Neuropsychological functioning after COVID-19: minor differences between individuals with and without persistent complaints after SARS-CoV-2 infection.

Objective: It is unclear how self-reported severe fatigue and difficulty concentrating after SARS-CoV-2 infection relate to objective neuropsychological functioning. The study aimed to compare neuropsychological functioning between individuals with and without these persistent subjective complaints. Method: Individuals with and without persistent severe fatigue (Checklist Individual Strength (CIS) fatigue ≥ 35) and difficulty concentrating (CIS concentration ≥ 18) at least 3 months after SARS-CoV-2 infection were included. Neuropsychological assessment was performed on overall cognitive functioning, attention, processing speed, executive functioning, memory, visuo-construction, and language (18 tests). T-scores -1.5 SD below population normative data (T ≤ 35) were classified as "impaired". Results: 230 participants were included in the study, of whom 22 were excluded from the analysis due to invalid performance. Of the participants included in the analysis, 111 reported persistent complaints of severe fatigue and difficulty concentrating and 97 did not. Median age was 54 years, 59% (n = 126) were female, and participants were assessed a median of 23 months after first infection (IQR: 16-28). With bivariate logistic regression, individuals with persistent complaints had an increased likelihood of slower information processing speed performance on the Stroop word reading (OR = 2.45, 95%CI = 1.02-5.84) compared to those without persistent complaints. Demographic or clinical covariates (e.g. hospitalization) did not influence this association. With linear regression techniques, persistent complaints were associated with lower t-scores on the D2 CP, TMT B, and TMT B|A. There were no differences in performance on the other neuropsychological tests. Conclusions: Individuals with subjective severe fatigue and difficulty concentrating after COVID-19 do not typically demonstrate cognitive impairment on extensive neuropsychological testing.

Modelling bone metastasis in spheroids to study cancer progression and screen cisplatin efficacy.

Most bone metastases are caused by primary breast or prostate cancer cells settling in the bone microenvironment, affecting normal bone physiology and function and reducing 5-year survival rates to 10% and 6%, respectively. To expedite clinical availability of novel and effective bone metastases treatments, reliable and predictive in vitro models are urgently required to screen for novel therapies as current in vitro 2D planar mono-culture models do not accurately predict the clinical efficacy. We herein engineered a novel human in vitro 3D co-culture model based on spheroids to study dynamic cellular quantities of (breast or prostate) cancer cells and human bone marrow stromal cells and screen chemotherapeutic efficacy and specificity of the common anticancer drug cisplatin. Bone metastatic spheroids (BMSs) were formed rapidly within 24 h, while the morphology of breast versus prostate cancer BMS differed in terms of size and circularity upon prolonged culture periods. Prestaining cell types prior to BMS formation enabled confocal imaging and quantitative image analysis of in-spheroid cellular dynamics for up to 7 days of BMS culture. We found that cancer cells in BMS proliferated faster and were less susceptible to cisplatin treatment compared to 2D control cultures. Based on these findings and the versatility of our methodology, BMS represent a feasible 3D in vitro model for screening of new bone cancer metastases therapies.

Biofunctionalization of dental abutments by a zinc/chitosan/gelatin coating to optimize fibroblast behavior and antibacterial properties.

Tightly sealed peri-implant gingival tissue provides a barrier against oral bacterial invasion, protecting the alveolar bone and maintaining long-term implant survival. To investigate if zinc can enhance the integration between peri-implant gingival tissue and abutment surface, we herein present novel zinc/chitosan/gelatin (Zn/CS/Gel) coatings prepared using the electrophoretic deposition (EPD) technique. The effect of these coatings on human gingival fibroblasts (hGFs) was investigated by culturing these cells on top of the EPD coatings. Surface characterization demonstrated that Zn2+ were released in a sustained and pH-responsive manner. The preclinical cell culture evaluation of these coatings indicated that the zinc-containing coatings enhanced cell migration, adhesion and collagen secretion of hGFs. Moreover, the zinc-containing coatings exhibited antibacterial efficacy by inhibiting the growth of Porphyromonas gingivalis and reducing attachment of Staphylococcus aureus. Notably, zinc-free CS/Gel coatings prevented attachment of P. gingivalis as well. The coatings were also shown to be cytocompatible with epithelial cells and osteoblasts, which are other relevant cell types which surround dental implants after clinical placement. Based on our findings, it can be concluded that Zn-containing coatings hold promise to enhance the adhesion of gingival tissue to the implant surface, which may potentially contribute to the formation of a robust peri-implant soft sealing counteracting bacterial invasion.

