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Background: Vaginoplasty is a surgical solution to multiple disorders, including Mayer-Rokitansky-Küster-Hauser syndrome and male-to-female gender dysphoria. Using nonvaginal tissues for these reconstructions is associated with many complications, and autologous vaginal tissue may not be sufficient. The potential of tissue engineering for vaginoplasty was studied through a systematic bibliography search. Cell types, biomaterials, and signaling factors were analyzed by investigating advantages, disadvantages, complications, and research quantity. Search Methods: A systematic search was performed in Medline, EMBASE, Web of Science, and Scopus until March 8, 2022. Term combinations for tissue engineering, guided tissue regeneration, regenerative medicine, and tissue scaffold were applied, together with vaginoplasty and neovagina. The snowball method was performed on references and a Google Scholar search on the first 200 hits. Original research articles on human and/or animal subjects that met the inclusion (reconstruction of vaginal tissue and tissue engineering method) and no exclusion criteria (not available as full text; written in foreign language; nonoriginal study article; genital surgery other than neovaginal reconstruction; and vaginal reconstruction with autologous or allogenic tissue without tissue engineering or scaffold) were assessed. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist, the Newcastle-Ottawa Scale, and the Gold Standard Publication Checklist were used to evaluate article quality and bias. Outcomes: A total of 31 out of 1569 articles were included. Data extraction was based on cell origin and type, biomaterial nature and composition, host species, number of hosts and controls, neovaginal size, replacement fraction, and signaling factors. An overview of used tissue engineering methods for neovaginal formation was created, showing high variance of cell types, biomaterials, and signaling factors and the same topics were rarely covered multiple times. Autologous vaginal cells and extracellular matrix-based biomaterials showed preferential properties, and stem cells carry potential. However, quality confirmation of orthotopic cell-seeded acellular vaginal matrix by clinical trials is needed as well as exploration of signaling factors for vaginoplasty. General article quality was weak to sufficient due to unreported cofounders and incomplete animal study descriptions. Article quality and heterogenicity made identification of optimal cell types, biomaterials, or signaling factors unreliable. However, trends showed that autologous cells prevent complications and compatibility issues such as healthy cell destruction, whereas stem cells prevent cross talk (interference of signaling pathways by signals from other cell types) and rejection (but need confirmation testing beyond animal trials). Natural (orthotopic) extracellular matrix biomaterials have great preferential properties that encourage future research, and signaling factors for vascularization are important for tissue engineering of full-sized neovagina.

Purpose: To create an updated and comprehensive overview of the modeling studies that have been done to understand the mechanics underlying deformities of adolescent idiopathic scoliosis (AIS), to predict the risk of curve progression and thereby substantiate etiopathogenetic theories. Methods: In this systematic review, an online search in Scopus and PubMed together with an analysis in secondary references was done, which yielded 86 studies. The modeling types were extracted and the studies were categorized accordingly. Results: Animal modeling, together with machine learning modeling, forms the category of black box models. This category is perceived as the most clinically relevant. While animal models provide a tangible idea of the biomechanical effects in scoliotic deformities, machine learning modeling was found to be the best curve-progression predictor. The second category, that of artificial models, has, just as animal modeling, a tangible model as a result, but focusses more on the biomechanical process of the scoliotic deformity. The third category is formed by computational models, which are very popular in etiopathogenetic parameter-based studies. They are also the best in calculating stresses and strains on vertebrae, intervertebral discs, and other surrounding tissues. Conclusion: This study presents a comprehensive overview of the current modeling techniques to understand the mechanics of the scoliotic deformities, predict the risk of curve progression in AIS and thereby substantiate etiopathogenetic theories. Although AIS remains to be seen as a complex and multifactorial problem, the progression of its deformity can be predicted with good accuracy. Modeling of AIS develops rapidly and may lead to the identification of risk factors and mitigation strategies in the near future. The overview presented provides a basis to follow this development.

Background The general aim of this study was to investigate the effectiveness of blended Cognitive Behavioral Therapy (bCBT) as compared to Treatment as Usual (TAU) for depression in specialized routine mental healthcare in the Netherlands. We further explored a range of secondary outcome variables, including quality of life, clinical response, remission and reliable improvement, as well as clinical deterioration and potential negative effects of treatment. Methods n = 103 patients with Major Depressive Disorder were recruited as part of the E-COMPARED project, and randomly allocated to bCBT (n = 53) or TAU (n = 50). Measurements took place at baseline, 3-, 6- and 12-months follow-up. Treatment effects were analyzed using linear mixed-effects models for repeated measures. Results Depressive symptoms significantly declined and quality of life significantly improved over time in both bCBT and TAU during 12-months follow-up. No significant interaction effects between treatment group and assessment point were found. Likewise, there were no significant differences between the two treatment groups on secondary outcomes. Patients following bCBT went from severe to mild symptom severity, along with large within-group effects. Conclusion Applying bCBT in routine specialized mental health care seems promising, but is a relatively new form of treatment that is still under development and more research is needed. Clinical Trial Registration Netherlands Trials Register NTR4962. Registered on 5 January 2015.

