Use of an artificial intelligence-generated vascular severity score improved plus disease diagnosis in retinopathy of prematurity.

OBJECTIVE: To evaluate whether providing clinicians with an artificial intelligence-based vascular severity score (AI-VSS) improves consistency in diagnosis of plus disease in retinopathy of prematurity (ROP). DESIGN: This is a multi-reader diagnostic accuracy imaging study. PARTICIPANTS: Eleven ROP experts (4 pediatric ophthalmologists, 7 retina specialists), 9 of which had been in practice for 10 or more years. METHODS: Retcam (Natus Medical Incorporated) fundus images were obtained from premature infants during routine ROP screening as part of the Imaging and Informatics in ROP study between January 2012 and July 2020. From all available exams, a subset of 150 eye exams from 110 infants were selected for grading. An AI-VSS was assigned to each set of images using the i-ROP DL system. The clinicians were asked to diagnose plus disease for each exam and assign an estimated VSS (range 1-9) at baseline, and then again one month later with AI-VSS assistance. A reference standard diagnosis (RSD) was assigned to each eye exam from the i-ROP study based on 3 masked expert labels and the ophthalmoscopic diagnosis. MAIN OUTCOME MEASURE: Mean linearly weighted kappa for plus disease diagnosis compared to the RSD. Area under the receiver operating characteristic and precision-recall curves (AUROC, AUPR) for 1-9 labels compared to RSD for plus disease. RESULTS: Expert agreement improved significantly from substantial (κ: 0.69 [0.59, 0.75]) to near perfect (κ: 0.81 [0.71, 0.86]) when AI-VSS was integrated. Additionally, there was a significant improvement in plus disease discrimination as measured by mean [95% confidence interval] AUROC (0.94 [0.92, 0.96] to 0.98 [0.96, 0.99], difference: 0.04 [0.01, 0.06]) and AUPR (0.86 [0.81, 0.90] to 0.95 [0.91, 0.97], difference: 0.09 [0.03, 0.14]). CONCLUSIONS: Providing ROP clinicians with an AI-based measurement of vascular severity in ROP was associated with both improved plus disease diagnosis and improved continuous severity labeling, as compared to a reference standard diagnosis for plus disease. If implemented in practice, AI-VSS could reduce inter-observer variability and standardize treatment for infants with ROP.

The Creation and Circulation of Evidence and Knowledge in American Medicine through the Lens of the "Husband's Stitch".

Physicians in the twentieth century routinely used episiotomy-a cut made during childbirth-to better facilitate labor, using the evidence of their experiences that it was useful. But physicians were not alone in producing evidence regarding episiotomy and its repair. Here I consider how three groups-male physicians, husbands, and laboring women-were involved in creating evidence and circulating knowledge about episiotomies, specifically, the intention of its repair, the so-called "husband's stitch," to sexually benefit men. By doing so I seek to consider the meanings of evidence within medicine, evidence as a basis for challenging the hegemony of medicine by lay women, and how medical knowledge is produced and shared among physicians and non-physicians.

Impaired creative cognition after surgery for an IDH-mutated glioma: A proof-of-concept study.

Assessment of high cognitive functions, such as creativity, is often overlooked in medical practice. However, it is crucial to understand the impact of brain tumors, specifically low-grade gliomas, on creative cognition, as these tumors predominantly affect brain regions associated with cognitive creativity. In this study, we investigated creative cognition using the Alternative Uses Task (AUT) and the Combination of Associates Task (CAT) in a cohort of 29 patients who underwent brain surgery for a low-grade glioma, along with 27 control participants. While the group of patients did not exhibit deficits in clinical neuropsychological assessments, our results revealed significant impairment in generating original and creative ideas compared to the control group. Furthermore, when analyzing the specific brain regions affected by the tumors, patients with lesions overlapping the left rostro-lateral prefrontal cortex, a critical region for creativity, displayed more pronounced impairments in the CAT compared to patients with lesions outside this region. These findings provide proof of concept that patients can experience impaired creative cognition following surgery for low-grade glioma, highlighting the importance of assessing higher-order cognitive functions, including creativity, in neurosurgical patients. Moreover, beyond its clinical relevance, our study contributes to advancing our understanding of the neuroscience of creativity.

Stability of the Motor Optimality Score Revised (MOS-R) in medically complex infants.

