Bone is the second most transplanted tissue in the world, resulting in increased demand for bone grafts leading to the fabrication of synthetic scaffold grafting alternatives. Fracture sites are ...under increased oxidative stress after injuries, affecting osteoblast function and hindering fracture healing and remodeling. To counter oxidative stress, free radical scavenging agents, such as cerium oxide nanoparticles, have gained traction in tissue engineering. Toward the goal of developing a functional synthetic system for bone tissue engineering, we characterized the biocompatibility of a porous, bioactive, free radical scavenging nanocomposite scaffold composed of poly(1,8 octanediol‐co‐citrate), beta‐tricalcium phosphate, and cerium oxide nanoparticles. We studied cellular and tissue compatibility utilizing in vitro and in vivo models to assess nanocomposite interactions with both human osteoblast cells and rat subcutaneous tissue. We found the scaffolds were biocompatible in both models and supported cell attachment, proliferation, mineralization, and infiltration. Using hydrogen peroxide, we simulated oxidative stress to study the protective properties of the nanocomposite scaffolds via a reduction in cytotoxicity and recovered mineralization of osteoblast cells in vitro. We also found after implantation in vivo the scaffolds exhibited biocompatible properties essential for successful scaffolds for bone tissue engineering. Cells were able to infiltrate through the scaffolds, the surrounding tissues elicited a minimal immune response, and there were signs of scaffold degradation after 30 days of implantation. After the array of biological characterization, we had confirmed the development of a nanocomposite scaffold system capable of supporting bone‐remodeling processes while providing a protective free radical scavenging effect.
•This co-produced study explores how young people experience and conceptualise ‘feeling (mis)understood’ by adults.•Feeling understood by adults has a positive impact on young people’s mental health ...and help-seeking.•When young people feel misunderstood by health and social care professionals, it can negatively impact help-seeking.•Health and social care professionals should help young people to feel understood in to support engagement.
The subjective and emotional experience of feeling (mis)understood by another person is distinct from being literally (mis)understood. While there is literature exploring young people’s experiences of feeling (mis)understood in therapeutic or clinical settings by adults and the impacts thereof, there is limited exploration of young people’s conceptualisations and perspectives of feeling (mis)understood within a range of young person-supporting adult relationships. This paper reports on the first stage of a project that was co-designed and co-produced by young people, exploring how young people experience and conceptualise ‘feeling (mis)understood’ in the context of receiving support from adults in their lives. This initial stage of the project captures young people’s views on what feeling (mis)understood feels like, its impact on their mental health, and how adults can help young people to feel understood. Conceptualisation, design, fieldwork, analysis and writing were all co-produced with peer-researchers. Data for this project was generated through four workshops each held in England, Scotland, Wales and Northern Ireland. A total of 26 participants aged between 16 and 24 years of age took part in these workshops, and each workshop was facilitated by two peer-researchers and a member of university staff. Data was analysed through collaborative thematic analysis. The study found that feeling understood by supporting adults has a very positive impact on young people’s wellbeing, mental health and help-seeking behaviour. Feeling misunderstood was found to have the converse effect, and in addition was found to make young people less likely to seek further support. Young people also identified a number of key actions adults can take to help the young people they support feel better understood. The findings of this research suggest that practitioners in the health and social care sector working with young people should consider the ways in which they can help young people feel better understood.
Neurosurgery can be a daunting career choice for medical students, with preparation for trainee application often being inaccessible and expensive. This article describes a student-led neurosurgical ...skills event supported by local neurosurgery faculty members. Such event was designed to offer a means to bridge this gap by providing an opportunity to practice neurosurgical techniques in simulation, and learn about what a career in neurosurgery involves.
Pre- and postskills laboratory surveys were used to ascertain the baseline confidence and knowledge of common neurosurgical techniques, as well as to what both the application to neurosurgery and the typical workload of a neurosurgeon involves. The conference offered six neurosurgical workshops as well as three lectures to provide practical and theoretical learning opportunities. The session included introduction to the candidates and faculty, identification of learning objectives, and career discussion. Postcourse feedback also was also used to assess learning outcomes.
Eighteen students attended the event. Postskills event, students were significantly more likely to understand the principles behind all of the relevant neurosurgical skills included on the day. Additionally, students were more likely to understand what a career in neurosurgery involves, and how to approach applying for a training number. Respondents enjoyed the workshops, valued hands-on experience and interactions with consultants, found it affordable, and would recommend to their peers.
