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Abstract Objective Phenotypes are important for patient classification, disease prognostication, and treatment customization. We aimed to identify distinct clinical phenotypes of children and adolescents hospitalized with SARS-CoV-2 infection, and to evaluate their prognostic differences. Methods The German Society of Pediatric Infectious Diseases (DGPI) registry is a nationwide, prospective registry for children and adolescents hospitalized with a SARS-CoV-2 infection in Germany. We applied hierarchical clustering for phenotype identification with variables including sex, SARS-CoV-2-related symptoms on admission, pre-existing comorbidities, clinically relevant coinfection, and SARS-CoV-2 risk factors. Outcomes of this study were: discharge status and ICU admission. Discharge status was categorized as: full recovery, residual symptoms, and unfavorable prognosis (including consequential damage that has already been identified as potentially irreversible at the time of discharge and SARS-CoV-2-related death). After acquiring the phenotypes, we evaluated their correlation with discharge status by multinomial logistic regression model, and correlation with ICU admission by binary logistic regression model. We conducted an analogous subgroup analysis for those aged

Abstract Immune checkpoint inhibitors (ICI) have significantly improved overall survival in melanoma patients. However, 60% experience severe adverse events and early response markers are lacking. Circulating tumour DNA (ctDNA) is a promising biomarker for treatment-response and recurrence detection. The prospective PET/LIT study included 104 patients with palliative combined or adjuvant ICI. Tumour-informed sequencing panels to monitor 30 patient-specific variants were designed and 321 liquid biopsies of 87 patients sequenced. Mean sequencing depth after deduplication using UMIs was 6000x and the error rate of UMI-corrected reads was 2.47×10−4. Variant allele fractions correlated with PET/CT MTV (rho=0.69), S100 (rho=0.72), and LDH (rho=0.54). A decrease of allele fractions between T1 and T2 was associated with improved PFS and OS in the palliative cohort (p = 0.008 and p

Abstract Pupillary contagion occurs when one’s pupil size unconsciously adapts to the pupil size of an observed individual and is presumed to reflect the transfer of arousal. Importantly, when estimating pupil contagion, low level stimuli properties need to be controlled for, to ensure that observations of pupillary changes are due to internal change in arousal rather than the external differences between stimuli. Here, naturalistic images of children’s faces depicting either small or large pupils were presented to a group of children and adolescents with a wide range of autistic traits, a third of whom had been diagnosed with autism. We examined the extent to which pupillary contagion reflects autonomic nervous system reaction through pupil size change, heart rate and skin conductance response. Our second aim was to determine the association between arousal reaction to stimuli and degree of autistic traits. Results show that pupil contagion and concomitant heart rate change, but not skin conductance change, was evident when gaze was restricted to the eye region of face stimuli. A positive association was also observed between pupillary contagion and autistic traits when participants’ gaze was constrained to the eye region. Findings add to a broader understanding of the mechanisms underlying pupillary contagion and its association with autism.

Abstract Background This experimental study aimed at directly comparing conventional and endoscopic-assisted curettage towards (1) amount of residual tumour tissue (RTT) and (2) differences between techniques regarding surgical time and surgeons’ experience level. Methods Three orthopaedic surgeons (trainee, consultant, senior consultant) performed both conventional (4x each) and endoscopic-assisted curettages (4x each) on specifically prepared cortical-soft cancellous femur and tibia sawbone models. “Tumours” consisted of radio-opaque polyurethane-based foam injected into prepared holes. Pre- and postinterventional CT-scans were carried out and RTT assessed on CT-scans. For statistical analyses, percentage of RTT in relation to total lesion’s volume was used. T-tests, Wilcoxon rank-sum tests, and Kruskal-Wallis tests were applied to assess differences between surgeons and surgical techniques regarding RTT and timing. Results Median overall RTT was 1% (IQR 1 – 4%). Endoscopic-assisted curettage was associated with lower amount of RTT (median, 1%, IQR 0 − 5%) compared to conventional curettage (median, 4%, IQR 0 − 15%, p = 0.024). Mean surgical time was prolonged with endoscopic-assisted (9.2 ± 2.9 min) versus conventional curettage (5.9 ± 2.0 min; p = 0.004). No significant difference in RTT amount (p = 0.571) or curetting time (p = 0.251) depending on surgeons’ experience level was found. Conclusions Endoscopic-assisted curettage appears superior to conventional curettage regarding complete tissue removal, yet at expenses of prolonged curetting time. In clinical practice, this procedure may be reserved for cases at high risk of recurrence (e.g. anatomy, histology).

Background: The second generation of a custom total knee arthroplasty (TKA) implant cast from a 3D-printed mold was introduced into the market in 2012. The purpose of this retrospective study was to investigate short- to mid-term survivorship and complication rates of this novel implant. Methods: This study is a retrospective analysis of 314 TKA procedures (264 patients) performed by a single surgeon using a customized TKA from September 2012 to November 2015. Patient demographics, rate of implant revision, rate of reoperation for any reason, and rate of postoperative complications were recorded. Results: At the time of index surgery, the mean patient age was 64.7 years, and the mean follow-up duration was 3 years. At the final follow-up, implant survivorship free from revision was 98.1%, and survivorship free from reoperation for any reason was 92.4%. Conclusions: Our analysis revealed favorable short- to mid-term survivorship for a customized TKA implant. While the short- to mid-term outcomes for this implant are promising, future studies are required to assess long-term outcomes and durability.

Little is known about the evolution and dynamics of icebergs in alpine lakes. We analyzed the movement and ablation patterns of icebergs at an ice-contact lake at Pasterze Glacier, Austria, using time-lapse images. Iceberg evolution was quantified for two timescales and related to meteorological as well as glacier ablation data from the adjacent glacier tongue. On a multiyear scale, ablation and movement of one iceberg (IB1) was monitored during a twenty-five-month period. On a single-day scale, the movement paths of eighty-four icebergs were tracked over 16 hours. Results for IB1 revealed an average iceberg ablation of 72 mm d−1 from June to September and no winter ablation. Iceberg ablation rates rose over time, explained by a rising surface area-to-volume ratio. Monitoring lake-wide iceberg movement for one day shows that a persistent katabatic glacier wind and a valley wind are the main influences on horizontal iceberg movement. Iceberg velocity is roughly 0.6 percent of the wind velocity. The existence of a wind-driven current on the lake surface is proposed. Sudden changes in movement rates, which are not explained by wind data, suggest that iceberg grounding is common. This study provides insight into iceberg melt rates in the absence of wave erosion.

Introduction: Cannabis sativa L. inflorescences are widely used in the medicinal field as treatments for a variety of symptoms and illnesses due to their unique phytochemicals such as cannabinoids and terpenes. Common postharvest procedures for cannabis inflorescence include trimming, followed by drying, curing, and subsequent storage. The postharvest trimming step, particularly its timing (pre- or post-drying) and the extent of trimming, is not optimally refined in terms of its impact on the cannabinoid and terpene content. In this study, our objective was to identify the optimal trimming conditions for a commercially available medicinal cannabis hybrid chemovar, with the goal of maximizing its cannabinoid and terpene content. Methods: To achieve this, we investigated the effects of pre- versus post-drying trimming and evaluated the impact of mild versus aggressive trimming prior to drying on the cannabinoid and terpene profiles using liquid and gas chromatography. Results: Our results indicated that pre-drying mild trimming yielded the highest cannabinoid concentration, possibly due to optimal balance between stress signals and precursor influx from the sugar leaves to the inflorescence. On the other, post-drying trimming yielded the highest terpene content. Conclusion: Identifying the optimal trimming conditions that maximize both cannabinoid and terpene levels in cannabis is challenging. Therefore, growers face a decision in their trimming practices: to prioritize either enhanced cannabinoid content or increased aromatic terpene concentrations, as optimizing for both simultaneously appears to be difficult.

