Is the UN receiving ethical approval for its research with human participants?

This paper examines the institutional mechanisms supporting the ethical oversight of human participant research conducted by the United Nations (UN). The UN has served an instrumental role in shaping international standards on research ethics, which invariably require ethical oversight of all research studies with human participants. The authors' experiences of conducting research collaboratively with UN agencies, in contrast, have led to concern that the UN frequently sponsors, or participates in, studies with human participants that have not received appropriate ethical oversight. It is argued that the institutional mechanisms in place to prevent research with human participants from being undertaken by the UN without ethical oversight do not, at present, extend substantively beyond the provision of guidelines and online training offered by a minority of UN bodies. The WHO and UNICEF are identified as notable exceptions, having implemented various measures to prevent health research with human participants from being undertaken without ethical oversight. Yet, it is highlighted that the WHO and UNICEF are not the only UN bodies that undertake health research with human participants and there are countless actors under the umbrella of the UN system that are regularly involved in non-health research with human participants. Arguments for the pursuit of the highest standard of ethical oversight by UN bodies are presented. Moving forward, the paper asks the question: is it time for the UN to set the standards for the oversight of ethical oversight?

Long-Term Impact of a Smartphone App on Prescriber Adherence to Antibiotic Guidelines for Adult Patients With Community-Acquired Pneumonia: Interrupted Time-Series Study.

BACKGROUND: Mobile health platforms like smartphone apps that provide clinical guidelines are ubiquitous, yet their long-term impact on guideline adherence remains unclear. In 2016, an antibiotic guidelines app, called SCRIPT, was introduced in Auckland City Hospital, New Zealand, to provide local antibiotic guidelines to clinicians on their smartphones. OBJECTIVE: We aimed to assess whether the provision of antibiotic guidelines in a smartphone app resulted in sustained changes in antibiotic guideline adherence by prescribers. METHODS: We analyzed antibiotic guideline adherence rates during the first 24 hours of hospital admission in adults diagnosed with community-acquired pneumonia using an interrupted time-series study with 3 distinct periods post app implementation (ie, 3, 12, and 24 months). RESULTS: Adherence increased from 23% (46/200) at baseline to 31% (73/237) at 3 months and 34% (69/200) at 12 months, reducing to 31% (62/200) at 24 months post app implementation (P=.07 vs baseline). However, increased adherence was sustained in patients with pulmonary consolidation on x-ray (9/63, 14% at baseline; 23/77, 30% after 3 months; 32/92, 35% after 12 month; and 32/102, 31% after 24 months; P=.04 vs baseline). CONCLUSIONS: An antibiotic guidelines app increased overall adherence, but this was not sustained. In patients with pulmonary consolidation, the increased adherence was sustained.

Mortality risks associated with empirical antibiotic activity in Escherichia coli bacteraemia: an analysis of electronic health records.

BACKGROUND: Reported bacteraemia outcomes following inactive empirical antibiotics (based on in vitro testing) are conflicting, potentially reflecting heterogeneity in causative species, MIC breakpoints defining resistance/susceptibility, and times to rescue therapy. METHODS: We investigated adult inpatients with Escherichia coli bacteraemia at Oxford University Hospitals, UK, from 4 February 2014 to 30 June 2021 who were receiving empirical amoxicillin/clavulanate with/without other antibiotics. We used Cox regression to analyse 30 day all-cause mortality by in vitro amoxicillin/clavulanate susceptibility (activity) using the EUCAST resistance breakpoint (>8/2 mg/L), categorical MIC, and a higher resistance breakpoint (>32/2 mg/L), adjusting for other antibiotic activity and confounders including comorbidities, vital signs and blood tests. RESULTS: A total of 1720 E. coli bacteraemias (1626 patients) were treated with empirical amoxicillin/clavulanate. Thirty-day mortality was 193/1400 (14%) for any active baseline therapy and 52/320 (16%) for inactive baseline therapy (P = 0.17). With EUCAST breakpoints, there was no evidence that mortality differed for inactive versus active amoxicillin/clavulanate [adjusted HR (aHR) = 1.27 (95% CI 0.83-1.93); P = 0.28], nor of an association with active aminoglycoside (P = 0.93) or other active antibiotics (P = 0.18). Considering categorical amoxicillin/clavulanate MIC, MICs > 32/2 mg/L were associated with mortality [aHR = 1.85 versus MIC = 2/2 mg/L (95% CI 0.99-3.73); P = 0.054]. A higher resistance breakpoint (>32/2 mg/L) was independently associated with higher mortality [aHR = 1.82 (95% CI 1.07-3.10); P = 0.027], as were MICs > 32/2 mg/L with active empirical aminoglycosides [aHR = 2.34 (95% CI 1.40-3.89); P = 0.001], but not MICs > 32/2 mg/L with active non-aminoglycoside antibiotic(s) [aHR = 0.87 (95% CI 0.40-1.89); P = 0.72]. CONCLUSIONS: We found no evidence that EUCAST-defined amoxicillin/clavulanate resistance was associated with increased mortality, but a higher resistance breakpoint (MIC > 32/2 mg/L) was. Additional active baseline non-aminoglycoside antibiotics attenuated amoxicillin/clavulanate resistance-associated mortality, but aminoglycosides did not. Granular phenotyping and comparison with clinical outcomes may improve AMR breakpoints.

