Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations

Congenital myasthenic syndromes are inherited disorders of neuromuscular transmission characterized by fatigable muscle weakness. Autosomal recessive acetylcholine receptor (AChR) deficiency syndromes, in which levels of this receptor at the neuromuscular junction are severely reduced, may be caused by mutations within genes encoding the AChR or the AChR-clustering protein, rapsyn. Most patients have mutations within the rapsyn coding region and are either homozygous for N88K or heteroallelic for N88K and a second mutation. In some cases the second allele carries a null mutation but in many the mutations are missense, and are located in different functional domains. Little is known about the functional effects of these mutations, but we hypothesize that they would have an effect on AChR clustering by a variety of mechanisms that might correlate with disease severity. Here we expressed RAPSN mutations A25V, N88K, R91L, L361R and K373del in TE671 cells and in rapsyn−/− myotubes to determine their pathogenic mechanisms. The A25Vmutation impaired colocalization of rapsyn with AChR and prevented agrin-induced AChR clusters in rapsyn−/− myotubes. In TE671 cells, R91L reduced the ability of rapsyn to self-associate, and K373del-rapsyn was significantly less stable than wild-type. The effects of mutations L361R and N88K were more subtle: in TE671 cells, in comparison with wild-type rapsyn, L361R-rapsyn showed reduced expression/stability, and both N88K-rapsyn and L361R-rapsyn showed significantly reduced co-localization with AChR. N88K-rapsyn and L361R-rapsyn could effectively mediate agrin-induced AChR clusters, but these were reduced in number and were less stable than with wild-type rapsyn. The disease severity of patients harbouring the compound allelic mutations was greater than that of patients with homozygous rapsyn mutation N88K, suggesting that the second mutant allele may largely determine severit

A deep wound under my heart”: Constructions of complex trauma and implications for women’s wellbeing and safety from violence

This project sought to develop a comprehensive picture of how complex trauma is being constructed in public policy and practice, and how it is viewed by women with experiences of complex trauma. The research took the form of a multi-method study that combined policy and service analysis with qualitative research with women with experiences of complex trauma and the professionals who work with them, via: a policy audit of approaches to complex trauma service documentary analysis and qualitative interviews with professionals in Queensland and New South Wales qualitative interviews with women with experiences of complex trauma in Queensland and New South Wales online workshops in which professional stakeholders and women with experiences of complex trauma provided feedback on the findings of the study. The research found that at the policy level, complex trauma overlaps with frameworks on violence against women and mental health. However, the impact of complex trauma is not comprehensively addressed by these frameworks, which contributes to the fragmented response to women in distress. It demonstrated that there is a strong need for a whole-of-government commitment to the implementation and coordination of trauma-informed practice across sectors. The report includes recommendations for policy and practice

Using Minecraft to engage children with science at public events

Engagement with science and scientific skills is an important aspect of children's ability to navigate the world around them, but engagement with science is low in comparison with other subjects. The Lancaster University outreach project Science Hunters takes a novel approach to engaging children with environmental science research through a constructivist pedagogical approach using the popular computer game Minecraft. While Minecraft is extensively used in formal education settings, few data are available on its use in public engagement with scientific research, and the relationship between children's and adults' attitudes to science and computer games are complex. Through motivational surveys conducted as part of the project evaluation, we analysed feedback from participants who attended sessions as part of a programme at public events, to explore the basic demographics of children attending our events, and whether it is the prospect of learning about science, or the opportunity to play Minecraft that leads them to choose our activity. We also present evaluation of general feedback from participants at public events over four years to give a broader view of participants' response to the activities

Disability Rights as a Necessary Framework for Crisis Standards of Care and the Future of Health Care

In this essay, we suggest practical ways to shift the framing of crisis standards of care toward disability justice. We elaborate on the vision statement provided in the 2010 Institute of Medicine (National Academy of Medicine) “Summary of Guidance for Establishing Crisis Standards of Care for Use in Disaster Situations,” which emphasizes fairness; equitable processes; community and provider engagement, education, and communication; and the rule of law. We argue that interpreting these elements through disability justice entails a commitment to both distributive and recognitive justice. The disability rights movement\u27s demand “Nothing about us, without us” requires substantive inclusion of disabled people in decision-making related to their interests, including in crisis planning before, during, and after a pandemic like Covid-19

Humanizing Digital Literacies: A Road Trip in Search of Wisdom and Insight

Digital literacies abound in playing a foundational role in the rhythm and pattern of our lives, yet debates continue about how to harness them to teach and learn literacy. In an effort to humanize digital literacies, this department column offers a vast array of topics, from participatory work that pushes educators and researchers to communicate in local and global spaces to ways of redefining core reading and literacy skills through a screen‐based, multimodal logic. This column also provides a venue for research and practical applications that depict technology use as a part of the fabric of being human. The column helps educators reconceptualize the ways that children learn with technology, media, and new communication systems; honors educator success stories and burning questions and issues; and reimagines literacy futures

Disability Rights as a Necessary Framework for Crisis Standards of Care and the Future of Health Care

In this essay, we suggest practical ways to shift the framing of crisis standards of care toward disability justice. We elaborate on the vision statement provided in the 2010 Institute of Medicine (National Academy of Medicine) “Summary of Guidance for Establishing Crisis Standards of Care for Use in Disaster Situations,” which emphasizes fairness; equitable processes; community and provider engagement, education, and communication; and the rule of law. We argue that interpreting these elements through disability justice entails a commitment to both distributive and recognitive justice. The disability rights movement's demand “Nothing about us, without us” requires substantive inclusion of disabled people in decision-making related to their interests, including in crisis planning before, during, and after a pandemic like Covid-19

