Gelatin-tyramine addition and low hydrogel density improves cell attachment, migration, and metabolic activity in vitro and tissue response in vivo in enzymatically crosslinkable dextran-hyaluronic acid hydrogels.

Hydrogels are receiving increasing attention for their use in 3D cell culture, tissue engineering, and bioprinting applications. Each application places specific mechanical and biological demands on these hydrogels. We developed a hydrogel toolbox based on enzymatically crosslinkable polysaccharides via tyramine (TA) moieties, allowing for rapid and tunable crosslinking with well-defined stiffness and high cell viability. Including gelatin modified with TA moieties (Gel-TA) improved the hydrogels' biological properties; 3 T3 fibroblasts and HUVECs attached to and proliferated on the enriched hydrogels at minute Gel-TA concentrations, in contrast to bare or unmodified gelatin-enriched hydrogels. Moreover, we were able to switch HUVECs from a quiescent to a migratory phenotype simply by altering the ligand concentration, demonstrating the potential to easily control cell fate. In encapsulation studies, Gel-TA significantly improved the metabolic activity of 3 T3 fibroblasts in soft hydrogels. Furthermore, we showed rapid migration and network formation in Gel-TA enriched hydrogels in contrast to a non-migratory behavior in non-enriched polysaccharide hydrogels. Finally, low hydrogel density significantly improves tissue response in vivo with large infiltration and low fibrotic reaction. Further development by adding ECM proteins, peptides, and growth factor adhesion sites will lead to a toolbox for hydrogels tailored toward their desired application.

Kinetic characterization of SPR-based biomarker assays enables quality control, calibration free measurements and robust optimization for clinical application.

Biomarker measurements are essential for the early diagnosis of complex diseases. However, many current biomarker assays lack sensitivity and multiplexing capacity, work in a narrow detection range and importantly lack real time quality control opportunities, which hampers clinical translation. In this paper, we demonstrate a toolbox to kinetically characterize a biomarker measurement assay using Surface Plasmon Resonance imaging (SPRi) with ample opportunities for real time quality control by exploiting quantitative descriptions of the various biomolecular interactions. We show an accurate prediction of SPRi measurements at both low and high concentrations of various analytes with deviations <5% between actual measurements and predicted measurement. The biphasic binding sites model was accurate for fitting the experimental curves and enables optimal detection of heterophilic antibodies, cross-reactivity, spotting irregularities and/or other confounders. The toolbox can also be used to create a (simulated) calibration curve, enabling calibration-free measurements with good recovery, it allows for easy assay optimizations, and could help bridge the gap to bring new biomarker assays to the clinic.

High Titers of Low Affinity Antibodies in COVID-19 Patients Are Associated With Disease Severity.

Background: Almost 2 years from the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there is still a lot unknown how the humoral response affects disease progression. In this study, we investigated humoral antibody responses against specific SARS-CoV2 proteins, their strength of binding, and their relationship with COVID severity and clinical information. Furthermore, we studied the interactions of the specific receptor-binding domain (RBD) in more depth by characterizing specific antibody response to a peptide library. Materials and Methods: We measured specific antibodies of isotypes IgM, IgG, and IgA, as well as their binding strength against the SARS-CoV2 antigens RBD, NCP, S1, and S1S2 in sera of 76 COVID-19 patients using surface plasmon resonance imaging. In addition, these samples were analyzed using a peptide epitope mapping assay, which consists of a library of peptides originating from the RBD. Results: A positive association was observed between disease severity and IgG antibody titers against all SARS-CoV2 proteins and additionally for IgM and IgA antibodies directed against RBD. Interestingly, in contrast to the titer of antibodies, the binding strength went down with increasing disease severity. Within the critically ill patient group, a positive association with pulmonary embolism, d-dimer, and antibody titers was observed. Conclusion: In critically ill patients, antibody production is high, but affinity is low, and maturation is impaired. This may play a role in disease exacerbation and could be valuable as a prognostic marker for predicting severity.

Emulating the chondrocyte microenvironment using multi-directional mechanical stimulation in a cartilage-on-chip.

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-1ß 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.

Protective factors as uni- or bipolar factors and their incremental validity and accuracy in predicting general recidivism.

