The RNA-mediated disease model for myotonic dystrophy (DM) proposes that microsatellite C(C)TG expansions express toxic RNAs that disrupt splicing regulation by altering MBNL1 and CELF1 activities. ...While this model explains DM manifestations in muscle, less is known about the effects of C(C)UG expression on the brain. Here, we report that Mbnl2 knockout mice develop several DM-associated central nervous system (CNS) features including abnormal REM sleep propensity and deficits in spatial memory. Mbnl2 is prominently expressed in the hippocampus and Mbnl2 knockouts show a decrease in NMDA receptor (NMDAR) synaptic transmission and impaired hippocampal synaptic plasticity. While Mbnl2 loss did not significantly alter target transcript levels in the hippocampus, misregulated splicing of hundreds of exons was detected using splicing microarrays, RNA-seq, and HITS-CLIP. Importantly, the majority of the Mbnl2-regulated exons examined were similarly misregulated in DM. We propose that major pathological features of the DM brain result from disruption of the MBNL2-mediated developmental splicing program.
► Muscleblind-like 2 regulates alternative splicing in the brain ► Developmental regulation of splicing is disrupted in Mbnl2 knockout mice ► RNAs targeted by MBNL2 are misspliced in the myotonic dystrophy brain
Myotonic dystrophy, a disease caused by toxic RNAs, profoundly affects brain function. In this Article, Charizanis et al. demonstrate that the effect on brain function results from loss of muscleblind-like 2 RNA splicing regulation during brain development.
Background/aim
Occupation is a human right and a social determinant of health. It is also taken for granted. Having access to, and participating in, occupation, is intricately linked to positive ...health and wellbeing. Despite theory and evidence to support the link between occupation, health and wellbeing, occupational therapists can struggle with applying an occupation focus in practice and knowing how to use occupational frameworks to enable occupation. The purpose of this paper is to introduce the Capabilities, Opportunities, Resources and Environments (CORE) approach for inclusive and occupation‐focused practice. It provides occupational therapists with a means of operationalising occupational enablement and facilitating social inclusion.
Methods
The CORE approach is introduced by linking its main ideas to Economist and Nobel Prize Laureate Amartya Sen's capabilities approach, as well as findings from the author's doctoral research into entrenched disadvantage and social inclusion. Practical questions guided by the CORE approach's acronym are given to explore how the approach can be utilised alongside other occupational models and frameworks to encourage strategies for effective enablement through occupation for social inclusion.
Conclusion
As experts in enabling occupation, occupational therapists can use the CORE approach to design occupation‐focused interventions and promote inclusive occupational therapy.
Abstract Introduction Consumer contribution to occupational therapy student learning is mandated for Australian educational programs. However, there is limited research about how consumers contribute ...to student learning during practice placements. A scoping review was completed to explore the concepts of existing feedback systems for consumers to authentically contribute to student learning during practice placements. Methods Five databases were searched for all articles up to and including July 2023. All publications were included if they described and investigated authentic contribution to student learning during a practice placement experience. Data from the results and discussion sections of the papers were transformed into qualitative data and thematically analysed to develop a conceptual understanding of consumer feedback systems. Results Forty‐six papers met the eligibility criteria. Most articles originated from Medicine (30%) and Nursing (45%) education. Feedback systems were primarily designed to critique student communication and professional behaviours using a variety of standardised and non‐standardised methods. Five interconnected themes were created that addressed the concepts of consumer feedback systems. The themes were (1) creating value specific for each stakeholder is essential, (2) preparation is required and nuanced; (3) consumers do engage and provide critical feedback when the system is supportive of all stakeholders; (4) gathering approaches need to be responsive to the diversity of practice and learning; (5) processing feedback with a trusted mentor is critical for learning. Conclusions Consumers, academics, practice educators, and students recognised that consumers have an important role in contributing to student learning during practice placements. Future consumer feedback systems need to be co‐produced to create an optimal mode for consumers to authentically contribute to student learning constructively and safely. Consumer and community involvement A consumer consultant was a member of the advisory panel for the larger research project that this review is part of and provided advice to the research team at all stages of the project. PLAIN LANGUAGE SUMMARY In Australia, occupational therapy training programs require input from consumers to help students learn. However, there is not much research on how consumers help occupational therapy students during their practical training. We did a review to see how existing feedback systems let consumers genuinely help students during their training. We searched five databases for research up to July 2023. We included research that talked about how consumers help all health students learn during practical training. We found 46 articles, mostly from Medicine and Nursing education. We analysed them to understand how consumer feedback systems work and found five main themes: (1) making sure everyone involved gets value out of it, (2) being prepared is important, (3) consumers give useful feedback when the system supports everyone involved, (4) different approaches are needed because practices and learning vary, and (5) discussing feedback with other people helps students learn. Current feedback systems mostly focused on how students communicate and behave professionally. Consumers, educators, and students all agree that consumers play a vital role in helping students learn during practical training. In the future, we need to work together to make feedback systems that let consumers help students in the best way possible, making sure it is constructive and safe for everyone.
