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Contains fulltext : 247522.pdf (Publisher’s version ) (Open Access) Background: We evaluated the efficacy and safety of repetitive transcranial magnetic stimulation (rTMS) for obsessive-compulsive disorder (OCD), and ranked the relative efficacy of different stimulation protocols. Methods: We performed a search for randomised, sham-controlled trials of rTMS for OCD. The primary analysis included both a pairwise meta-analysis and a series of frequentist network meta-analyses (NMA) of OCD symptom severity. Secondary analyses were carried out on relevant clinical factors and safety. Results: 21 studies involving 662 patients were included. The pairwise meta-analysis showed that rTMS for OCD is efficacious across all protocols (Hedges' g=-0.502 [95%CI= -0.708, -0.296]). The first NMA, with stimulation protocols clustered only by anatomical location, showed that both dorsolateral prefrontal cortex (dlPFC) stimulation and medial frontal cortex stimulation were efficacious. In the second NMA, considering each unique combination of frequency and location separately, low frequency (LF) pre-supplementary motor area (preSMA) stimulation, high frequency (HF) bilateral dlPFC stimulation, and LF right dlPFC stimulation were all efficacious. LF right dlPFC was ranked highest in terms of efficacy, although the corresponding confidence intervals overlapped with the other two protocols. Limitations Evidence base included mostly small studies, with only a few studies using similar protocols, giving a sparse network. Studies were heterogeneous, and a risk of publication bias was found. Conclusions: rTMS for OCD was efficacious compared with sham stimulation. LF right dlPFC, HF bilateral dlPFC and LF preSMA stimulation were all efficacious protocols with significant and comparable clinical improvements. Future studies should further investigate the relative merits of these three protocols. 11 p.

An increasing number of long noncoding RNAs (lncRNAs) have experimentally confirmed functions, yet little is known about their transcriptional dynamics and it is challenging to determine their regulatory effects. Here, we used allele-sensitive single-cell RNA sequencing to demonstrate that, compared to messenger RNAs, lncRNAs have twice as long duration between two transcriptional bursts. Additionally, we observed increased cell-to-cell variability in lncRNA expression due to lower frequency bursting producing larger numbers of RNA molecules. Exploiting heterogeneity in asynchronously growing cells, we identified and experimentally validated lncRNAs with cell state-specific functions involved in cell cycle progression and apoptosis. Finally, we identified cis-functioning lncRNAs and showed that knockdown of these lncRNAs modulated the nearby protein-coding gene’s transcriptional burst frequency or size. In summary, we identified distinct transcriptional regulation of lncRNAs and demonstrated a role for lncRNAs in the regulation of mRNA transcriptional bursting.

The EU Water Framework Directive and Priority Substance Directive provide a framework to identify substances that potentially pose a risk to surface waters and provide a legal basis whereby member states are required to monitor and comply with environmental quality standards (EQSs) set for those substances. The cost and effort to continuously measure and analyse real world concentrations in all water bodies across Europe are high. Establishing the reliability of environmental exposure models to predict concentrations of priority substances is key, both to fill data gaps left by monitoring campaigns, and to predict the outcomes of actions that might be taken to reduce exposure. In this study, we aimed to validate the ePiE model for the pharmaceutical ibuprofen by comparing predictions made using the best possible consumption data with measured river concentrations. The results demonstrate that the ePiE model makes useful, conservative exposure predictions for ibuprofen, typically within a factor of 3 of mean measured values. This exercise was performed across a number of basins within Europe, representative of varying conditions, including consumption rates, population densities and climates. Incorporating specific information pertaining to the basin or country being assessed, such as custom WWTP removal rates, was found to improve the realism and accuracy of predictions. We found that the extrapolation of consumption data between countries should be kept to a minimum when modelling the exposure of pharmaceuticals, with the per capita consumption of ibuprofen varying by nearly a factor of 10.

An accurate assessment of the physical states of the Earth system is an essential component of many scientific, societal and economical considerations. These assessments are becoming an increasingly challenging computational task since we aim to resolve models with high resolutions in space and time, to consider complex coupled partial differential equations, and to estimate uncertainties, which often requires many realizations. Machine learning methods are becoming a very popular method for the construction of surrogate 5 models to address these computational issues. However, they also face major challenges in producing explainable, scalable, interpretable and robust models. In this manuscript, we evaluate the perspectives of geoscience applications of physics-based machine learning, which combines physics-based and data-driven methods to overcome the limitations of each approach taken alone. Through three designated examples (from the fields of geothermal energy, geodynamics, and hydrology), we show that the non-intrusive reduced basis method as a physics-based machine learning approach is able to 10 produce highly precise surrogate models that are explainable, scalable, interpretable, and robust.

We successfully predict distribution of nanoparticles (NPs) in human tissues applying surface energies for NPs, membranes, plasma and protein, considering various biochemical interactions. Phagocyte-rich and cancerous tissues accumulate NPs.

