics (NOAs, e.g., gabapentinoids) despite evidence of increasing recreational use. We present here an updated assessment by German addiction medicine experts, considering changing Western consumption trends–including those of NOAs.Methods: In an initial survey, 101 German addiction medicine physicians evaluated both physical and psychosocial harms (in 5 dimensions) of 33 psychoactive substances including opioids and NOAs, to both users and others. In a second survey, 36 addiction medicine physicians estimated the relative weight of each health and social harm dimension to determine the overall harm rank of an individual substance. We compared our ranking with the most recent European assessment from 2014.Results: Illicit drugs such as methamphetamine, heroin, cocaine and also alcohol were judged particularly harmful, and new psychoactive drugs (cathinones, synthetic cannabinoids) were ranked among the most harmful substances. Cannabis was ranked in the midrange, on par with benzodiazepines and ketamine—somewhat more favorable compared to the last European survey. Prescribed drugs including opioids (in contrast to the USA, Canada, and Australia) were judged less harmful. NOAs were at the bottom end of the ranking.Conclusion: In Germany, alcohol and illicit drugs (including new psychoactive substances) continue to rank among the most harmful addictive substances in contrast to prescribed agents including opioid analgesics and NOAs. Current laws are incongruent with these harm rankings. This study is the first of its kind to include comparative harm rankings of several novel abused substances, both licit/prescribed and illicit.

BackgroundAbout 15 years ago, a diverse group of new recreational psychotropic substances began to emerge, which were marketed for example as “legal highs,” “research chemicals,” or “designer drugs.” These substances were later subsumed under the label “Novel Psychoactive Substances” (NPS). Important NPS classes are cathinones, synthetic cannabimimetics, phenethylamines, and herbal drugs. The health care system for psychotropic substance use disorders (SUDs) traditionally focused on a few substances, such as alcohol, heroin, cocaine, amphetamines, or cannabis. Users of illicit substances often engage in polydrug use. However little is known about the prevalence of NPS use within the group of “classical” illicit substance users.ObjectiveWe investigated lifetime and recent use of NPS and other drugs in patients who underwent in-patient detoxification treatment from illicit drugs in Germany.MethodsIn a multicenter study with eight participating facilities, patients admitted to treatment underwent a standardized interview at admission, concerning their past and current substance use. The interview comprised classical substances of abuse, NPS, and rarely used substances such as LSD. In addition, participating sites had the opportunity to analyze their patients’ routine drug screenings by means of gas chromatography/mass spectrometry (GC/MS), which permitted detection of NPS.ResultsInterviews from 295 patients could be analyzed. Most patients were opiate dependent and multiple substance users. About 32% reported use of synthetic cannabimimetics during lifetime, but usually only a few times. An important reason for their use was that NPS were not detected by drug testing in prisons or drug treatment facilities. Cathinones, herbal drugs or other NPS had rarely been used during lifetime. NPS use during the last 30 days before admission was nearly zero. This was confirmed by urine analysis results. In contrast, lifetime and current use of opiates, alcohol, cocaine, benzodiazepines, and cannabis was high. In addition, 18% reported of regular unprescribed pregabalin use during lifetime, and 20% had recently used pregabalin.ConclusionPatients admitted to drug detoxification treatment showed multiple substance use, but this did not include NPS use. The diversion of legal medications such as pregabalin in this group is a serious concern.