Urbanisation can affect mating opportunities and thereby alter inter- and intra-sexual selection pressures on sexual traits. Biotic and abiotic urban conditions can influence an individual's success in pre- and post-copulatory mating, for example through impacts on mate attraction and mate preference, fertilisation success, resource competition or rival interactions. Divergent sexual selection pressures can lead to differences in behavioural, physiological, morphological or life-history traits between urban and non-urban populations, ultimately driving adaptation and speciation. Most studies on urban sexual selection and mating interactions report differences between urban and non-urban populations or correlations between sexual traits and factors associated with increased urbanisation, such as pollution, food availability and risk of predation and parasitism. Here we review the literature on sexual selection and sexual traits in relation to urbanisation or urban-associated conditions. We provide an extensive list of abiotic and biotic factors that can influence processes involved in mating interactions, such as signal production and transmission, mate choice and mating opportunities. We discuss all relevant data through the lens of two, non-mutually exclusive theories on sexual selection, namely indicator and sensory models. Where possible, we indicate whether these models provide the same or different predictions regarding urban-adapted sexual signals and describe different experimental designs that can be useful for the different models as well as to investigate the drivers of sexual selection. We argue that we lack a good understanding of: (i) the factors driving urban sexual selection; (ii) whether reported changes in traits result in adaptive benefits; and (iii) whether these changes reflect a short-term ecological, or long-term evolutionary response. We highlight that urbanisation provides a unique opportunity to study the process and outcomes of sexual selection, but that this requires a highly integrative approach combining experimental and observational work.

BACKGROUND: To investigate associations between psychological problems and the use of healthcare and informal care and total costs among head and neck cancer (HNC) patients.METHOD: Data were used of the NETherlands QUality of Life and Biomedical Cohort study. Anxiety and depression disorder (diagnostic interview), distress, symptoms of anxiety and depression (HADS), and fear of cancer recurrence (FCR) and cancer worry scale (CWS) were measured at baseline and at 12-month follow-up. Care use and costs (questionnaire) were measured at baseline, 3-, 6-, 12-, and 24-month follow-up. Associations between psychological problems and care use/costs were investigated using logistic and multiple regression analyses.RESULTS: Data of 558 patients were used. Distress, symptoms of anxiety or depression, FCR, and/or anxiety disorder at baseline were significantly associated with higher use of primary care, supportive care, and/or informal care (odds ratios (ORs) between 1.55 and 4.76). Symptoms of anxiety, FCR, and/or depression disorder at 12-month follow-up were significantly associated with use of primary care, supportive care, and/or informal care (ORs between 1.74 and 6.42). Distress, symptoms of anxiety, and FCR at baseline were associated with higher total costs.DISCUSSION: HNC patients with psychological problems make more use of healthcare and informal care and have higher costs. This is not the result of worse clinical outcomes.

Contains fulltext : 246727.pdf (Publisher’s version ) (Open Access) Background: This study assessed the course of fear of cancer recurrence (FCR) in patients newly diagnosed with head and neck cancer (HNC), identified FCR trajectories and factors associated with FCR trajectories. Methods: Six hundred and seventeen HNC patients from the NET-QUBIC cohort study completed the Cancer Worry Scale-6 at diagnosis, 3 and 6 months post-treatment. FCR trajectories were identified using Latent Class Growth Analysis. Associations were explored between FCR trajectories and baseline demographic and medical variables, coping and self-efficacy. Results: Overall, FCR decreased slightly between baseline and 3 months post-treatment and remained stable up to 6 months. Two FCR trajectories were identified: "high stable" (n = 125) and "low declining" (n = 492). Patients with high stable FCR were younger, reported more negative adjustment, passive coping, and reassuring thoughts, and less avoidance. Conclusions: The majority of HNC patients have low declining FCR after diagnosis, but one in five patients experience persistent high FCR up to 6 months post-treatment. 12 p.

Purpose of Review Osteocytes are the conductors of bone adaptation and remodelling. Buried inside the calcified matrix, they sense mechanical cues and signal osteoclasts in case of low activity, and osteoblasts when stresses are high. How do osteocytes detect mechanical stress? What physical signal do they perceive? Finite element analysis is a useful tool to address these questions as it allows calculating stresses, strains and fluid flow where they cannot be measured. The purpose of this review is to evaluate the capabilities and challenges of finite element models of bone, in particular the osteocytes and load-induced activation mechanisms. Recent Findings High-resolution imaging and increased computational power allow ever more detailed modelling of osteocytes, either in isolation or embedded within the mineralised matrix. Over the years, homogeneous models of bone and osteocytes got replaced by heterogeneous and microstructural models, including, e.g. the lacuno-canalicular network and the cytoskeleton. Summary The lacuno-canalicular network induces strain amplifications and the osteocyte protrusions seem to be stimulated much more than the cell body, both by strain and fluid flow. More realistic cell geometries, like minute constrictions of the canaliculi, increase this effect. Microstructural osteocyte models describe the transduction of external stimuli to the nucleus. Supracellular multiscale models (e.g. of a tunnelling osteon) allow to study differential loading of osteocytes and to distinguish between strain and fluid flow as the pivotal stimulatory cue. In the future, the finite element models may be enhanced by including chemical transport and intercellular communication between osteocytes, osteoclasts and osteoblasts.