En este artículo analizamos el caso del Perú. Nuestro énfasis está en la acumulación (de derechos de) del agua con fines agrarios y su relación con la acumulación de tierras. Es importante observar, sin embargo, que de manera creciente el fenómeno de despojo del agua adquiere dimensiones mucho más amplias, sobre todo en los sectores de uso minero, hidroeléctrico, energético y de agua para consumo humano (véase por ejemplo, Van den Berge, 2011; Mehta et al., 2012; Isch et al., 2012). Las características de las amenazas para la seguridad de las comunidades locales varían por sector. de uso. Por ejemplo, la amenaza del sector minero y del hidrocarburo frente al uso local se centra en el tema de la contaminación ambiental en perjuicio de las comunidades campesinas, territorios indígenas y cuencas hidrográficas (por ejemplo, Sosa, 2012; Budds, 2004, 2010; Budds e Hinojosa, 2012).

Insights into transcriptional bursting kinetics and regulation have emerged from real-time nascent RNA imaging and analyses of static RNA counts over cells. Here, we developed sensitive single-cell profiling of newly transcribed (or new) RNA in cells (NASC-seq2) that can easily be applied to tens of thousands of single cells to help shed new light on bursting dynamics and coordination.

Item does not contain fulltext Objectives: This study aimed to describe lifetime and current rates of occurrence of comorbid eating disorders (ED) in a large clinical OCD sample, and to investigate whether comorbid ED in OCD (OCD+ED) are associated with specific demographic, somatic or clinical characteristics. Method: Data were obtained from the Netherlands Obsessive Compulsive Disorder Association (NOCDA) study. A sample of 419 participants with lifetime OCD was evaluated on co-occurrence with ED. Results: Lifetime comorbidity with ED occurred in 44 patients (10.5% of the sample), a frequency that exceeds prevalence rates in the normal population. Patients with OCD+ED were on average overweight compared to OCD-ED. The OCD+ED group reported more aggression and checking symptoms and had a younger age of onset of OCD. Further, more comorbidity with MDD, social phobia, PTSD, and depression and anxiety symptoms was reported. Conclusion: Patients with OCD+ED seem to clinically represent a sub-group of OCD with more severe psychopathology, and specifically with trauma-related factors and comorbid anxiety and depressive symptoms. Future studies using a longitudinal design should focus on whether patients with OCD+ED differ regarding course characteristics from patients with OCD-ED. Finally, comorbidity with depression, social anxiety and trauma should be taken into account in treatment of patients with OCD+ED. 8 p.

Contains fulltext : 245998.pdf (Publisher’s version ) (Open Access) Objectives: Frailty marks an increased risk for adverse health outcomes. Since childhood trauma is associated with the onset of physical and mental health diseases during the lifespan, we examined the link between childhood trauma and multidimensional frailty. Method: A cross-sectional study embedded in a clinical cohort study (ROM-GPS) of older (>=60 years) patients (n=182) with a unipolar depressive-, anxiety- and/or somatic symptom disorder according to DSM-criteria referred to specialized geriatric mental health care. Frailty was assessed with the Tilburg Frailty Indicator (TFI), comprising a physical, psychological, and social dimension. Physical, sexual and psychological abuse and emotional neglect before the age of 16 years was measured with a structured interview. Results: Of 182 patients, 103 (56.6%) had experienced any childhood trauma and 154 (84.6%) were frail (TFI sum score >=5). Linear regression analyses, adjusted for lifestyle, psychological and physical-health factors, showed that the presence of any type of childhood trauma was not associated with the TFI sum score, however when considered separately, physical abuse was (ß=0.16, p=.037). Regarding the specific frailty dimensions, any childhood trauma was associated with social frailty (ß=0.18, p=.019), with emotional neglect as main contributor. Conclusion: These findings demonstrate a complex link between different types of childhood trauma and multidimensional frailty among older psychiatric patients. Regarding the three dimensions of frailty, social frailty seems most affected by childhood trauma. This may have been underestimated until now and should receive more attention in clinical care and future research. 7 p.

Abstract Pharmaceuticals find their way to the aquatic environment via wastewater treatment plants (WWTPs). Biotransformation plays an important role in mitigating environmental risks; however, a mechanistic understanding of involved processes is limited. The aim of this study was to evaluate potential relationships between first-order biotransformation rate constants (kb) of nine pharmaceuticals and initial concentration of the selected compounds, and sampling season of the used activated sludge inocula. Four-day bottle experiments were performed with activated sludge from WWTP Groesbeek (The Netherlands) of two different seasons, summer and winter, spiked with two environmentally relevant concentrations (3 and 30 nM) of pharmaceuticals. Concentrations of the compounds were measured by LC–MS/MS, microbial community composition was assessed by 16S rRNA gene amplicon sequencing, and kb values were calculated. The biodegradable pharmaceuticals were acetaminophen, metformin, metoprolol, terbutaline, and phenazone (ranked from high to low biotransformation rates). Carbamazepine, diatrizoic acid, diclofenac, and fluoxetine were not converted. Summer and winter inocula did not show significant differences in microbial community composition, but resulted in a slightly different kb for some pharmaceuticals. Likely microbial activity was responsible instead of community composition. In the same inoculum, different kb values were measured, depending on initial concentration. In general, biodegradable compounds had a higher kb when the initial concentration was higher. This demonstrates that Michealis-Menten kinetic theory has shortcomings for some pharmaceuticals at low, environmentally relevant concentrations and that the pharmaceutical concentration should be taken into account when measuring the kb in order to reliably predict the fate of pharmaceuticals in the WWTP. Key points • Biotransformation and sorption of pharmaceuticals were assessed in activated sludge. • Higher initial concentrations resulted in higher biotransformation rate constants for biodegradable pharmaceuticals. • Summer and winter inocula produced slightly different biotransformation rate constants although microbial community composition did not significantly change. Graphical abstract

