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Objectives To elucidate the functional epigenomic landscape of articular cartilage in osteoarthritis (OA) affected knee and hip joints in relation to gene expression. Methods Using Illumina Infinium HumanMethylation450 BeadChip arrays, genome-wide DNA methylation was measured in 31 preserved and lesioned cartilage sample pairs (14 knees and 17 hips) from patients who underwent a total joint replacement due to primary OA. Using previously published genome-wide expression data of 33 pairs of cartilage samples, of which 13 pairs were overlapping with the current methylation dataset, we assessed gene expression differences in differentially methylated regions (DMRs). Results Principal component analysis of the methylation data revealed distinct clustering of knee and hip samples, irrespective of OA pathophysiology. A total of 6272 CpG dinucleotides were differentially methylated between the two joints, comprising a total of 357 DMRs containing 1817 CpGs and 245 unique genes. Enrichment analysis of genes proximal of the DMRs revealed significant enrichment for developmental pathways and homeobox (HOX) genes. Subsequent transcriptomic analysis of DMR genes exposed distinct knee and hip expression patterns. Conclusions Our findings reveal consistent DMRs between knee and hip articular cartilage that marked transcriptomic differences among HOX genes, which were not reflecting the temporal sequential HOX expression pattern during development. This implies distinct mechanisms for maintaining cartilage integrity in adulthood, thereby contributing to our understanding of cartilage homeostasis and future tissue regeneration approaches.

IntroductionAlmost 5 million people worldwide have lost their lives due to SARS-CoV-2 (source: WHO coronavirus (COVID-19) dashboard, data of 1.10.2021; https://covid19.who.int/) and therefore, globally, there is an increase of people in grief due to the death of a significant other.ObjectivesTo study psychological correlates of grief during the COVID-19 pandemic.Methods591 university students, with a mean age of 23.84±7.95 years (range 18-65 years; 76.8% women; 91.2% Portuguese) completed an online questionnaire during the second COVID-19 confinement (from 15.02 to 13.03.2021), with sociodemographic questions, the Pandemic Stress Index, the Mental Health Inventory, Insomnia Scale, questions on physical/ psychological health, and social isolation.ResultsStudents bereaving the death of a significant other (n=93, 15.7%; n=25, 26.9% reported cause was SARS-CoV-2; time since death: < 3 months to 1-year), compared to those who did not (n= 498; 84.3%), described poorer psychological health, higher psychological distress (depression, anxiety, lack of control) and sleep difficulties, higher levels of stress (higher impact of COVID pandemic in daily life, and higher behavior changes in response to COVID-19) and more social isolation.ConclusionsCOVID-19 pandemic-related stress is a source of additional stress for bereaved students. Grief is also associated with social isolation, poor mental health (depression, anxiety, lack of control) and sleep difficulties. Screening efforts, guidance, and counseling from professionals of mental health care, primary health care, and universities health care services during and after the COVID-19 pandemic could be extremely beneficial for bereaved students, particularly for those at higher risk of developing prolonged grief disorder.DisclosureNo significant relationships.

Objectives To determine whether there is a difference in frequency and clinical relevance of incidental findings detected by total-body computed tomography scanning (TBCT) compared to those by the standard work-up (STWU) with selective computed tomography (CT) scanning. Methods Trauma patients from five trauma centres were randomized between April 2011 and January 2014 to TBCT imaging or STWU consisting of conventional imaging with selective CT scanning. Incidental findings were divided into three categories: 1) major finding, may cause mortality; 2) moderate finding, may cause morbidity; and 3) minor finding, hardly relevant. Generalized estimating equations were applied to assess differences in incidental findings. Results In total, 1083 patients were enrolled, of which 541 patients (49.9 %) were randomized for TBCT and 542 patients (50.1 %) for STWU. Major findings were detected in 23 patients (4.3 %) in the TBCT group compared to 9 patients (1.7 %) in the STWU group (adjusted rate ratio 2.851; 95%CI 1.337–6.077; p  < 0.007). Findings of moderate relevance were detected in 120 patients (22.2 %) in the TBCT group compared to 86 patients (15.9 %) in the STWU group (adjusted rate ratio 1.421; 95%CI 1.088–1.854; p  < 0.010). Conclusions Compared to selective CT scanning, more patients with clinically relevant incidental findings can be expected by TBCT scanning. Key points • Total - body CT scanning in trauma results in 1.5 times more incidental findings . • Evaluation by TBCT in trauma results in more patients with incidental findings . • In every category of clinical relevance , TBCT detects more incidental findings .