Empirical research conducted by education researchers over a period of approximately 20 years confirms that uncertainty exists whether the provisions of the Occupational Health and Safety Act (OHSA) apply to technology workshops at academic, technical and special schools; whether compliance with the safety provisions of the OHSA is lacking; and whether serious injuries at technology workshops at schools occur from time to time. A comparative study of foreign law regarding occupational safety at technology workshops at high schools confirms that many countries have national or federal occupational safety and health statutes that apply to workplaces as well as public schools, although some have specific statutes or regulations addressing occupational safety at public schools. Countries like Germany, the Netherlands and some states of the United States of America define school-going children and students as "workers" in terms of their occupational safety legislation. Germany includes all school-going children in its statutory accident insurance scheme to provide for faultless compensation in case of injury. In determining whether the OHSA applies to technical workshops at high schools, the fundamental rights, as well as its spirit and purport, must be considered through the prism of the Constitution of the Republic of South Africa. Applying the traditional literalist-cum-intentionalist approach to the interpretation of the OHSA, the conclusion is that this Act does indeed apply to technology workshops at schools. In terms of section 60(1)(a) of the South African Schools Act state liability for damages occurring as a result of school activities does provide essential legal protection. However, the South African Schools Act, school safety policies and school infrastructure regulations do not make explicit provision for the application of health and safety standards at school premises that use potentially dangerous machinery and equipment in places such as technical workshops and science laboratories. It is therefore recommended that the OHSA, the Compensation for Occupational Injuries and Diseases Act, the Schools Act and the School Infrastructure Regulations be amended to provide legal certainty in respect of the application of occupational safety to technical workshops at high schools.

BACKGROUND: In a substantial subgroup of depressed patients, atypical, energy-related depression symptoms (e.g. increased appetite/weight, hypersomnia, loss of energy) tend to cluster with immuno-metabolic dysregulations (e.g. increased BMI and inflammatory markers). This clustering is proposed to reflect a more homogeneous depression pathology. This study examines to what extent energy-related symptoms are associated and share sociodemographic, lifestyle and clinical characteristics.METHODS: Data were available from 13,965 participants from eight Dutch cohorts with DSM-5 lifetime major depression assessed by the Lifetime Depression Assessment Self-report (LIDAS) questionnaire. Information on four energy-related depression symptoms were extracted: energy loss, increased appetite, increased weight, and hypersomnia. Tetrachoric correlations between these symptoms, and associations of these symptoms with sociodemographic (sex, age, education), lifestyle (physical activity, BMI, smoking) and clinical characteristics (age of onset, episode duration, history, treatment and recency, and self-reported comorbidity) were computed.RESULTS: Correlations between energy-related symptoms were overall higher than those with other depression symptoms and varied from 0.90 (increased appetite vs increased weight) to 0.11 (increased appetite vs energy loss). All energy-related symptoms were strongly associated with higher BMI and a more severe clinical profile. Patients with increased appetite were more often smokers, and only patients with increased appetite or weight more often had a self-reported diagnosis of PTSD (OR = 1.17, p = 2.91E-08) and eating disorder (OR = 1.40, p = 4.08E-17).CONCLUSIONS: The symptom-specific associations may have consequences for a profile integrating these symptoms, which can be used to reflect immuno-metabolic depression. They indicate the need to study immuno-metabolic depression at individual symptom resolution as a starting point.

Background Internet-based cognitive behavioral therapy (iCBT) services for common mental health disorders have been found to be effective. There is a need for strategies that improve implementation in routine practice. One-size-fits-all strategies are likely to be ineffective. Tailored implementation is considered as a promising approach. The self-guided integrated theory-based Framework for intervention tailoring strategies toolkit (ItFits-toolkit) supports local implementers in developing tailored implementation strategies. Tailoring involves identifying local barriers; matching selected barriers to implementation strategies; developing an actionable work plan; and applying, monitoring, and adapting where necessary. Objective This study aimed to compare the effectiveness of the ItFits-toolkit with implementation-as-usual (IAU) in implementing iCBT services in 12 routine mental health care organizations in 9 countries in Europe and Australia. Methods A stepped-wedge cluster randomized trial design with repeated measures was applied. The trial period lasted 30 months. The primary outcome was the normalization of iCBT delivery by service providers (therapists, referrers, IT developers, and administrators), which was measured with the Normalization Measure Development as a proxy for implementation success. A 3-level linear mixed-effects modeling was applied to estimate the effects. iCBT service uptake (referral and treatment completion rates) and implementation effort (hours) were used as secondary outcomes. The perceived satisfaction (Client Satisfaction Questionnaire), usability (System Usability Scale), and impact of the ItFits-toolkit by implementers were used to assess the acceptability of the ItFits-toolkit. Results In total, 456 mental health service providers were included in this study. Compared with IAU, the ItFits-toolkit had a small positive statistically significant effect on normalization levels in service providers (mean 0.09, SD 0.04; P=.02; Cohen d=0.12). The uptake of iCBT by patients was similar to that of IAU. Implementers did not spend more time on implementation work when using the ItFits-toolkit and generally regarded the ItFits-toolkit as usable and were satisfied with it. Conclusions The ItFits-toolkit performed better than the usual implementation activities in implementing iCBT services in routine practice. There is practical utility in the ItFits-toolkit for supporting implementers in developing and applying effective tailored implementation strategies. However, the effect on normalization levels among mental health service providers was small. These findings warrant modesty regarding the effectiveness of self-guided tailored implementation of iCBT services in routine practice. Trial Registration ClinicalTrials.gov NCT03652883; https://clinicaltrials.gov/ct2/show/NCT03652883 International Registered Report Identifier (IRRID) RR2-10.1186/s13063-020-04686-4

Background: Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than 1 year. Methods: We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants. Results: We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume. Conclusions: Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.