Biocompatible adipose extracellular matrix and reduced graphene oxide nanocomposite for tissue engineering applications.

Despite the immense need for effective treatment of spinal cord injury (SCI), no successful repair strategy has yet been clinically implemented. Multifunctional biomaterials, based on porcine adipose tissue-derived extracellular matrix (adECM) and reduced graphene oxide (rGO), were recently shown to stimulate in vitro neural stem cell growth and differentiation. Nevertheless, their functional performance in clinically more relevant in vivo conditions remains largely unknown. Before clinical application of these adECM-rGO nanocomposites can be considered, a rigorous assessment of the cytotoxicity and biocompatibility of these biomaterials is required. For instance, xenogeneic adECM scaffolds could still harbour potential immunogenicity following decellularization. In addition, the toxicity of rGO has been studied before, yet often in experimental settings that do not bear relevance to regenerative medicine. Therefore, the present study aimed to assess both the in vitro as well as in vivo safety of adECM and adECM-rGO scaffolds. First, pulmonary, renal and hepato-cytotoxicity as well as macrophage polarization studies showed that scaffolds were benign invitro. Then, a laminectomy was performed at the 10th thoracic vertebra, and scaffolds were implanted directly contacting the spinal cord. For a total duration of 6 weeks, animal welfare was not negatively affected. Histological analysis demonstrated the degradation of adECM scaffolds and subsequent tissue remodeling. Graphene-based scaffolds showed a very limited fibrous encapsulation, while rGO sheets were engulfed by foreign body giant cells. Furthermore, all scaffolds were infiltrated by macrophages, which were largely polarized towards a pro-regenerative phenotype. Lastly, organ-specific histopathology and biochemical analysis of blood did not reveal any adverse effects. In summary, both adECM and adECM-rGO implants were biocompatible upon laminectomy while establishing a pro-regenerative microenvironment, which justifies further research on their therapeutic potential for treatment of SCI.

Encapsulation of pristine and silica-coated human adipose-derived mesenchymal stem cells in gelatin colloidal hydrogels for tissue engineering and bioprinting applications.

Colloidal gels assembled from gelatin nanoparticles (GNPs) as particulate building blocks show strong promise to solve challenges in cell delivery and biofabrication, such as low cell survival and limited spatial retention. These gels offer evident advantages to facilitate cell encapsulation, but research on this topic is still limited, which hampers our understanding of the relationship between the physicochemical and biological properties of cell-laden colloidal gels. Human adipose-derived mesenchymal stem cells were successfully encapsulated in gelatin colloidal gels and evaluated their mechanical and biological performance over 7 days. The cells dispersed well within the gels without compromising gel cohesiveness, remained viable, and spread throughout the gels. Cells partially coated with silica were introduced into these gels, which increased their storage moduli and decreased their self-healing capacity after 7 days. This finding demonstrates the ability to modulate gel stiffness by incorporating cells partially coated with silica, without altering the solid content or introducing additional particles. Our work presents an efficient method for cell encapsulation while preserving gel integrity, expanding the applicability of colloidal hydrogels for tissue engineering and bioprinting. Overall, our study contributes to the design of improved cell delivery systems and biofabrication techniques.

Predictive Factors for Toxicity After Primary Chemoradiation for Locally Advanced Cervical Cancer: A Systematic Review.