For medical students interested in a career in neurosurgery, opportunities to learn relevant techniques and skills are often expensive and difficult to come across. Here, we highlight affordable methods of simulation to result in significant student satisfaction. Additionally, providing ample opportunity to practice different neurosurgical techniques under almost 1:1 level tutoring enables significant increases in students' confidence and understanding of different neurosurgical concepts. We greatly encourage other medical student groups to develop their own hands-on simulation events to attract medical students to a surgical field often considered daunting and inaccessible, and address gaps in the medical school curriculum.
Osteogenic factors, such as osteoprotegerin (OPG), are protective against vascular calcification. However, OPG is also positively associated with cardiovascular damage, particularly in pulmonary ...hypertension, possibly through processes beyond effects on calcification. In the present study, we focused on calcification-independent vascular effects of OPG through activation of syndecan-1 and NADPH oxidases (Noxs) 1 and 4. Isolated resistance arteries from Wistar-Kyoto (WKY) rats, exposed to exogenous OPG, studied by myography exhibited endothelial and smooth muscle dysfunction. OPG decreased nitric oxide (NO) production, eNOS activation and increased reactive oxygen species (ROS) production in endothelial cells. In VSMCs, OPG increased ROS production, H2O2/peroxynitrite levels and activation of Rho kinase and myosin light chain. OPG vascular and redox effects were also inhibited by the syndecan-1 inhibitor synstatin (SSNT). Additionally, heparinase and chondroitinase abolished OPG effects on VSMCs-ROS production, confirming syndecan-1 as OPG molecular partner and suggesting that OPG binds to heparan/chondroitin sulphate chains of syndecan-1. OPG-induced ROS production was abrogated by NoxA1ds (Nox1 inhibitor) and GKT137831 (dual Nox1/Nox4 inhibitor). Tempol (SOD mimetic) inhibited vascular dysfunction induced by OPG. In addition, we studied arteries from Nox1 and Nox4 knockout (KO) mice. Nox1 and Nox4 KO abrogated OPG-induced vascular dysfunction. Vascular dysfunction elicited by OPG is mediated by a complex signalling cascade involving syndecan-1, Nox1 and Nox4. Our data identify novel molecular mechanisms beyond calcification for OPG, which may underlie vascular injurious effects of osteogenic factors in conditions such as hypertension and/or diabetes.
Families do not fully disengage from care responsibilities following relatives' admissions to residential long-term (RLTC) care settings such as nursing homes. Caregiver stress, depression, or other ...key outcomes remain stable or sometimes increase following a relative's RLTC entry. Some interventions have attempted to increase family involvement after institutionalization, but few rigorous studies have demonstrated whether these interventions are effective in helping families navigate the potential emotional and psychological upheaval presented by relatives' transitions to RLTC environments. The Residential Care Transition Module (RCTM) provides six formal sessions of consultation (one-to-one and family sessions) over a 4-month period to family caregivers who have admitted a relative to a RLTC setting.
In this embedded mixed methods randomized controlled evaluation, family members who have admitted a cognitively impaired relative to a RLTC setting are randomly assigned to the RCTM (n = 120) or a usual care control condition (n = 120). Primary outcomes include reductions in family members' primary subjective stress and negative mental health outcomes; secondary role strains; and residential care stress. The mixed methods design will allow for an analysis of intervention action mechanisms by "embedding" qualitative components (up to 30 semi-structured interviews) at the conclusion of the 12-month evaluation.
This evaluation will fill an important clinical and research gap by evaluating a psychosocial intervention designed for families following RLTC admission that determines whether and how the RCTM can help families better navigate the emotional and psychological challenges of residential care transitions.
ClinicalTrials.gov (NCT02915939, prospectively registered).