Alpha-synuclein (αSynAgg) are pathological hallmarks of Parkinson's disease (PD) and other synucleinopathies that induce microglial activation and immune-mediated neurotoxicity, but the molecular mechanisms of αSynAgg-induced immune activation are poorly defined. We performed quantitative proteomics by mass spectrometry coupled with PCR, immunohistochemical and functional validations studies to define the molecular characteristics of alpha synuclein mediated microglial activation. In mouse microglia, αSynAgg induced robust pro-inflammatory activation (increased expression of 864 genes including Irg1, Ifit1, and Pyhin) and increased nuclear proteins involved in RNA synthesis, splicing, and anti-viral defense mechanisms. Conversely, αSynAgg decreased expression several proteins (including Cdc123, Sod1, and Grn), which were predominantly cytosolic and involved in metabolic, proteasomal and lysosomal mechanisms. Pathway analyses and confirmatory in vitro studies suggested that αSynAgg partly mediates its effects via Stat3 activation. As predicted by our proteomic findings, we verified that αSynAgg induces mitochondrial dysfunction in microglia. Twenty-six proteins differentially expressed by αSynAgg were also identified as PD risk genes in genome-wide association studies (upregulated: Brd2, Clk1, Siglec1; down-regulated: Memo1, Arhgap18, Fyn, and Pgrn/Grn). We validated progranulin (PGRN) as a lysosomal PD-associated protein that is downregulated by αSynAgg in microglia in-vivo and is expressed by microglia in post-mortem PD brain, congruent with our in vitro findings.Conclusion: Together, proteomics approach both reveals novel molecular insights into αSyn-mediated neuroinflammation in PD and other synucleinopathies.

Behavioral phenotyping of mice is often compromised by manual interventions of the experimenter and limited throughput. Here, we describe a fully automated behavior setup that allows for quantitative analysis of mouse olfaction with minimized experimenter involvement. Mice are group-housed and tagged with unique RFID chips. They can freely initiate trials and are automatically trained on a go/no-go task, learning to distinguish a rewarded from an unrewarded odor. Further, odor discrimination tasks and detailed training aspects can be set for each animal individually for automated execution without direct experimenter intervention. The procedure described here, from initial RFID implantation to discrimination of complex odor mixtures at high accuracy, can be completed within

In the locoregional advanced group of larynx and hypopharyngeal squamous cell carcinomas (LHSCC), there are two kinds of patients: those who are candidates for functional larynx organ preservation (LP) by avoiding ablative surgery and those who are not. Currently, the distinction between them is depending on the patient's needs and desires, the experience and recommendation of the surgeon, the philosophy of the institution and others. The milestone VA trial established non-surgical LP in advanced LHSCC utilizing induction-chemotherapy (IC) with PF (cisplatin, P plus 5-fluorouracil, F) followed by irradiation (IC+RT) as appropriate alternative treatment to total laryngectomy (TL) already in the 1990s. Even thou the VA trial's findings were verified by the EORTC 24891 trial we have an ongoing debate about the best protocol balancing survival and laryngectomy-free survival (LFS) with acceptable late toxicity and good functional outcome. In advanced LHSCC without surgical options preserving the larynx, only IC+RT and primary concurrent chemo-radiotherapy (CRT) are accepted treatment options aiming to preserve a functional larynx. In the US, cisplatin-based CRT is still recommended as best protocol to achieve cure of the disease and LP. But current views on long term survival with functional organ preservation and still high failure rates are addressing the need of better selection of patients which will be discussed as follows taking the current debate in literature and in particular the recently published data of the DeLOS-II trial in consideration.

The objective of the present research was to investigate associations of dispositional and momentary self-control and the presence of other individuals consuming SSBs with the consumption frequency of sugar-sweetened beverages (SSBs) in a multi-country pilot study. We conducted an Ambulatory Assessment in which 75 university students (52 females) from four study sites carried smartphones and received prompts six times a day in their everyday environments to capture information regarding momentary self-control and the presence of other individuals consuming SSBs. Multilevel models revealed a statistically significant negative association between dispositional self-control and SSB consumption. Moreover, having more self-control than usual was only beneficial in regard to lower SSB consumption frequency, when other individuals consuming SSBs were not present but not when they were present. The findings support the hypothesis that self-control is an important factor regarding SSB consumption. This early evidence highlights self-control as a candidate to design interventions to promote healthier drinking through improved self-control.