PURPOSE: Women with locally advanced cervical cancer (LACC) undergoing primary platinum-based chemoradiotherapy and brachytherapy often experience toxicities. Normal-tissue complication probability (NTCP) models quantify toxicity risk and aid in optimizing radiation therapy to minimize side effects. However, it is unclear which predictors to include in an NTCP model. The aim of this systematic review was to provide an overview of the identified predictors contributing to gastrointestinal (GI), genitourinary (GU), and vaginal toxicities and insufficiency fractures for LACC. METHODS AND MATERIALS: A systematic search was performed and articles evaluating the relationship between predictors and toxicities in women with LACC treated with primary chemoradiation were included. The Quality In Prognosis Studies tool was used to assess risk of bias, with high-risk studies being excluded from further analysis. Relationships between dose-volume parameters, patient and treatment characteristics, and toxicity endpoints were analyzed. RESULTS: Seventy-three studies were identified. Twenty-six had a low or moderate risk of bias and were therefore included. Brachytherapy-related dose-volume parameters of the GI tract, including rectum and bowel equivalent dose in 2 Gy fractions (EQD2) D2 cm3, were frequently related to toxicities, unlike GU dose-volume parameters. Furthermore, (recto)vaginal point doses predicted toxicities. Few studies evaluated external beam radiation therapy dose-volume parameters and identified rectum EQD2 V30 Gy, V40 Gy, and V55 Gy, bowel and bladder EQD2 V40 Gy as toxicity predictors. Also, total reference air kerma and vaginal reference length were associated with toxicities. Relationships between patient characteristics and GI toxicity were inconsistent. The extent of vaginal involvement at diagnosis, baseline symptoms, and obesity predicted GU or vaginal toxicities. Only 1 study evaluated insufficiency fractures and demonstrated lower pretreatment bone densities to be associated. CONCLUSIONS: This review detected multiple candidate predictors of toxicity. Larger studies should consider insufficiency fractures, assess dose levels from external beam radiation therapy, and quantify the relationship between the predictors and treatment-related toxicities in women with LACC to further facilitate NTCP model development for clinical use.

The Effects of a Digital, Transdiagnostic, Clinically and Peer-Moderated Treatment Platform for Young People With Emerging Mental Health Complaints: Repeated Measures Within-Subjects Study.

BACKGROUND: To address the growing prevalence of youth mental health problems, early intervention is crucial to minimize individual, societal, and economic impacts. Indicative prevention aims to target emerging mental health complaints before the onset of a full-blown disorder. When intervening at this early stage, individuals are more responsive to treatment, resulting in cost-effective outcomes. The Moderated Online Social Therapy platform, which was successfully implemented and proven effective in Australia, is a digital, peer- and clinically moderated treatment platform designed for young people. The Netherlands was the first country outside Australia to implement this platform, under the name Engage Young People Early (ENYOY). It has the potential to reduce the likelihood of young people developing serious mental health disorders. OBJECTIVE: This study aims to investigate the effects on young people using the ENYOY-platform in relation to psychological distress, psychosocial functioning, and positive health parameters. METHODS: Dutch-speaking young people with emerging mental health complaints (N=131) participated in the ENYOY-platform for 6 months in a repeated measures within-subjects study. Psychological distress, psychosocial functioning, and positive health parameters were assessed at baseline and 3, 6, and 12 months. Repeated measures ANOVA was conducted and adjusted for age, sex, therapy, and community activity. The Reliable Change Index and Clinically Significant Index were computed to compare the baseline with the 6- and 12-month measurements. The missing data rate was 22.54% and the dropout rate 62.6% (82/131). RESULTS: The primary analysis (77/131, 58.8%) showed that psychological distress decreased and psychosocial functioning improved over time with large effect sizes (P<.001 in both cases; ηp2=0.239 and 0.318, respectively) independent of age (P=.76 for psychological distress and P=.48 for psychosocial functioning), sex (P=.24 and P=.88, respectively), therapy activity (P=.49 and P=.80, respectively), or community activity (P=.59 and P=.48, respectively). Similarly, secondary analyses (51/131, 38.9%) showed significant effects of time on the quality of life, well-being, and meaningfulness positive health parameters (P<.05; ηp2=0.062, 0.140, and 0.121, respectively). Improvements in all outcome measures were found between baseline and 3 and 6 months (P≤.001-.01; d=0.23-0.62) and sustained at follow-up (P=.18-.97; d=0.01-0.16). The Reliable Change Index indicated psychological distress improvements in 38% (39/102) of cases, no change in 54.9% (56/102) of cases, and worsening in 5.9% (6/102) of cases. Regarding psychosocial functioning, the percentages were 50% (51/102), 43.1% (44/102), and 6.9% (7/102), respectively. The Clinically Significant Index demonstrated clinically significant changes in 75.5% (77/102) of cases for distress and 89.2% (91/102) for functioning. CONCLUSIONS: This trial demonstrated that the ENYOY-platform holds promise as a transdiagnostic intervention for addressing emerging mental health complaints among young people in the Netherlands and laid the groundwork for further clinical research. It would be of great relevance to expand the population on and service delivery of the platform. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12888-021-03315-x.