BACKGROUND: The Motor Optimality Score-Revised (MOS-R) is a clinical test of infant spontaneous movement at 3-5 months of age and has been associated with neurodevelopmental outcomes in infants with medical complexity. However the stability of the MOS-R tested at different developmental ages is not yet known. AIM: To determine if the repeated scoring of the MOS-R remained consistent when tested at two developmental ages in young infants. STUDY DESIGN: In this prospective cohort study, infants were tested twice with the MOS-R between 12 and 13 weeks corrected age (CA) and 14-16 weeks CA. Bland Altman Plots were used to calculate agreement between the scores. Infants were grouped as having higher or lower medical complexity. MOS-R threshold scores were analyzed to assess changes over time within each group using Fisher's exact test. SUBJECTS: 85 infants with history of hospitalization in a neonatal intensive care unit (NICU). RESULTS: The MOS-R scores had a high agreement with negligible bias (0.058) between timepoints (95 % CI -1.10, 1.22). Using a MOS-R cut point of 19, infants with higher medical complexity were more likely to change groups between timepoints than infants with lower medical complexity (p = 0.008), but this was not significantly different using cut points of 20 or 21. CONCLUSION: The MOS-R scores were stable when measured repeatedly in infants who were hospitalized in a NICU. Infants with high medical complexity had less stable MOS-R scores using certain cut points than infants with lower medical complexity.

Assessing Neonatal Intensive Care Unit (NICU) Graduates Across Varied Settings: A Study on the Feasibility of the Baby Moves App.

We assessed the feasibility of obtaining parent-collected General Movement Assessment videos using the Baby Moves app. Among 261 participants from 4 Chicago NICUs, 70% submitted videos. Families living in higher areas of childhood opportunity used the app more than those from areas of lower opportunity.

Racial Differences in Choroidal Vascularity Index in Healthy Patients: Novel Insights.

BACKGROUND AND OBJECTIVE: Choroidal vascularity index (CVI) measures the ratio of blood vessels in the choroid to the total choroidal area. We aimed to compare CVI between young Black and White patients without a history of ocular or systemic disease. PATIENTS AND METHODS: We used a previously validated algorithm for shadow compensation and choroidal vessel binarization to measure CVI across the Early Treatment of Diabetic Retinopathy Study grid. RESULTS: Black patients had a lower CVI (ß = -0.05, P < 0.001) compared to White patients. Choroidal volume or luminal volume did not significantly differ with respect to race, whereas there was a trend for Black patients to have a greater stromal volume (ß = 3.08, P = 0.01). CONCLUSIONS: Black patients have a lower CVI than do White patients, likely due to a greater proportion of stromal volume. Further study of this parameter is warranted to validate the findings of this exploratory study. [Ophthalmic Surg Lasers Imaging Retina 2024;55:30-38.].

How subjective idea valuation energizes and guides creative idea generation.

What drives us to search for creative ideas, and why does it feel good to find one? While previous studies demonstrated the positive influence of motivation on creative abilities, how reward and subjective values play a role in creativity remains unknown. This study proposes to characterize the role of individual preferences (how people value ideas) in creative ideation via behavioral experiments and computational modeling. Using the Free Generation of Associates Task coupled with rating tasks, we demonstrate the involvement of valuation processes during idea generation: Preferred ideas are provided faster. We found that valuation depends on the adequacy and originality of ideas and guides response selection and creativity. Finally, our computational model correctly predicts the speed and quality of human creative responses, as well as interindividual differences in creative abilities. Altogether, this model introduces the mechanistic role of valuation in creativity. It paves the way for a neurocomputational account of creativity mechanisms. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

FULL-THICKNESS MACULAR HOLE CLOSURE WITH TOPICAL MEDICAL THERAPY.

PURPOSE: To examine the efficacy and clinical characteristics of successful full-thickness macular hole closure with topical therapy. METHODS: Retrospective case series of full-thickness macular holes managed by a single retinal physician (DS) diagnosed and treated from 2017 to 22. RESULTS: Of 168 patients with full-thickness macular holes, 71 patients were started on steroid, carbonic anhydrase inhibitor, and nonsteroidal antiinflammatory (NSAID) drops. 49 patients (mean 67 years, 59% women) were included in the analysis, and 22 patients were excluded for poor follow-up. In total, 7/49 were secondary post-PPV holes and 42/49 were idiopathic. In addition, 18/49 eyes (36.7%) achieved closure on topical therapy, of which 13 were idiopathic. Hole size was directly correlated with odds of closure: for every 10 µm decrease in size and odds of closure increased by 1.2× ( P = 0.001, CI 1.1-1.4). Average time to closure was 107.2 days (range 20-512 days) and was not correlated with hole size ( P = 0.217, CI -0.478 to +1.938). The presence of VMT was found to be inversely related to successful closure (OR 6.1, P = 0.029, CI 1.2-31.3). There was no significant difference in final best-corrected visual acuity for eyes undergoing primary pars plana vitrectomy versus those trialing drops before undergoing pars plana vitrectomy ( P = 0.318, CI -0.094 to +0.112). CONCLUSION: In the first study to date to report the overall efficacy and clinical characteristics of successful macular hole closure with topical therapy, drops achieved an overall closure rate of 36.7%, with higher efficacy in smaller holes and those without VMT. Rates of MH narrowing and reduction in central foveal thickness acted as predictors of effectiveness of drop therapy.