Abstract Sex-specific gonadal differentiation is directed by complex signalling promoting development in either male or female direction, while simultaneously inhibiting the opposite pathway. In mice, the WNT/β-catenin pathway promotes ovarian development and the importance of actively inhibiting this pathway to ensure normal testis development has been recognised. However, the implications of alterations in the tightly regulated WNT/β-catenin signalling during human fetal gonad development has not yet been examined in detail. Thus, the aim of this study was to examine the consequences of dysregulating the WNT/β-catenin signalling pathway in the supporting cell lineage during sex-specific human fetal gonad development using an established and extensively validated ex vivo culture model. Inhibition of WNT/β-catenin signalling in human fetal ovary cultures resulted in only minor effects, including reduced secretion of RSPO1 and reduced cell proliferation although this was not consistently found in all treatment groups. In contrast, promotion of WNT/β-catenin signalling in testes severely affected development and function. This included disrupted seminiferous cord structures, reduced cell proliferation, reduced expression of SOX9/AMH, reduced secretion of Inhibin B and AMH as well as loss of the germ cell population. Additionally, Leydig cell function was markedly impaired with reduced secretion of testosterone, androstenedione and INSL3. Together, this study suggests that dysregulated WNT/β-catenin signalling during human fetal gonad development severely impairs testicular development and function. Importantly, our study highlights the notion that sufficient inhibition of the opposite pathway during sex-specific gonadal differentiation is essential to ensure normal development and function also applies to human fetal gonads.

Abstract Eye contact is a central component in face-to-face interactions. It is important in structuring communicative exchanges and offers critical insights into others' interests and intentions. To better understand eye contact in face-to-face interactions, we applied a novel, non-intrusive deep-learning-based dual-camera system and investigated associations between eye contact and autistic traits as well as self-reported eye contact discomfort during a referential communication task, where participants and the experimenter had to guess, in turn, a word known by the other individual. Corroborating previous research, we found that participants’ eye gaze and mutual eye contact were inversely related to autistic traits. In addition, our findings revealed different behaviors depending on the role in the dyad: listening and guessing were associated with increased eye contact compared with describing words. In the listening and guessing condition, only a subgroup who reported eye contact discomfort had a lower amount of eye gaze and eye contact. When describing words, higher autistic traits were associated with reduced eye gaze and eye contact. Our data indicate that eye contact is inversely associated with autistic traits when describing words, and that eye gaze is modulated by the communicative role in a conversation.

Abstract Background Research on genetic and environmental influences on speech and/or language difficulties (SaLD) is sparse, with inconsistent heritability estimates. We aimed to estimate the prevalence of parental reported SaLD and the relative contributions of genetic and environmental factors for the phenotype using a Swedish population‐based twin sample. We hypothesized that there would be a stronger genetic than environmental effect on SaLD. Methods Data were collected from The Child and Adolescent Twin Study in Sweden. The study sample included 16,774 twin pairs (16,946 males, 16,602 females), of which 5141 were monozygotic, 5861 dizygotic (DZ), and 5772 opposite‐sex DZ pairs. The language items in the Autism–Tics, Attention‐Deficit Hyperactivity Disorder, and other Comorbidities inventory were used to categorize individuals as having parental‐reported SaLD. A classical twin design was used to estimate the relative contribution of genetic and environmental factors to the liability of SaLD. Results The prevalence of SaLD was 7.85% (95% confidence interval (CI) [7.57%–8.15%]) and 7.27% (95% CI [6.99%–7.55%]) when excluding individuals with autism and intellectual disability (ID). We also found that SaLD were significantly more prevalent in males than females with a ratio of 2:1. The heritability was estimated to be 75% (95% CI [67%–83%]) for SaLD. Shared environment played a significant role with an estimated contribution of 22% (95% CI [14%–30%]). The heritability estimate was reduced to 70% but with overlapping CI when excluding individuals with autism and ID. Conclusions We provide evidence that SaLD is common in the population and under strong genetic influence. Future studies should focus on mapping the genetic architecture of SaLD and related disorders.

Abstract Cobalt is considered an essential element for layered cathode active materials supporting enhanced lithium‐ion conductivity and structural stability. Herein, we investigated the influence of Co concentration on the physicochemical properties and electrochemical performance of lithium‐rich layered oxides (LRLOs) with different Co content (Li1.2Ni0.2‐x/2Mn0.6‐x/2CoxO2, x=0, 0.04, and 0.08). Though the presence of Co grants structural stability to LRLOs, superior long‐term cycling stability is achieved with the Co‐free LRLO retaining 88.1 % of the initial specific capacity (vs. 75.9 % of Li1.2Ni0.16Mn0.56Co0.08O2) after 300 galvanostatic cycles at 250 mA g−1 (1 C). The chemical stability on the surface of LRLOs containing Co declines faster, indicating a higher bulk structural stability not being the primary determinant of the LRLOs’ cycling performance. Ex‐situ investigations indicate that the superior cycling stability of Co‐free LRLO is obtained by reducing the Mn‐related redox at discharge, which contributes to the large degree of polarization and low energy efficiency. Finally, the full‐cell configured with the optimized LRLO as cathode and graphite anode delivers an energy density of 464 Wh kg−1 at C/10, and 74.4 % and 94.3 % of retention in discharge specific capacity and average voltage at the 1000th cycle, demonstrating the applicability of Co‐free LRLO for sustainable LIBs.

Abstract The consequences of short‐term disuse are well known, but effective countermeasures remain elusive. This study investigated the effects of neuromuscular electrical stimulation (NMES) during 5 days of bed rest on retaining lower limb muscle mass and muscle function in healthy young and old participants. One leg received NMES of the quadriceps muscle (3 × 30min/day) (NMES), and the other served as a control (CON). Isometric quadriceps strength (MVC), rate of force development (RFD), lower limb lean mass, and muscle thickness were assessed pre‐and post‐intervention. Muscle thickness remained unaltered with NMES in young and increased in old following bed rest, while it decreased in CON legs. In old participants, mid‐thigh lean mass (MTLM) was preserved with NMES while decreased in CON legs. In the young, only a tendency to change with bed rest was detected for MTLM. MVC and early‐phase RFD decreased in young and old, irrespective of NMES. In contrast, late‐phase RFD was retained in young participants with NMES, while it decreased in young CON legs, and in the old, irrespective of NMES. NMES during short‐term bed rest preserved muscle thickness but not maximal muscle strength. While young and old adults demonstrated similar adaptive responses in preventing the loss of skeletal muscle thickness, RFD was retained in the young only.

Brain white matter is a dynamic environment that continuously adapts and reorganizes in response to stimuli and pathological changes. Glial cells, especially, play a key role in tissue repair, inflammation modulation, and neural recovery. The movements of glial cells and changes in their concentrations can influence the surrounding axon morphology. We introduce the White Matter Generator (WMG) tool to enable the study of how axon morphology is influenced through such dynamical processes, and how this, in turn, influences the diffusion-weighted MRI signal. This is made possible by allowing interactive changes to the configuration of the phantom generation throughout the optimization process. The phantoms can consist of myelinated axons, unmyelinated axons, and cell clusters, separated by extra-cellular space. Due to morphological flexibility and computational advantages during the optimization, the tool uses ellipsoids as building blocks for all structures; chains of ellipsoids for axons, and individual ellipsoids for cell clusters. After optimization, the ellipsoid representation can be converted to a mesh representation which can be employed in Monte-Carlo diffusion simulations. This offers an effective method for evaluating tissue microstructure models for diffusion-weighted MRI in controlled bio-mimicking white matter environments. Hence, the WMG offers valuable insights into white matter's adaptive nature and implications for diffusion-weighted MRI microstructure models, and thereby holds the potential to advance clinical diagnosis, treatment, and rehabilitation strategies for various neurological disorders and injuries.