Item does not contain fulltext The Dimensional Obsessive-Compulsive Scale (DOCS) is a self-report questionnaire aimed to measure the severity of obsessive-compulsive symptoms on four thematically different symptom dimensions (contamination, responsibility for harm, unacceptable thoughts, and symmetry and completeness). The DOCS was developed in the US in response to the insufficiency of existing OCD measures. The 20-item scale is used in research and clinical settings. We translated the DOCS into Dutch and examined the psychometric properties in a clinical sample. In addition, we further examined the US version of DOCS with respect to measurement invariance between patient and non-patients and also between the US and the Dutch version of the DOCS. The analyses showed that the Dutch version is a valid and reliable version of the DOCS. Measurement invariance tests indicated that patient scores can be validly compared with non-patient scores. Therefore, the DOCS is a good instrument to monitor the development of OCD, for example, during treatment. The same result was found for the US DOCS and the Dutch DOCS, hence US scores and Dutch scores can be validly compared. With these two studies we have extended our knowledge of the DOCS, beyond the common psychometric properties. 10 p.

The stenohaline zebra mussel, Dreissena polymorpha, is uniquely sensitive to the ionic composition of its aquatic environment. Waterborne copper (Cu) uptake and accumulation in zebra mussels were examined at various conditions in an environmentally relevant range in freshwater, i.e. Cu exposure levels (nominal concentrations of 25 and 50 μg/L), pH (5.8-8.3), and sodium (Na+) concentrations (up to 4.0 mM). Copper accumulation was simulated by a kinetic model covering two compartments, the gills and the remaining tissues. The Cu uptake rate constant decreased with decreasing pH from 8.3 down to 6.5, indicating interactions between H+ and Cu at uptake sites. The kinetic simulation showed dose-dependent effects of Na+ on Cu uptake. At 25 μg/L Cu, addition of Na+ at 0.5 mM significantly inhibited the Cu uptake rate, while no significant differences were found in the uptake rate upon further addition of Na+ up to a concentration of 4.0 mM. At 50 μg/L Cu, the Cu uptake rate was not influenced by Na+ addition. Calibration results exhibited dose-dependent elimination rates with more profound elimination with increasing exposure levels. With kinetic parameters calibrated at environmentally relevant conditions, in terms of pH and Na+ concentrations, the model performed well in predicting Cu accumulation based on independent data sets. Estimates of the Cu concentration in mussels were within a factor of 2 of the measurements. This demonstrates potential application of kinetic models that are calibrated in environmentally relevant freshwater conditions.

We aimed to identify patterns in the internal distribution of persistent organic pollutants (POPs) and assess contributing factors using sea turtles and their offspring as a case study of a long-lived wildlife species. We systematically synthesized 40 years of data and developed a lipid database to test whether lipid-normalized POP concentrations are equal among tissues as expected under steady state for lipophilic compounds. Results supported equal partitioning among tissues with high blood flow or perfusion including the heart, kidney, muscle, and lung. Observed differences in the brain, fat, and blood plasma, however, suggest the physiological influence of the blood–brain barrier, limited perfusion, and protein content, respectively. Polybrominated diphenyl ethers partitioned comparably to legacy POPs. Polycyclic aromatic hydrocarbons, meanwhile, partitioned more into the lung, colon, and muscle compared to the liver under chronic and acute field exposure. Partitioning ratios of individual POPs among tissues were significantly related to the lipophilicity of compounds (as estimated by Kow) in half of the observed cases, and significant differences between juveniles and adults underscore physiological differences across life stages. The comprehensive tissue partitioning patterns presented here provide a quantitative basis to support comparative assessments of POP pollution derived from biomonitoring among multiple tissues., Partitioning of persistent organic pollutants between internal and offspring tissues was quantified, and driving factors were evaluated for sea turtles, long-lived marine species.