The reduction of neuronal responses to repeated stimulus presentation occurs in many sensory neurons, also in the inferior colliculus of birds. The cellular mechanisms that cause response adaptation are not well described. Adaptation must be explicable by changes in the activity of input neurons, short-term synaptic plasticity of the incoming connections, excitability changes of the neuron under consideration or influences of inhibitory or modulatory network connections. Using whole-cell recordings in acute brain slices of the embryonic chicken brain we wanted to understand the intrinsic and synaptic contributions to adaptation in the core of the central nucleus of the inferior colliculus (ICCc). We described two neuron types in the chicken ICCc based on their action potential firing patterns: Phasic/onset neurons showed strong intrinsic adaptation but recovered more rapidly. Tonic/sustained firing neurons had weaker adaptation but often had additional slow components of recovery from adaptation. Morphological analysis suggested two neuron classes, but no physiological parameter aligned with this classification. Chicken ICCc neurons received mostly mixed AMPA- and NMDA-type glutamatergic synaptic inputs. In the majority of ICCc neurons the input synapses underwent short-term depression. With a simulation of the putative population output activity of the chicken ICCc we showed that the different adaptation profiles of the neuron classes could shift the emphasize of stimulus encoding from transients at long intervals to ongoing parts at short intervals. Thus, we report here that description of biophysical and synaptic properties can help to explain adaptive phenomena in central auditory neurons.

Fc fusion proteins and Fc fusion peptides or peptibodies are chimeric molecules composed of an active pharmacological protein or peptide and the Fc fragment of an immunoglobulin. The primary aim of this drug construct is to prolong the half-life of the active component. This molecular architecture is seen in drugs, such as etanercept, romiplostim, and the recombinant factor VIII (efmoroctocog alfa). A considerable number of Fc fusion proteins and peptibodies are currently in pre-clinical and clinical development. The isolated effect of the Fc fragment has been studied intensively during last years, but is still poorly understood in the clinical setting and in relation with the active drug and underlying disease. In this short review, we will propose new hypotheses of possible immunomodulatory functions of the Fc fragment of romiplostim in patients with primary immune thrombocytopenia.

Neuronal intracellular Cl− concentration ([Cl−]i) influences a wide range of processes such as neuronal inhibition, membrane potential dynamics, intracellular pH (pHi) or cell volume. Up to date, neuronal [Cl−]i has predominantly been studied in model systems of reduced complexity. Here, we implemented the genetically encoded ratiometric Cl− indicator Superclomeleon (SCLM) to estimate the steady-state [Cl−]i in cortical neurons from anesthetized and awake mice using 2-photon microscopy. Additionally, we implemented superecliptic pHluorin (SE-pHluorin) as a ratiometric sensor to estimate the intracellular steady-state pH (pHi) of mouse cortical neurons in vivo. We estimated an average resting [Cl−]i of 6 ± 2 mM with no evidence of subcellular gradients in the proximal somato-dendritic domain and an average somatic pHi of 7.1 ± 0.2. Neither [Cl−]i nor pHi were affected by isoflurane anesthesia. We deleted the cation-Cl− co-transporter KCC2 in single identified neurons of adult mice and found an increase of [Cl−]i to approximately 26 ± 8 mM, demonstrating that under in vivo conditions KCC2 produces low [Cl−]i in adult mouse neurons. In summary, neurons of the brain of awake adult mice exhibit a low and evenly distributed [Cl−]i in the proximal somato-dendritic compartment that is independent of anesthesia and requires KCC2 expression for its maintenance.

In this study, we investigated the barley yellow mosaic virus (BaYMV, genus Bymovirus) factor(s) responsible for breaking eIF4E-mediated recessive resistance genes (rym4/5/6) in barley. Genome mapping analysis using chimeric infectious cDNA clones between rym5-breaking (JT10) and rym5-non-breaking (JK05) isolates indicated that genome-linked viral protein (VPg) is the determinant protein for breaking the rym5 resistance. Likewise, VPg is also responsible for overcoming the resistances of rym4 and rym6 alleles. Mutational analysis identified that amino acids Ser-118, Thr-120 and His-142 in JT10 VPg are the most critical residues for overcoming rym5 resistance in protoplasts. Moreover, the rym5-non-breaking JK05 could accumulate in the rym5 protoplasts when eIF4E derived from a susceptible barley cultivar was expressed from the viral genome. Thus, the compatibility between VPg and host eIF4E determines the ability of BaYMV to infect barley plants.