IntroductionThe peptide hormone Insulin-like Factor 3 (INSL3) is a biomarker of testicular Leydig cells in the male but is also expressed by the theca cells of the ovaries. With the advent of sensitive assays INSL3 can be quantified in female circulation, and we suggest that circulating INSL3 is a novel biomarker for pubertal development in girls. The aim of the study is to quantify INSL3 by LC-MS/MS in sera from normal girls during pubertal transition, and during gonadal suppression by GnRH agonist therapy in girls with central precocious puberty (CPP).MethodThe sensitivity of an established LC-MS/MS-based method for serum INSL3 was improved by switching to a state-of-the-art triple quadruple mass spectrometer (Altis Plus, Thermo).ResultsThe limit of detection of the improved LC-MS/MS method for serum INSL3 was 0.01 ug/L (1.5 pM) and the inter-assay CV was < 12%. Serum INSL3 increased during the pubertal transition in healthy girls and changes correlated with the concomitant rise in other measured hormones. In some girls, but not all, INSL3, FSH, inhibin B and estradiol serum concentrations increased prior to first clinical signs of puberty. Serum INSL3 concentrations were increased at baseline in girls with CPP compared to prepubertal controls and decreased during treatment with GnRH agonist followed by a steep rise and normalization after cessation of treatment.ConclusionThe improved method allowed for quantification of INSL3 in longitudinally collected serum samples during pubertal transition in healthy girls as well as in girls with CPP before, during and after treatment with GnRH agonist. Future studies are needed to clarify if INSL3 in combination with other biomarkers enhances the predictive value of differentiating between premature thelarche and CPP.

Abstract In the era of precision medicine, genome sequencing (GS) has become more affordable and the importance of genomics and multi-omics in clinical care is increasingly being recognized. However, how to scale and effectively implement GS on an institutional level remains a challenge for many. Here, we present Genome First and Ge-Med, two clinical implementation studies focused on identifying the key pillars and processes that are required to make routine GS and predictive genomics a reality in the clinical setting. We describe our experience and lessons learned for a variety of topics including test logistics, patient care processes, data reporting, and infrastructure. Our model of providing clinical care and comprehensive genomic analysis from a single source may be used by other centers with a similar structure to facilitate the implementation of omics-based personalized health concepts in medicine.

Abstract By means of a nationwide, prospective, multicenter, observational cohort registry collecting data on 7375 patients with laboratory-confirmed SARS-CoV-2 admitted to children's hospitals in Germany, March 2020–November 2022, our study assessed the clinical features of children and adolescents hospitalized due to SARS-CoV-2, evaluated which of these patients might be at highest risk for severe COVID-19, and identified underlying risk factors. Outcomes tracked included: symptomatic infection, case fatality, sequelae at discharge and severe disease. Among reported cases, median age was one year, with 42% being infants. Half were admitted for reasons other than SARS-CoV-2. In 27%, preexisting comorbidities were present, most frequently obesity, neurological/neuromuscular disorders, premature birth, and respiratory, cardiovascular or gastrointestinal diseases. 3.0% of cases were admitted to ICU, but ICU admission rates varied as different SARS-CoV-2 variants gained prevalence. Main risk factors linked to ICU admission due to COVID-19 were: patient age (> 12 and 1–4 years old), obesity, neurological/neuromuscular diseases, Trisomy 21 or other genetic syndromes, and coinfections at time of hospitalization. With Omicron, the group at highest risk shifted to 1–4-year-olds. For both health care providers and the general public, understanding risk factors for severe disease is critical to informing decisions about risk-reduction measures, including vaccination and masking guidelines.

Abstract Background The influence of anaesthetic depth and the potential influence of different anaesthetic beds and thus different handling procedures were investigated in 86 severe combined immunodeficient (SCID) mice using semi-stationary dynamic single photon emission computed tomography (SPECT) for kidney scintigraphy. Therefore, isoflurane concentrations were adjusted using respiratory rate for low (80–90 breath/min) and deep anaesthesia (40–45 breath/min). At low anaesthesia, we additionally tested the influence of single bed versus 3-mouse bed hotel; the hotel mice were anaesthetized consecutively at ~ 30, 20, and 10 min before tracer injections for positions 1, 2, and 3, respectively. Intravenous [99mTc]Tc-MAG3 injection of ~ 28 MBq was performed after SPECT start. Time-activity curves were used to calculate time-to-peak (Tmax), T50 (50% clearance) and T25 (75% clearance). Results Low and deep anaesthesia corresponded to median isoflurane concentrations of 1.3% and 1.5%, respectively, with no significant differences in heart rate (p = 0.74). Low anaesthesia resulted in shorter aortic blood clearance half-life (p = 0.091) and increased relative renal tracer influx rate (p = 0.018). A tendency toward earlier Tmax occurred under low anaesthesia (p = 0.063) with no differences in T50 (p = 0.40) and T25 (p = 0.24). Variance increased with deep anaesthesia. Compared to single mouse scans, hotel mice in position 1 showed a delayed Tmax, T50, and T25 (p

Abstract Ultrafast electron dynamics drive phenomena such as photochemical reactions, catalysis, and light harvesting. To capture such dynamics in real-time, femtosecond to attosecond light sources are extensively used. However, an exact match between the excitation photon energy and a characteristic resonance is crucial. High-harmonic generation sources are advantageous in terms of pulse duration but limited in spectral tunability in the vacuum ultraviolet range. Here, we present a monochromatic femtosecond source continuously tunable around 21 eV photon energy utilizing the second harmonic of an optical parametric chirped pulse amplification laser system to drive high-harmonic generation. The unique tunability of the source is verified in an experiment probing the interatomic Coulombic decay in doped He nanodroplets across the He absorption bands. Moreover, we achieved intensities sufficient for driving collective processes in multiply excited helium nanodroplets, which have been previously observed only at free electron lasers.

The porcine reproductive and respiratory syndrome virus (PRRSV) causes high economical costs due to reduced productivity and losses in pig production. The virus can infect sow herds through various routes. One possible risk factor is the transmission of PRRSV through artificial insemination with infected boar semen. For these reasons, conventional boar studs should be closely monitored to detect an outbreak of PRRSV at an early stage. In the presented retrospective study, 2184 fresh semen samples from 336 boars were investigated (RT-qPCR) after an accidental PRRSV introduction to the herd. Hence, the different shedding profiles of PRRSV via semen resulted in 42.2% where no virus was detected, 2.0% intermittent shedding, and 8.4% permanent shedding. The duration of viral shedding varies from 2 days to 83 days post outbreak (on average 33 days). A significant impact of breed on PRRSV shedding duration could not be shown. Also, the distribution of the shedding profile does not follow a consistent mode, indicating that not every boar is shedding the virus via semen.

Abstract A growing number of druggable targets and national initiatives for precision oncology necessitate broad genomic profiling for many cancer patients. Whole exome sequencing (WES) offers unbiased analysis of the entire coding sequence, segmentation-based detection of copy number alterations (CNAs), and accurate determination of complex biomarkers including tumor mutational burden (TMB), homologous recombination repair deficiency (HRD), and microsatellite instability (MSI). To assess the inter-institution variability of clinical WES, we performed a comparative pilot study between German Centers of Personalized Medicine (ZPMs) from five participating institutions. Tumor and matched normal DNA from 30 patients were analyzed using custom sequencing protocols and bioinformatic pipelines. Calling of somatic variants was highly concordant with a positive percentage agreement (PPA) between 91 and 95% and a positive predictive value (PPV) between 82 and 95% compared with a three-institution consensus and full agreement for 16 of 17 druggable targets. Explanations for deviations included low VAF or coverage, differing annotations, and different filter protocols. CNAs showed overall agreement in 76% for the genomic sequence with high wet-lab variability. Complex biomarkers correlated strongly between institutions (HRD: 0.79–1, TMB: 0.97–0.99) and all institutions agreed on microsatellite instability. This study will contribute to the development of quality control frameworks for comprehensive genomic profiling and sheds light onto parameters that require stringent standardization.