The inter-relationship between equine thoracolumbar motion and muscle activation during normal locomotion and lameness is poorly understood.To compare thoracolumbar and pelvic kinematics and longissimus dorsi (longissimus) activity of trotting horses between baseline and induced forelimb (iFL) and hindlimb (iHL) lameness.Controlled experimental cross-over study.Three-dimensional kinematic data from the thoracolumbar vertebrae and pelvis, and bilateral surface electromyography (sEMG) data from longissimus at T14 and L1, were collected synchronously from clinically non-lame horses (n = 8) trotting overground during a baseline evaluation, and during iFL and iHL conditions (2-3/5 AAEP), induced on separate days using a lameness model (modified horseshoe). Motion asymmetry parameters, maximal thoracolumbar flexion/extension and lateral bending angles, and pelvis range of motion (ROM) were calculated from kinematic data. Normalised average rectified value (ARV) and muscle activation onset, offset and activity duration were calculated from sEMG signals. Mixed model analysis and statistical parametric mapping compared discrete and continuous variables between conditions (α=0.05).Asymmetry parameters reflected the degree of iFL and iHL. Maximal thoracolumbar flexion and pelvis pitch ROM increased significantly following iFL and iHL. During iHL, peak lateral bending increased towards the non-lame side (NLS) and decreased towards the lame side (LS). Longissimus ARV significantly increased bilaterally at T14 and L1 for iHL, but only at LS L1 for iFL. Longissimus activation was significantly delayed on the NLS and precipitated on the LS during iHL, but these clear phasic shifts were not observed in iFL.Findings should be confirmed in clinical cases.Distinctive, significant adaptations in thoracolumbar and pelvic motion and underlying longissimus activity occur during iFL and iHL and are detectable using combined motion capture and sEMG. For iFL, these adaptations occur primarily in a cranio-caudal direction, whereas for iHL, lateral bending and axial rotation are also involved. This article is protected by copyright. All rights reserved.

In people living with HIV (PLWH), a positive association is often found between depressive symptoms and unsafe sex, which means sex without a condom. However, the results of such studies are inconclusive. The present study compared the numbers of safe and unsafe sexual contacts from men who have sex with men (MSM) (N = 159), living with HIV and attending a mental health clinic, with those of HIV-negative MSM in the general population (N = 198). We determined whether the presence of depressive symptoms was associated with unsafe sex in either of the two study populations. The depressive symptoms were measured with the Inventory of Depressive Symptoms (IDS), (MSM living with HIV) and with the 2012 Sexual Health Monitor (HIV-negative MSM). Finally, we determined whether MSM living with HIV with depressive symptoms, who received psychiatric treatment as usual, engaged in fewer unsafe sexual contacts one year after baseline. The mental-health-treatment-seeking MSM living with HIV engaged in more unsafe sexual contact than the MSM comparison group without HIV. Neither the treatment-seeking MSM living with HIV nor the MSM without HIV in the general population exhibited a relationship between depressive symptoms and unsafe sex. Moreover, the successful treatment of depressive symptoms in the treatment group did not lead to any reduction in the number of unsafe sexual contacts. Further research is needed to develop interventions that might be effective for MSM living with HIV with mental health symptoms to reduce the number of unsafe sexual contacts.

Back pain is the leading cause of disability with half of cases attributed to intervertebral disc (IVD) degeneration, yet currently no therapies target this cause. We previously reported an ex vivo caprine loaded disc culture system (LDCS) that accurately represents the cellular phenotype and biomechanical environment of human IVD degeneration. Here, the efficacy of an injectable hydrogel system (LAPONITE® crosslinked pNIPAM-co-DMAc, (NPgel)) to halt or reverse the catabolic processes of IVD degeneration was investigated within the LDCS. Following enzymatic induction of degeneration using 1 mg mL −1 collagenase and 2 U mL −1 chondroitinase ABC within the LDCS for 7 days, IVDs were injected with NPgel alone or with encapsulated human bone marrow progenitor cells (BMPCs). Un-injected caprine discs served as degenerate controls. IVDs were cultured for a further 21 days within the LDCS. Tissues were then processed for histology and immunohistochemistry. No extrusion of NPgel was observed during culture. A significant decrease in histological grade of degeneration was seen in both IVDs injected with NPgel alone and NPgel seeded with BMPCs, compared to un-injected controls. Fissures within degenerate tissue were filled by NPgel and there was evidence of native cell migration into injected NPgel. The expression of healthy NP matrix markers (collagen type II and aggrecan) was increased, whereas the expression of catabolic proteins (MMP3, ADAMTS4, IL-1β and IL-8) was decreased in NPgel (±BMPCs) injected discs, compared to degenerate controls. This demonstrates that NPgel promotes new matrix production at the same time as halting the degenerative cascade within a physiologically relevant testing platform. This highlights the potential of NPgel as a future therapy for IVD degeneration.