Prophylactic Medication during Radioembolization in Metastatic Liver Disease: Is It Really Necessary? A Retrospective Cohort Study and Systematic Review of the Literature.

PURPOSE: Trans-arterial radioembolization is a well-studied tumoricidal treatment for liver malignancies; however, consensus and evidence regarding periprocedural prophylactic medication (PPM) are lacking. METHODS: A single-center retrospective analysis from 2014 to 2020 was performed in patients treated with 90Y-glass microspheres for neuroendocrine or colorectal liver metastases. Inclusion criteria were the availability of at least 3 months of clinical, biochemical, and imaging follow-up and post-treatment 90Y-PET/CT imaging for the determination of the whole non-tumorous liver absorbed dose (Dh). Logistic regression models were used to investigate if variables (among which are P/UDCA and Dh) were associated with either clinical toxicity, biochemical toxicity, or hepatotoxicity. Additionally, a structured literature search was performed in November 2022 to identify all publications related to PPM use in radioembolization treatments. RESULTS: Fifty-one patients received P/UDCA as post-treatment medication, while 19 did not. No correlation was found between toxicity and P/UDCA use. Dh was associated with biochemical toxicity (p = 0.05). A literature review resulted in eight relevant articles, including a total of 534 patients, in which no consistent advice regarding PPM was provided. CONCLUSION: In this single-center, retrospective review, P/UDCA use did not reduce liver toxicity in patients with metastatic liver disease. The whole non-tumorous liver-absorbed dose was the only significant factor for hepatotoxicity. No standardized international guidelines or supporting evidence exist for PPM in radioembolization.

Eye Size and Shape in Relation to Refractive Error in Children: A Magnetic Resonance Imaging Study.

Purpose: The purpose of this study was to determine the association between eye shape and volume measured with magnetic resonance imaging (MRI) and optical biometry and with spherical equivalent (SE) in children. Methods: For this study, there were 3637 10-year-old children from a population-based birth-cohort study that underwent optical biometry (IOL-master 500) and T2-weighted MRI scanning (height, width, and volume). Cycloplegic refractive error was determined by automated refraction. The MRI images of the eyes were segmented using an automated algorithm combining atlas registration with voxel classification. Associations among optical biometry, anthropometry, MRI measurements, and RE were tested using Pearson correlation. Differences between refractive error groups were tested using ANOVA. Results: The mean volume of the posterior segment was 6350 (±680) mm3. Myopic eyes (SE ≤ -0.5 diopters [D]) had 470 mm3 (P < 0.001) and 970 mm3 (P < 0.001) larger posterior segment volume than emmetropic and hyperopic eyes (SE ≥ +2.0D), respectively. The majority of eyes (77.1%) had an oblate shape, but 47.4% of myopic eyes had a prolate shape versus 3.9% of hyperopic eyes. The correlation between SE and MRI-derived posterior segment length (r -0.51, P < 0.001) was stronger than the correlation with height (r -0.30, P < 0.001) or width of the eye (r -0.10, P < 0.001). Conclusions: In this study, eye shape at 10 years of age was predominantly oblate, even in eyes with myopia. Of all MRI measurements, posterior segment length was most prominently associated with SE. Whether eye shape predicts future myopia development or progression should be investigated in longitudinal studies.

