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The IBER study: a feasibility randomised controlled trial of imagery based emotion regulation for the treatment of anxiety in bipolar disorder.
BACKGROUND: Intrusive mental imagery is associated with anxiety and mood instability within bipolar disorder and therefore represents a novel treatment target. Imagery Based Emotion Regulation (IBER) is a brief structured psychological intervention developed to enable people to use the skills required to regulate the emotional impact of these images. METHODS: Participants aged 18 and over with a diagnosis of bipolar disorder and at least a mild level of anxiety were randomly assigned (1:1) to receive IBER plus treatment as usual (IBER + TAU) or treatment as usual alone (TAU). IBER was delivered in up to 12 sessions overs 16 weeks. Clinical and health economic data were collected at baseline, end of treatment and 16-weeks follow-up. Objectives were to inform the recruitment process, timeline and sample size estimate for a definitive trial and to refine trial procedures. We also explored the impact on participant outcomes of anxiety, depression, mania, and mood stability at 16-weeks and 32-weeks follow-up. RESULTS: Fifty-seven (28: IBER + TAU, 27: TAU) participants from two sites were randomised, with 50 being recruited within the first 12 months. Forty-seven (82%) participants provided outcome data at 16 and 32-weeks follow-up. Thirty-five participants engaged in daily mood monitoring at the 32-week follow-up stage. Retention in IBER treatment was high with 27 (96%) attending ≥ 7 sessions. No study participants experienced a serious adverse event. DISCUSSION: The feasibility criteria of recruitment, outcome completion, and intervention retention were broadly achieved, indicating that imagery-focused interventions for bipolar disorder are worthy of further investigation.
Adopting human factors in early phase and experimental medicine research: A nested pilot study observing controlled human infection with SARS-CoV-2.
AIM: The influence of human factors on safety in healthcare settings is well established, with targeted interventions reducing risk and enhancing team performance. In experimental and early phase clinical research participant safety is paramount and safeguarded by guidelines, protocolised care and staff training, however the real-world interaction and implementation of these risk-mitigating measures has never been subjected to formal system-based assessment. METHODS: Independent structured observations, systematic review of study documents, and interviews and focus groups were used to collate data on three key tasks undertaken in an a Clinical Research Facilty (CRF) during a SARS CoV-2 controlled human infection model (CHIM) study. The Systems Engineering Initiative for Patient Safety (SEIPS) was employed to analyse and categorise findings, and develop recommendations for safety interventions. RESULTS: High levels of team functioning and a clear focus on participant safety were evident throughout the study. Despite this, latent risks in both study-specific and CRF work systems were identified in all four SEIPS domains (people, environment, tasks and tools). 14 actionable recommendations were generated collaboratively. These included inter-organisation and inter-study standardisation, optimised checklists for safety critical tasks, and use of simulation for team training and exploration of work systems. CONCLUSION: This pioneering application of human factors techniques to analyse work systems during the conduct of research in a CRF revealed risks unidentified by routine review and appraisal, and despite international guideline adherence. SEIPS may aid categorisation of system problems and the formulation of recommendations that reduce risk and mitigate potential harm applicable across a trials portfolio.
The Role of Inflammation in Age-Related Macular Degeneration—Therapeutic Landscapes in Geographic Atrophy
Age-related macular degeneration (AMD) is the leading cause of vision loss and visual impairment in people over 50 years of age. In the current therapeutic landscape, intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapies have been central to the management of neovascular AMD (also known as wet AMD), whereas treatments for geographic atrophy have lagged behind. Several therapeutic approaches are being developed for geographic atrophy with the goal of either slowing down disease progression or reversing sight loss. Such strategies target the inflammatory pathways, complement cascade, visual cycle or neuroprotective mechanisms to slow down the degeneration. In addition, retinal implants have been tried for vision restoration and stem cell therapies for potentially a dual purpose of slowing down the degeneration and restoring visual function. In particular, therapies focusing on the complement pathway have shown promising results with the FDA approved pegcetacoplan, a complement C3 inhibitor, and avacincaptad pegol, a complement C5 inhibitor. In this review, we discuss the mechanisms of inflammation in AMD and outline the therapeutic landscapes of atrophy AMD. Improved understanding of the various pathway components and their interplay in this complex neuroinflammatory degeneration will guide the development of current and future therapeutic options, such as optogenetic therapy.
CERKL-Associated Retinal Dystrophy: Genetics, Phenotype, and Natural History.
PurposeTo analyze the clinical characteristics, natural history, and genetics of CERKL-associated retinal dystrophy in the largest series to date.DesignMulticenter retrospective cohort study.SubjectsForty-seven patients (37 families) with likely disease-causing CERKL variants.MethodsReview of clinical notes, ophthalmic images, and molecular diagnosis from 2 international centers.Main outcome measuresVisual function, retinal imaging, and characteristics were evaluated and correlated.ResultsThe mean age at the first visit was 29.6 ± 13.9 years, and the mean follow-up time was 9.1 ± 7.4 years. The most frequent initial symptom was central vision loss (40%), and the most common retinal feature was well-demarcated areas of macular atrophy (57%). Seventy-seven percent of the participants had double-null genotypes, and 64% had electrophysiological assessment. Among the latter, 53% showed similar severity of rod and cone dysfunction, 27% revealed a rod-cone, 10% a cone-rod, and 10% a macular dystrophy dysfunction pattern. Patients without double-null genotypes tended to have fewer pigment deposits and included a higher proportion of older patients with a relatively mild electrophysiological phenotype. Longitudinal analysis showed that over half of the cohort lost 15 ETDRS letters or more in ≥ 1 eye during the first 5 years of follow-up.ConclusionsThe phenotype of CERKL-retinal dystrophy is broad, encompassing isolated macular disease to severe retina-wide involvement, with a range of functional phenotypes, generally not fitting in the rod-cone/cone-rod dichotomy. Disease onset is often earlier, with more severe retinal degenerative changes and photoreceptor dysfunction, in nullizygous cases.Financial disclosure(s)Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Papillorenal syndrome: a systemic diagnosis not to be missed on funduscopy.
A 45-year-old man presented to the ophthalmology department with visual symptoms in his left eye. Almost two decades ago, he required a renal transplant for focal segmental glomerular sclerosis and a detailed enquiry revealed a strong family history of renal and ocular disease. Fundus examination demonstrated significant optic disc dysplasia in his left eye and optical coherence tomography showed intraretinal fluid bilaterally. The diagnosis of papillorenal syndrome was suspected and genetic testing identified a heterozygous pathogenic variant in the PAX2 gene c.76dupG, p.Val26Glyfs*28, confirming the diagnosis. The patient was treated conservatively, and his vision eventually improved and stabilised. His renal disease and transplant were concurrently monitored by nephrologists. In this case, history-taking and ophthalmic examination raised suspicion of this rare systemic condition, which led to genetic testing and molecular confirmation of the diagnosis. We therefore highlight this case to raise awareness of papillorenal syndrome, which has significant systemic implications and also impacts familial screening and genetic counselling.
Vitreous Haemorrhage and Retinal Neovascularization Secondary to Peripheral Retinal Ischemia as the Presenting Sign of a Disseminated Melanoma.
PurposeWe describe a case of vitreous haemorrhage and retinal neovascularization secondary to peripheral retinal ischemia associated with disseminated melanoma.MethodsA retrospective case report.ResultsA 48-year-old man presented with vitreous haemorrhage in the right eye, peripheral retinal ischemia, and retinal neovascularization in both eyes. CT and MRI scans were suggestive of disseminated malignancy and an ultrasound-guided biopsy of the abdominal mass confirmed metastatic melanoma. Immune checkpoint inhibitor therapy with ipilimumab/nivolumab was initiated. Regarding his ocular status, the vitreous haemorrhage cleared spontaneously, visual acuity improved to 6/7.5 and the patient underwent bilateral peripheral scatter laser photocoagulation to stabilize the retinopathy. The patient passed away 1 year after the initial presentation.Conclusion Our patient presented with melanoma and peripheral retinal ischaemia, leading to retinal neovascularization and vitreous haemorrhage. Therefore, melanoma should be considered as a differential diagnosis when investigating the aetiology of peripheral retinal ischaemia.
