Investigating Biomarkers for USH2A Retinopathy Using Multimodal Retinal Imaging.

Pathogenic mutations in USH2A are a leading cause of visual loss secondary to non-syndromic or Usher syndrome-associated retinitis pigmentosa (RP). With an increasing number of RP-targeted clinical trials in progress, we sought to evaluate the photoreceptor topography underlying patterns of loss observed on clinical retinal imaging to guide surrogate endpoint selection in USH2A retinopathy. In this prospective cross-sectional study, twenty-five patients with molecularly confirmed USH2A-RP underwent fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT) and adaptive optics scanning laser ophthalmoscopy (AOSLO) retinal imaging. Analysis comprised measurement of FAF horizontal inner (IR) and outer (OR) hyperautofluorescent ring diameter; SD-OCT ellipsoid zone (EZ) and external limiting membrane (ELM) width, normalised EZ reflectance; AOSLO foveal cone density and intact macular photoreceptor mosaic (IMPM) diameter. Thirty-two eyes from 16 patients (mean age ± SD, 36.0 ± 14.2 years) with USH2A-associated Usher syndrome type 2 (n = 14) or non-syndromic RP (n = 2) met the inclusion criteria. Spatial alignment was observed between IR-EZ and OR-ELM diameters/widths (p < 0.001). The IMPM border occurred just lateral to EZ loss (p < 0.001), although sparser intact photoreceptor inner segments were detected until ELM disruption. EZ width and IR diameter displayed a biphasic relationship with cone density whereby slow cone loss occurred until retinal degeneration reached ~1350 µm from the fovea, beyond which greater reduction in cone density followed. Normalised EZ reflectance and cone density were significantly associated (p < 0.001). As the strongest correlate of cone density (p < 0.001) and best-corrected visual acuity (p < 0.001), EZ width is the most sensitive biomarker of structural and functional decline in USH2A retinopathy, rendering it a promising trial endpoint.

Prevalence of Potentially Inappropriate Medications in Older Adults with Cognitive Impairment or Dementia Attending Memory Clinics: A Systematic Review and Meta-Analysis.

Background: Older adults with dementia who are on polypharmacy are more vulnerable to the use of potentially inappropriate medications (PIM), which can significantly increase the risk of adverse events and drug-related problems (DRPs). Objective: This systematic review and meta-analysis were conducted to map the prevalence of PIM use, polypharmacy, and hyper-polypharmacy among older adults with cognitive impairment or dementia attending memory clinics. Methods: Ovid MEDLINE, Ovid EMBASE, Scopus, Cochrane Library, EBSCOhost CINAHL, and Ovid International Pharmaceutical Abstracts (IPA) were systematically searched from inception to April 22, 2024. Observational studies assessing the PIMs use among older adults with CI or dementia were screened. A random- effects meta-analysis was conducted to pool the prevalence estimates. Results: Of 5,787 identified citations, 11 studies including 4,571 participants from 8 countries were included. Among all the included studies the pooled prevalence of PIM use was 38% (95% confidence interval (CIn): 27- 50%), highlighting a notable range from 20% to 78%. The analysis identified anticholinergics, benzodiazepines, and non-benzodiazepine sedatives as the most common PIMs. Subgroup analysis revealed a higher pooled prevalence of PIM in the USA (39%; 95% CIn: 10- 78, I2 (%) = 98, 3 studies) and Australia (36%, 95% CIn: 12- 70, I2 (%) = 96, 2 Studies). Additionally, pooled prevalence of polypharmacy and hyper-polypharmacy was reported as (60%; 95% CIn: 46- 73, I2 (%) = 95, 3 studies), and (The prevalence of hyper-polypharmacy was 17.6%; 1 study) respectively. Conclusions: The definition of PIMs significantly impacts study results, often more than geographical variations. The variability in criteria and tools like the Beers or Screening Tool of Older Persons' Prescriptions (STOPP) criteria across studies and regions leads to differing prevalence rates.

Use of Potentially Inappropriate Medications among Older Adults with Dementia or Cognitive Impairment Attending Memory Clinics: A Protocol for a Systematic Review and Meta-Analysis.

Introduction: Older adults with dementia who are on multiple medications are more vulnerable to the use of potentially inappropriate medications (PIMs), which can significantly increase the risk of adverse events and drug-related problems. PIMs use is prevalent and varies among older adults with dementia or cognitive impairment (CI) attending memory clinics. However, the prevalence of PIMs, polypharmacy, and hyper-polypharmacy among older adults with dementia or CI who are attending memory clinics is not well understood. We will conduct a systematic review and meta-analyses to examine the overall estimate of the prevalence of the PIMs, polypharmacy, and hyper-polypharmacy use among older adults attending memory clinics, with dementia or CI. The secondary objective of this study will be to compile a list of commonly implicated PIMs and to investigate factors that may be associated with using PIMs in this population. Methods: Ovid MEDLINE, Ovid Embase, Scopus, Cochrane library, EBSCOhost CINAHL, and Ovid International Pharmaceutical Abstracts (IPA) will be systematically searched by a researcher (R.S.) with the help of a librarian (C.C.). All databases will be searched from inception to May 05, 2023. Cross-sectional, cohort, randomized clinical trials, quasi-experimental, and case-control studies will be included if they assess PIM's use among older adults with dementia and/or CI. A step-by-step guide by Pai et al. [Natl Med J India. 2004;17(2):86-95] will be followed when conducting this systematic review (S.R.). The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist will be followed for reporting this SR. Conclusion: The findings from this SR/MA will identify the pooled prevalence of PIMs, providing a more precise estimate of the true prevalence of the PIMs, polypharmacy, hyper-polypharmacy in older adults with dementia or CI who are attending memory clinics at primary, secondary, or tertiary healthcare settings by considering the results of multiple studies.

Repetitive transcranial magnetic stimulation: Course and early prediction of response in depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression, yet few studies have mapped the trajectories of symptom change over treatment. Tracking clinical response during early treatment may be helpful to predict outcome, particularly non-response. METHODS: We used naturalistic data (N = 117) to examine changes in the Daily Symptom Index (DI-5) scores of adult patients with unipolar or bipolar depression who underwent ≥16 treatment sessions of left dorsolateral prefrontal cortex rTMS at a private psychiatric facility in Western Australia, between 2016 and 2019. RESULTS: Two response trajectories were charted: non-response (N = 71, 61%) and response (N = 46, 39%). Both trajectories diverged at 99% confidence interval at session 10, which was used as the point to predict treatment response at session 20. The response group showed a reduction of 4.21 in the mean DI-5 score from baseline at session 10. On this basis, a 4-point reduction in the DI-5 score at session 10 was defined as predictor of responder status at session 20. If the improvement is < 4 points at session 10, the probability of non-response at session 20 is 75%. If the improvement is ≥ 4 points, the probability of response at session 20 is 66%. LIMITATIONS: The DI-5 scores were not examined beyond 20 treatment sessions, which may have shown delayed responders in the non-response group. CONCLUSIONS: In this study of depression response trajectories with rTMS treatment, prediction of response at session 20 can be made at session 10 of treatment. Further research is required to generalise the current findings.

Characterisation of microvascular abnormalities using OCT angiography in patients with biallelic variants in USH2A and MYO7A.

AIMS: Using optical coherence tomography angiography (OCTA) to characterise microvascular changes in the retinal plexuses and choriocapillaris (CC) of patients with MYO7A and USH2A mutations and correlate with genotype, retinal structure and function. METHODS: Twenty-seven patients with molecularly confirmed USH2A (n=21) and MYO7A (n=6) mutations underwent macular 6×6 mm OCTA using the AngioVue. Heidelberg spectral-domain OCT scans and MAIA microperimetry were also performed, the preserved ellipsoid zone (EZ) band width and mean macular sensitivity (MS) were recorded. OCTA of the inner retina, superficial capillary plexus (SCP), deep capillary plexus (DCP) and CC were analysed. Vessel density (VD) was calculated from the en face OCT angiograms of retinal circulation. RESULTS: Forty-eight eyes with either USH2A (n=37, mean age: 34.4±12.2 years) or MYO7A (n=11, mean age: 37.1±12.4 years), and 35 eyes from 18 age-matched healthy participants were included. VD was significantly decreased in the retinal circulation of patients with USH2A and MYO7A mutations compared with controls (p<0.001). Changes were observed in both the SCP and DCP, but no differences in retinal perfusion were detected between USH2A and MYO7A groups. No vascular defects were detected in CC of the USH2A group, but peripheral defects were detected in older MYO7A patients from the fourth decade of life. VD in the DCP showed strong association with MS and EZ width (Spearman's rho =0.64 and 0.59, respectively, p<0.001). CONCLUSION: OCTA was able to detect similar retinal microvascular changes in patients with USH2A and MYO7A mutations. The CC was generally affected in MYO7A mutations. OCT angiography may further enhance our understanding of inherited eye diseases and their phenotype-genotype associations.

