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Scientific Reports Nov 2023To conduct a systematic review and meta-analysis of the association between children and adolescents with attention deficit hyperactivity disorder (ADHD) or autism... (Meta-Analysis)
Meta-Analysis
To conduct a systematic review and meta-analysis of the association between children and adolescents with attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) and ocular characteristics. Systematic review with meta-analysis. Six databases (PubMed, Scopus, APA PsycInfo, Embase, EBSCOhost, and Cochrane library) were selected for a systematic literature search from database inception to July 2022. The observational studies assessing and reporting at least one outcome regarding ocular characteristics in children and adolescents with ADHD or ASD aged 6-17 were included. Studies in languages other than English, studies of adult or elderly human populations, and animal studies were excluded. The results were analyzed following the PRISMA guideline 2020. The findings of 15 studies, including 433 participants with ADHD, 253 participants with ASD, and 514 participants with typical development (TD), revealed that there were no significant differences in retinal nerve fiber layer, ganglion cell complex, and macular thickness between the ADHD group and the TD group. In subgroup analysis, significant differences in inferior ganglion cell (MD = - 3.19; 95% CI = [- 6.06, - 0.31], p = 0.03) and nasal macular thickness (MD = 5.88; 95% CI = [- 0.01, 11.76], p = 0.05) were detected between the ADHD group and the TD group. A significant difference in pupillary light reflex (PLR) was also observed between the ASD group and the TD group (MD = 29.7; 95% CI = [18.79, 40.63], p < 0.001). Existing evidence suggests a possible association between children and adolescents with ADHD or ASD and ocular characteristics. Given the limited number of studies, further research on a larger cohort is necessary to claim a possible diagnosis of ADHD or ASD through ocular characteristics.
Topics: Adult; Animals; Aged; Adolescent; Child; Humans; Autism Spectrum Disorder; Face; Retina; Nose; Neurodevelopmental Disorders
PubMed: 37938638
DOI: 10.1038/s41598-023-46206-9 -
Life (Basel, Switzerland) Sep 2023Environmental light entrains many physiological and behavioural processes to the 24 h solar cycle. Such light-driven circadian rhythms are centrally controlled by the... (Review)
Review
Environmental light entrains many physiological and behavioural processes to the 24 h solar cycle. Such light-driven circadian rhythms are centrally controlled by the suprachiasmatic nucleus (SCN), which receives information from the short-wavelength-sensitive intrinsically photosensitive retinal ganglion cells. The SCN synchronizes local clocks throughout the body affecting sleep/wake routines and the secretion of neuroendocrine-linked hormones such as melatonin from the pineal gland and cortisol via the hypothalamic pituitary adrenal (HPA) axis. Although the effects of light parameters on melatonin have been recently reviewed, whether the experimental variation of the spectral power distribution and intensity of light can induce changes in cortisol rhythms remains unclear. Thus, this systematic review evaluated the effects of daytime exposure to lights of different spectral wavelength characteristics and luminance intensity on the cortisol levels in healthy individuals. A search of the PubMed, Web of Science, EMBASE, CINAHL, Medline, PsycINFO and Cochrane Library databases on 19 June 2023 identified 3418 articles, of which 12 studies (profiling 337 participants) met the inclusion and risk of bias criteria. An analysis of the literature indicated that exposure to bright lights of any colour during the late night or early morning can induce significant increases in cortisol secretion relative to time-matched dim light comparison conditions. Furthermore, exposure to bright lights with stronger short-wavelength (blue/green) components in the early morning typically induced greater increases in cortisol relative to lights with stronger long-wavelength (red) components. Thus, the circadian regulation of cortisol is sensitive to the wavelength composition of environmental lighting, in line with the more commonly studied melatonin. As such, wavelength characteristics should be optimized and reported in light intervention studies (particularly for the investigation of cortisol-associated disorders and HPA axis function), and exposure to short-wavelength light during sensitive periods should be carefully considered in constructed environments (e.g., bedroom and classroom lighting and device screens).