The purpose of this study was to evaluate the efficacy of the Residential Care Transition Module, a six-session, psychosocial, and psychoeducational telehealth intervention for family caregivers of ...cognitively impaired relatives living in a residential long-term care setting. Eligible participants (including care recipients, regardless of time since admission) were randomized to treatment or usual care control conditions. Survey data were collected at baseline, 4 months, 8 months, and 12 months (N = 240). Primary analytic outcomes included caregiver subjective stress (a stress process mechanism) and depressive symptoms (a measure of global well-being). Secondary analytic outcomes included secondary role strains, residential care stress, caregiver sense of competence, and self-efficacy (additional mechanisms of action). General linear models tested for the main effects of the intervention at 4 months, and longitudinal mixed models examined the 12-month effects of the intervention. Post hoc analyses also examined the influence of moderators. No significant differences between the treatment and control groups for any primary analytic outcome were apparent. Caregivers in the treatment group whose relatives were admitted to residential long-term care in the prior 3 months were more likely to indicate reductions in depressive symptoms over the first 4 months of participation. Over the 12-month study period, caregivers in the treatment group who were employed reported increased self-efficacy over time. The heterogeneity of dementia care requires a broader consideration of key contextual factors that may influence the efficacy of nonpharmacological interventions. Aligning measures with the preferences, goals, and values of dementia caregivers may further demonstrate the direct benefits of interventions such as the Residential Care Transition Module.
Public Significance Statement
Family members of cognitively impaired relatives may experience distress following a relative's admission to a residential long-term care setting. The goal of this study was to evaluate the efficacy of the Residential Care Transition Module, a support program for family caregivers of relatives with dementia living in residential long-term care. Although the findings did not indicate direct benefits, several contextual factors suggested for whom and when the Residential Care Transition Module may prove helpful.
Stimulus-related γ-band oscillations, which may be related to perceptual binding, are reduced in people with autism spectrum disorders (ASD). The purpose of this study was to examine auditory ...transient and steady-state γ-band findings in first-degree relatives of people with ASD to assess the potential familiality of these findings in ASD.
Magnetoencephalography (MEG) recordings in 21 parents who had a child with an autism spectrum disorder (pASD) and 20 healthy adult control subjects (HC) were obtained. Gamma-band phase locking factor (PLF), and evoked and induced power to 32, 40 and 48 Hz amplitude-modulated sounds were measured for transient and steady-state responses. Participants were also tested on a number of behavioral and cognitive assessments related to the broad autism phenotype (BAP).
Reliable group differences were seen primarily for steady-state responses. In the left hemisphere, pASD subjects exhibited lower phase-locked steady-state power in all three conditions. Total γ-band power, including the non-phase-locked component, was also reduced in the pASD group. In addition, pASD subjects had significantly lower PLF than the HC group. Correlations were seen between MEG measures and BAP measures.
The reduction in steady-state γ-band responses in the pASD group is consistent with previous results for children with ASD. Steady-state responses may be more sensitive than transient responses to phase-locking errors in ASD. Together with the lower PLF and phase-locked power in first-degree relatives, correlations between γ-band measures and behavioral measures relevant to the BAP highlight the potential of γ-band deficits as a potential new autism endophenotype.
Objective: We demonstrated that the MAS and ETB receptors physically interact and may be involved in the protective actions of Ang(1–7) in endothelial cells (ECs). We assessed the biological role of ...MAS/ETBR interaction in the vasculature, focusing on the NO pathway. Design and method: Human ECs were stimulated with Ang(1–7) (10-7 M) in the presence/absence of A779 (MAS antagonist, 10-5 M), BQ788 (ETBR antagonist, 10-5 M) and MAS/ETBR peptide disruptor (10-5 M). ETBR expression and AKT/eNOS activation were evaluated by immunoblotting and NO production by DAF-FM fluorescence. Results: Ang(1–7) increased ETBR expression (50%), an effect blocked by A779 (p < 0.05 vs control). Ang(1–7) also induced AKT (40%) and eNOS (35%) activation; followed by an increase in NO production (2 fold) (p < 0.05 vs control). These effects were inhibited by A779, BQ788 and the MAS/ETBR disruptor. In a high throughput screening of a 20K protein:protein interaction modulator library, we discovered 23 potential enhancers of the MAS/ETBR interaction, where we tested 4 in ECs (Enh1–4: 10–5 M). All four MAS/ETBR enhancers increased eNOS activation with variable responses (Enh1: 44.2%; Enh2: 65.4%; Enh3: 80.7%; Enh4: 94.9% vs control, p < 0.05), but only treatment with Enh1 and Enh2 increased NO production (Enh1: 109.4%; Enh2: 46.5% vs control, p < 0.05) in ECs. Mesenteric resistance arteries were pre-incubated with Enh1–4 for 30 minutes prior to acetylcholine (Ach) curves, to assess endothelium-dependent relaxation. Enh1 decreased ACh-induced relaxation (Emax: 52.8 ± 2.9 vs Emax control: 70.4 ± 3.3), while Enh4 increased ACh-induced relaxation (Emax: 96.7 ± 4.6 vs Emax control: 70.4 ± 3.3), p < 0.05. Conclusions: Promoting the MAS/ETBR interaction with specific enhancers leads to eNOS activation and vasorelaxation, where Enh1–4 have variable effects. Current studies are focusing on identifying the most sensitive enhancer that will provide vasoprotection, and potentially new strategies in the treatment of vascular disease.