Machine learning in medicine: should the pursuit of enhanced interpretability be abandoned?

We argue why interpretability should have primacy alongside empiricism for several reasons: first, if machine learning (ML) models are beginning to render some of the high-risk healthcare decisions instead of clinicians, these models pose a novel medicolegal and ethical frontier that is incompletely addressed by current methods of appraising medical interventions like pharmacological therapies; second, a number of judicial precedents underpinning medical liability and negligence are compromised when 'autonomous' ML recommendations are considered to be en par with human instruction in specific contexts; third, explainable algorithms may be more amenable to the ascertainment and minimisation of biases, with repercussions for racial equity as well as scientific reproducibility and generalisability. We conclude with some reasons for the ineludible importance of interpretability, such as the establishment of trust, in overcoming perhaps the most difficult challenge ML will face in a high-stakes environment like healthcare: professional and public acceptance.

Matrix metalloproteinase 9 is associated with conjunctival microbiota culture positivity in Korean patients with chronic Stevens-Johnson syndrome.

BACKGROUND: Stevens-Johnson syndrome (SJS) is an abnormal immune-response causing extensive exfoliation of the mucocutaneous tissue including conjunctiva. While several factors are associated with the alteration of conjunctival microbiota, the conjunctiva of SJS patients are found to harbor a different microbiota compared to healthy subjects. We investigated the conjunctival microbiota of Korean SJS patients, and identified factors associated with the conjunctival microbiota and its positive culture. METHODS: Medical records were retrospectively reviewed in 30 chronic SJS patients who had undergone conjunctival swab culture sampling. Demographic factors, chronic ocular surface complications score (COCS), tear break-up time (TBUT), tear secretion, tear matrix metalloproteinase 9 (MMP9), and results of conjunctival swab culture were assessed. RESULTS: Positive culture was seen in 58.1%. Gram positive bacteria was most commonly isolated, among which Coagulase-negative Staphylococci (45.5%) and Corynebacterium species (40.9%) were predominantly observed. Tear MMP9 positivity was observed significantly more in the positive culture group (100%) compared to the negative culture group (70%) (P = 0.041). Topical cyclosporine and corticosteroid were not associated with repetitive positive cultures. No significant differences in COCS, TBUT, and tear secretion were found between culture-positive and culture-negative groups. CONCLUSION: Our study suggests that tear MMP9 positivity may be related with the presence of an abnormal ocular surface microbiota in chronic SJS patients.

The Eyelid Meibomian Gland Deficiency in Fucosyltransferase 1 Knockout Mice.

To investigate the effect of fucosyltransferase (FUT) 1-mediated fucosylation on meibomian glands (MG), we first confirmed that FUT1 and its fucosylated products were expressed in the eyelid, conjunctiva and skin in wild-type (WT) mice, whereas their mRNA and protein levels were downregulated in Fut1 knock-out (KO) mice. We then evaluated age-dependent changes in the total and acinar areas of MG, meibocyte differentiation, lipid synthesis, and eyelid inflammation and oxidative stress in Fut1 KO and WT mice. Results show that both the total and acinar areas of MG were smaller in Fut1 KO mice than in WT mice in all evaluated age groups. Meibocyte differentiation, lipid-producing capacities and the enzyme levels responsible for lipid synthesis were reduced in Fut1 KO mice, compared to WT controls. The levels of pro-inflammatory cytokines and oxidative-stress-related markers were elevated in the eyelids and MG of FUT1 KO mice. These findings demonstrate the physiologic function of FUT1-mediated fucosylation in MG development and function, and indicate its potential role in ocular surface homeostasis.