Impact of foods enriched with n-3 long-chain polyunsaturated fatty acids on erythrocyte n-3 levels and cardiovascular risk factors

Consumption of fish or fish oils rich in the n-3 long chain PUFA EPA and DHA may improve multiple risk factors for CVD. The objective of this study was to determine whether regular consumption of foods enriched with n-3 long-chain PUFA can improve n-3 long-chain PUFA status (erythrocytes) and cardiovascular health. Overweight volunteers with high levels of triacylglycerols (TG; >1.6 mmol/l) were enrolled in a 6-month dietary intervention trial conducted in Adelaide (n 47) and Perth (n 39), and randomised to consume control foods or n-3-enriched foods to achieve an EPA + DHA intake of 1 g/d. Test foods were substituted for equivalent foods in their regular diet. Erythrocyte fatty acids, plasma TG and other CVD risk factors were monitored at 0, 3 and 6 months. There were no significant differences between groups for blood pressure, arterial compliance, glucose, insulin, lipids, C-reactive protein (CRP) or urinary 11-dehydro-thromboxane B2 (TXB2) over 6 months, even though regular consumption of n-3-enriched foods increased EPA + DHA intake from 0.2 to 1.0 g/d. However, the n-3 long-chain PUFA content of erythrocytes increased by 35 and 53 % at 3 and 6 months, respectively, in subjects consuming the n-3-enriched foods. These increases were positively associated with measures of arterial compliance and negatively associated with serum CRP and urinary 11-dehydro-TXB2 excretion. Sustainable increases in dietary intakes and erythrocyte levels of n-3 long-chain PUFA can be achieved through regular consumption of suitably enriched processed foods. Such increases may be associated with reduced CV risk.Karen J. Murphy, Barbara J. Meyer, Trevor A. Mori, Valerie Burke, Jackie Mansour, Craig S. Patch, Linda C. Tapsell, Manny Noakes, Peter A. Clifton, Anne Barden, Ian B. Puddey, Lawrence J. Beilin and Peter R. C. How

Digital play: a new classification

This paper draws on an ESRC-funded study of play and creativity in preschool-aged children’s use of apps in the UK. The main objectives of the study were to collect information about access to and use of apps in the home, establish the most popular apps and identify the features of those apps that are successful in promoting play and creativity. A mixed-method approach was used to collect data, including video filming of children using the most popular apps. In identifying play types that emerged in the analysis of data, the team utilised an established taxonomy, which outlines sixteen play types. This taxonomy was reviewed and adapted to analyse data from the project relating to digital play. Through this process, an additional type of play, transgressive play, was identified and added to the taxonomy. The paper outlines the implications of the revised taxonomy for future studies of play

Rheumatoid arthritis - treatment: 180. Utility of Body Weight Classified Low-Dose Leflunomide in Japanese Rheumatoid Arthritis

Background: In Japan, more than 20 rheumatoid arthritis (RA) patients died of interstitial pneumonia (IP) caused by leflunomide (LEF) were reported, but many of them were considered as the victims of opportunistic infection currently. In this paper, efficacy and safety of low-dose LEF classified by body weight (BW) were studied. Methods: Fifty-nine RA patients were started to administrate LEF from July 2007 to July 2009. Among them, 25 patients were excluded because of the combination with tacrolimus, and medication modification within 3 months before LEF. Remaining 34 RA patients administered 20 to 50 mg/week of LEF were followed up for 1 year and enrolled in this study. Dose of LEF was classified by BW (50 mg/week for over 50 kg, 40 mg/week for 40 to 50 kg and 20 to 30 mg/week for under 40 kg). The average age and RA duration of enrolled patients were 55.5 years old and 10.2 years. Prednisolone (PSL), methotrexate (MTX) and etanercept were used in 23, 28 and 2 patients, respectively. In case of insufficient response or adverse effect, dosage change or discontinuance of LEF were considered. Failure was defined as dosages up of PSL and MTX, or dosages down or discontinuance of LEF. Last observation carried forward method was used for the evaluation of failed patients at 1 year. Results: At 1 year after LEF start, good/ moderate/ no response assessed by the European League Against Rheumatism (EULAR) response criteria using Disease Activity Score, including a 28-joint count (DAS28)-C reactive protein (CRP) were showed in 14/ 10/ 10 patients, respectively. The dosage changes of LEF at 1 year were dosage up: 10, same dosage: 5, dosage down: 8 and discontinuance: 11 patients. The survival rate of patients in this study was 23.5% (24 patients failed) but actual LEF continuous rate was 67.6% (11 patients discontinued) at 1 year. The major reason of failure was liver dysfunction, and pneumocystis pneumonia was occurred in 1 patient resulted in full recovery. One patient died of sepsis caused by decubitus ulcer infection. DAS28-CRP score was decreased from 3.9 to 2.7 significantly. Although CRP was decreased from 1.50 to 0.93 mg/dl, it wasn't significant. Matrix metalloproteinase (MMP)-3 was decreased from 220.0 to 174.2 ng/ml significantly. Glutamate pyruvate transaminase (GPT) was increased from 19 to 35 U/l and number of leukocyte was decreased from 7832 to 6271 significantly. DAS28-CRP, CRP, and MMP-3 were improved significantly with MTX, although they weren't without MTX. Increase of GPT and leukopenia were seen significantly with MTX, although they weren't without MTX. Conclusions: It was reported that the risks of IP caused by LEF in Japanese RA patients were past IP history, loading dose administration and low BW. Addition of low-dose LEF is a potent safe alternative for the patients showing unsatisfactory response to current medicines, but need to pay attention for liver function and infection caused by leukopenia, especially with MTX. Disclosure statement: The authors have declared no conflicts of interes

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening