Following preterm birth, serum levels of insulin-like growth factor 1 (IGF-1) decrease compared to corresponding in utero levels. A recent clinical trial indicated that supplementation with recombinant human (rh) IGF-1/rhIGF-binding protein 3 (rhIGF-1/rhIGFBP-3) prevents severe intraventricular hemorrhage (IVH) in extremely preterm infants. In a preterm rabbit pup model, we characterized endogenous serum and hepatic IGF-1, along with brain distribution of IGF-1 and IGF-1 receptor (IGF1R). We then evaluated the effects of rhIGF-1/rhIGFBP-3 on gene expression of regulators of cerebrovascular maturation and structure. Similar to preterm infants, serum IGF-1 concentrations decreased rapidly after preterm birth in the rabbit pup. Administration of rhIGF-1/rhIGFBP-3 restored in utero serum levels but was rapidly eliminated. Immunolabeled IGF1R was widely distributed in multiple brain regions, displaying an abundant density in the choroid plexus and sub-ependymal germinal zones. Increased IGF-1 immunoreactivity, distributed as IGF1R, was detected 4 h after rhIGF-1/rhIGFBP-3 administration. The rhIGF-1/rhIGFBP-3 treatment led to upregulation of choroid plexus genes involved in vascular maturation and structure, with corresponding protein translation for most of these genes. The preterm rabbit pup model is well suited for evaluation of IGF-1-based prevention of IVH. Administration of rhIGF-1/rhIGFBP-3 affects cerebrovascular maturation, suggesting a role for it in preventing preterm IVH.

Our previous studies found that the C-X-C motif chemokine receptor 5 (CXCR5) loss leads to retinal pigment epithelium (RPE) dysfunction and AMD pathogenesis. The current study aimed to characterize the G protein-coupled receptor (GPCR) structure of CXCR5 and analyze its interactions with AMD-related risk genes. The sequence alignments, homology model of CXCR5 and structural assessment analysis were performed. Data and text mining were then performed to identify AMD-related risk genes and their interaction with CXCR5 using statistical and mathematical algorithms. Sequence alignment and phylogenetic tree analysis revealed that human CXCR5 was highly similar (85.4839%) to the rabbit. The least similarity (33.871%) was found to be in zebrafish compared to the other species. The CXCR5 model structural assessment and secondary structure analysis exhibited an excellent model. Network analysis revealed that IL10, TNF, ICAM1, CXCL1, CXCL8, APP, TLR4, SELL, C3, IL17A and CCR2 were the most connected genes CXCR5. These findings suggest that CXCR5 signaling may regulate the biological function of RPE and modulate AMD pathophysiology via GPCR signaling and interacting with identified AMD risk genes. In summary, the data presented here provide novel and crucial insights into the molecular mechanisms of CXCR5 involvement in AMD.Communicated by Ramaswamy H. Sarma.

BACKGROUND: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of end stage kidney disease (ESKD) in individuals with type 1 diabetes at advanced kidney disease stage. METHODS: Gene-based exome array analysis of 15,449 genes in 5 large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time-to-ESKD, testing the top gene in a 6th cohort (N=2,372/1,115 events all cohorts) and replicating in two retrospective case-control studies (N=1,072 cases, 752 controls). Deep resequencing of the top associated gene in 5 cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. RESULTS: Protein coding variants in the hydroxysteroid 17-beta dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (N=4,196; p-value=3.3x10-7). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other chronic kidney disease-associated renal pathologies. CONCLUSIONS: HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.

Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (Her2) - targeted antibody-drug conjugate that is approved for patients previously treated with trastuzumab and a taxane for Her2-positive advanced breast cancer and those who have progressed within 6 months of completion of adjuvant chemotherapy, as well as for patients with residual invasive Her2-positive disease after the completion of adjuvant chemotherapy. Peripheral neuropathy is a common adverse event; however, ocular events have also been described. With the current report we present the case of a 67-year old woman who developed transient grade 2-3 blurred vision after the first T-DM1 infusion, which was complicated with grade 2 diplopia causing vertigo after the second infusion. After extended investigation, this symptomatology was attributed to central neurotoxicity, and gradually resolved after T-DM1 discontinuation.