Priorities for content for a short‐course on postoperative care relevant for low‐ and middle‐income countries: an e‐Delphi process with training facilitators
SummaryMost surgical and anaesthetic mortality and morbidity occurs postoperatively, disproportionately affecting low‐ and middle‐income countries. Various short courses have been developed to improve patient outcomes in low‐ and middle‐income countries, but none specifically to address postoperative care and complications. We aimed to identify key features of a proposed short‐course addressing this topic using a Delphi process with low‐ and middle‐income country anaesthesia providers trained as short‐course facilitators. An initial questionnaire was co‐developed from literature review and exploratory workshops to include 108 potential course features. Features included content; teaching method; appropriate participants; and appropriate faculty. Over three Delphi rounds (panellists numbered 86, 64 and 35 in successive cycles), panellists indicated which features they considered most important. Responses were analysed by geographical regions: Africa, the Americas, south‐east Asia and Western Pacific. Ultimately, panellists identified 60, 40 and 54 core features for the proposed course in each region, respectively. There were high levels of consensus within regions on what constituted core course content, but not between regions. All panellists preferred the small group workshop teaching method irrespective of region. All regions considered anaesthetists to be key facilitators, while all agreed that both anaesthetists and operating theatre nurses were key participants. The African and Americas regional panels recommended more multidisciplinary healthcare professionals for participant roles. Faculty from high‐income countries were not considered high priority. Our study highlights variability between geographical regions as to which course features were perceived as most locally relevant, supporting regional adaptation of short‐course design rather than a one‐size‐fits‐all model.
Lessons from the design, development and implementation of a three-dimensional (3D) neonatal resuscitation training smartphone application: Life-saving Instruction for Emergencies (LIFE app)
AbstractNeonatal mortality remains disproportionately high in sub-Saharan Africa partly due to insufficient numbers of adequately trained and skilled front-line health workers. Opportunities for improving neonatal care may result from upskilling frontline health workers using innovative technological approaches. This practice paper describes the key steps involved in the design, development and implementation of an innovative smartphone-based training application using an agile, human-centred design approach. The Life-saving Instruction for Emergencies (LIFE) app is a three-dimension (3D) scenario-based mobile app for smartphones and is free to download. Two clinical modules are currently included with further scenarios planned. Whilst the focus of the practice paper is on the lessons learned during the design and development process, we also share key learning related to project management and sustainability plans, which we hope will help researchers working on similar projects.
Community acquired pneumonia and canoeing
We describe 2 cases of severe Leptospirosis in young people requiring admission to intensive care for multi-organ support.
Local anaesthetic pharmacology
Local anaesthetic drugs are used widely for the provision of anaesthesia and analgesia both intra-and post-operatively. Understanding the pharmacology of these agents as a group, as well as the differences between specific drugs, enables the anaesthetist to use them safely to maximum effect. This article focuses on the basic structure and function of local anaesthetics. Learning will be improved by trying to answer the questions posed in the text before moving on. More detail can be found in the "Further reading" section at the end.
Local anaesthetic pharmacology
Understanding the pharmacology of local anaesthetics enables the anaesthetist to predict the potency, speed of onset, duration of action and safety of a specific drug in a given clinical situation. This maximises the opportunity for safe and effective use of local anaesthesia in a wide variety of contexts.
Optogenetic approaches to therapy for inherited retinal degenerations.
Inherited retinal degenerations such as retinitis pigmentosa (RP) affect around one in 4000 people and are the leading cause of blindness in working age adults in several countries. In these typically monogenic conditions, there is progressive degeneration of photoreceptors; however, inner retinal neurons such as bipolar cells and ganglion cells remain largely structurally intact, even in end-stage disease. Therapeutic approaches aiming to stimulate these residual cells, independent of the underlying genetic cause, could potentially restore visual function in patients with advanced vision loss, and benefit many more patients than therapies directed at the specific gene implicated in each disorder. One approach investigated for this purpose is that of optogenetics, a method of neuromodulation that utilises light to activate neurons engineered to ectopically express a light-sensitive protein. Using gene therapy via adeno-associated viral vectors, a range of photosensitive proteins have been expressed in remaining retinal cells in advanced retinal degeneration with in vivo studies demonstrating restoration of visual function. Developing an effective optogenetic strategy requires consideration of multiple factors, including the light-sensitive protein that is used, the vector and method for gene delivery, and the target cell for expression because these in turn may affect the quality of vision that can be restored. Currently, at least four clinical trials are ongoing to investigate optogenetic therapies in patients, with the ultimate aim of reversing visual loss in end-stage disease.
A large animal model of RDH5-associated retinopathy recapitulates important features of the human phenotype.