To define technical specifications for artificial substitutes, it is necessary to model their mechanical behaviour. Here we studied the linear and nonlinear biphasic models for Nucleus Pulposus (NP) and Annulus Fibrosus (AF). The associated material parameters were obtained using confined compression stress relaxation tests on goat intervertebral disc (IVD) samples. The first parameter, aggregate modulus HA0, which essentially describes load-bearing capacity of the solid phase, was larger for AF (HA0 = 0.53 ± 0.06 MPa) than for NP (HA0 = 0.26 ± 0.04 MPa). For hydraulic permeability, which quantifies the ability to transmit interstitial fluid, it was the opposite (k0 = (0.20 ± 0.07) × 10-15 m4/Ns for AF and k0 = (0.67 ± 0.08)×10-15 m4/Ns for NP). The values of nonlinearity coefficients, nonlinear stiffening coefficient β and non-dimensional nonlinear permeability coefficient M, reflected that these tissues had nonlinear elastic behaviour and permeability. Also, investigating the effect of swelling conditions in sample preparation showed that for both AF and NP, confined-swollen samples had higher aggregate modulus and lower permeability values compared to the free-swollen ones. The quantitative description of the nonlinear properties of AF and NP provided a better understanding of IVD behaviour as well as technical specifications for their artificial substitutes.

Secretory preproteins of the Sec pathway are targeted post-translationally and cross cellular membranes through translocases. During cytoplasmic transit, mature domains remain non-folded for translocase recognition/translocation. After translocation and signal peptide cleavage, mature domains fold to native states in the bacterial periplasm or traffic further. We sought the structural basis for delayed mature domain folding and how signal peptides regulate it. We compared how evolution diversified a periplasmic peptidyl-prolyl isomerase PpiA mature domain from its structural cytoplasmic PpiB twin. Global and local hydrogen-deuterium exchange mass spectrometry showed that PpiA is a slower folder. We defined at near-residue resolution hierarchical folding initiated by similar foldons in the twins, at different order and rates. PpiA folding is delayed by less hydrophobic native contacts, frustrated residues and a β-turn in the earliest foldon and by signal peptide-mediated disruption of foldon hierarchy. When selected PpiA residues and/or its signal peptide were grafted onto PpiB, they converted it into a slow folder with enhanced in vivo secretion. These structural adaptations in a secretory protein facilitate trafficking. ispartof: EMBO JOURNAL vol:41 issue:23 ispartof: location:England status: published

Excitation transfer, the transfer of arousal from one emotion to another, might be a mechanism in the development of unusual sexual interests. In this pilot study, we investigated whether we could induce excitation transfer between various emotions and sexual arousal in a laboratory setting with 30 male volunteers. We induced low-level sexual arousal in four different emotional states (aggression/dominance, endearment, fear, disgust) and a neutral state. Sexual arousal was measured using penile plethysmography and self-report. Although there was no mean group effect, possibly due to large interindividual variations, 60% of the subjects showed more sexual arousal in response to sexual stimulation in at least one of the emotional states than in the neutral state. Excitation transfer was most prominent with aggression/dominance and least prominent with disgust. Genital excitation transfer was strongly related to lower penile reactivity and to higher self-reported erotophilia. This pilot study paves the way for further research into excitation transfer as a mechanism to increase the salience of stimuli that otherwise would not have been sexual in nature.

BackgroundSafety planning-type interventions (SPTIs) for patients at risk of suicide are often used in clinical practice, but it is unclear whether these interventions are effective.AimsThis article reports on a meta-analysis of studies that have evaluated the effectiveness of SPTIs in reducing suicidal behaviour and ideation.MethodWe searched Medline, EMBASE, PsycINFO, Web of Science and Scopus from their inception to 9 December 2019, for studies that compared an SPTI with a control condition and had suicidal behaviour or ideation as outcomes. Two researchers independently extracted the data. To assess suicidal behaviour, we used a random-effects model of relative risk based on a pooled measure of suicidal behaviour. For suicidal ideation, we calculated effect sizes with Hedges’ g. The study was registered at PROSPERO (registration number CRD42020129185).ResultsOf 1816 unique abstracts screened, 6 studies with 3536 participants were eligible for analysis. The relative risk of suicidal behaviour among patients who received an SPTI compared with control was 0.570 (95% CI 0.408–0.795, P = 0.001; number needed to treat, 16). No significant effect was found for suicidal ideation.ConclusionsTo our knowledge, this is the first study to report a meta-analysis on SPTIs for suicide prevention. Results support the use of SPTIs to help preventing suicidal behaviour and the inclusion of SPTIs in clinical guidelines for suicide prevention. We found no evidence for an effect of SPTIs on suicidal ideation, and other interventions may be needed for this purpose.

Urbanization drastically changes environmental conditions, including the introduction of sensory pollutants, such as artificial light at night (ALAN) and anthropogenic noise. To settle in urban habitats, animals need to cope with this new sensory environment. On a short timescale, animals might cope with sensory pollutants via behavioral adjustments, such as changes in sexual signaling, which can have important fitness consequences. While ALAN and anthropogenic noise generally co-occur in urban habitats and are known to be able to interact to modify behavioral responses, few studies have addressed their combined impact. Our aim was, therefore, to assess the effects of ALAN, anthropogenic noise, and their interaction on sexual signaling in túngara frogs (Engystomops pustulosus). We observed the calling behavior of frogs in urban and forest areas, and subsequently recorded these frogs in a laboratory set-up while independently manipulating light and noise levels. Frogs in urban areas called with a higher call rate and complexity, which was correlated with local sensory conditions. Furthermore, our lab experiment revealed that ALAN can directly alter sexual signaling independently as well as in combination with anthropogenic noise. Exposure to ALAN alone increased call amplitude, whereas a combination of ALAN and anthropogenic noise interacted to lead to a higher call complexity and amplitude. Overall, the response patterns consistently showed that exposure to ALAN and anthropogenic noise led to more conspicuous sexual signals than expected based on the additive effects of single pollutants. Our results support the notion that urban and forest population differences in sexual signaling can be partially explained by exposure to ALAN and anthropogenic noise. Furthermore, by demonstrating interactive effects between light and noise pollution, our study highlights the importance of examining the effects of multisensory pollution, instead of single pollutants, when trying to understand phenotypic divergence in urbanized vs. natural areas.