This study examined whether protective factors are unique or the opposite of risk factors and whether they have incremental validity in the prediction of general recidivism. Using a sample of 3306 Dutch forensic outpatients, this study was the first large-sample study ever performed on this topic. Results from exploratory factor analyses demonstrated a relatively stable factor structure of 14 factors, consisting of 32 of the initially included 68 risk factors and 11 of the initially included 17 protective items. The protective factors were found to be either bipolar (i.e., mirror images of risk factors) or responsivity characteristics (i.e., motivation for treatment, cognitive disability). Incremental validity for the recidivism prediction was found in one factor with internal protective items (e.g., empathy, financial management, life goals). This factor decreased the recidivism risk by 6%. However, weak predictive accuracy was found for this factor. Implications for clinical forensic practice are discussed with special focus on the risk-need-responsivity model.

High throughput surface plasmon resonance imaging method for clinical detection of presence and strength of binding of IgM, IgG and IgA antibodies against SARS-CoV-2 during CoViD-19 infection.

Surface Plasmon Resonance imaging (SPRi) was used to determine the presence and strength of binding of IgG, IgM and IgA against the Receptor Binding Domain (RBD) of SARS-CoV-2 in sera of 102 CoViD-19 and non-CoViD-19 patients. The SPRi assay simultaneously measures the antibody isotype levels and the strength of binding to the RBD of ultimate 384 patient samples in one run. It turns out that during the course of the disease, the IgG levels and strength of binding increased while generally the IgM and IgA levels go down. Recovered patients all show high strength of binding of the IgG type to the RBD protein. The anti-RBD immunoglobulins SPRi assay provides additional insights in the immune status of patients recovering from CoViD-19. This new high throughput method can be applied for the assessment of the quality of the immune reaction of healthy individuals to SARS-CoV-2 and its mutants in vaccination programs.•Surface Plasmon Resonance imaging is an unprecedented technology for high throughput screening of antibody profiling of CoViD19 patients.•Fingerprinting of isotypes IgM, IgG and IgA can be performed for 384 patients in one run.•An affinity maturation effect was shown for patients recovering from CoViD19.

Presence and strength of binding of IgM, IgG and IgA antibodies against SARS-CoV-2 during CoViD-19 infection.

Surface Plasmon Resonance imaging (SPRi) was used to determine the presence and strength of binding of IgG, IgM and IgA against the Receptor Binding Domain (RBD) of SARS-CoV-2 in sera of 119 CoViD-19 patients. The SPRi assay measures the antibody isotype levels and the strength of binding to the RBD of ultimate 384 patient samples in one run. It turns out that during the course of the disease, the IgG levels and strength of binding increased while generally the IgM and IgA levels go down. Recovered patients all show high strength of binding of the IgG type to the RBD protein. The anti-RBD immunoglobulins SPRi assay provides additional insights in the immune status of patients recovering from CoViD-19 and this new method can furthermore be applied for the assessment of the quality of the immune reaction of healthy individuals to SARS-CoV-2 in vaccination programs.

The Expressions of Dickkopf-Related Protein 1 and Frizzled-Related Protein Are Negatively Correlated to Local Inflammation and Osteoarthritis Severity.

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-1ß (IL1ß), 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 IL1ß. SF FRZB was negatively correlated with synovium NO, IL1ß, 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.

Spatiotemporal material functionalization via competitive supramolecular complexation of avidin and biotin analogs.

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.

A cost analysis of producing vaccines in developing countries.

Developing country vaccine manufacturers (DCVMs) supply over half of the vaccines used in developing country immunisation programs. Decisions by developing countries to establish vaccine manufacturing should be based on economic viability, however reliable assessments of vaccine production costs are lacking. This study aimed to quantify the cost of establishing vaccine manufacturing facilities and producing vaccines in developing countries. This study estimates vaccine production costs in developing countries based on twelve vaccines produced by eight DCVMs. The results were based on estimates of the capital and operating costs required to establish vaccine manufacturing facilities under three hypothetical scenarios of production scale and scope. Cost patterns were then compared to vaccine prices paid by countries in both industrialized and developing country markets. The cost of producing vaccines in developing countries was estimated to be on average US$ 2.18 per dose, ranging between US$ 0.98 and US$ 4.85 for different vaccine types and formulations. Vaccine costs-per-dose decrease as production scale and scope increase. Cost-per-dose is mainly driven by fixed costs, but at a scale of production over 20 million doses per year it becomes driven by variable costs. Under the three hypothetical scenarios used, costs-per-dose of vaccines produced by developing countries were around 47% lower than vaccine prices in developing-country markets and 84% lower than prices in industrialized-country markets. This study has found that local production of vaccines in developing countries exhibits both economies of scale and economies of scope. The lower costs relative to prices suggests that a producer surplus and potential profits may be attainable in both developing and developed country markets, supporting sustainable production.