Factors associated with sexual quality of life among men living with HIV.

INTRODUCTION: This study aims to assess the prevalence of sexual difficulties and identify factors associated with the Sexual Quality of Life (SQoL) among people living with HIV (PLWHA). METHODS: The study included 107 heterosexual men and 474 men who have sex with men (MSM) from five countries. Participants self-reported variables related to physical and mental health, as well as HIV-related parameters. Erectile or ejaculation difficulty, as well as low sexual desire, were investigated. SQoL was measured using the PROQOL-SexLife questionnaire. RESULTS: Most of participants reported low sexual desire, predominantly among MSM. Among MSM, living with a partner and healthcare satisfaction were associated with SQoL scores in POP dimension, while consistent condom use, cardiovascular complications, and being single were associated with SQoL scores in STI dimension. Viagra use, anti-cholesterol treatment, and living with a partner were associated with SQoL scores in DIS dimension. Among heterosexual men, employment and African origin were associated with SQoL scores in the POP dimension. Alcohol consumption was associated with SQoL scores in STI dimension. CONCLUSION: This study underscores the importance of non-clinical determinants when assessing SQoL among PLWHA, emphasizing psychological factors and the perceived quality of healthcare. Tailored interventions should incorporate these findings to enhance overall SQoL outcomes.

Association of Health Insurance Status With Severity and Treatment Among Infants With Retinopathy of Prematurity.

This study describes retinopathy of prematurity treatment practices using Medicaid and commercial claims databases. Infants with Medicaid tend to be sicker overall and have higher rates of retinopathy of prematurity requiring treatment than those with commercial insurance. Among patients who required treatment, those with Medicaid were more likely to receive anti-vascular endothelial growth factor than laser treatment. [J Pediatr Ophthalmol Strabismus. 2023;60(6):e75-e78.].

Identifying novel candidate compounds for therapeutic strategies in retinopathy of prematurity via computational drug-gene association analysis.

Purpose: Retinopathy of prematurity (ROP) is the leading cause of preventable childhood blindness worldwide. Although interventions such as anti-VEGF and laser have high success rates in treating severe ROP, current treatment and preventative strategies still have their limitations. Thus, we aim to identify drugs and chemicals for ROP with comprehensive safety profiles and tolerability using a computational bioinformatics approach. Methods: We generated a list of genes associated with ROP to date by querying PubMed Gene which draws from animal models, human studies, and genomic studies in the NCBI database. Gene enrichment analysis was performed on the ROP gene list with the ToppGene program which draws from multiple drug-gene interaction databases to predict compounds with significant associations to the ROP gene list. Compounds with significant toxicities or without known clinical indications were filtered out from the final drug list. Results: The NCBI query identified 47 ROP genes with pharmacologic annotations present in ToppGene. Enrichment analysis revealed multiple drugs and chemical compounds related to the ROP gene list. The top ten most significant compounds associated with ROP include ascorbic acid, simvastatin, acetylcysteine, niacin, castor oil, penicillamine, curcumin, losartan, capsaicin, and metformin. Antioxidants, NSAIDs, antihypertensives, and anti-diabetics are the most common top drug classes derived from this analysis, and many of these compounds have potential to be readily repurposed for ROP as new prevention and treatment strategies. Conclusion: This bioinformatics analysis creates an unbiased approach for drug discovery by identifying compounds associated to the known genes and pathways of ROP. While predictions from bioinformatic studies require preclinical/clinical studies to validate their results, this technique could certainly guide future investigations for pathologies like ROP.

Pediatric cataracts of different etiologies contain insoluble, calcified particles.