Contains fulltext : 237225.pdf (Publisher’s version ) (Open Access) Background: Although anxiety and depression are highly comorbid disorders, it remains unclear whether and how a concurrent depression affects the outcome of anxiety treatment. Method: Using anonymized routine outcome monitoring (ROM) data of 740 patients having received specialized treatment for an anxiety disorder, OCD, or PTSD, this study investigates whether a comorbid diagnosis of depression and/or self-reported depression severity levels relate to the patients' improvement following anxiety treatment. Results: The results show that both the patients with and those without comorbid depression had profited similarly from the anxiety, OCD, or PTSD treatment, regardless of whether depression was merely diagnosed prior to treatment or based on self-reported severity (and assuming a smallest effect size of interest of d = 0.35/r = .2). Importantly, the post-treatment reductions in self-reported depressive symptoms were strongly and positively related to the reductions in self-reported anxiety symptoms and disorder-related disability. Limitations Causal inferences cannot be made due to the retrospective cross-sectional design. Conclusions: The outcomes obtained in a naturalistic patient sample support current treatment guidelines recommending evidence-based treatment for anxiety disorders, OCD, and PTSD in patients with and without a comorbid depression. Future treatment studies are recommended for investigate the (bi)directionality of anxiety and depressive symptoms throughout treatment. 7 p.

Contains fulltext : 233267.pdf (Publisher’s version ) (Open Access)

Agricultural, industrial and household chemicals are emitted in large rivers along populated areas, transported by water and deposited in sediments, posing (eco)toxicological risks. Sediments have received less attention than surface waters, likely because of the intrinsic complexity of interactions between sediment constituents complicating correct framing of exposures. Sadly, thorough assessment of the in situ behavior of sediment constituents in bioassays is often not practical. Alternatively, we related physicochemical properties of sediments from field testing to results from bioassays. The case study covers Flemish sediment (incl. Scheldt and Meuse) and mortality of Hyalella azteca, a sensitive bio-indicator. Though variable across Flanders’ main water bodies, heavy metals and ammoniacal nitrogen dominate the observed toxicity according to toxic unit (TU) assessments. Depending on the water body we explain between 50 and 90% of the variance in the observed H. azteca mortality, substantially more than previous ecotoxicity studies. We attribute the remaining variance to potential incoherently documented biophysicochemical sediment properties and concentrations of non-target biocides, testing conditions/set-ups and/or species variabilities. We discuss the relative influence of heavy metals/metaloxides, nitrogen (e.g. fertilizer), polycyclic aromatics and organochlorides. We highlight both direct and indirect mortality mechanisms. We note potential synergetic mixture effects between ammoniacal nitrogen and chromium. Such synergy may be phenomenological of ‘standard’ aerobic bioassays, and prove a complementary method alongside the ‘acid-volatile sulfide test’ to more effectively link concentration to toxicity. Future study ought to include variation in biophysicochemical properties between sampling locations and batch bioassays. Our approach enables water managers to interpret their monitoring data by converting sediment concentrations to H. azteca mortality and prioritize substances that contribute most.

An increasing number of pharmaceuticals found in the environment potentially impose adverse effects on organisms such as fish. Physiologically based kinetic (PBK) models are essential risk assessment tools, allowing a mechanistic approach to understanding chemical effects within organisms. However, fish PBK models have been restricted to a few species, limiting the overall applicability given the countless species. Moreover, many pharmaceuticals are ionizable, and fish PBK models accounting for ionization are rare. Here, we developed a generalized PBK model, estimating required parameters as functions of fish and chemical properties. We assessed the model performance for five pharmaceuticals (covering neutral and ionic structures). With biotransformation half-lives (HLs) from EPI Suite, 73 and 41% of the time-course estimations were within a 10-fold and a 3-fold difference from measurements, respectively. The performance improved using experimental biotransformation HLs (87 and 59%, respectively). Estimations for ionizable substances were more accurate than any of the existing species-specific PBK models. The present study is the first to develop a generalized fish PBK model focusing on mechanism-based parameterization and explicitly accounting for ionization. Our generalized model facilitates its application across chemicals and species, improving efficiency for environmental risk assessment and supporting an animal-free toxicity testing paradigm.

Deze studie rapporteert een verkennend onderzoek naar de predictieve validiteit van de J-SOAP II voor de voorspelling van het zeden- en algemene recidiverisico onder jeugdige mannelijke zedendelinquenten. Data van 630 onderzochte dan wel behandelde mannelijke zedendelinquenten tussen 12 en 19 jaar oud werden verzameld. Zowel het klinisch oordeel als het voorspelde recidiverisico middels de J-SOAP II en de feitelijke recidivecijfers werden vervolgens vastgesteld en vergeleken. De J-SOAP II overschat het risico op recidive naar een zedendelict sterk, terwijl het algemene recidiverisico enigszins wordt onderschat. Hierbij wordt een statistisch significante samenhang gevonden tussen de recidiveschatting van de J-SOAP II en het daadwerkelijke algemene recidivecijfer. Voor zedenrecidive wordt geen samenhang gevonden met de inschatting van het recidiverisico door middel van de J-SOAP II. Omdat risicotaxatie verstrekkende gevolgen kan hebben voor de behandeling van jeugdige zedendelinquenten, is adequate risicotaxatie van groot belang. Gelet op de overschatting van de kans op zedenrecidive door de J-SOAP II, lijkt het niet wenselijk om voor risicovoorspelling enkel af te gaan op deze vragenlijst. Verder onderzoek naar de validiteit en verbetering van het instrument is daarom noodzakelijk.