PubMed: 37895351
DOI: 10.3390/life13101968 -
Biology Direct Oct 2023The social impact of glaucoma is worth of note: primary open-angle glaucoma (POAG) is one of the leading causes of irreversible blindness worldwide, affecting some 68.56... (Meta-Analysis)
Meta-Analysis Review
The social impact of glaucoma is worth of note: primary open-angle glaucoma (POAG) is one of the leading causes of irreversible blindness worldwide, affecting some 68.56 million people with overall prevalence of 2.4%. Since one of the main risk factors for the development of POAG is the increase of intraocular pressure (IOP) causing retinal ganglion cells death, the medical treatment of POAG consists in the use of drugs endowed with neuroprotective effect and able to reduce IOP. These drugs include beta-blockers, prostaglandin analogues, carbonic anhydrase inhibitors, alpha or cholinergic agonists and rho kinase inhibitors. However, not all the patients respond to the same extent to the therapy in terms of efficacy and safety. Genetics and genome wide association studies have highlighted the occurrence of mutations and polymorphisms influencing the predisposition to develop POAG and its phenotype, as well as affecting the response to pharmacological treatment. The present systematic review and meta-analysis aims at identifying genetic variants and at verifying whether these can influence the responsiveness of patients to therapy for efficacy and safety. It follows the most updated Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 recommendations. The literature search was conducted consulting the most relevant scientific databases, i.e. PubMed/MEDLINE, Scopus, Web of Science and Public Health Genomics and Precision Health Knowledge Base up to June 14th, 2023. The search retrieved 1026 total records, among which eight met the eligibility criteria for inclusion in the analysis. The results demonstrated that the most investigated pharmacogenetic associations concern latanoprost and timolol, and that efficacy was studied more in depth than safety. Moreover, the heterogeneity of design and paucity of studies prompt further investigation in randomized clinical trials. In fact, adequately powered and designed pharmacogenetic association studies are needed to provide body of evidence with good certainty for a more appropriate use of medical therapy in POAG.PROSPERO registration: CRD42023434867.
Topics: Humans; Glaucoma, Open-Angle; Antihypertensive Agents; Genome-Wide Association Study; Timolol; Genotype
PubMed: 37833756
DOI: 10.1186/s13062-023-00423-4 -
PloS One 2023Glaucoma is a leading cause of irreversible blindness worldwide. Retinal ganglion cells (RGC), the neurons that connect the eyes to the brain, specifically die in...
PURPOSE
Glaucoma is a leading cause of irreversible blindness worldwide. Retinal ganglion cells (RGC), the neurons that connect the eyes to the brain, specifically die in glaucoma, leading to blindness. Elevated intraocular pressure (IOP) is the only modifiable risk factor, however, many patients progress despite excellent IOP control. Thus, alternative treatment strategies to prevent glaucoma progression are an unmet need. Citicoline has demonstrated neuroprotective properties in central neurodegenerative diseases. However, conclusive evidence of the effect of citicoline on glaucoma progression is missing. This systematic review investigates first-time the therapeutic potential of citicoline in glaucoma patients.
METHODS
The present study was conducted according to the PRISMA 2020 statement. PubMed, Web of Science, Google Scholar, and Embase were accessed in July 2023 to identify all clinical studies investigating the efficacy of citicoline on IOP, the mean deviation of the 24-2 visual field testing (MD 24-2), retinal nerve fibre layer (RNFL), and the pattern electroretinogram (PERG) P50-N95 amplitude in glaucoma patients. The risk of bias was assessed using the Review Manager 5.3 software (The Nordic Cochrane Collaboration, Copenhagen) and the Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I) tool.
RESULTS
Ten studies were eligible for this systematic review, including 424 patients. The mean length of the follow-up was 12.1 ± 11.6 months. The overall risk of bias was low to moderate. The mean age of the patients was 56.7 years. There were no significant differences in the IOP, MD 24-2, RNFL, or PERG P50-N95 amplitude between patients receiving citicoline and the control group. There was no improvement from baseline to the last follow-up in IOP, MD 24-2, RNFL, or PERG P50-N95 amplitude.
CONCLUSION
There is a lack of sufficient evidence to support that citicoline slows the progression of glaucoma.