Defining factors that govern CD8+ T cell immunodominance is critical for the rational design of vaccines for viral pathogens. Here, we assess the contribution of human leukocyte antigen (HLA) class-I-peptide stability for 186 optimal HIV epitopes across 18 HLA alleles using transporter associated with antigen processing (TAP)-deficient mono-allelic HLA-expressing cell lines. We find that immunodominant HIV epitopes increase surface stabilization of HLA class-I molecules in comparison to subdominant epitopes. HLA class-I-peptide stability is also strongly correlated with overall immunodominance hierarchies, particularly for epitopes from high-abundance proteins (e.g., Gag). Moreover, HLA alleles associated with HIV protection are preferentially stabilized by epitopes derived from topologically important viral regions at a greater frequency than neutral and risk alleles. These findings indicate that relative stabilization of HLA class-I is a key factor for CD8+ T cell epitope immunodominance hierarchies, with implications for HIV control and the design of T-cell-based vaccines.

PURPOSE: Interest in micro-invasive glaucoma surgery (MIGS) has exploded over the last 8 years with an increase in MIGS procedures of at least 400% in the United States, according to Medicare data. MIGS is an umbrella term that can cover many different types of surgeries. This review focuses on peer-reviewed evidence for Trabectome®, iStent inject®, Kahook Dual Blade®, XEN® Gel Stent, and Hydrus®. METHODS: We present key recent studies evaluating the efficacy and safety of MIGS in various types of glaucoma patients with different stages of disease. CONCLUSION: We conclude that MIGS is generally safe and efficacious, although only some MIGS have been studied through randomized clinical trials. When comparing and contrasting the different MIGS procedures, large prospective studies are not yet the norm. High-quality large prospective studies involving MIGS will be an important next step as ophthalmologists decide how to incorporate MIGS into their surgical armamentarium.

PURPOSE: To describe a case of new-onset benign paroxysmal positional vertigo (BPPV) after uncomplicated Descemet stripping automated endothelial keratoplasty. METHODS: Case report and review of literature. RESULTS: A 61-year-old woman with a history of steroid-induced glaucoma and penetrating keratoplasty for Fuchs endothelial dystrophy, and no history of BPPV or other vertigo, underwent Descemet stripping automated endothelial keratoplasty for penetrating keratoplasty graft failure. On the third postoperative day, she developed acute spinning vertigo, nausea, and headache on sitting up after 3 days of strict supine positioning. Her ophthalmic examination was benign, with no evidence of a pupillary block, and she was diagnosed by an otologist with BPPV. Her symptoms resolved after 1 week without further intervention. CONCLUSIONS: BPPV is a benign but rare complication of nonotologic surgery and has not been previously reported with ophthalmic surgery. The overlap in symptomatology between BPPV and other serious and potentially vision-threatening causes of postoperative nausea and headache, such as pupillary block glaucoma, makes this a relevant etiology to consider in the spectrum of postendothelial keratoplasty complications.

Conjunctival papillomas are common tumors that exhibit an exophytic growth pattern, comprised of multiple filiform fronds of squamous epithelium that contain fibrovascular cores. The inverted (endophytic) variety of papilloma, often termed "Schneiderian," rarely occurs on the conjunctiva, with only 15 cases reported to date. Endophytic and exophytic papillomas are well described arising in the sinonasal Schneiderian epithelium where a low rate of malignant transformation may occur in the endophytic type; malignant transformation in exophytic sinonasal papillomas is exceedingly rare. The authors describe 2 cases of exophytic conjunctival papillomas with the morphology of a sinonasal or Schneiderian-type papilloma. Both were pink, sessile acquired growths in women in the sixth decade of life involving the inferior conjunctival fornix or nasal limbus. Nonkeratinizing squamous epithelium along with numerous goblet cells, intraepithelial mucinous cysts, and microabscesses were present. Immunohistochemistry showed reactivity for cytokeratin 7 and wild-type staining for p16 and p53, paralleling the findings in common conjunctival papillomas; both were also driven by low-risk human papillomavirus.

