Transparency in Artificial Intelligence Reporting in Ophthalmology-A Scoping Review.

Topic: This scoping review summarizes artificial intelligence (AI) reporting in ophthalmology literature in respect to model development and validation. We characterize the state of transparency in reporting of studies prospectively validating models for disease classification. Clinical Relevance: Understanding what elements authors currently describe regarding their AI models may aid in the future standardization of reporting. This review highlights the need for transparency to facilitate the critical appraisal of models prior to clinical implementation, to minimize bias and inappropriate use. Transparent reporting can improve effective and equitable use in clinical settings. Methods: Eligible articles (as of January 2022) from PubMed, Embase, Web of Science, and CINAHL were independently screened by 2 reviewers. All observational and clinical trial studies evaluating the performance of an AI model for disease classification of ophthalmic conditions were included. Studies were evaluated for reporting of parameters derived from reporting guidelines (CONSORT-AI, MI-CLAIM) and our previously published editorial on model cards. The reporting of these factors, which included basic model and dataset details (source, demographics), and prospective validation outcomes, were summarized. Results: Thirty-seven prospective validation studies were included in the scoping review. Eleven additional associated training and/or retrospective validation studies were included if this information could not be determined from the primary articles. These 37 studies validated 27 unique AI models; multiple studies evaluated the same algorithms (EyeArt, IDx-DR, and Medios AI). Details of model development were variably reported; 18 of 27 models described training dataset annotation and 10 of 27 studies reported training data distribution. Demographic information of training data was rarely reported; 7 of the 27 unique models reported age and gender and only 2 reported race and/or ethnicity. At the level of prospective clinical validation, age and gender of populations was more consistently reported (29 and 28 of 37 studies, respectively), but only 9 studies reported race and/or ethnicity data. Scope of use was difficult to discern for the majority of models. Fifteen studies did not state or imply primary users. Conclusion: Our scoping review demonstrates variable reporting of information related to both model development and validation. The intention of our study was not to assess the quality of the factors we examined, but to characterize what information is, and is not, regularly reported. Our results suggest the need for greater transparency in the reporting of information necessary to determine the appropriateness and fairness of these tools prior to clinical use. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Age-associated impairment of T cell immunity is linked to sex-dimorphic elevation of N-glycan branching.

Impaired T cell immunity with aging increases mortality from infectious disease. The branching of Asparagine-linked glycans is a critical negative regulator of T cell immunity. Here we show that branching increases with age in females more than males, in naïve more than memory T cells, and in CD4+ more than CD8+ T cells. Female sex hormones and thymic output of naïve T cells (TN) decrease with age, however neither thymectomy nor ovariectomy altered branching. Interleukin-7 (IL-7) signaling was increased in old female more than male mouse TN cells, and triggered increased branching. N-acetylglucosamine, a rate-limiting metabolite for branching, increased with age in humans and synergized with IL-7 to raise branching. Reversing elevated branching rejuvenated T cell function and reduced severity of Salmonella infection in old female mice. These data suggest sex-dimorphic antagonistic pleiotropy, where IL-7 initially benefits immunity through TN maintenance but inhibits TN function by raising branching synergistically with age-dependent increases in N-acetylglucosamine.

Photodynamic Therapy with Verteporfin for Choroidal Metastasis Refractory to Radiotherapy.

A 54-year old female with longstanding metastatic breast cancer was referred for management of choroidal metastases. She was first treated with external beam radiotherapy and experienced some response before later suffering progression of her eye disease. We then treated her using full fluence Photodynamic therapy (PDT) with Verteporfin, which resulted in regression of her lesions until she passed away due to other illnesses. This is the first documented successful application of PDT for choroidal metastasis from a primary breast cancer refractory to external beam radiotherapy.

Risk of vigabatrin-associated brain abnormalities on MRI in the treatment of infantile spasms is dose-dependent.

