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Autoantibodies as drivers of neuropathic pain.
Emerging evidence, supported by clinical responses to immunotherapy and the recapitulation of sensory symptoms in passive transfer models, shows that autoantibodies (AAbs) may drive neuropathic pain. These findings highlight the importance of immune profiling to enhance diagnosis and treatment, and provide molecular insights into broader pain mechanisms in clinical contexts.
OPTOGENETIC VISION RESTORATION IN THE FACE OF SECONDARY AND TERTIARY REMODELLING IN THE RD1 MOUSE RETINA.
Photoreceptor loss in retinal degeneration is followed by progressive remodelling of the surviving retina, which may present a barrier to vision restoration. To determine the impact of remodelling on the retina's suitability for therapeutic interventions, we track changes in visual code produced by the optogenetic actuator ReaChR expressed in ON-bipolar cells of the rd1 mouse at 3,5,9 and 12 months. Anatomical analyses confirm these ages encompass phase II (photoreceptor degeneration) to phase III (inner retinal thinning, dysmorphia, pigment epithelium infiltration) remodelling. Multi-electrode array recording from retinal ganglion cells reveal that ReaChR-driven responses to a range of visual stimuli are stable across this age range. Response amplitude, sensitivity and reproducibility all increased between 3 and 5 months, remaining consistent thereafter. Receptive field sizes, contrast sensitivity, and temporal frequency tuning showed minor changes with age. The diversity of retinal ganglion cell coding was maintained, reflected by the diversity captured by unsupervised functional clustering with 11 distinct visual channels retained across ages. Our data indicate that remodelling does not significantly impair, and at early stages may even enhance the surviving retina's ability to support visual restoration. Clinical intervention thus remains viable throughout remodelling, suggesting a wide window in disease progression for therapeutic benefit.
The mouse motor system contains multiple premotor areas and partially follows human organizational principles.
While humans are known to have several premotor cortical areas, secondary motor cortex (M2) is often considered to be the only higher-order motor area of the mouse brain and is thought to combine properties of various human premotor cortices. Here, we show that axonal tracer, functional connectivity, myelin mapping, gene expression, and optogenetics data contradict this notion. Our analyses reveal three premotor areas in the mouse, anterior-lateral motor cortex (ALM), anterior-lateral M2 (aM2), and posterior-medial M2 (pM2), with distinct structural, functional, and behavioral properties. By using the same techniques across mice and humans, we show that ALM has strikingly similar functional and microstructural properties to human anterior ventral premotor areas and that aM2 and pM2 amalgamate properties of human pre-SMA and cingulate cortex. These results provide evidence for the existence of multiple premotor areas in the mouse and chart a comparative map between the motor systems of humans and mice.
Changes in corticosteroid and non-steroidal immunosuppressive therapy with long-term zilucoplan treatment in generalized myasthenia gravis.
BACKGROUND: The efficacy and safety of complement component 5 inhibitor zilucoplan in patients with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis (gMG) were assessed in two double-blind studies (NCT03315130/NCT04115293 [RAISE]). During these studies and the first 12 weeks of the open-label extension study, RAISE-XT, corticosteroid and non-steroidal immunosuppressive therapy (NSIST) doses were kept stable; thereafter doses could be changed at the investigator's discretion. We evaluated corticosteroid and NSIST dose changes in patients with gMG during zilucoplan treatment in RAISE-XT. METHODS: In RAISE-XT, patients who completed a qualifying double-blind study self-administered once-daily subcutaneous zilucoplan 0.3mg/kg. We assessed (post hoc) patients who changed their corticosteroid or NSIST dose relative to double-blind baseline at Week 120 (data cutoff: November 11, 2023). RESULTS: Overall, 200 patients enrolled. At Week 120, 61.1% (n = 33/54) of patients who were on corticosteroids at double-blind baseline had reduced or discontinued corticosteroids (mean 15.5mg dose reduction); mean change from baseline (CFB) in Myasthenia Gravis Activities of Daily Living (MG-ADL) score:-6.55 (standard deviation [SD] 3.65). Of patients on NSIST at double-blind baseline, 29.8% (n = 14/47) reduced or discontinued ≥ 1 NSIST; mean CFB in MG-ADL score:-7.57 (SD 4.69). Among all patients at Week 120, 9.3% (n = 8/86) had increased or started corticosteroids; 2.4% of patients (n = 2/85) had increased NSIST, including one who started a new NSIST. Zilucoplan was well tolerated. CONCLUSIONS: Treatment with zilucoplan allowed for reduction or discontinuation of corticosteroids in the majority of patients and NSIST in about a third of patients, while maintaining efficacy. TRIAL REGISTRATION: NCT04225871; October 2, 2019.
Neurological examinations for psychiatric patients: A systematic review.
The neurological examination is a key part of the diagnostic evaluation of psychiatric patients. There is general agreement that the canonical neurological examination should be modified for psychiatric patients, however there is a lack of consensus around what this should entail. We reviewed the literature on proposed neurological examinations for a psychiatric clinical setting. A systematic review, following PRISMA guidelines, was conducted to identify all published neurological examinations aimed at adult psychiatric patients. Information on items, length and target population was extracted for each examination. A total of 20 proposed neurological examinations were identified (9 general adult; 4 older adult; 7 general and older adult). All examinations covered the broad components of a canonical neurological examination, including assessments of the upper limbs, lower limbs, and cranial nerves. In addition to this, inspection for involuntary movements and assessment of primitive reflexes were commonly included. Neurological examinations for older adults were typically lengthier, and frequently recommended testing for olfaction and functional ability. However, the strength of the evidence supporting all proposed examinations was low, relying heavily on expert opinion. Existing neurological examinations in psychiatry exhibit several weaknesses, which limit their use in routine psychiatric care. There is a need for a brief, evidence-based neurological examination that is feasible to implement in a psychiatric setting.
Retinograd-AI: An Open-Source Automated Fundus Autofluorescence Retinal Image Gradability Assessment for Inherited Retinal Diseases.
PURPOSE: To develop an automated system for assessing the quality of fundus autofluorescence (FAF) images in patients with inherited retinal diseases (IRDs). DESIGN: A retrospective study of imaging data. PARTICIPANTS: Patients with a confirmed molecular diagnosis of IRD who have undergone FAF imaging at Moorfields Eye Hospital. METHODS: A dataset of 2445 FAF images from patients with IRD was marked by 3 expert graders as either gradable (acceptable quality) or ungradable (poor quality), following a strict grading protocol. This dataset was used to train an artificial intelligence (AI) algorithm, Retinograd-AI, which was then applied to predict the gradability label of our entire dataset of 136 631 FAF images. MAIN OUTCOME MEASURES: Fundus autofluorescence gradability of FAF images as predicted and validated against human assessment. RESULTS: Retinograd-AI achieves 91% accuracy on our held-out dataset of 133 images with an area under the receiver operator characteristic curve of 0.94, indicating high performance in distinguishing between gradable and ungradable images. Applying Retinograd-AI to our entire dataset, a small but significant positive association of gradability with age was found (ß = 0.002, P < 0.001). Excluding X-linked conditions, 77.1% of images were rated as gradable in men and 82.3% in women (odds ratio = 1.43, P < 0.001). By genotype, from the 30 most common genetic diagnoses in our dataset, the highest proportion of gradable images was in patients with disease-causing variants in PRPH2 (93.1%), while the lowest was in RDH12 (27.1%). Applying Retinograd-AI to filter images improved the accuracy of a gene prediction classifier from 33.8% to 68.9%. Retinograd-AI is open-sourced and available at https://github.com/Eye2Gene/retinograd-ai. CONCLUSIONS: Retinograd-AI is an open-source AI model for automated retinal image quality assessment of FAF images in IRDs. Automated gradability assessment through Retinograd-AI enables large-scale analysis of retinal images and the development of robust analysis pipelines. Quality assessment is essential for the deployment of AI algorithms, such as Eye2Gene, into clinical settings. Due to the diverse nature of IRD pathologies, Retinograd-AI will be extended to other conditions, either in its current form or through transfer learning and fine-tuning. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Interaction between native and prosthetic visual responses in optogenetic visual restoration.
Degenerative retinal disorders leading to irreversible photoreceptor death are a common cause of blindness. Optogenetic gene therapy aims to restore vision in affected individuals by introducing light sensitive opsins into the surviving neurons of the inner retina. While up until now the main focus of optogenetic therapy has been on terminally blind individuals, treating at stages where residual native vision is present could have several advantages. Yet, it is still unknown how residual native and optogenetic vision would interact if present at the same time. Using transgenic mice expressing the optogenetic tool ReaChR in ON-bipolar cells, we herein examine this interaction through electroretinography (ERG) and visually evoked potentials (VEP). We find that optogenetic responses show a peculiar ERG signature and are enhanced in retinas without photoreceptor loss. Conversely, native responses are dampened in the presence of ReaChR. Moreover, in VEP recordings we find that optogenetic responses reach the cortex asynchronous to the native response. These findings should be taken into consideration when planning future clinical trials and may direct future preclinical research to optimize optogenetic approaches for visual restoration. The identified ERG signatures moreover may serve to track treatment efficiency in clinical trials.