Topics: Humans; Middle Aged; Cytidine Diphosphate Choline; Glaucoma, Open-Angle; Intraocular Pressure; Glaucoma; Retinal Ganglion Cells; Blindness
PubMed: 37768938
DOI: 10.1371/journal.pone.0291836 -
Neuroprotective Strategies for Nonarteritic Anterior Ischemic Optic Neuropathy: A Systematic Review.Korean Journal of Ophthalmology : KJO Aug 2023Nonarteritic anterior ischemic optic neuropathy (NAION) is the second most common form of optic neuropathy. Most patients show no improvement over time. Until now, there...
PURPOSE
Nonarteritic anterior ischemic optic neuropathy (NAION) is the second most common form of optic neuropathy. Most patients show no improvement over time. Until now, there is still no definitive therapy for NAION. The available literatures on the possible treatment of NAION are quite diverse and controversial. Neuroprotection strategies have been suggested as one of the potential treatments for NAION. This review aims to critically evaluate the literature on neuroprotective strategy for NAION.
METHODS
This report was written in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. We performed a systematic literature search in Pubmed, Science Direct, Proquest, and Cochrane databases. Only neuroprotective agents that directly work in protecting neurons were included. The outcome of interest in this review is retinal ganglion cell density and apoptosis for animal studies and retinal nerve fiber layer thickness for human studies.
RESULTS
The systematic search identified 591 studies of which 24 met the eligibility criteria, including 21 animal studies and three human studies. Only a few of the studies evaluated the same treatments, showing how diverse neuroprotector treatments are currently being evaluated as NAION treatment. From 21 animal studies, 14 studies showed significantly higher retinal ganglion cell density (1.49- to 2.81-fold) with neuroprotective treatment compared to control group. Two of three human studies in this review had also found a beneficial effect of preserving retinal nerve fiber layer thickness in NAION patients.
CONCLUSIONS
This review suggests the potential of neuroprotection as a viable option in the quest for an effective treatment strategy for NAION. Further studies, particularly clinical studies, are necessary to establish its efficacy in NAION patients.
Topics: Animals; Humans; Optic Neuropathy, Ischemic; Optic Disk; Neuroprotection; Visual Acuity; Tomography, Optical Coherence
PubMed: 37563973
DOI: 10.3341/kjo.2022.0166 -
Journal of Traditional Chinese Medicine... Aug 2023To evaluate the effectiveness and safety of Xuebijing injection (XBJ) on coronavirus disease 2019 (COVID-19) in patients. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To evaluate the effectiveness and safety of Xuebijing injection (XBJ) on coronavirus disease 2019 (COVID-19) in patients.
METHODS
Related studies on multiple biological databases and websites were searched up to December 11, 2021 without language and publication time restrictions. Review Manager V.5.3 and Stata 14 software were used for data analysis.
RESULTS
Seven studies were finally included. The Metaanalysis showed that compared with the routine treatment alone, XBJ combined with the routine treatment can reduce the 28day mortality ( = 0.3, 95% : 0.12, 0.74), Creactive protein ( = -12.8, 95% : -23.13, 3.46), erythrocyte sedimentation rate ( = -9.32, 95% : -14.66, -3.98) and interleukin-6 (S = -0.6, 95% : -1.04, -0.17) levels and increase the leukocyte ( = 0.73, 95% : 0.42, 1.04) and lymphocyte count ( = 0.18, 95% : 0.07, 0.29) in peripheral blood; additionally, it has no obvious side effects ( = 1.11, 95% : 0.65, 1.9). There was no evidence that the XBJ combined therapy can improve the nucleic acid conversion rate and computed tomography improvement rate of COVID19 patients.
CONCLUSIONS
Preliminary evidence suggests that XBJ combined with routine treatment seems to be more effective than routine treatment for patients with COVID19. Limited by the number and quality of included papers, this finding still needs further validation by more studies.
Topics: Humans; COVID-19; Drugs, Chinese Herbal; Injections
PubMed: 37454247
DOI: 10.19852/j.cnki.jtcm.20230517.002 -
Plastic and Reconstructive Surgery.... Apr 2023There are over 43 million individuals in the world who are blind. As retinal ganglion cells are incapable of regeneration, treatment modalities for this condition are...
UNLABELLED
There are over 43 million individuals in the world who are blind. As retinal ganglion cells are incapable of regeneration, treatment modalities for this condition are limited. Since first incepted in 1885, whole-eye transplantation (WET) has been proposed as the ultimate cure for blindness. As the field evolves, different aspects of the surgery have been individually explored, including allograft viability, retinal survival, and optic nerve regeneration. Due to the paucity in the WET literature, we aimed to systematically review proposed WET surgical techniques to assess surgical feasibility. Additionally, we hope to identify barriers to future clinical application and potential ethical concerns that could be raised with surgery.
METHODS
We conducted a systematic review of PubMed, Embase, Cochrane Library, and Scopus from inception to June 10, 2022, to identify articles pertaining to WET. Data collection included model organisms studied, surgical techniques utilized, and postoperative functional outcomes.
RESULTS
Our results yielded 33 articles, including 14 mammalian and 19 cold-blooded models. In studies performing microvascular anastomosis in mammals, 96% of allografts survived after surgery. With nervous coaptation, 82.9% of retinas had positive electroretinogram signals after surgery, indicating functional retinal cells after transplantation. Results on optic nerve function were inconclusive. Ocular-motor functionality was rarely addressed.
CONCLUSIONS
Regarding allograft survival, WET appears feasible with no complications to the recipient recorded in previous literature. Functional restoration is potentially achievable with a demonstrated positive retinal survival in live models. Nevertheless, the potential of optic nerve regeneration remains undetermined.
PubMed: 37113307
DOI: 10.1097/GOX.0000000000004946 -
Frontiers in Medicine 2022Parkinson's disease (PD) is a multifaceted neurodegenerative disease. The optic nerve, as a window into the central nervous system (CNS), is known to be an important...
BACKGROUND
Parkinson's disease (PD) is a multifaceted neurodegenerative disease. The optic nerve, as a window into the central nervous system (CNS), is known to be an important part of the CNS and can be detected non-invasively. With the widespread availability of optical coherence tomography (OCT) devices, an increasing number of studies have paid attention to the neuropathological disorders in the retina of PD patients in recent years. However, it is still controversial whether OCT can be used as a complementary tool for PD diagnosis.
METHODS
This review is registered with PROSPERO, number CRD42022301258. The Embase, PUBMED, and The Cochrane Library databases were independently retrieved by 2 investigators to identify relevant papers published from 1 January 2017 to 24 January 2022. These studies used OCT or OCTA to evaluate the difference in the retinal nerve fiber layer (RNFL) thickness, ganglion cell layer(GCL) thickness, macula thickness, Cup and disk area superficial retinal capillary plexus (SCP), and deep retinal capillary plexus(DCP). The standard mean difference (SMD) with the 95% confidence interval (CI) was pooled for continuous outcomes.
RESULTS
In total, 26 studies had been enrolled in this meta-analysis with a total number of 2,790 eyes, including 1,343 eyes from the PD group along with 1,447 eyes from the HC group. The results revealed that the RNFL thickness (SMD: -0.53; 95%CI, -0.71∼-0.35; < 0.00001), GCL thickness (SMD: -0.43; 95%CI, -0.66 to -0.19; = 0.0003), macula thickness (SMD: -0.22; 95%CI, -0.22 to -0.11; < 0.0001) were significantly thinner in patients with PD. The SCP (SMD: -0.61; 95%CI, -1.31to -0.10; = 0.02) was significantly lower in PD patients. The DCP (SMD: -0.48; 95%CI, -1.02 to -0.06; = 0.08) is lower in PD patients, but the difference was statistically insignificant.
CONCLUSION
Retinal nerve fiber layer thickness, GCL thickness, macular thickness, and SVD of PD patients are lower than those of healthy control. OCT and OCTA could detect morphological retinal changes in PD and might be objective and reproducible auxiliary tools to assist clinician diagnosis.
SYSTEMATIC REVIEW REGISTRATION
[https://www.crd.york.ac.uk/prospero/], identifier [CRD42022301258].
PubMed: 36186761
DOI: 10.3389/fmed.2022.957700 -
BMJ Open Jun 2022To appraise the existing literature reporting an association between retinal markers and cognitive impairment in adults aged 65 years and over and to provide directions...
OBJECTIVES
To appraise the existing literature reporting an association between retinal markers and cognitive impairment in adults aged 65 years and over and to provide directions for future use of retinal scanning as a potential tool for dementia diagnosis.
DESIGN
Systematic review of peer-reviewed empirical articles investigating the association of retinal markers in assessing cognitive impairment.
DATA SOURCES
Three electronic databases, Medline, PsycINFO and EMBASE were searched from inception until March 2022.
ELIGIBILITY CRITERIA
All empirical articles in English investigating the association between retinal markers and cognition in humans aged ≥65 years using various retinal scanning methodologies were included. Studies with no explicit evaluation of retinal scanning and cognitive outcomes were excluded. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool.
DATA EXTRACTION AND SYNTHESIS
Data extraction was conducted by two authors (VJ, RS) and reviewed by another author (JS). Results were synthesised and described narratively.
RESULTS
Sixty-seven eligible studies examining 6815 older adults were included. Majority of studies were cross-sectional (n=60; 89.6%). Optical coherence tomography (OCT) was the most commonly used retinal scanning methodology to measure the thickness of retinal nerve fibre layer, the ganglion cell complex, choroid and macula. 51.1% of cross-sectional studies using OCT reported an association between the thinning of at least one retinal parameter and poor cognition. Longitudinal studies (n=6) using OCT also mostly identified significant reductions in retinal nerve fibre layer thickness with cognitive decline. Study quality was overall moderate.
CONCLUSION
Retinal nerve fibre layer thickness is linked with cognitive performance and therefore may have the potential to detect cognitive impairment in older adults. Further longitudinal studies are required to validate our synthesis and understand underlying mechanisms before recommending implementation of OCT as a dementia screening tool in clinical practice.
PROSPERO REGISTRATION NUMBER
CRD42020176757.
Topics: Aged; Cognition; Cognitive Dysfunction; Dementia; Humans; Retina; Tomography, Optical Coherence
PubMed: 35728906
DOI: 10.1136/bmjopen-2021-054657 -
The Cochrane Database of Systematic... Jun 2022Glaucoma is a group of optic neuropathies characterized by progressive degeneration of the retinal ganglion cells, axonal loss and irreversible visual field defects.... (Review)
Review
BACKGROUND
Glaucoma is a group of optic neuropathies characterized by progressive degeneration of the retinal ganglion cells, axonal loss and irreversible visual field defects. Glaucoma is classified as primary or secondary, and worldwide, primary glaucoma is a leading cause of irreversible blindness. Several subtypes of glaucoma exist, and primary open-angle glaucoma (POAG) is the most common. The etiology of POAG is unknown, but current treatments aim to reduce intraocular pressure (IOP), thus preventing the onset and progression of the disease. Compared with traditional antiglaucomatous treatments, rho kinase inhibitors (ROKi) have a different pharmacodynamic. ROKi is the only current treatment that effectively lowers IOP by modulating the drainage of aqueous humor through the trabecular meshwork and Schlemm's canal. As ROKi are introduced into the market more widely, it is important to assess the efficacy and potential AEs of the treatment.
OBJECTIVES
To compare the efficacy and safety of ROKi with placebo or other glaucoma medication in people diagnosed with open-angle glaucoma (OAG), primary open-angle glaucoma (POAG) or ocular hypertension (OHT).
SEARCH METHODS
We used standard Cochrane methods and searched databases on 11 December 2020.
SELECTION CRITERIA
We included randomized clinical trials examining commercially available ROKi-based monotherapy or combination therapy compared with placebo or other IOP-lowering medical treatments in people diagnosed with (P)OAG or OHT. We included trials where ROKi were administered according to official glaucoma guidelines. There were no restrictions regarding type, year or status of the publication.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Two review authors independently screened studies, extracted data, and evaluated risk of bias by using Cochrane's RoB 2 tool. MAIN RESULTS: We included 17 trials with 4953 participants diagnosed with (P)OAG or OHT. Fifteen were multicenter trials and 15 were masked trials. All participants were aged above 18 years. Trial duration varied from 24 hours to 12 months. Trials were conducted in the USA, Canada and Japan. Sixteen trials were funded by pharmaceutical companies, and one trial provided no information about funding sources. The trials compared ROKi monotherapy (netarsudil or ripasudil) or combination therapy with latanoprost (prostaglandin analog) or timolol (beta-blocker) with placebo, timolol, latanoprost or netarsudil. Reported outcomes were IOP and safety. Meta-analyses were applied to 13 trials (IOP reduction from baseline) and 15 trials (ocular AEs). Of the trials evaluating IOP, seven were at low risk, three had some concerns, and three were at high risk of bias. Three trials found that netarsudil monotherapy may be superior to placebo (mean difference [MD] 3.11 mmHg, 95% confidence interval [CI] 2.59 to 3.62; I = 0%; 155 participants; low-certainty evidence). Evidence from three trials found that timolol may be superior to netarsudil with an MD of 0.66 mmHg (95% CI 0.41 to 0.91; I = 0%; 1415 participants; low-certainty evidence). Evidence from four trials found that latanoprost may be superior to netarsudil with an MD of 0.97 mmHg (95% CI 0.67 to 1.27; I = 4%; 1283 participants; moderate-certainty evidence). Evidence from three trials showed that, compared with monotherapy with latanoprost, combination therapy with netarsudil and latanoprost probably led to an additional pooled mean IOP reduction from baseline of 1.64 mmHg (95% CI -2.16 to -1.11; 1114 participants). Evidence from three trials showed that, compared with monotherapy with netarsudil, combination therapy with netarsudil and latanoprost probably led to an additional pooled mean IOP reduction from baseline of 2.66 mmHg (95% CI -2.98 to -2.35; 1132 participants). The certainty of evidence was moderate. One trial showed that, compared with timolol monotherapy, combination therapy with ripasudil and timolol may lead to an IOP reduction from baseline of 0.75 mmHg (95% -1.29 to -CI 0.21; 208 participants). The certainty of evidence was moderate. Of the trials assessing total ocular AEs, three were at low risk, four had some concerns, and eight were at high risk of bias. We found very low-certainty evidence that netarsudil may lead to more ocular AEs compared with placebo, with 66 more ocular AEs per 100 person-months (95% CI 28 to 103; I = 86%; 4 trials, 188 participants). We found low-certainty evidence that netarsudil may lead to more ocular AEs compared with latanoprost, with 29 more ocular AEs per 100 person-months (95% CI 17 to 42; I = 95%; 4 trials, 1286 participants). We found moderate-certainty evidence that, compared with timolol, netarsudil probably led to 21 additional ocular AEs (95% CI 14 to 27; I = 93%; 4 trials, 1678 participants). Data from three trials (1132 participants) showed no evidence of differences in the incidence rate of AEs between combination therapy with netarsudil and latanoprost and netarsudil monotherapy (1 more event per 100 person-months, 95% CI 0 to 3); however, the certainty of evidence was low. Similarly, we found low-certainty evidence that, compared with latanoprost, combination therapy with netarsudil and latanoprost may cause 29 more ocular events per 100 person-months (95% CI 11 to 47; 3 trials, 1116 participants). We found moderate-certainty evidence that, compared with timolol monotherapy, combination therapy with ripasudil and timolol probably causes 35 more ocular events per 100 person-months (95% CI 25 to 45; 1 trial, 208 participants). In all included trials, ROKi was reportedly not associated with any particular serious AEs.
AUTHORS' CONCLUSIONS
The current evidence suggests that in people diagnosed with OHT or (P)OAG, the hypotensive effect of netarsudil may be inferior to latanoprost and slightly inferior to timolol. Combining netarsudil and latanoprost probably further reduces IOP compared with monotherapy. Netarsudil as mono- or combination therapy may result in more ocular AEs. However, the certainty of evidence was very low or low for all comparisons except timolol. In general, AEs were described as mild, transient, and reversible upon treatment discontinuation. ROKi was not associated with any particular serious AEs. Future trials of sufficient size and follow-up should be conducted to provide reliable information about glaucoma progression, relevant IOP measurements and a detailed description of AEs using similar terminology. This would ensure the robustness and confidence of the results and assess the intermediate- and long-term efficacy and safety of ROKi.
Topics: Glaucoma, Open-Angle; Humans; Ocular Hypertension; Randomized Controlled Trials as Topic; Treatment Outcome; rho-Associated Kinases
PubMed: 35686679
DOI: 10.1002/14651858.CD013817.pub2