Articular cartilage damage is a major challenge in healthcare due to the lack of long-term repair options. There are several promising regenerative implant-based approaches for the treatment, but the fixation of the implant remains a significant challenge. This study evaluated the potential for repair of an osteochondral implant produced through a novel combined bioprinting-based chondral-bone integration, with and without cells, in an equine model. Implants consisted of a melt electrowritten polycaprolactone (PCL) framework for the chondral compartment, which was firmly integrated with a bone anchor. The bone anchor was produced by extrusion-based printing of a low-temperature setting bioceramic material that had been proven to be effective for osteo-regeneration in an orthotopic, non-load bearing and non-articular site in the same species in an earlier in vivo study. Articular cartilage-derived progenitor cells were seeded into the PCL framework and cultured for 28 days in vitro in the presence of bone morphogenetic protein-9 (BMP-9), resulting in the formation of abundant extracellular matrix rich in glycosaminoglycans (GAGs) and type II collagen. The constructs were implanted in the stifle joints of Shetland ponies with cell-free scaffolds as controls. Clinical signs were monitored, and progression of healing was observed non-invasively through radiographic examinations and quantitative gait analysis. Biochemical and histological analyses 6 months after implantation revealed minimal deposition of GAGs and type II collagen in the chondral compartment of the defect site for both types of implants. Quantitative micro-computed tomography showed collapse of the bone anchor with low volume of mineralized neo-bone formation in both groups. Histology confirmed that the PCL framework within the chondral compartment was still present. It was concluded that the collapse of the osteal anchor, resulting in loss of the mechanical support of the chondral compartment, strongly affected overall outcome, precluding evaluation of the influence of BMP-9 stimulated cells on in vivo cartilage regeneration.Keywords: cartilage, 3D (bio)printing, equine model, osteochondral, articular cartilage-derived progenitor cells

Secretory preproteins of the Sec pathway bear signal peptides and are targeted post-translationally to cross the plasma membrane or ER through translocases. After translocation and signal peptide cleavage, mature domains fold to native states in the bacterial periplasm or after further trafficking. During cytoplasmic transit, mature domains must remain non-folded for translocase recognition and translocation. Here, we sought the structural basis for the delayed folding mechanism of mature domains and how this is regulated by signal peptides. To address this, we compared how evolution diversified a periplasmic peptidyl-prolyl isomerase PpiA mature domain from its structural twin cytoplasmic PpiB. Using global and local hydrogen deuterium exchange mass spectrometry we showed that PpiA is a slower folder. We defined at near-residue resolution hierarchical folding initiated by similar foldons in the twins, that displayed different order and rates. Folding is delayed in PpiA by less hydrophobic/bulky native contacts, frustrated residues and a critical β -turn in the early folding region and by signal peptide-driven disorder, which disrupts foldon hierarchy. When selected PpiA residues and its signal peptide were grafted onto PpiB they converted it into a slow folder with enhanced in vivo secretion. These data reveal the structural basis of non-folding in a secretory protein, that allows its trafficking.

Background: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction.Methods: Genome-wide analysis of remission (nremit = 1852, nnonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism–based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA.Results: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism–based heritability was significantly different from zero for remission (h2 = 0.132, SE = 0.056) but not for percentage improvement (h2 = −0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response.Conclusions: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

Nuij and colleagues are too sanguine in concluding that their reviewhas demonstrated the effectiveness of safety planning in reducingsuicidal behaviour. They note the methodological limitations ofthe studies they summarise and the evidence of clinical heterogeneity and publication bias that make meta-analysis problematic, butthey could say more about the problem of interpreting their primaryoutcome.

This study documents a variety of deposits created by submarine landslides within the Upper Cretaceous to lowermost Paleocene Chalk Group in the Danish Central Graben and investigates the impact of remobilization on porosity. Improved visualization of the landslides in 3D seismic data compared with previous studies was facilitated by better seismic data quality for the Chalk Group, the availability of a large stack of stratigraphy-consistent horizons and the use of spectral decomposition data. The illustrated examples are chosen to reflect the spectrum of deformation styles seen in the chalk and all have a well penetrating the affected succession. They include a large collapse (375 km 2 ) of an inversion ridge within the Kraka and Gorm formations, a field of large slide blocks (100–1000 m, 10–26 m) of likely lowermost Danian age embedded in the uppermost Ekofisk Formation, a debris flow system within the uppermost Tor Formation probably originating from the Ringkøbing–Fyn High and fine-grained bottom current sediment waves within the lowermost Danian Ekofisk Formation. In general, porosities are higher (10–25 porosity units) in the remobilized chalk compared with time-equivalent pelagic chalk in nearby reference wells. In earlier studies this has been linked to lack of bioturbation (resulting in limited grain repacking) in the remobilized chalks owing to high sedimentation rates, resulting in a relatively open fabric during initial burial. In contrast, surrounding and covering pelagic deposits could be much more effectively bioturbated, leading to tighter grain packing during burial. The insights of this study help in the seismic characterization of mud-grade carbonate oozes and have important applications in the reservoir modelling of mud-grade carbonate reservoirs (also in light of carbon capture and storage), and in palaeo-reconstructions of pelagic seafloors since submarine landslides provide kinematic indicators.