Myasthenic syndromes: mistaking genetic for acquired.
Congenital myasthenic syndromes (CMS) are a rare, heterogeneous group of disorders caused by pathogenic variants in genes encoding proteins essential for neuromuscular transmission. DOK7 variants are among the most common causes of CMS and one of the subtypes that may worsen with pyridostigmine. We report two patients who presented in adulthood with fatigable limb girdle weakness, initially diagnosed with seronegative myasthenia gravis, who slowly progressed over time despite escalating treatment and eventually needed intensive care admission. Revisiting the history led to the diagnosis of DOK7 CMS. Both patients improved after stopping immunosuppressants and pyridostigmine and starting salbutamol. These cases highlight the importance of considering CMS in patients with seronegative myasthenia gravis.
Occurrence, associated factors, and outcomes of delirium in patients in an adult acute general medicine service in England: a 10-year longitudinal, observational study.
BACKGROUND: Reliable estimates of delirium occurrence and outcomes are necessary to inform hospital services, research, and policy, but inclusive cohorts with long-term follow-up are scarce. We aimed to assess the age-specific occurrence of delirium in acute general (internal) medicine, associated factors, and 10-year outcomes stratified by age and comorbid dementia status. METHODS: This longitudinal, observational study was done at the John Radcliffe Hospital (Oxford, UK). We included consecutive adult patients aged 16 years and older in an acute general (internal) medicine service over six 8-week periods (between Sept 4, 2010, and Nov 15, 2018). Delirium was diagnosed prospectively using the Confusion Assessment Method and Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria and subcategorised as prevalent (≤48 h of admission) or incident (>48 h postadmission). Odds ratios adjusted (adjORs) for demographics, comorbidity, frailty, and illness severity were calculated for binarised outcomes and adjusted hazard ratios (adjHRs) were calculated for time to death. FINDINGS: 1846 patients were admitted to acute general (internal) medicine (mean age 68·2 years [SD 20·0], age range 16-102 years), 426 (23% [95% CI 21-25]) of whom had delirium (prevalent n=290 [68%], incident n=73 [17%], both prevalent and incident n=63 [15%]), of whom 134 (31·5%) had dementia. 950 (51·5%) patients were female, 895 (48·5%) were male, and sex data were missing for one patient. Delirium increased with age, from six (2% [95% CI 1-4]) of 340 patients younger than 50 years and 31 (9% [6-13]) of 333 patients at age 50-64 years to 57 (20% [16-25]) of 281 at age 65-74 years, 245 (35% [31-38]) of 704 at age 75-89 years, and 87 (46% [39-54]) of 188 at age 90 years and older. Of the 37 patients younger than 65 years who had delirium, 28 (76%) had an underlying neurological or neuropsychiatric disorder. In those aged 65 years or older, delirium was overall associated (all p<0·001, age and sex adjusted) with dementia (adjOR 3·63 [95% CI 2·65-4·98]), pre-admission dependency (2·63 [2·02-3·43]), comorbidity burden (1·04 [1·02-1·05]), and frailty (moderate vs low risk 3·62 [2·70-4·85] and high vs low risk 11·85 [7·24-19·42]), with stronger associations in patients without comorbid dementia than in those with comorbid dementia. Delirium predicted inpatient stay longer than 7 days (adjOR 2·48 [1·84-3·35]), discharge care needs (2·41 [1·70-3·40]), and mortality during admission (2·45 [1·52-3·94]). The increased risk of death in the delirium group was highest in the immediate postadmission period and attenuated thereafter, but was maintained for up to 10 years of follow-up (adjHR 2·03 [95% CI 1·40-2·97] for 30-day mortality vs 1·52 [1·30-1·77] for 10-year mortality). Excess inpatient mortality was highest in younger age groups versus older age groups (adjOR 4·38 [95% CI 1·18-16·31]; p=0·028 at age 65-74 years vs 1·96 [1·02-3·75]; p=0·043 at age 75-89 years and 2·86 [1·14-7·16]; p=0·025 at age 90 years or older) and in those without versus with comorbid dementia (adjOR 3·02 [1·73-5·25]; p<0·001 vs 1·47 [0·58-3·75]; p=0·42). INTERPRETATION: Our findings support current guidelines for routine on-admission delirium screening from age 65 years. Delirium outcomes are relatively more adverse in those aged 65-74 years without comorbid dementia in whom interventions and clinical trials should be prioritised. FUNDING: National Institute for Health and Care Research and the Medical Research Council.