Importance: Big data studies may allow for the aggregation of patients with rare diseases such as uveitis to answer important clinical questions. Standardization of uveitis-related variables will be necessary, including the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes used to identify patients of interest. There are currently limited data on the uniformity of diagnosis mapping to ICD-10 codes for uveitis diagnoses among different health systems. Objective: To assess the degree of uniformity in mapping of uveitis clinical concepts to ICD-10 codes across health care systems using the same electronic health record (EHR) system. Design, Setting, and Participants: This multicenter survey study was conducted between September 14 and October 9, 2020, at 5 academic health care systems that use the Epic EHR. Researchers from the University of Washington, Harvard University, Stanford University, Yale University, and the University of California, San Francisco queried 54 uveitis-related diagnostic terms and recorded the associated ICD-10 codes. Main Outcomes and Measures: The degree of uniformity for uveitis clinical concepts and associated ICD-10 codes. Results: Fifty-four uveitis-related diagnostic terms were queried within the Epic EHR at 5 different health care systems. There was perfect agreement among all 5 centers for 52 of the 54 diagnostic terms. Two diagnostic terms had differences in ICD-10 coding: juvenile idiopathic arthritis associated chronic uveitis and intermediate uveitis. Intermediate uveitis was associated with codes H20.1x (ICD-10 description: chronic iridocyclitis) or H20.9 (ICD-10 description: unspecified iridocyclitis) in 3 centers while being associated with code H30.2x (ICD-10 description: posterior cyclitis) at the 2 remaining centers. The discrepancies appear to be related to a recent update in diagnostic mapping in the Epic EHR. Conclusions and Relevance: This study suggests that ICD-10 code mapping to uveitis diagnostic terminology appears to be highly uniform at different centers with the Epic EHR. However, temporal changes in diagnosis mapping to ICD-10 codes and a lack of 1-to-1 mapping of diagnosis to ICD-10 code add additional sources of complexity to the interpretation of big data studies in uveitis.

BACKGROUND: Glaucoma is a leading cause of visual disability and blindness. Release of iris pigment within the eye, pigment dispersion syndrome (PDS), can lead to one type of glaucoma known as pigmentary glaucoma. PDS has a genetic component, however, the genes involved with this condition are largely unknown. We sought to discover genes that cause PDS by testing cohorts of patients and controls for mutations using a tiered analysis of exome data. RESULTS: Our primary analysis evaluated melanosome-related genes that cause dispersion of iris pigment in mice (TYRP1, GPNMB, LYST, DCT, and MITF). We identified rare mutations, but they were not statistically enriched in PDS patients. Our secondary analyses examined PMEL (previously linked with PDS), MRAP, and 19 other genes. Four MRAP mutations were identified in PDS cases but not in controls (p = 0.016). Immunohistochemical analysis of human donor eyes revealed abundant MRAP protein in the iris, the source of pigment in PDS. However, analysis of MRAP in additional cohorts (415 cases and 1645 controls) did not support an association with PDS. We also did not confirm a link between PMEL and PDS in our cohorts due to lack of reported mutations and similar frequency of the variants in PDS patients as in control subjects. CONCLUSIONS: We did not detect a statistical enrichment of mutations in melanosome-related genes in human PDS patients and we found conflicting data about the likely pathogenicity of MRAP mutations. PDS may have a complex genetic basis that is not easily unraveled with exome analyses.

Bacterial infections of the cornea, or bacterial keratitis (BK), are notorious for causing rapidly fulminant disease and permanent vision loss, even among treated patients. In the last sixty years, dramatic upward trajectories in the frequency of BK have been observed internationally, driven in large part by the commercialization of hydrogel contact lenses in the late 1960s. Despite this worsening burden of disease, current evidence-based therapies for BK - including broad-spectrum topical antibiotics and, if indicated, topical corticosteroids - fail to salvage vision in a substantial proportion of affected patients. Amid growing concerns of rapidly diminishing antibiotic utility, there has been renewed interest in urgently needed novel treatments that may improve clinical outcomes on an individual and public health level. Bridging the translational gap in the care of BK requires the identification of new therapeutic targets and rational treatment design, but neither of these aims can be achieved without understanding the complex biological processes that determine how bacterial corneal infections arise, progress, and resolve. In this chapter, we synthesize the current wealth of human and animal experimental data that now inform our understanding of basic BK pathophysiology, in context with modern concepts in ocular immunology and microbiology. By identifying the key molecular determinants of clinical disease, we explore how novel treatments can be developed and translated into routine patient care.