Pathogenic variants in retinol dehydrogenase 5 (RDH5) attenuate supply of 11-cis-retinal to photoreceptors leading to a range of clinical phenotypes including night blindness because of markedly slowed rod dark adaptation and in some patients, macular atrophy. Current animal models (such as Rdh5-/- mice) fail to recapitulate the functional or degenerative phenotype. Addressing this need for a relevant animal model we present a new domestic cat model with a loss-of-function missense mutation in RDH5 (c.542G > T; p.Gly181Val). As with patients, affected cats have a marked delay in recovery of dark adaptation. In addition, the cats develop a degeneration of the area centralis (equivalent to the human macula). This recapitulates the development of macular atrophy that is reported in a subset of patients with RDH5 mutations and is shown in this paper in seven patients with biallelic RDH5 mutations. There is notable variability in the age at onset of the area centralis changes in the cat, with most developing changes as juveniles but some not showing changes over the first few years of age. There is similar variability in development of macular atrophy in patients and while age is a risk factor, it is hypothesized that genetic modifying loci influence disease severity, and we suspect the same is true in the cat model. This novel cat model provides opportunities to improve molecular understanding of macular atrophy and test therapeutic interventions for RDH5-associated retinopathies.
Treatment of cystoid macular oedema secondary to pentosan polysulfate maculopathy using anti-VEGF and intravitreal steroid injections.
BACKGROUND: Pentosan polysulfate-related maculopathy is a recently described clinical entity, related to dose and long term use of this medication, and may progress despite drug cessation. Cystoid macular oedema (CMO) has been reported in some cases, but there are few reports of treatment outcomes in the literature. AIMS: We present the case of a 55 year old female, with CMO secondary to pentosan polysulfate maculopathy, that was responsive to treatment with both intravitreal anti-VEGF and steroid injections, stabilising vision over a four year follow up period. CONCLUSIONS: This is the first report, to our knowledge, of CMO related to pentosan polysulfate maculopathy responding to intravitreal steroid injections, broadening the therapeutic options for preserving vision in these patients.
Domain-specific cognitive impairment 6 months after stroke: The value of early cognitive screening.
BACKGROUND: Cognitive screening following stroke is widely recommended, yet few studies have considered the prognostic value of acute domain-specific function for longer-term cognitive outcome. Identifying which post-stroke cognitive impairments more commonly occur, recover, and persist, and which impairments hold prognostic value, could inform care planning, and resource allocation. AIMS: This study aimed to determine the prevalence of domain-specific impairment acutely and at 6 months, assess the proportion of change in cognitive performance, and examine the prognostic value of acute domain-specific cognitive screening. METHODS: A prospective stroke cohort completed the Oxford Cognitive Screen acutely (⩽2 weeks) and 6 months post-stroke. We determined the prevalence of acute and 6-month domain-specific impairment and proportion of change in performance from acute to 6 months. Hierarchical multivariable regression was used to predict global and domain-specific cognitive impairment at 6 months adjusted for demographic/vascular factors, stroke severity, and lesion volume. RESULTS: A total of 430 stroke survivors (mean/SD age 73.9/12.5 years, 46.5% female, median/interquartile range (IQR) National Institute of Health Stroke Scale (NIHSS) 5/2-10) completed 6-month follow-up. Acutely, domain-specific impairments were highly prevalent ranging from 26.7% (n = 112) in praxis to 46.8% (n = 183) in attention. At 6 months, the proportion of domain-specific recovery was highest in praxis (n = 73, 71%) and lowest in language (n = 89, 46%) and memory (n = 82, 48%). Severity of 6-month cognitive impairment was best predicted by the addition of acute cognitive impairment (adj R2 = 0.298, p
Allosteric TYK2 inhibition: redefining autoimmune disease therapy beyond JAK1-3 inhibitors.
JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders. However, their broad reach also poses safety concerns, which have fuelled a demand for increasingly selective JAK inhibitors. Deucravacitinib, a first-in-class allosteric TYK2 inhibitor, represents a remarkable advancement in the field. Rather than competing at kinase domain catalytic sites as classical JAK1-3 inhibitors, deucravacitinib targets the regulatory pseudokinase domain of TYK2. It strikingly mirrors the functional effect of an evolutionary conserved naturally occurring TYK2 variant, P1104A, known to protect against multiple autoimmune diseases yet provide sufficient TYK2-mediated cytokine signalling required to prevent immune deficiency. The unprecedentedly high functional selectivity and efficacy-safety profile of deucravacitinib, initially demonstrated in psoriasis, combined with genetic support, and promising outcomes in early SLE clinical trials make this inhibitor ripe for exploration in other autoimmune diseases for which better, safe, and efficacious treatments are urgently needed.