Our recent studies in mice suggest that a crucial event for the development of cataracts is the formation of calcium-containing deposits. To examine the generality of pathologic mineralization as a novel mechanism of cataract formation, we analyzed lens material from different human cataract surgeries. Human lens material was obtained from routine cataract surgeries performed on three patients with dense, white cataracts: a 10-month-old with congenital cataracts, a 9-year-old with a uveitic cataract, and a 17-year-old with a traumatic cataract. The aspirated material from the cataract surgeries contained insoluble material that could be isolated by centrifugation. Many particles within the insoluble fraction stained with Alizarin red, a dye that stains insoluble calcified material. The appearance of these human insoluble, Alizarin red-stained particles was similar to some of those detected in homogenates from cataractous mouse lenses. These results support the hypothesis that pathologic mineralization may have a mechanistic role in the formation of cataracts of different etiologies.

Biomarkers of Pediatric Cataracts: A Proteomics Analysis of Aqueous Fluid.

Cataracts are among the most common causes of childhood vision loss worldwide. This study seeks to identify differentially expressed proteins in the aqueous humor of pediatric cataract patients. Samples of aqueous humor were collected from pediatric and adult cataract patients and subjected to mass spectrometry-based proteomic analysis. Samples of pediatric cataracts were grouped by subtype and compared to adult samples. Differentially expressed proteins in each subtype were identified. Gene ontology analysis was performed using WikiPaths for each cataract subtype. Seven pediatric patients and ten adult patients were included in the study. Of the pediatric samples, all seven (100%) were male, three (43%) had traumatic cataracts, two (29%) had congenital cataracts, and two (29%) had posterior polar cataracts. Of the adult patients, seven (70%) were female and seven (70%) had predominantly nuclear sclerotic cataracts. A total of 128 proteins were upregulated in the pediatric samples, and 127 proteins were upregulated in the adult samples, with 75 proteins shared by both groups. Gene ontology analysis identified inflammatory and oxidative stress pathways as upregulated in pediatric cataracts. Inflammatory and oxidative stress mechanisms may be involved in pediatric cataract formation and warrant further investigation.

A leucine-rich repeat kinase 2 (LRRK2) pathway biomarker characterization study in patients with Parkinson's disease with and without LRRK2 mutations and healthy controls.

Increased leucine-rich repeat kinase 2 (LRRK2) kinase activity is an established risk factor for Parkinson's disease (PD), and several LRRK2 kinase inhibitors are in clinical development as potential novel disease-modifying therapeutics. This biomarker characterization study explored within- and between-subject variability of multiple LRRK2 pathway biomarkers (total LRRK2 [tLRRK2], phosphorylation of the serine 935 (Ser935) residue on LRRK2 [pS935], phosphorylation of Rab10 [pRab10], and total Rab10 [tRab10]) in different biological sources (whole blood, peripheral blood mononuclear cells [PBMCs], neutrophils) as candidate human target engagement and pharmacodynamic biomarkers for implementation in phase I/II pharmacological studies of LRRK2 inhibitors. PD patients with a LRRK2 mutation (n = 6), idiopathic PD patients (n = 6), and healthy matched control subjects (n = 10) were recruited for repeated blood and cerebrospinal fluid (CSF) sampling split over 2 days. Within-subject variability (geometric coefficient of variation [CV], %) of these biomarkers was lowest in whole blood and neutrophils (range: 12.64%-51.32%) and considerably higher in PBMCs (range: 34.81%-273.88%). Between-subject variability displayed a similar pattern, with relatively lower variability in neutrophils (range: 61.30%-66.26%) and whole blood (range: 44.94%-123.11%), and considerably higher variability in PBMCs (range: 189.60%-415.19%). Group-level differences were observed with elevated mean pRab10 levels in neutrophils and a reduced mean pS935/tLRRK2 ratio in PBMCs in PD LRRK2-mutation carriers compared to healthy controls. These findings suggest that the evaluated biomarkers and assays could be used to verify pharmacological mechanisms of action and help explore the dose-response of LRRK2 inhibitors in early-phase clinical studies. In addition, comparable α-synuclein aggregation in CSF was observed in LRRK2-mutation carriers compared to idiopathic PD patients.

Racial differences in quantitative optical coherence tomography angiography findings between older non-diabetics with co-morbidities.