Changes in Fluorescence Recovery After Photobleaching (FRAP) as an indicator of SOX9 transcription factor activity.

Cells respond to their environment via an intricate cellular signaling network, directing cell fate. Changes in cell fate are characterized by changes in gene transcription, dictated by (master) transcription factor activity. SOX9 is the master transcription factor for chondrocyte development. Its impaired function is implicated in osteoarthritis and growth disorders, such as dwarfism. However, the factors regulating SOX9 transcriptional activity are not yet fully mapped. Current methods to study transcription factor activity are indirect and largely limited to quantification of SOX9 target gene and protein expression levels after several hours or days of stimulation, leading to poor temporal resolution. We used Fluorescence Recovery After Photobleaching (FRAP) to study the mobility of SOX9 and correlated the changes in mobility to changes in its transcriptional activity by cross-validating with chromatin immunoprecipitation and qPCR. We show that using FRAP, we can quantify the changes in SOX9 mobility on short time scales as an indication of transcriptional activity, which correlated to changes of SOX9 DNA-binding and long-term target gene expression.

Different response of human chondrocytes from healthy looking areas and damaged regions to IL1ß stimulation under different oxygen tension.

Due to its avascular nature, articular cartilage is relatively hypoxic. The aim of this study was to elucidate the functional changes of macroscopically healthy looking areas chondrocytes (MHC) and macroscopically damaged regions chondrocytes (MDC) at a cellular level in response to the inflammatory cytokine IL1ß under different oxygen tension levels. In this study, two-dimensional (2-D) expanded MHC and MDC were redifferentiated in 3-D pellet cultures in chondrogenic differentiation medium, supplemented with or without IL1ß at conventional culture (normoxia) or 2.5% O2 (hypoxia) for 3 weeks. qPCR, immunohistochemistry and ELISA were used to detect the expression of anabolic and catabolic gene expression. Alcian blue/Safranin O staining and GAG assay were used to measure cartilage matrix production. Cell proliferation and apoptosis were assessed by EdU staining and TUNEL assay, respectively. The results showed that hypoxia enhanced matrix production in both MHC and MDC and this effect was stronger on MDC. Under normoxia, MHC showed higher expression of cartilage markers and lower catabolic genes expression than MDC. Interestingly, hypoxia diminished the difference between MHC and MDC. IL1ß potently induced MMPs expression regardless of cell population and oxygen tension. The fold induction of these MMPs in hypoxia was however much higher than in normoxia. In addition, hypoxia promoted the expression of HIF1α and HIF2α in MHC, while it only enhanced HIF1α expression but decreased the HIF2α expression in MDC. We concluded that hypoxia stimulated the redifferentiation of cultured chondrocytes, particularly in MDC derived from macroscopically diseased cartilage. Oxygen tension may profoundly and differentially influence inflammation-associated cartilage injury and diseases by regulating the expression of HIF1α and HIF2α. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:XX-XX, 2018.

Palliative care consultations in primary care: a cross-sectional survey among Dutch general practitioners.