Purpose: The purpose of this study was to determine factors affecting predominantly peripheral lesion (PPL) grading, such as qualitative versus quantitative assessment, device type, and severity of diabetic retinopathy (DR) in ultrawide field color images (UWF-CIs). Methods: Patients with DR had UWF-CI qualitatively graded for PPL using standardized techniques and had hemorrhages/microaneurysms (H/Mas) individually annotated for quantitative PPL grading on two different ultrawide field devices. Results: Among 791 eyes of 481 patients, 38.2% had mild nonproliferative DR (NPDR), 34.7% had moderate NPDR, and 27.1% had severe NPDR to proliferative DR (PDR). The overall agreement between qualitative and quantitative PPL grading was moderate (ĸ = 0.423, P < 0.001). Agreement rates were fair in eyes with mild NPDR (ĸ = 0.336, P < 0.001) but moderate in eyes with moderate NPDR (ĸ = 0.525, P < 0.001) and severe NPDR-PDR (ĸ = 0.409, P < 0.001). Increasing thresholds for quantitative PPL determination improved agreement rates, with peak agreements at H/Ma count differences of six for mild NPDR, five for moderate NPDR, and nine for severe NPDR-PDR. Based on ultrawide field device type (California = 412 eyes vs. 200Tx = 379 eyes), agreement between qualitative and quantitative PPL grading was moderate for all DR severities in both devices (ĸ = 0.369-0.526, P < 0.001) except for mild NPDR on the 200Tx, which had poor agreement (ĸ = 0.055, P = 0.478). Conclusions: Determination of PPL varies between standard qualitative and quantitative grading and is dependent on NPDR severity, device type, and magnitude of lesion differences used for quantitative assessment. Translational Relevance: Prior UWF studies have not accounted for imaging and grading factors that affect PPL, such factors need to be reviewed when assessing thresholds for DR progression rates.

Purpose: To develop and test machine learning classifiers (MLCs) for determining visual field progression. Methods: In total, 90,713 visual fields from 13,156 eyes were included. Six different progression algorithms (linear regression of mean deviation, linear regression of the visual field index, Advanced Glaucoma Intervention Study algorithm, Collaborative Initial Glaucoma Treatment Study algorithm, pointwise linear regression [PLR], and permutation of PLR) were applied to classify each eye as progressing or stable. Six MLCs were applied (logistic regression, random forest, extreme gradient boosting, support vector classifier, convolutional neural network, fully connected neural network) using a training and testing set. For MLC input, visual fields for a given eye were divided into the first and second half and each location averaged over time within each half. Each algorithm was tested for accuracy, sensitivity, positive predictive value, and class bias with a subset of visual fields labeled by a panel of three experts from 161 eyes. Results: MLCs had similar performance metrics as some of the conventional algorithms and ranged from 87% to 91% accurate with sensitivity ranging from 0.83 to 0.88 and specificity from 0.92 to 0.96. All conventional algorithms showed significant class bias, meaning each individual algorithm was more likely to grade uncertain cases as either progressing or stable (P ≤ 0.01). Conversely, all MLCs were balanced, meaning they were equally likely to grade uncertain cases as either progressing or stable (P ≥ 0.08). Conclusions: MLCs showed a moderate to high level of accuracy, sensitivity, and specificity and were more balanced than conventional algorithms. Translational Relevance: MLCs may help to determine visual field progression.