Contains fulltext : 219370.pdf (Publisher’s version ) (Closed access) Background: Comorbid personality disorders are assumed to negatively interfere with the treatment outcome of affective disorders. Data on late-life panic disorder remain unknown. We examined the association of personality pathology and treatment outcome related to age and treatment modality. Methods: An observational study on the effectiveness of cognitive-behavioral therapy (CBT) for panic disorder with agoraphobia among patients 18 to 74 years of age and randomized controlled comparison of paroxetine and CBT in older patients (60 y of age or older) were performed. The diagnosis of panic disorder was confirmed by the Anxiety Disorder Interview Schedule-Revised (ADIS-IV) and personality features were assessed with the Personality Diagnostic Questionnaire. The impact of personality features on either agoraphobic cognitions (Agoraphobic Cognitions Questionnaire) or avoidance behavior (Mobility Inventory Avoidance Scale) was examined by multiple linear regression analyses adjusted for sex, level of education, duration of illness, comorbid psychopathology, and baseline severity. The interaction between personality and age was examined among those treated with CBT (n=90); the interaction between personality and treatment modality was examined among the older subgroup (n=34). Results: Cluster B personality pathology (evaluated on the basis of either Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R) or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria depending on the date of assessment) was negatively associated with outcomes of CBT in both younger and older adults with panic disorder and agoraphobia. Older adults with a higher number of features of any personality pathology or cluster A pathology had worse treatment outcomes when treated with paroxetine compared with CBT. Conclusions: Cluster B pathology had a detrimental effect on CBT treatment outcome for panic disorder in both age groups. In late-life panic disorder with comorbid personality pathology, CBT may be preferred over treatment with paroxetine. 11 p.

Chemical pollution of surface waters is considered an important driver for recent declines in biodiversity. Species sensitivity distributions (SSDs) are commonly used to evaluate the ecological risks of chemical exposure, accounting for variation in interspecies sensitivity. However, SSDs do not reflect the effects of chemical exposure on species abundance, considered an important endpoint in biological conservation. Although complex population modeling approaches lack practical applicability when it comes to the routine practice of lower tier chemical risk assessment, in the present study we show how information from widely available laboratory toxicity tests can be used to derive the change in mean species abundance (MSA) as a function of chemical exposure. These exposure–response MSA relationships combine insights into intraspecies exposure–response relationships and population growth theory. We showcase the practical applicability of our method for cadmium, copper, and zinc, and include a quantification of the associated statistical uncertainty. For all 3 metals, we found that concentrations hazardous for 5% of the species (HC5s) based on MSA relationships are systematically higher than SSD‐based HC5 values. Our proposed framework can be useful to derive abundance‐based ecological protective criteria for chemical exposure, and creates the opportunity to assess abundance impacts of chemical exposure in the context of various other anthropogenic stressors. Environ Toxicol Chem 2020;39:2304–2313. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., Workflow for computing the Mean Species Abundance (MSA) relationship using exposure‐response data. Species‐specific exposure‐response curves for survival and reproduction endpoints are combined into a single exposure‐abundance curve. Multiple species‐specific exposure‐abundance curves are then aggregated into one MSA relationship.

The occurrence of persistent organic pollutants (POPs) in the Arctic has been of constant concern, as these chemicals cause reproductive effects and mortality in organisms. The Arctic acts as a chemical sink, which makes this system an interesting case for bioaccumulation studies. However, as conducting empirical studies for all Arctic species and POPs individually is unfeasible, in silico methods have been developed. Existing bioaccumulation models are predominately validated for temperate food chains, and do not account for a large variation in trophic levels. This study applies Monte Carlo simulations to account for variability in trophic ecology on Svalbard when predicting bioaccumulation of POPs using the optimal modeling for ecotoxicological applications (OMEGA) bioaccumulation model. Trophic magnification factors (TMFs) were calculated accordingly. Comparing our model results with monitored POP residues in biota revealed that, on average, all predictions fell within a factor 6 of the monitored POP residues in biota. Trophic variability did not affect model performance tremendously, with up to a 25% variability in performance metrics. To our knowledge, we were the first to include trophic variability in predicting biomagnification in Arctic ecosystems using a mechanistic biomagnification model. However, considerable amounts of data are required to quantify the implications of trophic variability on biomagnification of POPs in Arctic food webs.