This cross-sectional study compared optical coherence tomography angiography (OCTA) parameters between older Black and White adults with systemic comorbidities in an effort to further understand racial differences in the retinal microvasculature. We analyzed vessel density at the superficial (SCP), intermediate (ICP), and deep capillary plexuses (DCP), foveal avascular zone (FAZ) parameters, and blood flow area (BFA) at the choriocapillaris. We used a mixed-effects linear regression model, controlling for hypertension and two eyes from the same subject, to compare OCTA parameters. Black subjects had lower foveal vessel density at the SCP and ICP, while no differences were observed at the parafovea or 3x3 mm macular area of any capillary layer. Black subjects had greater FAZ area, perimeter, and FD-300, a measurement of vessel density in a 300 µm wide ring around the FAZ. Black subjects also had lower BFA at the choriocapillaris. Within a cohort of subjects without hypertension, these differences remained statistically significant, with the exception of foveal vessel density at the SCP and foveal BFA of the choriocapillaris. These findings suggest that normative databases of OCTA parameters must strive to be diverse in nature to adequately capture differences across patient populations. Further study is required to understand if baseline differences in OCTA parameters contribute to epidemiological disparities in ocular diseases.

Retinopathy of Prematurity in the 21st Century and the Complex Impact of Supplemental Oxygen.

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. Not only do the epidemiologic determinants and distributions of patients with ROP vary worldwide, but clinical differences have also been described. The Third Edition of the International Classification of ROP (ICROP3) acknowledges that aggressive ROP (AROP) can occur in larger preterm infants and involve areas of the more anterior retina, particularly in low-resource settings with unmonitored oxygen supplementation. As sub-specialty training programs are underway to address an epidemic of ROP in sub-Saharan Africa, recognizing characteristic retinal pathology in preterm infants exposed to unmonitored supplemental oxygen is important to proper diagnosis and treatment. This paper describes specific features associated with various ROP presentations: oxygen-induced retinopathy in animal models, traditional ROP seen in high-income countries with modern oxygen management, and ROP related to excessive oxygen supplementation in low- and middle-income countries: oxygen-associated ROP (OA-ROP).

LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease.

BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising therapeutic approach for the treatment of Parkinson's disease (PD). OBJECTIVE: The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the potent, selective, CNS-penetrant LRRK2 inhibitor BIIB122 (DNL151) in healthy participants and patients with PD. METHODS: Two randomized, double-blind, placebo-controlled studies were completed. The phase 1 study (DNLI-C-0001) evaluated single and multiple doses of BIIB122 for up to 28 days in healthy participants. The phase 1b study (DNLI-C-0003) evaluated BIIB122 for 28 days in patients with mild to moderate PD. The primary objectives were to investigate the safety, tolerability, and plasma pharmacokinetics of BIIB122. Pharmacodynamic outcomes included peripheral and central target inhibition and lysosomal pathway engagement biomarkers. RESULTS: A total of 186/184 healthy participants (146/145 BIIB122, 40/39 placebo) and 36/36 patients (26/26 BIIB122, 10/10 placebo) were randomized/treated in the phase 1 and phase 1b studies, respectively. In both studies, BIIB122 was generally well tolerated; no serious adverse events were reported, and the majority of treatment-emergent adverse events were mild. BIIB122 cerebrospinal fluid/unbound plasma concentration ratio was ~1 (range, 0.7-1.8). Dose-dependent median reductions from baseline were observed in whole-blood phosphorylated serine 935 LRRK2 (≤98%), peripheral blood mononuclear cell phosphorylated threonine 73 pRab10 (≤93%), cerebrospinal fluid total LRRK2 (≤50%), and urine bis (monoacylglycerol) phosphate (≤74%). CONCLUSIONS: At generally safe and well-tolerated doses, BIIB122 achieved substantial peripheral LRRK2 kinase inhibition and modulation of lysosomal pathways downstream of LRRK2, with evidence of CNS distribution and target inhibition. These studies support continued investigation of LRRK2 inhibition with BIIB122 for the treatment of PD. © 2023 Denali Therapeutics Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Gut Microbiome and Retinopathy of Prematurity.

Retinopathy of prematurity (ROP), a leading cause of childhood blindness worldwide, is strongly associated with gestational age and weight at birth. Yet, many extremely preterm infants never develop ROP or develop only mild ROP with spontaneous regression. In addition, a myriad of other factors play a role in the retinal pathology, one of which may include the early gut microbiome. The complications associated with early gestational age include dysbiosis of the dynamic neonatal gut microbiome, as evidenced by the development of often concomitant conditions, such as necrotizing enterocolitis. Given this, alongside growing evidence for a gut-retina axis, there is an increasing interest in how the early intestinal environment may play a role in the pathophysiology of ROP. Potential mechanisms include dysregulation of vascular endothelial growth factor and insulin-like growth factor 1. Furthermore, the gut microbiome may be impacted by other known risk factors for ROP, such as intermittent hypoxia and sepsis treated with antibiotics. This mini-review summarizes the literature supporting these proposed avenues, establishing a foundation to guide future studies.