Unraveling the Formation of Gelatin Nanospheres by Means of Desolvation.

Gelatin nanoparticles (GNPs) have been widely studied for a plethora of biomedical applications, but their formation mechanism remains poorly understood, which precludes precise control over their physicochemical properties. This leads to time-consuming parameter adjustments without a fundamental grasp of the underlying mechanism. Here, we analyze and visualize in a time-resolved manner the mechanism by which GNPs are formed during desolvation of gelatin as a function of gelatin molecular weight and type of desolvating agent. Through various analytical and imaging techniques, we unveil a multistage process that is initiated by the formation of primary particles that are ∼18 nm in diameter (wet state). These primary particles subsequently assemble into colloidally stable GNPs with a raspberry-like structure and a hydrodynamic diameter of ∼300 nm. Our results create a basic understanding of the formation mechanism of gelatin nanoparticles, which opens new opportunities for precisely tuning their physicochemical and biofunctional properties.

Time Spent Outdoors Partly Accounts for the Effect of Education on Myopia.

Purpose: The purpose of this study was to investigate if education contributes to the risk of myopia because educational activities typically occur indoors or because of other factors, such as prolonged near viewing. Methods: This was a two-sample Mendelian randomization study. Participants were from the UK Biobank, Avon Longitudinal Study of Parents and Children, and Generation R. Genetic variants associated with years spent in education or time spent outdoors were used as instrumental variables. The main outcome measures were: (1) spherical equivalent refractive error attained by adulthood, and (2) risk of an early age-of-onset of spectacle wear (EAOSW), defined as an age-of-onset of 15 years or below. Results: Time spent outdoors was found to have a small genetic component (heritability 9.8%) that tracked from childhood to adulthood. A polygenic score for time outdoors was associated with children's time outdoors; a polygenic score for years spent in education was inversely associated with children's time outdoors. Accounting for the relationship between time spent outdoors and myopia in a multivariable Mendelian randomization analysis reduced the size of the causal effect of more years in education on myopia to -0.17 diopters (D) per additional year of formal education (95% confidence interval [CI] = -0.32 to -0.01) compared with the estimate from a univariable Mendelian randomization analysis of -0.27 D per year (95% CI = -0.41 to -0.13). Comparable results were obtained for the outcome EAOSW. Conclusions: Accounting for the effects of time outdoors reduced the estimated causal effect of education on myopia by 40%. These results suggest about half of the relationship between education and myopia may be mediated by children not being outdoors during schooling.

Performance of a [18F]Flortaucipir PET Visual Read Method Across the Alzheimer Disease Continuum and in Dementia With Lewy Bodies.

BACKGROUND AND OBJECTIVES: Recently, the US Food and Drug Administration approved the tau-binding radiotracer [18F]flortaucipir and an accompanying visual read method to support the diagnostic process in cognitively impaired patients assessed for Alzheimer disease (AD). Studies evaluating this visual read method are limited. In this study, we evaluated the performance of the visual read method in participants along the AD continuum and dementia with Lewy bodies (DLB) by determining its reliability, accordance with semiquantitative analyses, and associations with clinically relevant variables. METHODS: We included participants who underwent tau-PET at Amsterdam University Medical Center. A subset underwent follow-up tau-PET. Two trained nuclear medicine physicians visually assessed all scans. Inter-reader agreement was calculated using Cohen κ. To examine the concordance of visual read tau positivity with semiquantification, we defined standardized uptake value ratio (SUVr) positivity using different threshold approaches. To evaluate the prognostic value of tau-PET visual read, we performed linear mixed models with longitudinal Mini-Mental State Examination (MMSE). RESULTS: We included 263 participants (mean age 68.5 years, 45.6% female), including 147 cognitively unimpaired (CU) participants, 97 amyloid-positive participants with mild cognitive impairment or AD dementia (AD), and 19 participants with DLB. The visual read inter-reader agreement was excellent (κ = 0.95, CI 0.91-0.99). None of the amyloid-negative CU participants (0/92 [0%]) and 1 amyloid-negative participant with DLB (1/12 [8.3%]) were tau-positive. Among amyloid-positive participants, 13 CU participants (13/52 [25.0%]), 85 with AD (85/97 [87.6%]), and 3 with DLB (3/7 [42.9%]) were tau-positive. Two-year follow-up visual read status was identical to baseline. Tau-PET visual read corresponded strongly to SUVr status, with up to 90.4% concordance. Visual read tau positivity was associated with a decline on the MMSE in CU participants (ß = -0.52, CI -0.74 to -0.30, p < 0.001) and participants with AD (ß = -0.30, CI -0.58 to -0.02, p = 0.04). DISCUSSION: The excellent inter-reader agreement, strong correspondence with SUVr, and longitudinal stability indicate that the visual read method is reliable and robust, supporting clinical application. Furthermore, visual read tau positivity was associated with prospective cognitive decline, highlighting its additional prognostic potential. Future studies in unselected cohorts are needed for a better generalizability to the clinical population. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that [18F]flortaucipir visual read accurately distinguishes patients with low tau-tracer binding from those with high tau-tracer binding and is associated with amyloid positivity and cognitive decline.