The temporomandibular joint disc is a fibrocartilaginous structure, composed of collagen fibers, elastin fibers, and proteoglycans. Despite the crucial role of elastin fibers in load‐bearing properties of connective tissues, its contribution in temporomandibular joint disc biomechanics has been disregarded. This study attempts to characterize the structural–functional contribution of elastin in the temporomandibular joint disc. Using elastase, we selectively perturbed the elastin fiber network in porcine temporomandibular joint discs and investigated the structural, compositional, and mechanical regional changes through: (a) analysis of collagen and elastin fibers by immunolabeling and transmission electron microscopy; (b) quantitative analysis of collagen tortuosity, cell shape, and disc volume; (c) biochemical quantification of collagen, glycosaminoglycan and elastin content; and (d) cyclic compression test. Following elastase treatment, microscopic examination revealed fragmentation of elastin fibers across the temporomandibular joint disc, with a more pronounced effect in the intermediate regions. Also, biochemical analyses of the intermediate regions showed significant depletion of elastin (50%), and substantial decrease in collagen (20%) and glycosaminoglycan (49%) content, likely due to non‐specific activity of elastase. Degradation of elastin fibers affected the homeostatic configuration of the disc, reflected in its significant volume enlargement accompanied by remarkable reduction of collagen tortuosity and cell elongation. Mechanically, elastase treatment nearly doubled the maximal energy dissipation across the intermediate regions while the instantaneous modulus was not significantly affected. We conclude that elastin fibers contribute to the restoration and maintenance of the disc resting shape and actively interact with collagen fibers to provide mechanical resilience to the temporomandibular joint disc.

BACKGROUND Gait kinematics measured during equine gait analysis are typically evaluated by analysing (asymmetry-based) discrete variables (eg, peak values) obtained from continuous kinematic signals (eg, timeseries of datapoints). However, when used for the assessment of complex cases of lameness, such as bilateral lameness, discrete variable analysis might overlook relevant functional adaptations. OBJECTIVES The overall aim of this paper is to compare continuous and discrete data analysis techniques to evaluate kinematic gait adaptations to lameness. STUDY DESIGN Method comparison. METHODS Sixteen healthy Shetland ponies, enrolled in a research programme in which osteochondral defects were created on the medial trochlear ridges of both femurs, were used in this study. Kinematic data were collected at trot on a treadmill before and at 3 and 6 months after surgical intervention. Statistical parametric mapping and linear mixed models were used to compare kinematic variables between and within timepoints. RESULTS Both continuous and discrete data analyses identified changes in pelvis and forelimb kinematics. Discrete data analyses showed significant changes in hindlimb and back kinematics, where such differences were not found to be significant by continuous data analysis. In contrast, continuous data analysis provided additional information on the timing and duration of the differences found. MAIN LIMITATIONS A limited number of ponies were included. CONCLUSIONS The use of continuous data provides additional information regarding gait adaptations to bilateral lameness that is complementary to the analysis of discrete variables. The main advantage lies in the additional information regarding time dependence and duration of adaptations, which offers the opportunity to identify functional adaptations during all phases of the stride cycle, not just the events related to peak values.

Aims: The aim of this systematic review is to assess the effects of community pharmacist-led interventions to optimise the use of antibiotics and identify which interventions are most effective. Methods: This review was conducted according to the PRISMA guidelines (PROSPERO: CRD42020188552). PubMed, EMBASE and the Cochrane Central Register of Controlled Trials were searched for (randomised) controlled trials. Included interventions were required to target antibiotic use, be set in the community pharmacy context, and be pharmacist-led. Primary outcomes were quality of antibiotic supply and adverse effects while secondary outcomes included patient-reported outcomes. Risk of bias was assessed using the ‘Cochrane suggested risk of bias criteria’ and narrative synthesis of primary outcomes conducted. Results: Seventeen studies were included covering in total 3822 patients (mean age 45.6 years, 61.9% female). Most studies used educational interventions. Three studies reported on primary outcomes, 12 on secondary outcomes and two on both. Three studies reported improvements in quality of dispensing, interventions led to more intensive symptom assessment (up to 30% more advice given) and a reduction of over-the-counter supply up to 53%. Three studies led to higher consumer satisfaction, effects on adherence from nine studies were mixed (risk difference 0.04 [−0.02, 0.10]). All studies had unclear or high risks of bias across at least one domain, with large heterogeneity between studies. Conclusions: Our review suggests some positive results from pharmacist-led interventions, but the interventions do not seem sufficiently effective as currently implemented. This review should be interpreted as exploratory research, as more high-quality research is needed.