Abstract only Mas and ET B receptors physically interact in endothelial cells (ECs) and are involved in the protective actions of angiotensin 1-7 (Ang (1-7)). We assessed whether the MAS/ET B R ...interaction plays a role in EC signalling and whether strategies to enhance MAS/ET B R association influence vascular responses. Human ECs were stimulated with Ang (1-7) (10 -7 M) in the presence/absence of A779 (Mas receptor antagonist, 10 -5 M) and BQ788 (ET B R antagonist, 10 -5 M). Protein expression and signalling activation were assessed by immunoblotting. NO production was evaluated by DAF-FM fluorescence and ROS production by chemiluminescence (superoxide anion) or amplex red (hydrogen peroxide (H 2 O 2 )). mRNA expression was assessed by qPCR. Endothelial function was assessed in mouse intact arteries by myography. Ang (1-7), through Mas and ET B R induced phosphorylation of eNOS (35%); followed by an increase in NO production (2.0 fold) (p<0.05 vs ctl). High throughput screening of protein:protein interaction compounds in an in-house library identified 23 potential enhancers of the MAS/ET B R interaction. Fluorescence polarization assays were used to further select the most potent enhancers and define their working concentration for testing in ECs (Enh1-4: 10 -5 M). Enh4 increased superoxide anion (55.6±26.3% vs ctl, p<0.05) and H 2 O 2 production (54.7±11.1% vs ctl, p<0.05), while Enh3 increased H 2 O 2 generation (48.1±15.4% vs ctl, p<0.05) in ECs. Moreover, Enh4 increased Nrf2 (3.0 fold), Sod1 (2.0 fold) and Nqo1 (3.1 fold) mRNA expression (p<0.05 vs ctl). Enh3 and Enh4 increased NO production (Enh3: 21.2±7.4%; Enh4: 23.6±8.2% vs veh, p<0.05) in ECs. Acetylcholine (Ach) curves were performed to assess endothelium-dependent relaxation in the absence and presence of enhancers. Enh4 increased ACh-induced relaxation (Emax%: 96.7±4.6 vs ctl: 70.4±3.3, p<0.05), while other enhancers did not improve endothelial function. Taken together, increasing MAS/ET B R interaction with specific enhancers augments protective signalling in ECs and promotes endothelial-dependent vasorelaxation, particularly with Enh4. In conclusion, enhancing interactions between MasR and ET B R may be a new vasoprotective strategy to improve vascular function in cardiovascular disease.
ABSTRACT
Many informal caregivers of persons with dementia suffer adverse health consequences. Although established psychoeducation programs are known to benefit caregivers, attending in‐person ...programs is challenging for them. To address this challenge, the Savvy Caregiver Program, an evidence‐based psychoeducation program with demonstrated effectiveness for caregiving and disease‐related outcomes, was transformed into an on‐line program, Tele‐Savvy. This article describes the rationale for and design of a prospective longitudinal randomized controlled trial (targeted N = 215), currently underway. The trial aims to establish Tele‐Savvy's efficacy in (i) reducing the negative effects of caregiving on caregivers; (ii) promoting care recipients’ quality of life; (iii) improving caregiver mastery; and to explore (iv) Tele‐Savvy's efficacy among caregivers of different races/ethnicities. The mediating role of mastery will be assessed. Participants are randomized to the active condition (immediate Tele‐Savvy participation), attention control, or usual care. Participants in the two latter conditions will complete Tele‐Savvy 6 months post‐baseline. Multilevel mixed effects models will be used to examine changes in outcomes and to model group by time (months since baseline) interactions. The exploratory aim will be addressed using analysis of covariance and qualitative analysis. This trial's results may be used by healthcare and community organizations to implement Tele‐Savvy in dementia care, increasing caregivers’ access to this evidence‐based intervention.
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