Association between aging-dependent gut microbiome dysbiosis and dry eye severity in C57BL/6 male mouse model: a pilot study.

BACKGROUND: While aging is a potent risk factor of dry eye disease, age-related gut dysbiosis is associated with inflammation and chronic geriatric diseases. Emerging evidence have demonstrated that gut dysbiosis contributes to the pathophysiology or exacerbation of ocular diseases including dry eye disease. However, the relationship between aging-related changes in gut microbiota and dry eye disease has not been elucidated. In this pilot study, we investigated the association between aging-dependent microbiome changes and dry eye severity in C57BL/6 male mice. RESULTS: Eight-week-old (8 W, n = 15), one-year-old (1Y, n = 10), and two-year-old (2Y, n = 8) C57BL/6 male mice were used. Dry eye severity was assessed by corneal staining scores and tear secretion. Bacterial genomic 16 s rRNA from feces was analyzed. Main outcomes were microbiome compositional differences among the groups and their correlation to dry eye severity. In aged mice (1Y and 2Y), corneal staining increased and tear secretion decreased with statistical significance. Gut microbiome α-diversity was not different among the groups. However, ß-diversity was significantly different among the groups. In univariate analysis, phylum Firmicutes, Proteobacteria, and Cyanobacteria, Firmicutes/Bacteroidetes ratio, and genus Alistipes, Bacteroides, Prevotella, Paraprevotella, and Helicobacter were significantly related to dry eye severity. After adjustment of age, multivariate analysis revealed phylum Proteobacteria, Firmicutes/Bacteroidetes ratio, and genus Lactobacillus, Alistipes, Prevotella, Paraprevotella, and Helicobacter to be significantly associated with dry eye severity. CONCLUSIONS: Our pilot study suggests that aging-dependent changes in microbiome composition are related to severity of dry eye signs in C57BL/6 male mice.

Comparison of ocular biometric measurements in patients with cataract using three swept-source optical coherence tomography devices.

BACKGROUND: Precise measurement of ocular biometry is critical for determining intraocular lens power. Newly developed swept-source optical coherence tomography (SS-OCT) - based ocular biometric devices, ANTERION and CASIA2 provide ocular biometric measurements as IOLMaster 700. This study aimed to assess agreement between three devices. METHODS: This retrospective comparative study includes patients with cataract who underwent ocular biometric measurements with three devices, ANTERION, CASIA2, and IOLMaster 700, at Seoul National University Hospital, in April 2020. Anterior keratometry, total keratometry, central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), and axial length (AL) were the main parameters for the comparison. To assess the agreement between the devices, intraclass coefficient (ICC) and Bland-Altman analysis with 95% limits of agreement (LoA) were used. RESULTS: A total of 47 eyes of 29 patients were measured with three devices. Average anterior keratometry showed excellent agreement (ICC ≥ 0.989), and the mean difference was less than 0.1 D. However, the ICC of the total average keratometry ranged from 0.808 to 0.952, and the difference was more than 0.43 D. The AL measured by ANTERION and IOLMaster 700 showed excellent agreement (ICC = 0.999), and the mean difference was 0.005 mm. The ANTERION and IOLMaster 700 did not obtain AL in six (12.8%) and three (6.4%) cases, respectively (P = 0.001 by Fisher's exact test). The CCT, ACD, and LT also showed excellent agreement (ICC > 0.9). CONCLUSIONS: The new SS-OCT-based devices, ANTERION, and CASIA2 showed a good agreement with IOLMaster 700 in measuring ocular biometry except for the total keratometry. The AL of ANTERION and IOLMaster 700 showed excellent agreement.

Inhibition of Aberrant α(1,2)-Fucosylation at Ocular Surface Ameliorates Dry Eye Disease.

Fucosylation is involved in a wide range of biological processes from cellular adhesion to immune regulation. Although the upregulation of fucosylated glycans was reported in diseased corneas, its implication in ocular surface disorders remains largely unknown. In this study, we analyzed the expression of a fucosylated glycan on the ocular surface in two mouse models of dry eye disease (DED), the NOD.B10.H2b mouse model and the environmental desiccating stress model. We furthermore investigated the effects of aberrant fucosylation inhibition on the ocular surface and DED. Results demonstrated that the level of type 2 H antigen, an α(1,2)-fucosylated glycan, was highly increased in the cornea and conjunctiva both in NOD.B10.H2b mice and in BALB/c mice subjected to desiccating stress. Inhibition of α(1,2)-fucosylation by 2-deoxy-D-galactose (2-D-gal) reduced corneal epithelial defects and increased tear production in both DED models. Moreover, 2-D-gal treatment suppressed the levels of inflammatory cytokines in the ocular surface and the percentages of IFN-γ+CD4+ cells in draining lymph nodes, whereas it did not affect the number of conjunctival goblet cells, the MUC5AC level or the meibomian gland area. Together, the findings indicate that aberrant fucosylation underlies the pathogenesis of DED and may be a novel target for DED therapy.