Do values and political attitudes affect help-seeking? Exploring reported help-seeking for mental health problems in a general population sample using a milieu framework.

AIMS: Help-seeking for mental health problems is facilitated and hindered by several factors at the individual, interpersonal and community level. The most frequently researched factors contributing to differences in help-seeking behaviour are based on classical socio-demographic variables, such as age, gender and education, but explanations for the observed differences are often absent or remain vague. The present study complements traditional approaches in help-seeking research by introducing a milieu approach, focusing on values and political attitudes as a possible explanation for differences in help-seeking for emotional mental health problems. METHODS: A representative cross-sectional survey of N = 3,042 respondents in Germany was conducted through face-to-face interviews about past help-seeking for mental health problems, socio-demographic characteristics and values and political attitudes. RESULTS: Multivariate logistic regression analyses indicated that belonging to a cosmopolitan intellectual milieu group was significantly associated with an increased likelihood of past help-seeking for mental health issues (psychotherapeutic/psychological help-seeking [OR = 2.09, 95% CI: 1.11-3.93, p < 0.05) and primary care (OR = 2.21, 95% CI: 1.15-4.24, p < 0.05]), whereas members of individualist and conservative milieu groups were less likely to report having sought help from a psychotherapist, but not from a general practitioner. Increased odds ratios were also found for a number of socio-demographic variables, such as being aged 26 years and over, a female gender and more than 12 years of formal education. Associations between socio-demographic variables remained significant, and the explained variance of the used models improved considerably when milieu variables were added. CONCLUSIONS: We discuss how milieu-specific patterns were relevant for explaining differences in mental health service use in addition to socio-demographic factors. It seems promising to consider help-seeking from a milieu perspective to improve disparities in access to and the use of psychotherapy as well as to resource allocation.

Altered brain metabolism in frontotemporal dementia and psychiatric disorders: involvement of the anterior cingulate cortex.

BACKGROUND: Behavioural symptoms and frontotemporal hypometabolism overlap between behavioural variant of frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD), hampering diagnostic distinction. Voxel-wise comparisons of brain metabolism might identify specific frontotemporal-(hypo)metabolic regions between bvFTD and PPD. We investigated brain metabolism in bvFTD and PPD and its relationship with behavioural symptoms, social cognition, severity of depressive symptoms and cognitive functioning. RESULTS: Compared to controls, bvFTD showed decreased metabolism in the dorsal anterior cingulate cortex (dACC) (p < 0.001), orbitofrontal cortex (OFC), temporal pole, dorsolateral prefrontal cortex (dlPFC) and caudate, whereas PPD showed no hypometabolism. Compared to PPD, bvFTD showed decreased metabolism in the dACC (p < 0.001, p < 0.05FWE), insula, Broca's area, caudate, thalamus, OFC and temporal cortex (p < 0.001), whereas PPD showed decreased metabolism in the motor cortex (p < 0.001). Across bvFTD and PPD, decreased metabolism in the temporal cortex (p < 0.001, p < 0.05FWE), dACC and frontal cortex was associated with worse social cognition. Decreased metabolism in the dlPFC was associated with compulsiveness (p < 0.001). Across bvFTD, PPD and controls, decreased metabolism in the PFC and motor cortex was associated with executive dysfunctioning (p < 0.001). CONCLUSIONS: Our findings indicate subtle but distinct metabolic patterns in bvFTD and PPD, most strongly in the dACC. The degree of frontotemporal and cingulate hypometabolism was related to impaired social cognition, compulsiveness and executive dysfunctioning. Our findings suggest that the dACC might be an important region to differentiate between bvFTD and PPD but needs further validation.