Insertion‐type Nb2O5 is a promising candidate for high‐power lithium‐ion anodes. Among the various polymorphs, monoclinic Nb2O5 (H‐Nb2O5) is considered as one of the most promising materials. Herein, the impact of decreasing the lower cutoff potential, i.e., increasing the amount of lithium that is inserted into the crystal structure, from the commonly used 1.0 V versus Li+/Li to 0.8 V and even 0.01 V is explored, yielding reversible specific capacities of 260, 280, and 400 mAh g−1, respectively, at a specific current of 0.05 A g−1. Remarkably, such increase in capacity does not come along with a deterioration of the cycling stability—at least initially. In fact, the comprehensive investigation of the reaction mechanism via operando/ex situ X‐ray diffraction, operando/ex situ X‐ray absorption spectroscopy, ex situ high‐resolution transmission electron microscopy, and operando isothermal microcalorimetry reveals that the extension of the voltage range does not affect the crystal structure during the first couple of cycles, but there is a continuous evolution upon long‐term cycling.

Levels of the male sex hormone testosterone are generally stable in the age interval 20–70 years, but several studies indicate an earlier, age-dependent decline. Testosterone deficiency is often underdiagnosed and under-treated, but replacement therapy has nonetheless increased during the last couple of years. Owing to possible negative side effects, alternative treatments have been investigated, including different supplementation protocols. The aim of this study was to investigate the effect of probiotic supplementation on the testosterone level in healthy men aged between 55 and 65. Hence, 12 weeks randomized, double-blinded, placebo-controlled trial was conducted to investigate the effect on testosterone levels following supplementation of the recognized probiotic Limosilactobacillus reuteri ATCC PTA 6475 on testosterone levels, using high-, low- or placebo treatment. Venous blood samples were collected at baseline, 6 and 12 weeks, for analysis of bloodwork, lipid profile, hormones, and electrolytes. Subjects were also asked to complete a questionnaire. The supplementation had no effect on testosterone levels, neither using high- or low dose, nor placebo. However, a significant decrease of triglyceride levels was observed in the high-dose group. No other parameters showed any significant change. The present study does not support the hypothesis that a probiotic supplementation can increase testosterone levels in ageing men.

Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is a heritable proteinopathy disorder, whose causative gene, ATXN3, undergoes alternative splicing. Ataxin-3 protein isoforms differ in their toxicity, suggesting that certain ATXN3 splice variants may be crucial in driving the selective toxicity in SCA3. Using RNA-seq datasets we identified and determined the abundance of annotated ATXN3 transcripts in blood (n = 60) and cerebellum (n = 12) of SCA3 subjects and controls. The reference transcript (ATXN3–251), translating into an ataxin-3 isoform harbouring three ubiquitin-interacting motifs (UIMs), showed the highest abundance in blood, while the most abundant transcript in the cerebellum (ATXN3–208) was of unclear function. Noteworthy, two of the four transcripts that encode full-length ataxin-3 isoforms but differ in the C-terminus were strongly related with tissue expression specificity: ATXN3–251 (3UIM) was expressed in blood 50-fold more than in the cerebellum, whereas ATXN3–214 (2UIM) was expressed in the cerebellum 20-fold more than in the blood. These findings shed light on ATXN3 alternative splicing, aiding in the comprehension of SCA3 pathogenesis and providing guidance in the design of future ATXN3 mRNA-lowering therapies.

Climate change and air pollution are two significant challenges facing our society and represent a major driver for new developments in the transport sector. As a consequence, automotive manufacturers have focused on the electrification of vehicle propulsion systems and offer a wide range of hybrid and full-electric vehicles in different classes. However, in the world’s most densely populated metropolitan areas, small and lightweight vehicles are key for the mobility of millions. Traditionally these vehicles have provided cost-effective transportation which is difficult to preserve with vehicle electrification. Many of these light vehicles, such as scooters and all-terrain vehicles, use internal combustion engines in combination with a continuously variable rubber belt transmission which provides a simple, comfortable and cost-effective transmission technology but with poor efficiency and high maintenance costs. In this contribution, a novel full hybrid powertrain concept is proposed that offers a similar driving experience to conventional continuously variable transmissions while providing significantly improved performance and fuel economy combined with low system complexity. In its basic configuration, the hybrid powertrain can operate without active actuators and even with mechanical throttle control of the internal combustion engine. This minimalist approach reduces system costs and helps to create a competitive solution for price-sensitive markets. The hybrid system is based on a planetary gear set that combines the internal combustion engine and an electric motor. It is complemented by a centrifugal clutch and one-way clutch, resulting in different operating modes for low and high speeds as well as for electric driving. This paper describes the mechanical design and control approach of the proposed hybrid powertrain layout. In order to evaluate the basic functionalities, a prototype vehicle was built and tested. This contribution shows the integration of the hybrid powertrain concept in a prototype vehicle and proves the fulfilment of all required full hybrid functionalities.

Abstract Recent research has demonstrated that cooperative and automated driving functions can improve traffic efficiency and safety. Traffic efficiency can be increased and the overall vehicle energy consumption can be reduced through cooperative driving functions not only on the highway, but also in urban areas. To this end, this paper presents a linear model predictive control (MPC) algorithm for the optimization of velocity trajectories of vehicles in a platoon in an urban traffic environment. A novel centralized approach is implemented to optimize the total energy consumption of all vehicles while improving traffic efficiency. To solve the optimal control problem, for the first time, an additional data‐driven velocity prediction model of the vehicle in front of the platoon is used to consider the influence of realistic prediction errors when evaluating the developed control strategy in a vehicle simulation environment. The simulated total energy consumption is compared with a rule‐based cooperative adaptive cruise control (CACC) algorithm. Furthermore, the traffic density and the platoon string stability, the robustness and computer time of the centralized approach are also included in the evaluation. Simulation results indicate that, considering all evaluation criteria, the centralized cooperative control strategy can improve energy efficiency by up to 15% in the investigated urban scenario.

Although approximately half of all metastatic colorectal cancers (mCRCs) harbour mutations in KRAS or NRAS, hardly any progress has been made regarding targeted treatment for this group over the last few years. Here, we investigated the efficacy of vertical inhibition of the RAS‐pathway by targeting epidermal growth factor receptor (EGFR) and mitogen‐activated protein kinase kinase (MEK) in patient‐derived xenograft (PDX) tumours with primary KRAS mutation. In total, 19 different PDX models comprising 127 tumours were tested. Responses were evaluated according to baseline tumour volume changes and graded as partial response (PR; ≤ − 30%), stable disease (SD; between −30% and +20%) or progressive disease (PD; ≥ + 20%). Vertical inhibition with trametinib and cetuximab induced SD or PR in 74% of analysed models, compared to 24% by monotherapy with trametinib. In cases of PR by vertical inhibition (47%), responses were lasting (as long as day 137), with a low incidence of secondary resistance (SR). Molecular analyses revealed that primary and SR was driven by transcriptional reprogramming activating the RAS pathway in a substantial fraction of tumours. Together, these preclinical data strongly support the translation of this combination therapy into clinical trials for CRC patients.