BACKGROUND: Cardiovascular risk factors increase the risk of developing dementia, including Alzheimer's disease and vascular dementia. OBJECTIVE: Studying individuals with autosomal dominant mutations leading to the early onset of dementia, this study examines the effect of the global cardiovascular risk profile on early cognitive and neuroimaging features of Alzheimer's disease and vascular dementia. METHODS: We studied 85 non-demented and stroke-free individuals, including 20 subjects with Presenilin1 (PSEN1) E280A mutation leading to the early onset of autosomal dominant Alzheimer's disease (ADAD), 20 subjects with NOTCH3 mutations leading to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to the early onset of vascular dementia, and 45 non-affected family members (non-carriers). All subjects underwent clinical and neuropsychological evaluations and an MRI. The global cardiovascular risk profile was estimated using the office-based Framingham Cardiovascular Risk Profile (FCRP) score. RESULTS: In individuals with CADASIL, a higher FCRP score was associated with a reduced hippocampal volume (B = -0.06, p <  0.05) and an increased severity of cerebral microbleeds (B = 0.13, p <  0.001), lacunes (B = 0.30, p <  0.001), and perivascular space enlargement in the basal ganglia (B = 0.50, p <  0.05). There was no significant association between the FCRP score and neuroimaging measures in ADAD or non-carrier subjects. While the FCRP score was related to performance in executive function in non-carrier subjects (B = 0.06, p <  0.05), it was not significantly associated with cognitive performance in individuals with CADASIL or ADAD. CONCLUSION: Our results suggest that individuals with CADASIL and other forms of vascular cognitive impairment might particularly benefit from early interventions aimed at controlling cardiovascular risks.

Glaucoma is a neurodegenerative disease with a structural change of the optic nerve head, leading to visual field defects and ultimately blindness. It has been proposed that glaucoma is associated with increased mortality, but previous studies had methodological limitations (selective study samples, lack of data on potential confounders, self-reported or secondary data on glaucoma diagnoses). We evaluated the association between diagnosed glaucoma and mortality in the population-based National Health and Nutrition Examination Survey (NHANES), a representative health survey in the United States. The survey cycles 2005-2006 and 2007-2008 included an extensive ophthalmic examination with fundus photography, which were used to derive standardized glaucoma diagnoses. Risk of all-cause mortality was assessed with multivariable Cox proportional hazards regression models accounting for the complex survey design of NHANES. Time to death was calculated from the examination date to date of death or December 31, 2015 whichever came first. 5385 participants (52.5% women) were eligible, of which 138 had glaucoma at baseline, and 833 died during follow-up. Participants with glaucoma were more likely to be older than those without glaucoma (mean age 69.9 vs. 56.0 years). Mean follow-up time was 8.4 years for participants with glaucoma, and 8.6 years for participants without glaucoma. Glaucoma was associated with increased mortality in an unadjusted Cox regression model (hazard ratio 2.06, 95% confidence interval 1.16 to 3.66), but the association was no longer statistically significant after adjusting for age and sex (hazard ratio 0.74, 95% confidence interval 0.46 to 1.17). Additional adjustment for a range of potential confounders did not significantly change the results. In this representative population-based study, we found no evidence of increased mortality risk in glaucoma patients.

Chronic pain and depression are two frequently co-occurring and debilitating conditions. Even though the former is treated as a physical affliction, and the latter as a mental illness, both disorders closely share neural substrates. Here, we review the association of pain with depression, especially when symptoms are lateralized on either side of the body. We also explore the overlapping regions in the forebrain implicated in these conditions. Finally, we synthesize these findings into a model, which addresses gaps in our understanding of comorbid pain and depression. Our lateralized pain-depression dyad model suggests that individuals diagnosed with depression should be closely monitored for pain symptoms in the left hemibody. Conversely, for patients in pain, with the exception of acute pain with a known source, referrals in today's pain centers for psychological evaluation should be part of standard practice, within the framework of an interdisciplinary approach to pain treatment.