The multi-directional mechanical stimulation experienced by articular cartilage during motion is transferred to the chondrocytes through a thin layer of pericellular matrix around each cell; chondrocytes in turn respond by releasing matrix proteins and/or matrix-degrading enzymes. In the present study we investigated how different types of mechanical stimulation can affect a chondrocyte's phenotype and extracellular matrix (ECM) production. To this end, we employed a cartilage-on-chip system which allows exerting well-defined compressive and multi-directional mechanical stimulation on a 3D chondrocyte-laden agarose hydrogel using a thin deformable membrane and three individually addressed actuation chambers. First, the 3D chondrocyte culture in agarose responded to exposure to mechanical stimulation by an initial increase in IL-6 production and little-to-no change in IL-1β and TNF-α secretion after one day of on-chip culture. Exposure to mechanical stimulation enhanced COL2A1 (hyaline cartilage marker) and decreased COL1A1 (fibrotic cartilage) expression, this being more marked for the multi-directional stimulation. Remarkably, the production of glycosaminoglycans (GAGs), one of the main components of native cartilage ECM, was significantly increased after 15 days of on-chip culture and 14 days of mechanical stimulation. Specifically, a thin pericellular matrix shell (1–5 μm) surrounding the chondrocytes as well as an interstitial matrix, both reminiscent of the in vivo situation, were deposited. Matrix deposition was highest in chips exposed to multi-directional mechanical stimulation. Finally, exposure to mechanical cues enhanced the production of essential cartilage ECM markers, such as aggrecan, collagen II and collagen VI, a marker for the pericellular matrix. Altogether our results highlight the importance of mechanical cues, and using the right type of stimulation, to emulate in vitro, the chondrocyte microenvironment.

A toxicokinetic-toxicodynamic model was constructed to delineate the exposure-response causality. The model could be used: to predict metal accumulation considering the influence of water chemistry and biotic ligand characteristics; to simulate the dynamics of subcellular partitioning considering metabolism, detoxification, and elimination; and to predict chronic toxicity as represented by biomarker responses from the concentration of metals in the fraction of potentially toxic metal. The model was calibrated with data generated from an experiment in which the Zebra mussel Dreissena polymorpha was exposed to Cu at nominal concentrations of 25 and 50 mu g/L and with varied Na+ concentrations in water up to 4.0 mmol/L for 24 days. Data used in the calibration included physicochemical conditions of the exposure environment, Cu concentrations in subcellular fractions, and oxidative stress-induced responses, i.e. glutathione-S-transferase activity and lipid peroxidation. The model explained the dynamics of subcellular Cu partitioning and the effect mechanism reasonably well. With a low affinity constant for Na+ binding to Cu2+ uptake sites, Na+ had limited influence on Cu2+ uptake at low Na+ concentrations in water. Copper was taken up into the metabolically available pool (MAP) at a largely higher rate than into the cellular debris. Similar Cu concentrations were found in these two fractions at low exposure levels, which could be attributed to sequestration pathways (metabolism, detoxification, and elimination) in the MAP. However, such sequestration was inefficient as shown by similar Cu concentrations in detoxified fractions with increasing exposure level accompanied by the increasing Cu concentration in the MAP.

Summary This article discusses the strategies and trajectories deployed by the Forum for the Advancement of Immunization Research (FAIR) to rehabilitate Salk’s inactivated polio vaccine (IPV), at a time when Sabin’s oral polio vaccine (OPV) had come to dominate the global polio vaccine market. FAIR was an international coalition of scientists and institutions that undertook specific field studies to establish the conditions under which IPV could usefully be introduced in developing countries. Regardless of the evidence it gathered, FAIR failed to convince WHO to integrate IPV into the Expanded Programme on Immunization (EPI). This study of the life of IPV vaccine beyond its initial development and introduction, provides insights in the interplay of evidence and interests in the political decisions made around vaccination.

Microplastic pollution is a growing, yet poorly understood problem. Here, we assessed the relationship between microplastic concentration and distance to rivers, shorelines, cities, sediment grain size or water depth in sediments of the world's largest (semi-)enclosed aquatic basins. Microplastic was extracted from sediment using density separation, elutriation and hydrophobic adhesion. Fibers and transparent or white microplastic particles were the most abundant shape and color. The microplastic concentration in sediments of the Black Sea was about twice as high compared to that in the Caspian Sea. Fragment concentrations decreased with depth, while fiber concentrations were independent of depth. Overall, no relationship with distance to shores, rivers and cities or with grain size was observed. However, within some depth classes concentrations were related to the distance from rivers, shores and cities. ispartof: MARINE POLLUTION BULLETIN vol:173 issue:Pt A ispartof: location:England status: published