Neurobiological basis and risk factors of persistent fatigue and concentration problems after COVID-19: study protocol for a prospective case-control study (VeCosCO).

INTRODUCTION: The risk factors for persistent fatigue and cognitive complaints after infection with SARS-CoV-2 and the underlying pathophysiology are largely unknown. Both clinical factors and cognitive-behavioural factors have been suggested to play a role in the perpetuation of complaints. A neurobiological aetiology, such as neuroinflammation, could be the underlying pathophysiological mechanism for persisting complaints.To unravel factors associated with persisting complaints, VeCosCO will compare individuals with and without persistent fatigue and cognitive complaints >3 months after infection with SARS-CoV-2. The study consists of two work packages. The first work package aims to (1) investigate the relation between persisting complaints and neuropsychological functioning; (2) determine risk factors and at-risk phenotypes for the development of persistent fatigue and cognitive complaints, including the presence of postexertional malaise and (3) describe consequences of persistent complaints on quality of life, healthcare consumption and physical functioning. The second work package aims to (1) determine the presence of neuroinflammation with [18F]DPA-714 whole-body positron emission tomography (PET) scans in patients with persisting complaints and (2) explore the relationship between (neuro)inflammation and brain structure and functioning measured with MRI. METHODS AND ANALYSIS: This is a prospective case-control study in participants with and without persistent fatigue and cognitive complaints, >3 months after laboratory-confirmed SARS-CoV-2 infection. Participants will be mainly included from existing COVID-19 cohorts in the Netherlands covering the full spectrum of COVID-19 acute disease severity. Primary outcomes are neuropsychological functioning, postexertional malaise, neuroinflammation measured using [18F]DPA-714 PET, and brain functioning and structure using (f)MRI. ETHICS AND DISSEMINATION: Work package 1 (NL79575.018.21) and 2 (NL77033.029.21) were approved by the medical ethical review board of the Amsterdam University Medical Centers (The Netherlands). Informed consent is required prior to participation in the study. Results of this study will be submitted for publication in peer-reviewed journals and shared with the key population.

A Modular Platform for Cytocompatible Hydrogels with Tailored Mechanical Properties Based on Monolithic Matrices and Particulate Building Blocks.

We establish a versatile hydrogel platform based on modular building blocks that allows the design of hydrogels with tailored physical architecture and mechanical properties. We demonstrate its versatility by assembling (i) a fully monolithic gelatin methacryloyl (Gel-MA) hydrogel, (ii) a hybrid hydrogel composed of 1:1 Gel-MA and gelatin nanoparticles, and (iii) a fully particulate hydrogel based on methacryloyl-modified gelatin nanoparticles. The hydrogels were formulated to exhibit the same solid content and comparable storage modulus but different stiffness and viscoelastic stress relaxation. The incorporation of particles resulted in softer hydrogels with enhanced stress relaxation. Murine osteoblastic cells cultured in two-dimensional (2D) on hydrogels showed proliferation and metabolic activity comparable to established collagen hydrogels. Furthermore, the osteoblastic cells showed a trend of increased cell numbers, cell expansion, and more defined protrusions on stiffer hydrogels. Hence, modular assembly allows the design of hydrogels with tailored mechanical properties and the potential to alter cell behavior.

A cross-sectional study on gaming intensity and social vulnerability in adolescents that have a chronic condition.