BACKGROUND: Expert consultation supports general practitioners (GPs) in delivering adequate palliative homecare. Insight into consultation practices from a GP's perspective is needed in order to shape consultation services to their wishes and needs. AIM: To explore palliative care consultation practices from a GP's perspective. DESIGN AND SETTING: Cross-sectional web-based survey among all GPs (n=235) in the region of Nijmegen, the Netherlands. METHODS: Our questionnaire contained questions about the delivery of palliative care by GPs, their consultation practices and satisfaction with current services. Questions consisted mainly of 5-point Likert scales. We transformed these scales into numerical values to calculate mean scores. Linear mixed models for repeated measurements were used to study differences in scores. RESULTS: GPs most often consulted informal caregivers (mean score 3.6) or fellow GPs (mean score 3.3). Physical problems were discussed the most (mean score 3.5), while social and existential issues were discussed least (mean score 1.9 for both). In their choice of a particular consultation service, GPs considered the quality of the provided advice to be the most important factor. GPs were satisfied with current consultation services, with fellow GPs receiving the highest satisfaction scores (mean score 4.6). Finally, when recalling their last palliative patient, most GPs started requesting consultation during this patient's last month of life. CONCLUSIONS: Next to informal caregivers, GPs preferably seek advice from fellow GPs. Physical issues receive much attention during consultations; however, other vital aspects of palliative care seem to remain relatively neglected, such as social and existential issues and a proactive care approach.

Quadrivalent influenza vaccines in low and middle income countries: Cost-effectiveness, affordability and availability.

In high-income countries, there is an increased tendency to replace inactivated seasonal trivalent influenza (TIV) vaccines with quadrivalent (QIV) vaccines as these are considered to give a greater public health benefit. In addition, several recent studies from the USA and Europe indicate that replacement with QIV might also be cost-effective; however, the situation in low- and middle-income countries (LMIC) is less clear as few studies have investigated this aspect. The paper by de Boer et al. (2008) describes a dynamic modelling study commissioned by WHO that suggests that in LMICs, under certain conditions, QIV might also be more cost-effective than TIV. In this commentary, we discuss some important aspects that policymakers in LMICs might wish to take into account when considering replacing TIV by QIV. Indeed, from the data presented in the paper by de Boer et al. it can be inferred that replacing QIV for TIV would mean a 25-29% budget increase for seasonal influenza vaccination in South Africa and Vietnam, resulting in an incremental influenza-related health impact reduction of only 7-8% when a 10% symptomatic attack rate is assumed. We argue that national health budget considerations in LMIC might lead decision-makers to choose other investments with higher health impact for a budget equivalent to roughly a quarter of the yearly TIV immunization costs. In addition to an increased annual cost that would be associated with a decision to replace TIV with QIV, there would be an increased pressure on manufacturers to produce QIV in time for the influenza season requiring manufacturers to produce some components of the seasonal vaccine at risk prior to the WHO recommendations for influenza vaccines. Unless the current uncertainties, impracticalities and increased costs associated with QIVs are resolved, TIVs are likely to remain the more attractive option for many LMICs. Each country should establish its context-specific process for decision-making based on national data on disease burden and costs in order to determine whether the health gains out-weigh the additional cost of moving to QIV. For example, immunizing more people in the population, especially those in higher risk groups, with TIV might not only provide better value for money but also deliver better health outcomes in LMICs. Countries with local influenza vaccine manufacturing capacity should include in their seasonal influenza vaccine procurement process an analysis of the pros- and cons- of TIV versus QIV, to ensure both feasibility and sustainability of local manufacturing.

Nanoparticle Enhancement Cascade for Sensitive Multiplex Measurements of Biomarkers in Complex Fluids with Surface Plasmon Resonance Imaging.

There is a large unmet need for reliable biomarker measurement systems for clinical application. Such systems should meet challenging requirements for large scale use, including a large dynamic detection range, multiplexing capacity, and both high specificity and sensitivity. More importantly, these requirements need to apply to complex biological samples, which require extensive quality control. In this paper, we present the development of an enhancement detection cascade for surface plasmon resonance imaging (SPRi). The cascade applies an antibody sandwich assay, followed by neutravidin and a gold nanoparticle enhancement for quantitative biomarker measurements in small volumes of complex fluids. We present a feasibility study both in simple buffers and in spiked equine synovial fluid with four cytokines, IL-1ß, IL-6, IFN-γ, and TNF-α. Our enhancement cascade leads to an antibody dependent improvement in sensitivity up to 40 000 times, resulting in a limit of detection as low as 50 fg/mL and a dynamic detection range of more than 7 logs. Additionally, measurements at these low concentrations are highly reliable with intra- and interassay CVs between 2% and 20%. We subsequently showed this assay is suitable for multiplex measurements with good specificity and limited cross-reactivity. Moreover, we demonstrated robust detection of IL-6 and IL-1ß in spiked undiluted equine synovial fluid with small variation compared to buffer controls. In addition, the availability of real time measurements provides extensive quality control opportunities, essential for clinical applications. Therefore, we consider this method is suitable for broad application in SPRi for multiplex biomarker detection in both research and clinical settings.

The Effects of the WNT-Signaling Modulators BIO and PKF118-310 on the Chondrogenic Differentiation of Human Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) are multipotent cells, mainly from bone marrow, and an ideal source of cells in bone and cartilage tissue engineering. A study of the chondrogenic differentiation of MSCs is of particular interest for MSCs-based cartilage regeneration. In this study, we aimed to optimize the conditions for the chrondogenic differentiation of MSCs by regulating WNT signaling using the small molecule WNT inhibitor PKF118-310 and activator BIO. Human mesenchymal stem cells (hMSCs) were isolated from bone marrow aspirates and cultured in hMSCs proliferation medium. Pellet culture was subsequently established for three-dimensional chondrogenic differentiation of 5 weeks. WNT signaling was increased by the small molecule glycogen synthase kinase-3 inhibitor 6-bromoindirubin-3-oxim (BIO) and decreased by the WNT inhibitor PKF118-310 (PKF). The effects of BIO and PKF on the chondrogenesis of hMSCs was examined by real-time PCR, histological methods, and ELISA. We found that activation of canonical WNT-signaling by BIO significantly downregulated the expression of cartilage-specific genes SOX9, COL2A1, and ACAN, and matrix metalloproteinase genes MMP1/3/9/13, but increased ADAMTS 4/5. Inhibition of WNT signaling by PKF increased the expression of SOX9, COL2A1, ACAN, and MMP9, but decreased MMP13 and ADAMTS4/5. In addition, a high level of WNT signaling induced the expression of hypertrophic markers COL10A1, ALPL, and RUNX2, the dedifferentiation marker COL1A1, and glycolysis genes GULT1 and PGK1. Deposition of glycosaminoglycan (GAG) and collagen type II in the pellet matrix was significantly lost in the BIO-treated group and increased in the PKF-treated group. The protein level of COL10A1 was also highly induced in the BIO group. Interestingly, BIO decreased the number of apoptotic cells while PKF significantly induced apoptosis during chondrogenesis. The natural WNT antagonist DKK1 and the protein level of MMP1 in the pellet culture medium were decreased after PKF treatment. All of these chondrogenic effects appeared to be mediated through the canonical WNT signaling pathway, since the target gene Axin2 and other WNT members, such as TCF4 and ß-catenin, were upregulated by BIO and downregulated by PKF, respectively, and BIO induced nuclear translocation of ß-catenin while PKF inhibited ß-catenin translocation into the nucleus. We concluded that addition of BIO to a chondrogenic medium of hMSCs resulted in a loss of cartilage formation, while PKF induced chondrogenic differentiation and cartilage matrix deposition and inhibited hypertrophic differentiation. However, BIO promoted cell survival by inhibiting apoptosis while PKF induced cell apoptosis. This result indicates that either an overexpression or overinhibition of WNT signaling to some extent causes harmful effects on chondrogenic differentiation. Cartilage tissue engineering could benefit from the adjustment of the critical level of WNT signaling during chondrogenesis of hMSC.

The Allocation of Sexually Transgressive Juveniles to Intensive Specialized Treatment: An Assessment of the Application of RNR Principles.

The aim of this study was to compare results of and develop guidelines for mandatory allocation of sexually transgressive juveniles to Multisystemic Therapy - Problem Sexual Behavior (MST-PSB), Secure Youth Care (SYC), or Forensic Youth Care (FYC), based on the risk-need-responsivity model. Results of current allocation showed a population with relatively less treatment needs to receive community-based MST-PSB, compared with populations receiving residential SYC and FYC. Furthermore, estimated recidivism risk levels did not always support the need for risk reduction by the imposition of limitation of freedom of movement and maximum supervision, provided by all three treatment modalities. Based on the assessed sexual recidivism risk, 38% of the juveniles in FYC, 7% in SYC, and 24% in MST-PSB received treatment that was too intensive, which is considered detrimental to motivation and development. Future allocation practices could benefit from assessing treatment needs and recidivism risk, by use of an actuarial tool.

Treatment Effect on Recidivism for Juveniles Who Have Sexually Offended: a Multilevel Meta-Analysis.

The current study investigated the effect on recidivism of treatment aimed at juveniles who have sexually offended. It also assessed the potential moderating effect of type of recidivism, and several treatment, participant and study characteristics. In total, 14 published and unpublished primary studies, making use of a comparison group and reporting on official recidivism rates, were included in a multilevel meta-analysis. This resulted in the use of 77 effect sizes, and 1726 participants. A three-level meta-analytic model was used to calculate the combined effect sizes (Cohens d) and to perform moderator analyses. Study quality was assessed with the EPHPP Quality Assessment Tool for Quantitative Studies. A moderate effect size was found (d = 0.37), indicating that the treatment groups achieved an estimated relative reduction in recidivism of 20.5% as compared to comparison groups. However, after controlling for publication bias, a significant treatment effect was no longer found. Type of recidivism did not moderate the effect of treatment, indicating that treatment groups were equally effective for all types of recidivism. Also, no moderating effects of participant or treatment characteristics were found. Regarding study characteristics, a shorter follow up time showed a trend for larger effect sizes, and the effect size calculation based on proportions yielded larger effect sizes than calculation via mean frequency of offending. Implications for future research and clinical practice are discussed.

Arthroscopic Airbrush-Assisted Cell Spraying for Cartilage Repair: Design, Development, and Characterization of Custom-Made Arthroscopic Spray Nozzles.

INTRODUCTION: Airbrush-assisted cell spraying would facilitate fully arthroscopic filling of cartilage defects, thereby providing a minimally invasive procedure for cartilage repair. This study provides the development and characterization of custom-made spray nozzles that could serve as a foundation for the development of a BioAirbrush, a platform technology for the arthroscopic application of (cell laden) hydrogels. MATERIALS AND METHODS: Custom-made spray nozzles were designed and produced with 3D printing technology. A commercially available spraying system was used for comparison. Sprays were characterized based on spray angle, cone width, droplet size, velocity, and density. This was performed with conventional and high-speed imaging. Furthermore, cell survival of chondrocytes and mesenchymal stromal cells, as well as the chondrogenic capacity of chondrocytes after spraying were evaluated. RESULTS: Changing nozzle design from internal to external mixing significantly increased cell survival after spraying. Custom-made spray nozzles provide larger droplets compared to the current commercially available technology, potentially improving cell survival. Sufficient mixing of two gel components was confirmed for the custom-made nozzles. Overall, custom-made nozzles improved cell survival after spraying, without significantly affecting the chondrogenic capacity of the cells. CONCLUSIONS: This study provides a platform for the development of a BioAirbrush for spray-assisted cell implantations in arthroscopic cartilage repair procedures. Evaluation of the fundamental characteristics of a spray as well as a study of cell survival after spraying have further expanded the knowledge regarding cell spraying for cartilage repair. Nozzle design and air pressure characteristics are essential parameters to consider for the clinical implementation of spray-assisted cell implantations.

The Juvenile Sex Offender.

In this article, we investigate whether the life events of marriage, parenthood, and employment were associated with general offending for a Dutch sample of 498 juvenile sex offenders (JSOs). In previous empirical studies, these life events were found to limit adult general offending in the population as well as high-risk samples. A hybrid random effects model is used to investigate within-individual changes of these life events in association with general offending. We also investigated whether the findings differed for child abusers, peer abusers, and group offenders, as they have distinct background profiles. We found that JSOs make limited transitions into the state of marriage, parenthood, and employment, showing overall stagnating participation rates. For the entire sample of JSOs, employment was found to be associated with a decrease in offending. Group offenders benefited most from employment. Marriage and parenthood were not associated with the general offending patterns, whereas for child abusers, parenthood was associated with an increase in offending. We conclude that policies aimed at guidance toward employment, or inclusion into conventional society, may be effective for JSOs.