Cellular imaging of inherited retinal diseases using adaptive optics.

Adaptive optics (AO) is an insightful tool that has been increasingly applied to existing imaging systems for viewing the retina at a cellular level. By correcting for individual optical aberrations, AO offers an improvement in transverse resolution from 10-15 µm to ~2 µm, enabling assessment of individual retinal cell types. One of the settings in which its utility has been recognised is that of the inherited retinal diseases (IRDs), the genetic and clinical heterogeneity of which warrants better cellular characterisation. In this review, we provide a summary of the basic principles of AO, its integration into multiple retinal imaging modalities and its clinical applications, focusing primarily on IRDs. Furthermore, we present a comprehensive summary of AO-based cellular findings in IRDs according to their associated disease-causing genes.

Progressive cone and cone-rod dystrophies: clinical features, molecular genetics and prospects for therapy.

Progressive cone and cone-rod dystrophies are a clinically and genetically heterogeneous group of inherited retinal diseases characterised by cone photoreceptor degeneration, which may be followed by subsequent rod photoreceptor loss. These disorders typically present with progressive loss of central vision, colour vision disturbance and photophobia. Considerable progress has been made in elucidating the molecular genetics and genotype-phenotype correlations associated with these dystrophies, with mutations in at least 30 genes implicated in this group of disorders. We discuss the genetics, and clinical, psychophysical, electrophysiological and retinal imaging characteristics of cone and cone-rod dystrophies, focusing particularly on four of the most common disease-associated genes: GUCA1A, PRPH2, ABCA4 and RPGR Additionally, we briefly review the current management of these disorders and the prospects for novel therapies.

Stroke-induced resolution of primary blepharospasm: evidence for the lenticular nucleus as a control candidate.

Primary blepharospasm is an adult-onset focal dystonia characterised by involuntary contractions of the orbicularis oculi, leading to bilateral spasmodic closure of the eyelids. While spasms of this muscle constitute the hallmark of disease, other motor manifestations include increased spontaneous blinking and apraxia of eyelid opening. Originally misdiagnosed as a psychiatric condition, blepharospasm is now well established as being of neurological origin although questions remain as to its pathophysiological mechanisms.We report a 66-year-old woman who had a 14-year history of primary blepharospasm which completely resolved following a left medial cerebral artery thromboembolic infarct of the lenticular nucleus. This report provides supporting evidence of the lenticular nucleus as a key structure mediating the disease which can lead to functional blindness.

Presenting patient data in the electronic care record: the role of timelines.

OBJECTIVE: To establish the current level of awareness and investigate the use of timelines within clinical computing systems as an organized display of the electronic patient record (EPR). DESIGN: Multicentre survey conducted using questionnaires and interview. SETTING: Seven UK hospitals and several general practice surgeries. PARTICIPANTS: A total of 120 healthcare professionals completed a questionnaire which directed structured interviews. Participants fell into two cohorts according to whether or not they had used clinical timelines, which gave 60 'timeline users' and 60 'prospective timeline users'. MAIN OUTCOME MEASURES: To investigate the awareness of timelines, and the potential benefits of timelines within clinical computing systems. RESULTS: Fifty-eight percent of participants had not heard of the specific term 'timelines' despite 75% of users utilizing a form of timeline on a daily basis. The potential benefits of future timelines were clinical audit (95%CI 77.6-91.6), increased time efficiency (95%CI 77.7-91.6%), reduced clinical error (95%CI 71.0-86.7) and improved patient safety (95%CI 70.0-85.9). One continuous timeline view between primary and secondary care was considered to be of great potential benefit in allowing communication via a unified patient record. CONCLUSIONS: The concept of timelines has enjoyed proven success in healthcare in the USA and in other sectors worldwide. Clinicians are supportive of timelines in healthcare. Formal input from clinicians should be sought when designing and implementing computer systems in healthcare. Timelines in healthcare support clinicians' cognitive processes by improving the amount of data available and improving the way in which data are presented.