To evaluate the efficacy and safety of a single-dose intravitreal umedaptanib pegol (anti-FGF2, investigational new drug) for the treatment of neovascular age-related macular degeneration (nAMD).
...Nine participants who had a diagnosis of refractory nAMD were enrolled and received a single intravitreal injection of umedaptanib pegol at increasing doses of 0.2, 1.0 or 2.0 mg in the study eye.
All three doses of umedaptanib pegol evaluated in the study were safe and well tolerated. No severe adverse event (AE) was observed in the study. There was an improvement in retinal fluid measured by central subfield thickness (CST) in most subjects. Remarkably, all three subjects who received 2.0 mg/eye showed improvement of more than 150 μm.
Intravitreal umedaptanib pegol was safe, well tolerated, and demonstrated an indication of bioactivity in participants that have persistent subretinal fluid refractory to the treatment with anti-VEGFs.
Introduction
Collaborating with consumers in designing, delivering, and evaluating curricula is an ongoing initiative within occupational therapy tertiary courses in Australia. Within the Australian ...educational context, consumers are involved in on‐campus educational activities. Student occupational therapists must complete 1000 hours of practice placements as part of their education. To date, no research has explored how consumers could contribute to student occupational therapists' learning during practice placements. This study aimed to explore Australian occupational therapists' perceptions of consumers providing feedback to students during practice placements.
Methods
A qualitative descriptive approach was adopted to engage with the diversity of practice contexts and gain a rich dataset from the occupational therapy profession. A qualitative questionnaire was developed and distributed using snowballing techniques. The questionnaire asked recipients to reflect on the risks, challenges, and benefits of consumers providing feedback to student occupational therapists from all stakeholders' perspectives. Demographic data were collated, and reflexive thematic analysis was used to construct themes.
Findings
Responses were received from 81 participants. Most respondents identified as experienced occupational therapists from metropolitan locations across Australia. Reflective thematic analysis was used to construct three themes: Personal capability of consumers and students will enable, inhibit, and be developed by engaging in a feedback process; an educator‐controlled process to ensure safety for all stakeholders is required for time‐poor practice contexts; and us versus them: Shifting control to consumers can disempower practice educators.
Conclusion
Engaging with consumers throughout all aspects of student occupational therapists' educational programme is required, including practice placements. New educational initiatives need to consider all stakeholders' concerns to ensure that authentic contribution from consumers is made within the various practice contexts. A co‐design approach that involves all stakeholders to develop a feedback process may result in high‐quality learning experiences that assist students to become safer, consumer‐centred health professionals.
Intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents are the first-line treatment for exudative age-related macular degeneration (nAMD). Due to the limitations of these ...standard therapies, targeting alternative mechanisms of action may be helpful for treatment of this very common disease. Here, we investigated an anti-fibroblast growth factor-2 (FGF2) aptamer, umedaptanib pegol, a next generation therapeutic for the treatment of nAMD.
Three phase 2 studies were designed. First, a multicentre, randomized, double-masked TOFU study assessed the efficacy of intravitreal injections of umedaptanib pegol monotherapy or in combination with aflibercept, compared to aflibercept monotherapy in 86 subjects with anti-VEGF pretreated nAMD. Second, 22 subjects who had exited the TOFU study received 4 monthly intravitreal injections of umedaptanib pegol (extension, RAMEN study). Third, as an investigator-sponsored trial (TEMPURA study), a single-center, open-label, 4-month study was designed to evaluate the safety and treatment efficacy of umedaptanib pegol in five naïve nAMD patients who had not received any prior anti-VEGF treatment.