Background: Adolescents growing up with a chronic condition might experience more social vulnerabilities compared to their healthy peers as an indirect result of their conditions. This can lead to a relatedness need frustration for these adolescents. Consequently, they might spend more time playing video games compared to their peers. Research shows that both social vulnerability and gaming intensity are predictors for problematic gaming. Therefore, we investigated if social vulnerability and gaming intensity are more pronounced in adolescents that have a chronic condition compared to the general population; and if these levels reflect the levels of a clinical group being treated for Internet Gaming Disorder (IGD). Methods: Data on peer problems and gaming intensity were compared from three separate samples: a national representative sample of adolescents, a clinical sample of adolescents that are undergoing treatment for IGD, and a sample of adolescents diagnosed with a chronic condition. Results: No differences were found on either peer problems or gaming intensity between the group of adolescents that have chronic conditions and the national representative group. The group with chronic conditions scored significantly lower on gaming intensity than the clinical group. No significant differences were found between these groups on peer problems. We repeated the analyses for boys only. Similar results were found for the group with chronic conditions compared to the national representative group. The group with chronic conditions now scored significantly lower on both peer problems and gaming intensity than the clinical group. Conclusion: Adolescents growing up with a chronic condition appear similar in their gaming intensity and peer problems compared to their healthy peers.

Bone adhesive materials: From bench to bedside.

Biodegradable bone adhesives represent a highly sought-after type of biomaterial which would enable replacement of traditional metallic devices for fixation of bone. However, these biomaterials should fulfil an extremely large number of requirements. As a consequence, bone-adhesive biomaterials which meet all of these requirements are not yet commercially available. Therefore, this comprehensive review provides an extensive overview of the development of bone adhesives from a translational perspective. First, the definition, classification, and chemistry of various types of bone adhesives are highlighted to provide a detailed overview of this emerging class of biomaterials. In this review we particularly focused studies which describe the use of materials that are capable of gluing two pieces of bone together within a time frame of minutes to days. Second, this review critically reflects on i) the experimental conditions of commonly employed adhesion tests to assess bone adhesion and ii) the current state-of-the-art regarding their preclinical and clinical applicability.

Cellular Uptake of Modified Mesoporous Bioactive Glass Nanoparticles for Effective Intracellular Delivery of Therapeutic Agents.

Introduction: There has recently been a surge of interest in mesoporous bioactive glass nanoparticles (MBGNs) as multi-functional nanocarriers for application in bone-reconstructive and -regenerative surgery. Their excellent control over their structural and physicochemical properties renders these nanoparticles suitable for the intracellular delivery of therapeutic agents to combat degenerative bone diseases, such as bone infection, or bone cancer. Generally, the therapeutic efficacy of nanocarriers strongly depends on the efficacy of their cellular uptake, which is determined by numerous factors including cellular features and the physicochemical characteristics of nanocarriers, particularly surface charge. In this study, we have systematically investigated the effect of the surface charge of MBGNs doped with copper as a model therapeutic agent on cellular uptake by both macrophages and pre-osteoblast cells involved in bone healing and bone infections to guide the future design of MBGN-based nanocarriers. Methods: Cu-MBGNs with negative, neutral, and positive surface charges were synthesized and their cellular uptake efficiency was assessed. Additionally, the intracellular fate of internalized nanoparticles along with their ability to deliver therapeutic cargo was studied in detail. Results: The results showed that both cell types internalized Cu-MBGNs regardless of their surface charge, indicating that cellular uptake of nanoparticles is a complex process influenced by multiple factors. This similarity in cellular uptake was attributed to the formation of a protein corona surrounding the nanoparticles when exposed to protein-rich biological media, which masks the original nanoparticle surface. Once internalized, the nanoparticles were found to mainly colocalize with lysosomes, exposing them to a more compartmentalized and acidic environment. Furthermore, we verified that Cu-MBGNs released their ionic components (Si, Ca, and Cu ions) in both acidic and neutral environments, leading to the delivery of these therapeutic cargos intracellularly. Conclusion: The effective internalization of Cu-MBGNs and their ability to deliver cargos intracellularly highlight their potential as intracellular delivery nanocarriers for bone-regenerative and -healing applications.