Air temperature inversions, a situation in which atmospheric temperature increases with height, are key components of the Arctic planetary boundary layer. The present study investigates the spatial and temporal variations of temperature inversions over different surface types (rock, gravel, snow, ice) along the Mittivakkat valley (southeast Greenland). For this purpose, 113 vertical profiles with high spatio-temporal resolution of air temperature and relative humidity were collected with unoccupied aerial vehicles (UAVs) during a 13-day field campaign in summer 2019. Air temperature inversions were present in 83% of the profiles, of which 24% were surface-based inversions and 76% were elevated inversions. The proglacial area covered with bare rock and gravel induces surface heating and convection during the day and, through interaction with local circulation patterns, leads to the frequent formation of elevated inversions. In contrast, the glacier surface itself acts as a persistent cooling surface and leads to the formation of surface-based inversions. A low-level fog layer that forms under the inversion layer may be causing non-linear vertical ablation gradients on Mittivakkat Gletsjer. Furthermore, we demonstrate that atmospheric measurements using UAVs can better capture small-scale processes than other products like radiosonde or modeled reanalysis data.

The magnitude and azimuth of horizontal ice flow at Camp Century, Greenland have been measured several times since 1963. Here, we provide a further two independent measurements over the 2017–21 period. Our consensus estimate of horizontal ice flow from four independent satellite-positioning solutions is 3.65 ± 0.13 m a−1 at an azimuth of 236 ± 2°. A portion of the small, but significant, differences in ice velocity and azimuth reported between studies likely results from spatial gradients in ice flow. This highlights the importance of restricting inter-study comparisons of ice flow estimates to measurements surveyed within a horizontal distance of one ice thickness from each other. We suggest that ice flow at Camp Century is stable on seasonal to multi-decadal timescales. The airborne and satellite laser altimetry record indicates an ice thickening trend of 1.1 ± 0.3 cm a−1 since 1994. This thickening trend is qualitatively consistent with previously inferred ongoing millennial-scale ice thickening at Camp Century. The ice flow divide immediately north of Camp Century may now be migrating southward, although the reasons for this divide migration are poorly understood. The Camp Century flowlines presently terminate in the vicinity of Innaqqissorsuup Oqquani Sermeq (Gade Gletsjer) on the Melville Bay coast.

Abstract Background Despite the prevalence of Autism Spectrum Disorder (ASD) globally, there’s a knowledge gap pertaining to autism in Arabic nations. Recognizing the need for validated biomarkers for ASD, our study leverages eye-tracking technology to understand gaze patterns associated with ASD, focusing on joint attention (JA) and atypical gaze patterns during face perception. While previous studies typically evaluate a single eye-tracking metric, our research combines multiple metrics to capture the multidimensional nature of autism, focusing on dwell times on eyes, left facial side, and joint attention. Methods We recorded data from 104 participants (41 neurotypical, mean age: 8.21 ± 4.12 years; 63 with ASD, mean age 8 ± 3.89 years). The data collection consisted of a series of visual stimuli of cartoon faces of humans and animals, presented to the participants in a controlled environment. During each stimulus, the eye movements of the participants were recorded and analyzed, extracting metrics such as time to first fixation and dwell time. We then used these data to train a number of machine learning classification algorithms, to determine if these biomarkers can be used to diagnose ASD. Results We found no significant difference in eye-dwell time between autistic and control groups on human or animal eyes. However, autistic individuals focused less on the left side of both human and animal faces, indicating reduced left visual field (LVF) bias. They also showed slower response times and shorter dwell times on congruent objects during joint attention (JA) tasks, indicating diminished reflexive joint attention. No significant difference was found in time spent on incongruent objects during JA tasks. These results suggest potential eye-tracking biomarkers for autism. The best-performing algorithm was the random forest one, which achieved accuracy = 0.76 ± 0.08, precision = 0.78 ± 0.13, recall = 0.84 ± 0.07, and F1 = 0.80 ± 0.09. Conclusions Although the autism group displayed notable differences in reflexive joint attention and left visual field bias, the dwell time on eyes was not significantly different. Nevertheless, the machine algorithm model trained on these data proved effective at diagnosing ASD, showing the potential of these biomarkers. Our study shows promising results and opens up potential for further exploration in this under-researched geographical context.

Abstract Compared with silicon‐based Insulated Gate Bipolar Transistors (IGBTs), silicon carbide (SiC) Metal‐Oxide‐Semiconductor Field‐Effect Transistors (MOSFETs) are characterized by higher operating temperatures, switching speeds and switching frequencies, and are considered the next evolutionary step for future electric drives. The application of SiC MOSFETs in the field of electrified vehicles has brought many benefits, such as higher efficiency, higher power density, and simplified cooling system, and can be seen as an enabler for high‐power fast battery charging. This article reviews the benefits of SiC MOSFETs in different electrified vehicle (EV) application scenarios, including traction inverters, on‐board converters, and off‐board charging applications. However, replacing Si‐IGBTs with SiC MOSFETs introduces several new technical challenges, such as stronger electromagnetic interference (EMI), reliability issues, potential electric machine insulation failure due to high transient voltages, and cooling difficulties. Compared to mature silicon‐based semiconductor technologies, these challenges have so far hindered the widespread adoption of SiC MOSFETs in automotive applications. To fully exploit the advantages of SiC MOSFETs in automotive applications and enhance their reliability, this paper explores future technology developments in SiC MOSFET module packaging and driver design, as well as novel electric machine drive strategies with higher switching frequencies, and optimized high‐frequency machine design.

Automotive control functions are becoming increasingly complex and their development is becoming more and more elaborate, leading to a strong need for automated solutions within the development process. Here, reinforcement learning offers a significant potential for function development to generate optimized control functions in an automated manner. Despite its successful deployment in a variety of control tasks, there is still a lack of standard tooling solutions for function development based on reinforcement learning in the automotive industry. To address this gap, we present a flexible framework that couples the conventional development process with an open-source reinforcement learning library. It features modular, physical models for relevant vehicle components, a co-simulation with a microscopic traffic simulation to generate realistic scenarios, and enables distributed and parallelized training. We demonstrate the effectiveness of our proposed method in a feasibility study to learn a control function for automated longitudinal control of an electric vehicle in an urban traffic scenario. The evolved control strategy produces a smooth trajectory with energy savings of up to 14%. The results highlight the great potential of reinforcement learning for automated control function development and prove the effectiveness of the proposed framework.

Abstract Evidence is accumulating that the Coronavirus disease (COVID-19) can bring forth deficits in executive functioning via alterations in the dopaminergic system. Importantly, dopaminergic pathways have been shown to modulate how actions and perceptions are integrated within the brain. Such alterations in event file binding could thus underlie the cognitive deficits developing after a COVID-19 infection. We examined action-perception integration in a group of young people (11–19 years of age) that had been infected with COVID-19 before study participation (n = 34) and compared them to a group of uninfected healthy controls (n = 29) on the behavioral (i.e., task accuracy, reaction time) and neurophysiological (EEG) level using an established event file binding paradigm. Groups did not differ from each other regarding demographic variables or in reporting psychiatric symptoms. Overall, multiple lines of evidence (behavioral and neurophysiological) suggest that action-perception integration is preserved in adolescents who suffered from COVID-19 prior to study participation. Event file binding processes were intact in both groups on all levels. While cognitive impairments can occur following a COVID-19 infection, the study demonstrates that action-perception integration as one of the basic building blocks of cognition seems to be largely unaffected in adolescents with a rather mild course of the disease.