Objective To investigate the presence of WNT antagonists Dickkopf-related protein 1 (DKK1), Frizzled-related protein (FRZB) and BMP antagonist Gremlin 1 (GREM1) in synovial fluid (SF) and serum, respectively, from end-stage knee osteoarthritis (OA) patients, and correlate their expression with other markers of OA. Design In a cross-sectional study, SF and serum were collected from OA patients ( n = 132). The concentrations of DKK1, FRZB and GREM1 in SF and serum were determined using immunoassays. Correlation measurements were performed between groups and previously assessed disease markers, such as synovium nitric oxide (NO), inerleukin-1β (IL1β), tumor necrosis factor–α (TNFα), and prostaglandin E2 (PGE2). Results The OA patients with the celecoxib treatment till surgery have higher median SF FRZB values compared with the control (no treatment); the celecoxib 3-days before surgery stopped treatment group has higher median serum FRZB values than the control and the naproxen treatment group. The combinational analysis of SF DKK1 and SF FRZB negatively correlated with macroscopic cartilage scores and histological synovium scores in OA patients. The expression of DKK1 and FRZB in SF showed the same expression trend as their expression in serum. Furthermore, the SF concentration of DKK1 was positively correlated with FRZB in both SF and serum. In contrast, it was negatively correlated with synovium NO and IL1β. SF FRZB was negatively correlated with synovium NO, IL1β, cartilage PGE2, and age. Conclusions Our findings suggest DKK1 and FRZB were negatively correlated with OA severity and multiple pro-inflammatory cytokines. Our data indicate that DKK1 and FRZB can be joint disease–specific biomarkers.

Background Early identification of patients with an anxiety disorder, obsessive-compulsive disorder (OCD), or post-traumatic stress disorder (PTSD) in need of highly specialized care could facilitate the selection of the optimal initial treatment in these patients. This paper describes the development and psychometric evaluation of the Decision Tool Anxiety Disorders, OCD and PTSD (DTAOP), which aims to aid clinicians in the early identification of patients with an anxiety disorder, OCD, or PTSD in need of highly specialized mental healthcare. Methods A systematic literature review and a concept mapping procedure were carried out to inform the development of the DTAOP. To evaluate the psychometric properties of the DTAOP, a cross-sectional study in 454 patients with a DSM-IV-TR anxiety disorder was carried out. Feasibility was evaluated by the completion time and the content clarity of the DTAOP. Inter-rater reliability was assessed in a subsample of 87 patients. Spearman’s rank correlation coefficients between the DTAOP and EuroQol five-dimensional questionnaire (EQ-5D-5L) scores were computed to examine the convergent validity. Criterion validity was assessed against independent clinical judgments made by clinicians. Results The average time required to complete the eight-item DTAOP was 4.6 min and the total DTAOP was evaluated as clear in the majority (93%) of the evaluations. Krippendorff’s alpha estimates ranged from 0.427 to 0.839. Based on the qualitative feedback, item wording and instructions were improved. As hypothesized, the DTAOP correlated negatively with EQ-5D-5L scores. The area under the curve was 0.826 and the cut-off score of ≥4 optimized sensitivity (70%) and specificity (71%). Conclusions The DTAOP demonstrated excellent feasibility and good validity, but weak inter-rater reliability. Based on the qualitative feedback and reliability estimates, revisions and refinements of the wording and instructions were made, resulting in the final version of the DTAOP.

Single-cell sequencing methods rely on molecule-counting strategies to account for amplification biases, yet no experimental strategy to evaluate counting performance exists. Here, we introduce molecular spikes—RNA spike-ins containing built-in unique molecular identifiers (UMIs) that we use to identify critical experimental and computational conditions for accurate RNA counting in single-cell RNA-sequencing (scRNA-seq). Using molecular spikes, we uncovered impaired RNA counting in methods that were not informative for cellular RNA abundances due to inflated UMI counts. We further leverage molecular spikes to improve estimates of total endogenous RNA amounts in cells, and introduce a strategy to correct experiments with impaired RNA counting. The molecular spikes and the accompanying R package UMIcountR (https://github.com/cziegenhain/UMIcountR) will improve the validation of new methods, better estimate and adjust for cellular mRNA amounts and enable more indepth characterization of RNA counting in scRNA-seq.

Spatiotemporal control over engineered tissues is highly desirable for various biomedical applications as it emulates the dynamic behavior of natural tissues. Current spatiotemporal biomaterial functionalization approaches are based on cytotoxic, technically challenging, or non-scalable chemistries, which has hampered their widespread usage. Here we report a strategy to spatiotemporally functionalize (bio)materials based on competitive supramolecular complexation of avidin and biotin analogs. Specifically, an injectable hydrogel is orthogonally post-functionalized with desthiobiotinylated moieties using multivalent neutravidin. In situ exchange of desthiobiotin by biotin enables spatiotemporal material functionalization as demonstrated by the formation of long-range, conformal, and contra-directional biochemical gradients within complex-shaped 3D hydrogels. Temporal control over engineered tissue biochemistry is further demonstrated by timed presentation and sequestration of growth factors using desthiobiotinylated antibodies. The method’s universality is confirmed by modifying hydrogels with biotinylated fluorophores, peptides, nanoparticles, enzymes, and antibodies. Overall, this work provides a facile, cytocompatible, and universal strategy to spatiotemporally functionalize materials., Controlled patterning of functionality within hydrogels typically involves complex chemistry. Here, the authors report on a simple competitive binding strategy using avidin and biotin analogs in an injectable biomaterial for spatiotemporally controlled presentation of biochemical stimuli to cells.