Contains fulltext : 248656.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10(-8)), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10(-6)) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10(-7); rs73033497, p = 8.8 × 10(-7); rs7914279, p = 6.4 × 10(-7)), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10(-7)) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10(-7)), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10(-7)) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

It is critically important to correctly identify persons with a lifetime history (LTH) of suicide attempts (SA) from both a clinical and research perspective. Face-to-face interviews are often the best available method for researchers to collect data about a complex phenomenon like a LTH of SA. However, extensive survey methodology research has shown that probing sensitive topics like a LTH of SA are sensitive for interviewer-related errors or interviewer effects. Studies investigating these interviewer effects are scarce in the field of suicide studies. This study presents a possible roadmap for study of interviewerrelated measurement error and an exploration of role-dependent behaviour of interviewers by assessing the LTH of SA through an epidemiological design. Data from the baseline assessment of the Netherlands Study of Depression and Anxiety (N = 2981) was used to illustrate the proposed roadmap to study interviewer effects. Results show: : (1) that it was possible to identify the existence of interviewer effects in assessing a LTH of SA; (2) that interviewer effects occurred by probing and clarification activities of the interviewer but not with inadequate formulation of the original question and so give a possible explanation for these effects; and (3) that it was possible to study the impact of these effects on the association between a well-known risk factor and LTH of SA. Applying the Measurement Error framework for systematically examining errors in data collection on suicidality seems a promising method.

Background Longitudinal observational cohort studies in cancer patients are important to move research and clinical practice forward. Continued study participation (study retention) is of importance to maintain the statistical power of research and facilitate representativeness of study findings. This study aimed to investigate study retention and attrition (drop-out) and its associated sociodemographic and clinical factors among head and neck cancer (HNC) patients and informal caregivers included in the Netherlands Quality of Life and Biomedical Cohort Study (NET-QUBIC). Methods NET-QUBIC is a longitudinal cohort study among 739 HNC patients and 262 informal caregivers with collection of patient-reported outcome measures (PROMs), fieldwork data (interview, objective tests and medical examination) and biobank materials. Study retention and attrition was described from baseline (before treatment) up to 2-years follow-up (after treatment). Sociodemographic and clinical characteristics associated with retention in NET-QUBIC components at baseline (PROMs, fieldwork and biobank samples) and retention in general (participation in at least one component) were investigated using Chi-square, Fisher exact or independent t-tests (p Results Study retention at 2-years follow-up was 80% among patients alive (66% among all patients) and 70% among caregivers of patients who were alive and participating (52% among all caregivers). Attrition was most often caused by mortality, and logistic, physical, or psychological-related reasons. Tumor stage I/II, better physical performance and better (lower) comorbidity score were associated with participation in the PROMs component among patients. No factors associated with participation in the fieldwork component (patients), overall sample collection (patients and caregivers) or PROMs component (caregivers) were identified. A better performance and comorbidity score (among patients) and higher age (among caregivers) were associated with study retention at 2-years follow-up. Conclusions Retention rates were high at two years follow-up (i.e. 80% among HNC patients alive and 70% among informal caregivers with an active patient). Nevertheless, some selection was shown in terms of tumor stage, physical performance, comorbidity and age, which might limit representativeness of NET-QUBIC data and samples. To facilitate representativeness of study findings future cohort studies might benefit from oversampling specific subgroups, such as patients with poor clinical outcomes or higher comorbidity and younger caregivers.

BackgroundAlthough major depressive disorder (MDD) is characterized by a pervasive negative mood, research indicates that the mood of depressed patients is rarely entirely stagnant. It is often dynamic, distinguished by highs and lows, and it is highly responsive to external and internal regulatory processes. Mood dynamics can be defined as a combination of mood variability (the magnitude of the mood changes) and emotional inertia (the speed of mood shifts). The purpose of this study is to explore various distinctive profiles in real-time monitored mood dynamics among MDD patients in routine mental healthcare.MethodsEcological momentary assessment (EMA) data were collected as part of the cross-European E-COMPARED trial, in which approximately half of the patients were randomly assigned to receive the blended Cognitive Behavioral Therapy (bCBT). In this study a subsample of the bCBT group was included (n = 287). As part of bCBT, patients were prompted to rate their current mood (on a 1–10 scale) using a smartphone-based EMA application. During the first week of treatment, the patients were prompted to rate their mood on three separate occasions during the day. Latent profile analyses were subsequently applied to identify distinct profiles based on average mood, mood variability, and emotional inertia across the monitoring period.ResultsOverall, four profiles were identified, which we labeled as: (1) “very negative and least variable mood” (n = 14) (2) “negative and moderate variable mood” (n = 204), (3) “positive and moderate variable mood” (n = 41), and (4) “negative and highest variable mood” (n = 28). The degree of emotional inertia was virtually identical across the profiles.ConclusionsThe real-time monitoring conducted in the present study provides some preliminary indications of different patterns of both average mood and mood variability among MDD patients in treatment in mental health settings. Such varying patterns were not found for emotional inertia.

Protein machines undergo conformational motions to interact with and manipulate polymeric substrates. The Sec translocase promiscuously recognizes, becomes activated, and secretes >500 non-folded preprotein clients across bacterial cytoplasmic membranes. Here, we reveal that the intrinsic dynamics of the translocase ATPase, SecA, and of preproteins combine to achieve translocation. SecA possesses an intrinsically dynamic preprotein clamp attached to an equally dynamic ATPase motor. Alternating motor conformations are finely controlled by the γ-phosphate of ATP, while ADP causes motor stalling, independently of clamp motions. Functional preproteins physically bridge these independent dynamics. Their signal peptides promote clamp closing; their mature domain overcomes the rate-limiting ADP release. While repeated ATP cycles shift the motor between unique states, multiple conformationally frustrated prongs in the clamp repeatedly "catch and release" trapped preprotein segments until translocation completion. This universal mechanism allows any preprotein to promiscuously recognize the translocase, usurp its intrinsic dynamics, and become secreted. ispartof: CELL REPORTS vol:38 issue:6 ispartof: location:United States status: published