Long-term survival of full-thickness corneal xenografts from α1,3-galactosyltransferase gene-knockout miniature pigs in non-human primates.

BACKGROUND: We aimed to investigate (a) the long-term survival of corneal grafts from α1,3-galactosyltransferase gene-knockout miniature (GTKOm) pigs in non-human primates as a primary outcome and (b) the effect of anti-CD20 antibody on the survival of corneal grafts from GTKOm pigs as a secondary outcome. METHODS: Nine rhesus macaques undergoing full-thickness corneal xenotransplantation using GTKOm pigs were systemically administered steroid, basiliximab, intravenous immunoglobulin, and tacrolimus with (CD20 group) or without (control group) anti-CD20 antibody. RESULTS: Graft survival was significantly longer (P = .008) in the CD20 group (>375, >187, >187, >83 days) than control group (165, 91, 72, 55, 37 days). When we compared the graft survival time between older (>7- month-old) and younger (≤7-month-old) aged donor recipients, there was no significant difference. Activated B cells were lower in the CD20 group than control group (P = .026). Aqueous humor complement C3a was increased in the control group at last examination (P = .043) and was higher than that in the CD20 group (P = .014). Anti-αGal IgG/M levels were unchanged in both groups. At last examination, anti-non-Gal IgG was increased in the control group alone (P = .013). CONCLUSIONS: The GTKOm pig corneal graft achieved long-term survival when combined with anti-CD20 antibody treatment. Inhibition of activated B cells and complement is imperative even when using GTKO pig corneas.

Spontaneous regression of congenital corneal opacity.

PURPOSE: To determine the incidence of spontaneous regression of congenital corneal opacity (CCO) and identify clinical factors associated with the regression. METHODS: Medical records and anterior segment photographs were reviewed of 57 eyes in 35 patients with CCO that were not related to congenital glaucoma, tumors, infection, trauma, or metabolic disorders and were followed up without corneal transplantation for longer than one year at Seoul National University Hospital. Spontaneous regression of corneal opacity was defined as a decrease in corneal opacity significant enough for visual axis clearance. Data on demographics, systemic, and ocular characteristics were collected and compared between patients who had spontaneous regression of CCO and those who did not. RESULTS: Spontaneous regression of corneal opacity developed in 32 eyes (22 patients, 56.1%) out of 57 CCO eyes (35 patients) at the mean 8.2 ± 5.4 months of age (the median 6.7 months). Absence of combined ocular anomalies such as iris anomaly, lens opacity, and peripheral corneal vascularization was significantly associated with the regression of opacity. CONCLUSIONS: Corneal opacity can spontaneously regress in 56.1% of eyes with CCO during the first year of life. Careful follow-up with amblyopia management can be one of treatment options for CCO.

Comparative effects of various types of toric intraocular lenses on astigmatism correction.

BACKGROUND: Currently, various types of toric intraocular lenses (IOL) have been manufactured and can be divided into three types according to the location of correction component; front-toric IOL (correction on anterior IOL surface), back-toric IOL (correction on posterior IOL surface), and bi-toric IOL (correction on both anterior and posterior IOL surfaces). In this study, we aimed to investigate the effectiveness of reducing corneal astigmatism of either normal or post-penetrating keratoplasty (PKP) corneas according to the type of implanted toric IOLs. METHODS: Medical records were retrospectively reviewed in 370 patients who had undergone phacoemulsification with posterior chamber toric IOL insertion (front-toric IOL, back-toric IOL or bi-toric IOL). Subjects were divided into 2 groups; subjects who had no history of corneal disease with corneal astigmatism more than 1.00 diopters (D) (G1) and subjects who received previous PKP with all corneal sutures removed and had corneal astigmatism more than 1.25 D (G2). Preoperatively intended target from SRK/T was evaluated. Refractive astigmatism and its vector analysis (J0, J45), mean numerical error (MNE) and mean absolute error (MAE) were assessed at least a month after cataract surgery. RESULTS: Mean preoperative corneal astigmatisms were 2.2 D and 4.0 D in G1 and G2, respectively. There was significant reduction of mean postoperative refractive astigmatism to 0.89 D in G1 and to 2.33 D in G2. In G1, bi-toric IOL showed significantly more improved refractive astigmatism than back-toric IOL. In G2, no difference in refractive astigmatism according to toric IOL type was observed. While G2 showed no difference in MNE among toric IOLs, in G1, bi-toric IOL showed significant hyperopic shift compared to back-toric IOL. In both groups, there was no significant difference in MAE according to type of IOL. No postoperative complications were observed. CONCLUSION: Our study suggests that all types of toric IOL are beneficial in correcting astigmatism of normal and post-PKP corneas. Noticeably, bi-toric IOL showed significantly better results in refractive astigmatism than back-toric IOL in normal cornea. However, bi-toric IOL showed a more hyperopic shift compared to back-toric IOL. Among post-PKP corneas, all types of toric IOL showed similar results.