OBJECTIVE: Although the link between vigabatrin (VGB) and retinotoxicity is well known, little attention has been focused on the risk of VGB-associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM), namely reversible-and largely asymptomatic-signal changes in the thalami, basal ganglia, brainstem tegmentum, and cerebellar nuclei. Using a large infantile spasms cohort, we set out to identify predictors of these phenomena. METHODS: Children with infantile spasms were retrospectively identified. Brain MRI reports were serially reviewed without knowledge of VGB exposure. Upon VABAM discovery, records were systematically reviewed to ascertain presence of symptoms attributable to VGB. Separately, progress notes were sequentially reviewed to identify and quantify VGB exposure. RESULTS: We identified 507 brain MRI studies among 257 patients with infantile spasms. VGB treatment was documented in 143 children, with detailed exposure data available for 104, of whom 45 had at least one MRI study during VGB treatment. Among the limited subset of asymptomatic children who underwent MRI (n = 40), 6 exhibited VABAM. Risk of asymptomatic VABAM was dose-dependent, as peak (but not cumulative) VGB dosage was strongly associated with asymptomatic VABAM (p = 0.0028). In an exploratory analysis, we encountered 4 children with symptomatic VABAM among 104 patients with detailed VGB exposure data. Risk of symptomatic VABAM was seemingly dose-independent, and potentially associated with concomitant hormonal therapy (i.e., prednisolone and adrenocorticotropic hormone [ACTH]) (p = 0.039). SIGNIFICANCE: We have demonstrated dose-dependent risk of asymptomatic VABAM and uncovered a possible association between symptomatic VABAM and concomitant hormonal therapy. Caution should be exercised in the use of high VGB dosage (i.e., >175 mg/kg/day), and further study is warranted to confirm the potential impact of hormonal therapy.

Golgi self-correction generates bioequivalent glycans to preserve cellular homeostasis.

Essential biological systems employ self-correcting mechanisms to maintain cellular homeostasis. Mammalian cell function is dynamically regulated by the interaction of cell surface galectins with branched N-glycans. Here we report that N-glycan branching deficiency triggers the Golgi to generate bioequivalent N-glycans that preserve galectin-glycoprotein interactions and cellular homeostasis. Galectins bind N-acetyllactosamine (LacNAc) units within N-glycans initiated from UDP-GlcNAc by the medial-Golgi branching enzymes as well as the trans-Golgi poly-LacNAc extension enzyme ß1,3-N-acetylglucosaminyltransferase (B3GNT). Marginally reducing LacNAc content by limiting N-glycans to three branches results in T-cell hyperactivity and autoimmunity; yet further restricting branching does not produce a more hyperactive state. Rather, new poly-LacNAc extension by B3GNT maintains galectin binding and immune homeostasis. Poly-LacNAc extension is triggered by redistribution of unused UDP-GlcNAc from the medial to trans-Golgi via inter-cisternal tubules. These data demonstrate the functional equivalency of structurally dissimilar N-glycans and suggest a self-correcting feature of the Golgi that sustains cellular homeostasis.

A lack of clinically apparent vision loss among patients treated with vigabatrin with infantile spasms: The UCLA experience.

BACKGROUND: Vigabatrin (VGB) is one of two FDA-approved medications for treatment of infantile spasms. Despite demonstrated efficacy, its use has been curtailed by reports indicating a substantial risk of VGB-associated visual field loss (VAVFL). As these reports have conflicted with our clinical observations in routine practice, we systematically reviewed the experiences of patients treated with VGB at UCLA to estimate the prevalence of clinically apparent VAVFL. METHODS: Patients with video-EEG-confirmed infantile spasms evaluated at our center between February 2007 and February 2014 were retrospectively identified. Among patients with VGB exposure, we documented relevant clinical factors and determined the duration of therapy, peak dosage, and cumulative dosage. Based on a review of serial neurologic and ophthalmologic reports and aided by electroretinography (ERG) assessments when available, we ascertained whether each patient had evidence of clinically apparent vision impairment (i.e., recognized by a neurologist or ophthalmologist during any follow-up visit) and whether or not the vision loss was attributed to VGB exposure (i.e., evidence of bilateral, symmetric, and peripheral visual field loss), either by the treating physician or on retrospective review by the study team. RESULTS: During the study period, 257 patients with video-EEG-confirmed infantile spasms were identified. One hundred and forty-three (56%) patients received VGB. Although visual loss of any cause was common among patients with (31%) and without (32%) VGB exposure, there were no cases in which visual field defects were plausibly linked to VGB. We estimate that the risk of clinically significant VAVFL does not exceed 3.2% (95% CI upper bound). Vision loss was never characterized as exclusively peripheral and was always better explained by other causes (e.g., hemianopsia following hemispherectomy and cortical vision impairment after hypoxic ischemic encephalopathy). Precise quantitative exposure data were available for 104 (73%) patients treated with VGB, among whom the median duration of treatment was 8.6 (IQR: 3.7-16.2) months, the median peak dosage was 141.5 (IQR: 104.8-166.0) mg/kg/day, and the median cumulative dosage was 314 (IQR: 140.8-645.7) grams. CONCLUSIONS: We found that the risk of clinically apparent vision loss is quite low among young children treated for infantile spasms. Our estimate of risk contrasts with prior studies and likely reflects our ascertainment of vision loss without the aid of perimetry or serial ERG, the short treatment duration, and the relatively young age of our patients. In the treatment of infantile spasms, risk-benefit assessment should consider both the low prevalence of ERG-identified VAVFL among patients with brief (<6-9months) exposure and the very low prevalence of clinically apparent VAVFL in this population.

Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome.

There is a great need for safe and effective therapies for treatment of infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). Based on anecdotal reports and limited experience in an open-label trial, cannabidiol (CBD) has received tremendous attention as a potential treatment for pediatric epilepsy, especially Dravet syndrome. However, there is scant evidence of specific utility for treatment of IS and LGS. We sought to document the experiences of children with IS and/or LGS who have been treated with CBD-enriched cannabis preparations. We conducted a brief online survey of parents who administered CBD-enriched cannabis preparations for the treatment of their children's epilepsy. We specifically recruited parents of children with IS and LGS and focused on perceived efficacy, dosage, and tolerability. Survey respondents included 117 parents of children with epilepsy (including 53 with IS or LGS) who had administered CBD products to their children. Perceived efficacy and tolerability were similar across etiologic subgroups. Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. Epilepsy was characterized as highly refractory with median latency from epilepsy onset to CBD initiation of five years, during which the patient's seizures failed to improve after a median of eight antiseizure medication trials. The median duration and the median dosage of CBD exposure were 6.8 months and 4.3mg/kg/day, respectively. Reported side effects were far less common during CBD exposure, with the exception of increased appetite (30%). A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy. Although this study suggests a potential role for CBD in the treatment of refractory childhood epilepsy including IS and LGS, it does not represent compelling evidence of efficacy or safety. From a methodological standpoint, this study is extraordinarily vulnerable to participation bias and limited by lack of blinded outcome ascertainment. Appropriately controlled clinical trials are essential to establish efficacy and safety.

N-glycosylation bidirectionally extends the boundaries of thymocyte positive selection by decoupling Lck from Ca²âº signaling.

Positive selection of diverse yet self-tolerant thymocytes is vital to immunity and requires a limited degree of T cell antigen receptor (TCR) signaling in response to self peptide-major histocompatibility complexes (self peptide-MHCs). Affinity of newly generated TCR for peptide-MHC primarily sets the boundaries for positive selection. We report that N-glycan branching of TCR and the CD4 and CD8 coreceptors separately altered the upper and lower affinity boundaries from which interactions between peptide-MHC and TCR positively select T cells. During thymocyte development, N-glycan branching varied approximately 15-fold. N-glycan branching was required for positive selection and decoupled Lck signaling from TCR-driven Ca(2+) flux to simultaneously promote low-affinity peptide-MHC responses while inhibiting high-affinity ones. Therefore, N-glycan branching imposes a sliding scale on interactions between peptide-MHC and TCR that bidirectionally expands the affinity range for positive selection.

Hypomorphic MGAT5 polymorphisms promote multiple sclerosis cooperatively with MGAT1 and interleukin-2 and 7 receptor variants.

Deficiency of the Golgi N-glycan branching enzyme Mgat5 in mice promotes T cell hyperactivity, endocytosis of CTLA-4 and autoimmunity, including a spontaneous multiple sclerosis (MS)-like disease. Multiple genetic and environmental MS risk factors lower N-glycan branching in T cells. These include variants in interleukin-2 receptor-α (IL2RA), interleukin-7 receptor-α (IL7RA), and MGAT1, a Golgi branching enzyme upstream of MGAT5, as well as vitamin D3 deficiency and Golgi substrate metabolism. Here we describe linked intronic variants of MGAT5 that are associated with reduced N-glycan branching, CTLA-4 surface expression and MS (p=5.79×10(-9), n=7,741), the latter additive with the MGAT1, IL2RA and IL7RA MS risk variants (p=1.76×10(-9), OR=0.67-1.83, n=3,518).