PURPOSE: To review the available evidence comparing the effectiveness of extraocular muscle botulinum toxin type A (BTXA) injection with eye muscle surgery for restoring ocular alignment in children and adults with nonparalytic, nonrestrictive horizontal strabismus. METHODS: Literature searches in the PubMed Cochrane Library, and clinical trial databases with no date restrictions, but limited to articles published in English, were conducted last on January 10, 2021. The searches yielded 515 citations, 40 of which were reviewed in full text by the first author. Fourteen articles met the criteria for inclusion (randomized or nonrandomized comparative studies, or case series with a minimum 50 patients; evaluating extraocular muscle BTXA injection for initial or repeat treatment of horizontal, nonparalytic, nonrestrictive strabismus; with at least 6 months of follow-up) and were graded by a methodologist. RESULTS: The 14 included studies consisted of 2 randomized clinical trials, 3 nonrandomized comparative studies, and 9 case series. All 5 comparative studies were graded level II evidence, and the 9 case series were graded level III evidence. Successful motor outcomes after BTXA injection were relatively consistent across 4 of the 5 comparative studies at 60%, when adjustment was made for differential selection bias in 1 of the studies. In the 4 studies, successful motor outcomes after surgery ranged from 66% to 77% with a mean follow-up of 23 to 75 months, and the outcomes were not significantly different from those after BTXA injection. In the fifth level II study, success was significantly higher with BTXA injection than with surgery (94% vs. 72%). The level III BTXA case series demonstrated higher motor success rates of 87% to 89% when children were treated in 2 muscles at a time; rates were lower in adults treated with single-muscle BTXA injection. CONCLUSIONS: Extraocular muscle injection of BTXA achieves a high rate of successful motor alignment, comparable with that achieved after eye muscle surgery for nonparalytic, nonrestrictive horizontal strabismus. Good alignment may require multiple BTXA injections, and it is not yet clear whether sensory outcomes are equivalent for BTXA injections versus eye muscle surgery in young children.

Purpose: To assess microvascular beds in the optic nerve head (ONH), peripapillary tissue, and the nailfold in patients with primary open-angle glaucoma (POAG) versus controls. Methods: Patients with POAG (n = 22) and controls (n = 12) underwent swept-source optical coherence tomography angiography of ophthalmic microvasculature and nailfold video capillaroscopy of the hand. The main outcomes were vessel density (VD) and blood flow of the ONH, the peripapillary and the nailfold microvasculatures. Results: Patients with POAG were younger than controls (63.5 ± 9.4 vs. 69.9 ± 6.5 years, P = 0.03). Deep ONH VD and blood flow were lower in patients with POAG than controls (39.1% ± 3.5% vs. 43.8% ± 5.7%; 37.8% ± 5.3% vs. 46.0% ± 7.8%, respectively, P < 0.02 for both); similar results were observed with peripapillary VD (37.9 ± 2.6%, 43.4 ± 7.6%, respectively, P = 0.03). Nailfold capillary density and blood flow were lower in patients with POAG than controls (8.8 ± 1.0 vs. 9.8 ± 0.9 capillaries/mm; 19.9 ± 9.4 vs. 33.7 ± 9.8 pL/s, respectively; P < 0.009 for both). After adjusting for age and gender, deep ONH VD and blood flow, peripapillary VD, and nailfold capillary blood flow were lower in POAG than controls (β = -0.04, -0.07, -0.05, -13.19, respectively, P ≤ 0.046 for all). Among all participants, there were positive correlations between deep ONH and nailfold capillary blood flow (Pearson's correlation coefficient r = 0.42, P = 0.02), peripapillary and nailfold capillary density (r = 0.43, P = 0.03), and peripapillary and nailfold capillary blood flow (r = 0.49, P = 0.01). Conclusions: Patients with POAG demonstrated morphologic and hemodynamic alterations in both ophthalmic and nailfold microvascular beds compared to controls. Translational Relevance: The concomitant abnormalities in nailfold capillaries and relevant ocular vascular beds in POAG suggest that the microvasculature may be a target for POAG treatment.

The conjunctiva is the largest component of the ocular surface. It can be damaged by various pathological processes leading to scarring, loss of tissue and dysfunction. Depending on the amount of damage, restoration of function may require a conjunctival graft. Numerous studies have investigated biological and synthetic substrates in the search for optimal conditions for the ex vivo culture of conjunctival epithelial cells that can be used as tissue grafts for transplantation. These substrates have advantages and disadvantages that are specific to the characteristics of each material; the development of an improved material remains a priority. This review is the second of a two-part review in The Ocular Surface. In the first review, the structure and function of the conjunctiva was evaluated with a focus on the extracellular matrix and the basement membrane, and biological and mechanical characteristics of the ideal substrate with recommendations for further studies. In this review the types of biological and synthetic substrates used for conjunctival transplantation are discussed including substrates based on the extracellular matrix. .