IntroductionMentalization (MZ) is the capacity by which people make sense of their own’s and others’ mental states; when compromised, it is associated with several mental disorders (Bateman & Fonagy, 2010). A valid instrument to assess MZ is missing and required for the Portuguese population.ObjectivesTo develop and validate a Portuguese version (Questionário de Mentalização – QMZ) of the Mentalization Questionnaire (MZQ) (Hausberg et al., 2012).MethodsA sample of 184 Portuguese medical students (mean age = 21.6 ± 2.47 years, 59.8% female) was used to explore the psychometric properties of the scale, using reliability and factor analysis (varimax rotation method).ResultsThe QMZ exhibited a Cronbach’s alpha score of .80. All items contributed to its reliability. Based on the scree plot of Cattell and interpretability of items, a 2-factor and a 5-factor structures were further explored. The former explained 38.8% of the total variance (VE) and included a regulation of affect (VE= 27.3%, α=.79) and a self-reflection and emotional awareness (VE= 11.5%, α=.62) factors. The latter explained 60.6% of the total variance and incorporated the following dimensions: self-control (VE= 27.3%, α=.74), daily relationships (VE= 11.5%, α=.67), self-comprehension (VE= 8.1%, α=.54), close relationships (VE= 7.0%, α=.41) and self-monitoring (VE= 6.7%, α=.52). The 5-factor structure was closer to the dimensional concept of mentalization.ConclusionsThe QMZ has proved to be a promising instrument, with adequate psychometric properties, confirmed by its acceptable construct, criterion and factorial validity and reliability to assess mentalization in Portuguese language.

Anelasticity may decrease the shear modulus of the asthenosphere by 8 %–10 % at semidiurnal tidal periods compared with the reference 1 s period of seismological Earth models. We show that such anelastic effects are likely to be significant for ocean tide loading displacement at the M2 tidal period around the East China Sea. By comparison with tide gauge observations, we establish that from nine selected ocean tide models (DTU10, EOT11a, FES2014b, GOT4.10c, HAMTIDE11a, NAO99b, NAO99Jb, OSU12, and TPXO9-Atlas), the regional model NAO99Jb is the most accurate in this region and that related errors in the predicted M2 vertical ocean tide loading displacements will be 0.2–0.5 mm. In contrast, GPS observations on the Ryukyu Islands (Japan), with an uncertainty of 0.2–0.3 mm, show 90th-percentile discrepancies of 1.3 mm with respect to ocean tide loading displacements predicted using the purely elastic radial Preliminary Reference Earth Model (PREM). We show that the use of an anelastic PREM-based Earth model reduces these 90th-percentile discrepancies to 0.9 mm. Use of an anelastic radial Earth model consisting of a regional average of the laterally varying S362ANI model reduces the 90th-percentile to 0.7 mm, which is of the same order as the sum of the remaining errors due to uncertainties in the ocean tide model and the GPS observations.

Airway cholinergic nerves play a key role in airway physiology and disease. In asthma and other diseases of the respiratory tract, airway cholinergic neurons undergo plasticity and contribute to airway hyperresponsiveness and mucus secretion. We currently lack human in vitro models for airway cholinergic neurons. Here, we aimed to develop a human in vitro model for peripheral cholinergic neurons using human pluripotent stem cell (hPSC) technology. hPSCs were differentiated towards vagal neural crest precursors and subsequently directed towards functional airway cholinergic neurons using the neurotrophin brain-derived neurotrophic factor (BDNF). Cholinergic neurons were characterized by ChAT and VAChT expression, and responded to chemical stimulation with changes in Ca 2+ mobilization. To culture these cells, allowing axonal separation from the neuronal cell bodies, a two-compartment PDMS microfluidic chip was subsequently fabricated. The two compartments were connected via microchannels to enable axonal outgrowth. On-chip cell culture did not compromise phenotypical characteristics of the cells compared to standard culture plates. When the hPSC-derived peripheral cholinergic neurons were cultured in the chip, axonal outgrowth was visible, while the somal bodies of the neurons were confined to their compartment. Neurons formed contacts with airway smooth muscle cells cultured in the axonal compartment. The microfluidic chip developed in this study represents a human in vitro platform to model neuro-effector interactions in the airways that may be used for mechanistic studies into neuroplasticity in asthma and other lung diseases.