The TOFU study demonstrated that umedaptanib pegol alone or in combination with aflibercept did not improve best-corrected visual acuity (BCVA) and central subfield thickness (CST) over aflibercept alone. However, the change in BCVA and CST at primary endpoint was marginal in all the three treatment groups, suggesting that umedaptanib pegol is effective to prevent the disease progression. The RAMEN study confirmed the cessation of disease progression. In the TEMPURA study, naïve nAMD patients showed improvement and no further macular degeneration, with striking improvement of visual acuity and central subfield thickness in some of the patients.
These results demonstrate, for the first time, clinical proof of concept for aptamer based anti-FGF2 therapy of nAMD.
Background/Aim
Occupational participation is often claimed as a human right and determinant of health by occupational science and therapy scholars. Yet, maintaining occupation at the centre of ...practice is a challenge. The Capabilities, Opportunities, Resources and Environments (CORE) approach provides a mechanism for occupational therapists to address this challenge by viewing their practice through an inclusive lens, and enacting inclusive, occupation‐centred occupational therapy. This paper presents applications of the CORE approach via three case narratives. The aim is to increase occupational therapists’ understanding of how to apply the CORE approach and to facilitate research‐to‐practice knowledge translation.
Methods
The CORE approach is introduced and applied through three case narratives, each highlighting one of the CORE elements within the context of the broader approach.
Findings
The narratives contain critical reflective case narratives on the application of the CORE approach in the context of three different practice settings in Australia based on the authors’ experiences. Practice settings include working within the National Disability Insurance Scheme, in a secure forensic mental health facility, and in rural community health. The forensic health case narrative documents findings from the authors’ research which applied the CORE approach as an analytical tool, providing an additional layer of analysis of the identified themes from the original study.
Conclusion
This paper provides occupational therapists with a practical understanding of how to apply the CORE approach through diverse case narrative examples. The practical “how to” questions that guided the development of the case narratives can be used by occupational therapists and occupational therapy students in individual or group critical reflection to support development and application of socially inclusive and occupation‐centred praxis. If occupational therapists are to claim expertise in enabling occupation and social inclusion, then using the CORE approach is vital to designing and implementing inclusive, occupation‐centred interventions.
Current advances in combined antiretroviral therapy have rendered HIV infection a chronic, manageable disease; however, the problem of persistent immune activation still remains despite treatment. ...The immune cell receptor SLAMF7 has been shown to be upregulated in diseases characterized by chronic immune activation. In this study, we studied the function of the SLAMF7 receptor in immune cells of HIV patients and the impacts of SLAMF7 signaling on peripheral immune activation. We observed increased frequencies of SLAMF7
PBMCs in HIV
individuals in a clinical phenotype-dependent manner, with discordant and long-term nonprogressor patients showing elevated SLAMF7 levels, and elite controllers showing levels comparable to healthy controls. We also noted that SLAMF7 was sensitive to IFN-⍺ stimulation, a factor elevated during HIV infection. Further studies revealed SLAMF7 to be a potent inhibitor of the monocyte-derived proinflammatory chemokine CXCL10 (IP-10) and other CXCR3 ligands, except in a subset of HIV
patients termed SLAMF7 silent (SF7S). Studies utilizing small molecule inhibitors revealed that the mechanism of CXCL10 inhibition is independent of known SLAMF7 binding partners. Furthermore, we determined that SLAMF7 activation on monocytes is able to decrease their susceptibility to HIV-1 infection in vitro via downregulation of CCR5 and upregulation of the CCL3L1 chemokine. Finally, we discovered that neutrophils do not express SLAMF7, are CXCL10
at baseline, are able to secrete CXCL10 in response to IFN-⍺ and LPS, and are nonresponsive to SLAMF7 signaling. These findings implicate the SLAMF7 receptor as an important regulator of IFN-⍺-driven innate immune responses during HIV infection.
Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together ...with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect-especially in the setting of stable disease-calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE).
We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles.
Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE.
Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy.
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