Congenital adrenal hyperplasia (CAH) is a recessive condition t hat affects the adrenal glands. Despite life-long replacement therapy with glucocorticoids and mineralocorticoids, adult patients with CAH often experience impaired gonadal function. In pubertal boys and in men with CAH, circulating testosterone is produced by the adrenal glands as well as the testicular, steroidogenic cells. In this European two-center study, we evaluated the function of Leydig and Sertoli cells in 61 boys and men with CAH, primarily due to 21-hydroxylase deficiency. Despite conventional hormone replacement therapy, our results indicated a significant reduction in serum concentrations of both Leydig cel l-derived hormones (i.e. insulin-like factor 3 (INSL3) and testosterone) and Sertoli cell-derived hormones (i.e. inhibin B and anti-Müllerian hormone) in adult males with CAH. Serum concentrations of INSL3 were particularly reduced in those with testicular adrenal rest tumors. To our knowledge, this is the first study to evaluate circulating INSL3 as a candi date biomarker to monitor Leydig cell function in patients with CAH.

Abstract Background Braak’s hypothesis states that sporadic Parkinson’s disease (PD) follows a specific progression of pathology from the peripheral to the central nervous system, and this progression can be monitored by detecting the accumulation of alpha-Synuclein (α-Syn) protein. Consequently, there is growing interest in understanding how the gut (commensal) microbiome can regulate α-Syn accumulation, as this could potentially lead to PD. Methods We used 16S rRNA and shotgun sequencing to characterise microbial diversity. 1H-NMR was employed to understand the metabolite production and intestinal inflammation estimated using ELISA and RNA-sequencing from feces and the intestinal epithelial layer respectively. The Na+ channel current and gut permeability were measured using an Ussing chamber. Immunohistochemistry and immunofluorescence imaging were applied to detect the α-Syn protein. LC-MS/MS was used for characterization of proteins from metabolite treated neuronal cells. Finally, Metascape and Ingenuity Pathway Analysis (IPA) bioinformatics tools were used for identification of dysregulated pathways. Results We studied a transgenic (TG) rat model overexpressing the human SNCA gene and found that a progressive gut microbial composition alteration characterized by the reduction of Firmicutes to Bacteroidetes ratio could be detected in the young TG rats. Interestingly, this ratio then increased with ageing. The dynamics of Lactobacillus and Alistipes were monitored and reduced Lactobacillus and increased Alistipes abundance was discerned in ageing TG rats. Additionally, the SNCA gene overexpression resulted in gut α-Syn protein expression and increased with advanced age. Further, older TG animals had increased intestinal inflammation, decreased Na+ current and a robust alteration in metabolite production characterized by the increase of succinate levels in feces and serum. Manipulation of the gut bacteria by short-term antibiotic cocktail treatment revealed a complete loss of short-chain fatty acids and a reduction in succinate levels. Although antibiotic cocktail treatment did not change α-Syn expression in the enteric nervous system of the colon, however, reduced α-Syn expression was detected in the olfactory bulbs (forebrain) of the TG rats. Conclusion Our data emphasize that the gut microbiome dysbiosis synchronous with ageing leads to a specific alteration of gut metabolites and can be modulated by antibiotics which may affect PD pathology.

BackgroundAn increased intestinal permeability is a common feature in patients with diarrhoea-predominant irritable bowel syndrome (IBS-D). Probiotics have shown to improve IBS symptoms and might also affect intestinal barrier function.AimThe aim of this study was to investigate the effects of a 6-week intervention with Limosilactobacillus reuteri ATCC PTA 6475 alone (single strain) or in combination with Limosilactobacillus reuteri DSM 17938 (dual strain) on gut barrier function, immune markers, and symptoms in IBS-D patients (ClinicalTrials.gov registration number: NCT03986476).Methods65 IBS-D patients were randomised into three groups (placebo, single strain, dual strain). Small and large intestinal permeability were assessed using a multi-sugar urinary recovery test. Blood, saliva, faecal samples, and several symptom scales were collected before, and after three and six weeks of intervention.ResultsSmall and large intestinal permeability as well as other markers of gut barrier function were not significantly affected by the probiotic interventions. Serum IL-6 levels showed a tendency to be reduced in the single strain group (descriptive p = 0.052). In addition, high-sensitivity C-reactive protein was significantly reduced in the dual strain group (p = 0.041). The participants in both treatment groups reported less gastrointestinal symptoms after three weeks, but this reached significance only in the dual strain group (total score: p = 0.032, pain subscore: p = 0.028). After six weeks, none of the assessed symptoms were significantly different from the placebo.ConclusionThe probiotic compounds investigated in this study did not seem to affect IBS-D patients' gut barrier function, but showed potential anti-inflammatory and symptom-improving properties, which need to be confirmed in larger study cohorts.

Abstract: Objectives: Adolescent elite athletes are generally exposed to considerable stress. This study investigated the extent and intensity of burnout in adolescent athletes attending an elite Austrian sports school. Methods: The German version of the Athlete Burnout Questionnaire (ABQ) and additional questions on burnout-related risk factors were applied to a sample of 63 students. Results: The data show a substantial burden of burnout in the student sample, compared to a sample of adult endurance athletes. Burnout was negatively associated with training duration and with a perspective onto a professional sports career, and positively associated with thoughts about finalizing sports, with the number of injuries, and with high levels of success-related psychic pressure. Conclusions: Burnout in adolescent elite athletes at an Austrian sports school was evident in number and severity. Psychological factors like doubts on the career, perceiving a professional perspective in sports, self-efficacy, or sense-making may interact with contextual factors in a circular way.

Abstract The connection between Pediatric Inflammatory Multisystem Syndrome (PIMS) and Kawasaki Disease (KD) is not yet fully understood. Using the same national registry, clinical features and outcome of children hospitalized in Germany, and Innsbruck (Austria) were compared. Reported to the registry were 395 PIMS and 69 KD hospitalized patients. Patient age in PIMS cases was higher than in KD cases (median 7 [IQR 4–11] vs. 3 [IQR 1–4] years). A majority of both PIMS and KD patients were male and without comorbidities. PIMS patients more frequently presented with organ dysfunction, with the gastrointestinal (80%), cardiovascular (74%), and respiratory (52%) systems being most commonly affected. By contrast, KD patients more often displayed dermatological (99% vs. 68%) and mucosal changes (94% vs. 64%), plus cervical lymph node swelling (51% vs. 34%). Intensive care admission (48% vs. 19%), pulmonary support (32% vs. 10%), and use of inotropes/vasodilators (28% vs. 3%) were higher among PIMS cases. No patients died. Upon patient discharge, potentially irreversible sequelae—mainly cardiovascular—were reported (7% PIMS vs. 12% KD). Despite differences in age distribution and disease severity, PIMS and KD cases shared many common clinical and prognostic characteristics. This supports the hypothesis that the two entities represent a syndrome continuum.

This paper gives an overview over all currently available data sets for the European Long-term Ecosystem Research (eLTER) monitoring site Gesäuse-Johnsbachtal. The site is part of the LTSER platform Eisenwurzen in the Alps of the province of Styria, Austria. It contains both protected (National Park Gesäuse) and non-protected areas (Johnsbachtal). Although the main research focus of the eLTER monitoring site Gesäuse-Johnsbachtal is on inland surface running waters, forests and other wooded land, the eLTER whole system (WAILS) approach was followed in regard to the data selection, systematically screening all available data in regard to its suitability as eLTER’s Standard Observations (SOs). Thus, data from all system strata was included, incorporating Geosphere, Atmosphere, Hydrosphere, Biosphere and Sociosphere. In the WAILS approach these SOs are key data for a whole system approach towards long term ecosystem research. Altogether, 54 data sets have been collected for the eLTER monitoring site Gesäuse-Johnsbachtal and included in the Dynamical Ecological Information Management System – Site and Data Registry (DEIMS-SDR), which is the eLTER data platform. The presented work provides all these data sets through dedicated data repositories for FAIR use. This paper gives an overview on all compiled data sets and their main properties. Additionally, the available data are evaluated in a concluding gap analysis with regard to the needed observation data according to WAILS, followed by an outlook on how to fill these gaps.

A limited number of studies have examined how drying conditions affect the cannabinoid and terpene content in cannabis inflorescences. In the present study, we evaluated the potential of controlled atmosphere drying chambers for drying medicinal cannabis inflorescence. Controlled atmosphere drying chambers were found to reduce the drying and curing time by at least 60% compared to traditional drying methods, while preserving the volatile terpene content. On the other hand, inflorescences subjected to traditional drying were highly infested by Alternaria alternata and also revealed low infestation of Botrytis cinerea. In the high-THC chemovar (“240”), controlled N2 and atm drying conditions preserved THCA concentration as compared to the initial time point (t0). On the other hand, in the hybrid chemovar (“Gen12”) all of the employed drying conditions preserved THCA and CBDA content. The optimal drying conditions for preserving monoterpenes and sesquiterpenes in both chemovars were C5O5 (5% CO2, 5% O2, and 90% N2) and pure N2, respectively. The results of this study suggest that each chemovar may require tailored drying conditions in order to preserve specific terpenes and cannabinoids. Controlled atmosphere drying chambers could offer a cost-effective, fast, and efficient drying method for preserving cannabinoids and terpenes during the drying process while reducing the risk of mold growth.

ABSTRACTThe aim of this paper is to improve the knowledge of collaborative challenges when planning and implementing Bus Rapid Transit (BRT). Collaborative challenges are here understood as the barriers that may arise in BRT planning and implementation as a consequence of several formally independent actors, occasionally with different interests, participating in the planning. The results are based on an analysis of actor interactions in Swedish BRT projects. These projects are analysed in relation to the state of the art in the research field of collaborative approaches. The results show two main and interrelated collaborative challenges. The first category of challenges concerns difficulties for actors in creating a common understanding of what a BRT system is, the second category concerns details of bus priority measures, e.g. busways, priority at intersections, and how to handle and deal with conflicting interests when removing speed bumps or pedestrian and cycle crossings. In terms of policy is in the early stages of the planning processes. This can be generated by working practices and tools that facilitate agreements on how to handle different interests and trade-offs. BRT guidelines adapted to national transport policy, legal and organisational conditions could function as tools in assisting actor dialogue.

ABSTRACTStudies have shown that probiotics can decrease the symptoms of respiratory tract infections as well as increase antibody responses following certain vaccinations. We examined the effect of probiotic supplementation on anti-SARS-CoV-2 specific antibody responses upon SARS-CoV-2 infection as well as after COVID-19 vaccination. In this randomized, triple-blinded, placebo-controlled intervention study with a parallel design, 159 healthy adults without prior SARS-CoV-2 infection or COVID-19 vaccination and any known risk factors for severe COVID-19 were randomly allocated into two study arms. The active treatment arm consumed a probiotic product containing a minimum of 1 × 108 colony-forming units of Limosilactobacillus reuteri DSM 17938 + 10 μg vitamin D3 twice daily for 6 months. The placebo arm consumed identical tablets containing only 10 μg vitamin D3. Anti-SARS-CoV-2 specific antibodies and virus neutralizing antibody titers were analyzed from blood samples collected at baseline, after 3 months, and after 6 months. Differences in serum antibody titers between the two study arms were tested with independent t-test using log-transformed values. In the intention-to-treat (ITT) analysis, SARS-CoV-2 infected individuals in the active treatment arm (n = 6) tended to have higher serum anti-spike IgG (609 [168–1480] BAU/ml vs 111 [36.1–1210] BAU/ml, p = 0.080) and anti-receptor binding domain (RBD) IgG (928 [212–3449] BAU/ml vs (83.7 [22.8–2094] BAU/ml, p = 0.066) levels than individuals in the placebo arm (n = 6). Considering individuals who were fully vaccinated with mRNA-based COVID-19 vaccines, the active treatment arm (n = 10) exhibited significantly higher serum levels of anti-RBD IgA (135 [32.9–976] BAU/ml vs 61.3 [26.7–97.1] BAU/ml, p = 0.036) than the placebo arm (n = 7) >28 days postvaccination. Supplementation with specific probiotics might improve the long-term efficacy of mRNA-based COVID-19 vaccines via enhanced IgA response.

Abstract Background Prior research has shown that memory for action sentences is stronger when stimuli are enacted during encoding than simply listened to: the so‐called enactment effect. The goal of the present study was to explore how writing during encoding—through handwriting and through keyboarding—fares compared with enacting, in supporting memory recall. Methods One hundred Norwegian high school students (64 girls, 36 boys) aged 16–21 years (M = 17.1) participated in the study. Four lists of verb–noun sentences with 12 sentences in each list were presented in four encoding conditions: (i) motor enactment, (ii) verbal listening, (iii) handwriting, and (iv) keyboarding. Results Results revealed a significant main effect of encoding condition, with the best memory gained in the enactment condition. Regarding writing, results showed that handwriting and keyboarding during encoding produced the lowest recall in comparison with the enactment and verbal listening conditions. Conclusion These results thus provide additional support for the enactment effect. While there has been much discussion on the relative benefits of handwriting versus keyboarding on student performance, both seemed to be equally poor strategies for the particular learning task explored here, potentially through increased cognitive load.

Summary: Background: Genomic characterisation has led to an improved understanding of adult melanoma. However, the aetiology of melanoma in children is still unclear and identifying the correct diagnosis and therapeutic strategies remains challenging. Methods: Exome sequencing of matched tumour-normal pairs from 26 paediatric patients was performed to study the mutational spectrum of melanomas. The cohort was grouped into different categories: spitzoid melanoma (SM), conventional melanoma (CM), and other melanomas (OT). Findings: In all patients with CM (n = 10) germline variants associated with melanoma were found in low to moderate melanoma risk genes: in 8 patients MC1R variants, in 2 patients variants in MITF, PTEN and BRCA2. Somatic BRAF mutations were detected in 60% of CMs, homozygous deletions of CDKN2A in 20%, TERTp mutations in 30%. In the SM group (n = 12), 5 patients carried at least one MC1R variant; somatic BRAF mutations were detected in 8.3%, fusions in 25% of the cases. No SM showed a homozygous CDKN2A deletion nor a TERTp mutation. In 81.8% of the CM/SM cases the UV damage signatures SBS7 and/or DBS1 were detected. The patient with melanoma arising in giant congenital nevus (CNM) demonstrated the characteristic NRAS Q61K mutation. Interpretation: UV-radiation and MC1R germline variants are risk factors in the development of conventional and spitzoid paediatric melanomas. Paediatric CMs share genomic similarities with adult CMs while the SMs differ genetically from the CM group. Consistent genetic characterization of all paediatric melanomas will potentially lead to better subtype differentiation, treatment, and prevention in the future. Funding: Found in Acknowledgement.

Abstract Aims Sinus tachycardia potentially leads to a deterioration of cardiac function in critically ill infants. The ultrashort‐acting beta‐blocker landiolol hydrochloride is a new pharmacological option for a selective heart rate (HR) control in patients with sinus tachycardia and heart failure. Methods and results This study was a monocentric retrospective medical chart review study at the University Children's Hospital Bonn (Germany) from 01 January 2018 until 30 June 2020. This study included a cohort of 62 term and preterm infants with a diagnosis of ventricular dysfunction and/or pulmonary hypertension (PH), in combination with preexisting tachycardia and treatment with landiolol hydrochloride. Infants were allocated to subgroups according to weeks of gestational age (GA): born at 35 weeks of GA (Group B). Tachycardia was defined depending on GA (170 b.p.m.; ≥ 35 weeks of GA: >150 b.p.m.). The primary endpoint was defined as percentage of patients achieving HR normalization during the first 24 h of landiolol treatment. Twenty‐nine infants were allocated to Group A and 33 infants to Group B. The overall median GA of the infants was 35.3 (23.3/41.3), with 53% female infants. The primary endpoint was achieved in 57 patients (91.9%). The median time to reach target HR was 1.8 (0.3–24) h. The median starting dose of landiolol was 8.8 (3.9–25.3) μk/kg/min, with a median dosing during the first 24 h of landiolol treatment of 9.9 (2.8–35.4) μk/kg/min. The median landiolol dose while achieving the target HR was 10 (2.4–44.4) μk/kg/min. The right ventricular dysfunction improved significantly in both groups 24 h after onset of landiolol infusion (P = 0.001 in Group A and P = 0.045 in Group B). The left ventricular and biventricular dysfunction improved significantly 24 h after onset of landiolol infusion in infants of Group B (P = 0.004 and P = 0.006, respectively). The severity of PH improved significantly after 24 h in infants of Group A (P

Ice cliffs are features along ice sheet margins, along tropical mountain glaciers, at termini of mountain glaciers and on debris-covered glacier tongues, that have received scattered attention in literature. They cover small relative areas of glacier or margin surface respectively, but have been involved in two apparent anomalies. On the one hand, they have been identified as potential hotspots of extreme melt rates on debris-covered tongues contributing to their relatively rapid ablation, compared to the surrounding glacier surface. On the other hand, they appear where the ice margin is stable (or temporarily advancing) even under conditions of negative mass balance. In this manuscript, we recapitulate why ice cliffs remain interesting features to investigate and what we know about them so far. We conclude by suggesting to further investigate their genesis and variable morphology and their potential as windows into past climates and processes.

Abstract Background Computer-assisted techniques for surgical treatment of femoral deformities have become increasingly important. In state-of-the-art 3D deformity assessments, the contralateral side is used as template for correction as it commonly represents normal anatomy. Contributing to this, an iterative closest point (ICP) algorithm is used for registration. However, the anatomical sections of the femur with idiosyncratic features, which allow for a consistent deformity assessment with ICP algorithms being unknown. Furthermore, if there is a side-to-side difference, this is not considered in error quantification. The aim of this study was to analyze the influence and value of the different sections of the femur in 3D assessment of femoral deformities based on the contralateral anatomy. Material and methods 3D triangular surface models were created from CT of 100 paired femurs (50 cadavers) without pathological anatomy. The femurs were divided into sections of eponymous anatomy of a predefined percentage of the whole femoral length. A surface registration algorithm was applied to superimpose the ipsilateral on the contralateral side. We evaluated 3D femoral contralateral registration (FCR) errors, defined as difference in 3D rotation of the respective femoral section before and after registration to the contralateral side. To compare this method, we quantified the landmark-based femoral torsion (LB FT). This was defined as the intra-individual difference in overall femoral torsion using with a landmark-based method. Results Contralateral rotational deviation ranged from 0° to 9.3° of the assessed femoral sections, depending on the section. Among the sections, the FCR error using the proximal diaphyseal area for registration was larger than any other sectional error. A combination of the lesser trochanter and the proximal diaphyseal area showed the smallest error. The LB FT error was significantly larger than any sectional error (p

Abstract Background Reduced androgen action during early fetal development has been suggested as the origin of reproductive disorders comprised within the testicular dysgenesis syndrome (TDS). This hypothesis has been supported by studies in rats demonstrating that normal male development and adult reproductive function depend on sufficient androgen exposure during a sensitive fetal period, called the masculinization programming window (MPW). The main aim of this study was therefore to examine the effects of manipulating androgen production during different timepoints during early human fetal testis development to identify the existence and timing of a possible window of androgen sensitivity resembling the MPW in rats. Methods The effects of experimentally reduced androgen exposure during different periods of human fetal testis development and function were examined using an established and validated human ex vivo tissue culture model. The androgen production was reduced by treatment with ketoconazole and validated by treatment with flutamide which blocks the androgen receptor. Testicular hormone production ex vivo was measured by liquid chromatography-tandem mass spectrometry or ELISA assays, and selected protein markers were assessed by immunohistochemistry. Results Ketoconazole reduced androgen production in testes from gestational weeks (GW) 7–21, which were subsequently divided into four age groups: GW 7–10, 10–12, 12–16 and 16–21. Additionally, reduced secretion of testicular hormones INSL3, AMH and Inhibin B was observed, but only in the age groups GW 7–10 and 10–12, while a decrease in the total density of germ cells and OCT4+ gonocytes was found in the GW 7–10 age group. Flutamide treatment in specimens aged GW 7–12 did not alter androgen production, but the secretion of INSL3, AMH and Inhibin B was reduced, and a reduced number of pre-spermatogonia was observed. Conclusions This study showed that reduced androgen action during early development affects the function and density of several cell types in the human fetal testis, with similar effects observed after ketoconazole and flutamide treatment. The effects were only observed within the GW 7–14 period—thereby indicating the presence of a window of androgen sensitivity in the human fetal testis.

Background Greater body mass index is associated with cardiovascular remodeling in adolescents. However, body mass index cannot differentiate between adipose and nonadipose tissues. We examined how visceral and subcutaneous adipose tissue are linked with markers of early cardiovascular remodeling, independently from nonadipose tissue. Methods and Results Whole‐body magnetic resonance imaging was done in 82 adolescents (39 overweight/obese; 36 female; median age, 16.3 [interquartile range, 14.4–18.1] years) to measure body composition and cardiovascular remodeling markers. Left ventricular diastolic function was assessed by echocardiography. Waist, waist:height ratio, and body mass index z scores were calculated. Residualized nonadipose tissue, subcutaneous adipose tissue, and visceral adipose tissue variables, uncorrelated with each other, were constructed using partial regression modeling to allow comparison of their individual contributions in a 3‐compartment body composition model. Cardiovascular variables mostly related to nonadipose rather than adipose tissue. Nonadipose tissue was correlated positively with left ventricular mass (r=0.81), end‐diastolic volume (r=0.70), stroke volume (r=0.64), left ventricular mass:end‐diastolic volume (r=0.37), and systolic blood pressure (r=0.35), and negatively with heart rate (r=−0.33) (all P

The effort to maintain cannabinoid and terpene levels in harvested medicinal cannabis inflorescence is crucial, as many studies demonstrated a significant concentration decrease in these compounds during the drying, curing, and storage steps. These stages are critical for the preparation and preservation of medicinal cannabis for end-use, and any decline in cannabinoid and terpene content could potentially reduce the therapeutic efficacy of the product. Consequently, in the present study, we determined the efficacy of pre-harvest hexanoic acid treatment alongside four months of post-harvest vacuum storage in prolonging the shelf life of high THCA cannabis inflorescence. Our findings indicate that hexanoic acid treatment led to elevated concentrations of certain cannabinoids and terpenes on the day of harvest and subsequent to the drying and curing processes. Furthermore, the combination of hexanoic acid treatment and vacuum storage yielded the longest shelf life and the highest cannabinoid and mono-terpene content as compared to all other groups studied. Specifically, the major cannabinoid’s—(-)-Δ9-trans-tetrahydrocannabinolic acid (THCA)—concentration decreased by 4–23% during the four months of storage with the lowest reduction observed following hexanoic acid pre-harvest treatment and post-harvest vacuum storage. Hexanoic acid spray application displayed a more pronounced impact on mono-terpene preservation than storage under vacuum without hexanoic acid treatment. Conversely, sesqui-terpenes were observed to be less prone to degradation than mono-terpenes over an extended storage duration. In summation, appropriate pre-harvest treatment coupled with optimized storage conditions can significantly extend the shelf life of cannabis inflorescence and preserve high active compound concentration over an extended time period.