By receiving Global Navigation Satellite System (GNSS) signals that are reflected off the sea surface, together with directly received GNSS signals (using standard geodetic‐type receivers), it is possible to monitor the sea level using regular single difference geodetic processing. We show results from our analysis of three months of data from the GNSS‐based tide gauge at the Onsala Space Observatory (OSO) on the west coast of Sweden. The GNSS‐derived time series of local sea level is compared with independent data from two stilling well gauges at Ringhals and Gothenburg about 18 km south and 33 km north of OSO, respectively. A high degree of agreement is found in the time domain, with correlation coefficients of up to 0.96. The root‐mean‐square differences between the GNSS‐derived sea level and the stilling well gauge observations are 5.9 cm and 5.5 cm, which is lower than for the stilling well gauges together (6.1 cm). A frequency domain comparison reveals high coherence of the data sets up to 6 cycles per day, which corresponds well to the propagation of gravity waves in the shallow waters at the Kattegat coast. Amplitudes and phases of some major tides were determined by a tidal harmonic analysis and compared to model predictions. From the GNSS‐based tide gauge results we find significant ocean tidal signals at fortnightly, diurnal, semi‐diurnal, and quarter‐diurnal periods. As an example, the amplitudes of the semi‐diurnal M2 and the diurnal O1 tide are determined with 1σ uncertainties of 11 mm and 12 mm, respectively. The comparison to model calculations shows that global ocean tide models have limited accuracy in the Kattegat area. Key Points Standard geodetic GNSS receivers can measure reflections from the sea surface Possible to monitor the sea‐level using regular single difference processing From the GNSS‐based tide gauge results we find significant ocean tidal signals

The coordinate time series determined with the Global Positioning System (GPS) contain annual and semi-annual periods that are routinely modeled by two periodic signals with constant amplitude and phase-lag. However, the amplitude and phase-lag of the seasonal signals vary slightly over time. Various methods have been proposed to model these variations such as Wavelet Decomposition (WD), writing the amplitude of the seasonal signal as a Chebyshev polynomial that is a function of time (CP), Singular Spectrum Analysis (SSA), and using a Kalman Filter (KF). Using synthetic time series, we investigate the ability of each method to capture the time-varying seasonal signal in time series with different noise levels. We demonstrate that the precision by which the varying seasonal signal can be estimated depends on the ratio of the variations in the seasonal signal to the noise level. For most GPS time series, this ratio is between 0.05 and 0.1. Within this range, the WD and CP have the most trouble in separating the seasonal signal from the noise. The most precise estimates of the variations are given by the SSA and KF methods. For real GPS data, SSA and KF can model 49–84 and 77–90% of the variance of the true varying seasonal signal, respectively.

Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system that develops in genetically susceptible individuals. The majority of the MS-associated gene variants are located in genetic regions with importance for T-cell differentiation. Vitamin D is a potent immunomodulator, and vitamin D deficiency has been suggested to be associated with increased MS disease susceptibility and activity. In CD4+ T cells, we have analyzed in vitro vitamin D responsiveness of genes that contain an MS-associated single-nucleotide polymorphism (SNP) and with one or more vitamin D response elements in their regulatory regions. We identify IL2RA and TAGAP as novel vitamin D target genes. The vitamin D response is observed in samples from both MS patients and controls, and is not dependent on the genotype of MS-associated SNPs in the respective genes.

In KMT2A -rearranged acute lymphoblastic leukemia (ALL), an aggressive malignancy, oncogenic KMT2A-fusion proteins inappropriately recruit DOT1L to promote leukemogenesis, highlighting DOT1L as an attractive therapeutic target. Unfortunately, treatment with the first-in-class DOT1L inhibitor pinometostat eventually leads to non-responsiveness. To understand this we established acquired pinometostat resistance in pediatric KMT2A::AFF1 + B-ALL cells. Interestingly, these cells became mostly independent of DOT1L-mediated H3K79 methylation, but still relied on the physical presence of DOT1L, HOXA9 and the KMT2A::AFF1 fusion. Moreover, these cells selectively lost the epigenetic regulation and expression of various KMT2A-fusion target genes such as PROM1/ CD133, while other KMT2A::AFF1 target genes, including HOXA9 and CDK6  remained unaffected. Concomitantly, these pinometostat-resistant cells showed upregulation of several myeloid-associated genes, including CD33 and LILRB4/CD85k. Taken together, this model comprehensively shows the adaptive potential of KMT2A -rearranged ALL cells upon losing dependency on one of its main oncogenic properties.