This study investigated neurologic changes in patients with dry eye (DE) by functional magnetic resonance imaging (fMRI) and to used regional homogeneity (ReHo) analysis to clarify the relationship between these changes and clinical features of DE. A total of 28 patients with DE and 28 matched healthy control (HC) subjects (10 males and 18 females in each group) were enrolled. fMRI scans were performed in both groups. We carried out ReHo analysis to assess differences in neural activity between the 2 groups, and receiver operating characteristic curve (ROC) analysis was performed to evaluate the performance of ReHo values of specific brain areas in distinguishing DE patients from HCs. The relationship between average ReHo values and clinical characteristics was assessed by correlation analysis. ReHo values of the middle frontal gyrus, inferior frontal gyrus, and superior frontal gyrus were significantly lower in DE patients compared to HCs. The ROC analysis showed that ReHo value had high accuracy in distinguishing between DE patients and HCs (P < 0.0001). The ReHo values of the middle frontal gyrus and dorsolateral superior frontal gyrus were correlated to disease duration (P < 0.05). Symptoms of ocular surface injury in DE patients are associated with dysfunction in specific brain regions, which may underlie the cognitive impairment, psychiatric symptoms, and depressive mood observed in DE patients. The decreased ReHo values of some brain gyri in this study may provide a reference for clinical diagnosis and determination of treatment efficacy.

Neuronal ceroid lipofuscinoses (NCLs) are a group of rare neurodegenerative storage disorders associated with devastating visual prognosis, with an incidence of 1/1,000,000 in the United States and comparatively higher incidence in European countries. The pathophysiological mechanisms causing NCLs occur due to enzymatic or transmembrane defects in various sub-cellular organelles including lysosomes, endoplasmic reticulum, and cytoplasmic vesicles. NCLs are categorized into different types depending upon the underlying cause i.e., soluble lysosomal enzyme deficiencies or non-enzymatic deficiencies (functions of identified proteins), which are sub-divided based on an axial classification system. In this review, we have evaluated the current evidence in the literature and reported the incidence rates, underlying mechanisms and currently available management protocols for these rare set of neuroophthalmological disorders. Additionally, we also highlighted the potential therapies under development that can expand the treatment of these rare disorders beyond symptomatic relief.

PURPOSE: Previous studies in patients with Alzheimer's disease have shown amyloid beta accumulation in the brain and abnormal brain activity, with mild cognitive impairment (MCI) in early stages of the disease. The aim of the current study was to investigate functional connectivity in patients with MCI. METHODS: We recruited 24 subjects in total, including 12 patients with MCI (6 men and 6 women) and 12 healthy controls (HCs) (6 men and 6 women), matched for age, gender, and lifestyle factors. All subjects underwent resting-state functional magnetic resonance imaging scans and voxel-wise degree centrality (DC) was used to evaluate alterations in the strength of brain network connectivity. RESULTS: The DC value of the left inferior temporal gyrus was lower in MCI but significantly higher in the right fusiform gyrus and the left supplementary motor area, compared with HCs. The DC value in left inferior temporal gyrus correlated positively with disease duration and negatively with Mini-Mental State Examination. ROC curve analysis of brain regions showed acceptable specificity and accuracy of DC values between MCIs and HCs in the area under the curve (right fusiform gyrus, 0.955; left supplementary motor area, 0.992; left inferior temporal gyrus, 1.000). CONCLUSIONS: Abnormal functional connectivity in brain regions of patients with MCI may reflect the pathological process of Alzheimer's disease development and could prove useful in clinical diagnosis and treatment.

We are currently experiencing a deadly novel viral pandemic with no efficacious, readily available anti-viral therapies to SARS-CoV-2. Viruses will hijack host cellular machinery, including metabolic processes. Here, I provide theory and evidence for targeting the host de novo purine synthetic pathway for broad spectrum anti-viral drug development as well as the pursuit of basic science to mitigate the risks of future novel viral outbreaks.