Contains fulltext : 207225.pdf (Publisher’s version ) (Open Access) BACKGROUND: Affective disorders, encompassing depressive-, anxiety-, and somatic symptom disorders, are the most prevalent mental disorders in later life. Treatment protocols and guidelines largely rely on evidence from RCTs conducted in younger age samples and ignore comorbidity between these disorders. Moreover, studies in geriatric psychiatry are often limited to the "younger old" and rarely include the most frail. Therefore, the effectiveness of treatment in routine clinical care for older patients and impact of ageing characteristics is largely unknown. OBJECTIVE: The primary aim of the Routine Outcome Monitoring for Geriatric Psychiatry & Science (ROM-GPS) - project is to examine the impact of ageing characteristics on the effectiveness of treatment for affective disorders in specialised geriatric mental health care. METHODS: ROM-GPS is a two-stage, multicentre project. In stage one, all patients aged >/=60 years referred to participating outpatient clinics for specialised geriatric mental health care will be routinely screened with a semi-structured psychiatric interview, the Mini International Neuropsychiatric Interview and self-report symptom severity scales assessing depression, generalized anxiety, hypochondria, and alcohol use. Patients with a unipolar depressive, anxiety or somatic symptom disorder will be asked informed consent to participate in a second (research) stage to be extensively phenotyped at baseline and closely monitored during their first year of treatment with remission at one-year follow-up as the primary outcome parameter. In addition to a large test battery of potential confounders, specific attention is paid to cognitive functioning (including computerized tests with the Cogstate test battery as well as paper and pencil tests) and physical functioning (including multimorbidity, polypharmacy, and different frailty indicators). The study is designed as an ongoing project, enabling minor adaptations once a year (change of instruments). DISCUSSION: Although effectiveness studies using observational data can easily be biased, potential selection bias can be quantified and potentially corrected (e.g. by propensity scoring). Knowledge of age-related determinants of treatment effectiveness, may stimulate the development of new interventions. Moreover, studying late-life depressive, anxiety and somatic symptom disorders jointly enables data-driven studies for more optimal classification of these disorders in later life. TRIAL REGISTRATION: Dutch Trial Register: NL6704 ( www.trialregister.nl ). Retrospectively registered on 2017-12-05. 12 p.

Several meta-analyses have examined the Central Eight risk factors for reoffending in the general forensic population. To our knowledge, this is the first meta-analysis to focus exclusively on the predictive validity of risk factors for recidivism in forensic outpatients. A multilevel meta-analysis was conducted of studies in which static and dynamic risk factors were investigated as predictors of violent and/or general recidivism in forensic outpatients. Twenty-seven studies were included, with 543 effect sizes in a unique population of 116,982 adult offenders. The Central Eight risk domains were found to be predictive of violent and general recidivism; however, these factors predicted recidivism with small-to-moderate effects. Overall, in the same domain, the dynamic risk factors were more strongly related to recidivism than the static risk factors. This knowledge may be used to guide future outpatient treatment.

The use of down-the-drain products and the resultant release of chemicals may lead to pressures on the freshwater environment. Ecotoxicological impact assessment is a commonly used approach to assess chemical products but is still influenced by several uncertainty and variability sources. As a result, the robustness and reliability of such assessments can be questioned. A comprehensive and systematic assessment of these sources is, therefore, needed to increase their utility and credibility. In this study, we present a method to systematically analyse the uncertainty and variability of the potential ecotoxicological impact (PEI) of chemicals using a portfolio of 54 shampoo products. We separately quantified the influence of the statistical uncertainty in the prediction of physicochemical properties and freshwater toxicity as predicted from Quantitative Structure-Property Relationships (QSPRs) and Quantitative Structure-Activity Relationships (QSARs) respectively, and of various sources of spatial and technological variability as well as variability in consumer habits via 2D Monte Carlo simulations. Overall, the variation in the PEIs of shampoo use was mainly the result of uncertainty due to the use of toxicity data from three species only. All uncertainty sources combined resulted in PEIs ranging on average over seven orders of magnitude (ratio of the 90th to the 10th percentile) so that an absolute quantification of the ecological risk would not be meaningful. In comparison, variation in shampoo composition was the most influential source of variability, although less than compared to uncertainty, leading to PEIs ranging over three orders of magnitude. Increasing the number of toxicity data by increasing the number of species, either through additional measurements or ecotoxicological modelling (e.g. using Interspecies Correlation Equations), should get priority to improve the reliability of PEIs. These conclusions are not limited to shampoos but are applicable more generally to the down-the-drain products since they all have similar data limitations and associated uncertainties relating to the availability of ecotoxicity data and variability in consumer habits and use. Keywords: Ecotoxicity, Shampoo, Environmental impact, Monte Carlo, QSAR, Parameter uncertainty