Vitamin C prevents hypogonadal bone loss.

Epidemiologic studies correlate low vitamin C intake with bone loss. The genetic deletion of enzymes involved in de novo vitamin C synthesis in mice, likewise, causes severe osteoporosis. However, very few studies have evaluated a protective role of this dietary supplement on the skeleton. Here, we show that the ingestion of vitamin C prevents the low-turnover bone loss following ovariectomy in mice. We show that this prevention in areal bone mineral density and micro-CT parameters results from the stimulation of bone formation, demonstrable in vivo by histomorphometry, bone marker measurements, and quantitative PCR. Notably, the reductions in the bone formation rate, plasma osteocalcin levels, and ex vivo osteoblast gene expression 8 weeks post-ovariectomy are all returned to levels of sham-operated controls. The study establishes vitamin C as a skeletal anabolic agent.

Pathogenesis of multiple sclerosis via environmental and genetic dysregulation of N-glycosylation.

Autoimmune diseases such as multiple sclerosis (MS) result from complex and poorly understood interactions of genetic and environmental factors. A central role for T cells in MS is supported by mouse models, association of the major histocompatibility complex region, and association of critical T cell growth regulator genes such as interleukin-2 receptor (IL-2RA) and interleukin-7 receptor (IL-7RA). Multiple environmental factors (vitamin D(3) deficiency and metabolism) converge with multiple genetic variants (IL-7RA, IL-2RA, MGAT1, and CTLA-4) to dysregulate Golgi N-glycosylation in MS, resulting in T cell hyperactivity, loss of self-tolerance and in mice, a spontaneous MS-like disease with neurodegeneration. Here, we review the genetic and biological interactions that regulate MS pathogenesis through dysregulation of N-glycosylation and how this may enable individualized therapeutic approaches.

Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis.

How environmental factors combine with genetic risk at the molecular level to promote complex trait diseases such as multiple sclerosis (MS) is largely unknown. In mice, N-glycan branching by the Golgi enzymes Mgat1 and/or Mgat5 prevents T cell hyperactivity, cytotoxic T-lymphocyte antigen 4 (CTLA-4) endocytosis, spontaneous inflammatory demyelination and neurodegeneration, the latter pathologies characteristic of MS. Here we show that MS risk modulators converge to alter N-glycosylation and/or CTLA-4 surface retention conditional on metabolism and vitamin D(3), including genetic variants in interleukin-7 receptor-α (IL7RA*C), interleukin-2 receptor-α (IL2RA*T), MGAT1 (IV(A)V(T-T)) and CTLA-4 (Thr17Ala). Downregulation of Mgat1 by IL7RA*C and IL2RA*T is opposed by MGAT1 (IV(A)V(T-T)) and vitamin D(3), optimizing branching and mitigating MS risk when combined with enhanced CTLA-4 N-glycosylation by CTLA-4 Thr17. Our data suggest a molecular mechanism in MS whereby multiple environmental and genetic inputs lead to dysregulation of a final common pathway, namely N-glycosylation.

Micropipette tips--the unsung heroes of mass spectrometry.

Micropipette tip (tip) pipetting accuracy and precision are functions of tip manufacture consistency, morphological variation, and retained inner tip wall particulate matter. Irregular tip inner wall surfaces and retained particulate matter cause pipetting inaccuracy. Washed and unwashed tips from seven manufacturers were compared using weight by difference (six), microscopic Luxol Fast Blue staining (seven), and matrix-assisted laser desorption/onization time-of-flight (MALDI-TOF) mass spectrometry (six). Photomicrographs revealed tip irregularity and inner wall retained particulate matter. Computer model analysis was used to identify tip irregularity and retained matter. These tests established the utility of a pipette solvent wash to increase the performance and the accuracy of tips and, thus, improve the MALDI mass spectra obtained.