Can Gut Microbiota Affect Dry Eye Syndrome?

Using metagenomics, continuing evidence has elicited how intestinal microbiota trigger distant autoimmunity. Sjögren's syndrome (SS) is an autoimmune disease that affects the ocular surface, with frequently unmet therapeutic needs requiring new interventions for dry eye management. Current studies also suggest the possible relation of autoimmune dry eye with gut microbiota. Herein, we review the current knowledge of how the gut microbiota interact with the immune system in homeostasis as well as its influence on rheumatic and ocular autoimmune diseases, and compare their characteristics with SS. Both rodent and human studies regarding gut microbiota in SS and environmental dry eye are explored, and the effects of prebiotics and probiotics on dry eye are discussed. Recent clinical studies have commonly observed a correlation between gut dysbiosis and clinical manifestations of SS, while environmental dry eye portrays characteristics in between normal and autoimmune. Moreover, a decrease in both the Firmicutes/Bacteroidetes ratio and genus Faecalibacterium have most commonly been observed in SS subjects. The presumable pathways forming the "gut dysbiosis-ocular surface-lacrimal gland axis" are introduced. This review may provide perspectives into the link between the gut microbiome and dry eye, enhance our understanding of the pathogenesis in autoimmune dry eye, and be useful in the development of future interventions.

Comparative Analysis of Age-Related Changes in Lacrimal Glands and Meibomian Glands of a C57BL/6 Male Mouse Model.

It is not known how biological changes in the lacrimal (LGs) and meibomian (MGs) glands contribute to dry eye disease (DED) in a time-dependent manner. In this study, we investigated time-sequenced changes in the inflammation, oxidative stress, and senescence of stem cells in both glands of an aging-related DED mouse model. Eight-week (8W)-, one-year (1Y)-, and two-year (2Y)-old C57BL/6 male mice were used. MG areas of the upper and lower eyelids were analyzed by transillumination meibography imaging. The number of CD45+, 8-OHdG+, Ki-67+, and BrdU+ cells was compared in both glands. Increased corneal staining and decreased tear secretion were observed in aged mice. The MG dropout area increased with aging, and the age-adjusted MG area in lower lids was negatively correlated with the National Eye Institute (NEI) score. Increased CD4+ interferon (IFN)-γ+ cells in LGs were found in both aged mice. An increase in 8-OHdG+ cells in both glands was evident in 2Y-old mice. Reduced Ki-67+ cells, but no change in CD45+ cells, was observed in the MGs of 1Y-old mice. Increased BrdU+ cells were observed in the LGs of aged mice. This suggests that age-dependent DED in C57BL/6 mice is related to inflammation of the LGs, the development of MG atrophy, and oxidative stress in both glands.

Effects of topical autologous serum on the ocular surface in patients with toxic corneal epitheliopathy induced by anti-glaucoma drugs.

PURPOSE: To investigate the effects of topical autologous serum application on the ocular surface in patients with toxic corneal epitheliopathy induced by anti-glaucoma drugs. METHODS: The patients who had corneal epitheliopathy because of preservative-containing anti-glaucoma eye drops were prospectively enrolled. The epitheliopathy was refractory to preservative-free artificial tear treatment. The patients topically applied 20% autologous serum to the eye eight times per day for 1 month. Baseline and one-month change in symptoms and signs were assessed by the Ocular Surface Disease Index (OSDI) questionnaire, tear film break-up time (TFBUT), Schirmer I values, corneoconjunctival staining scores, corneal sensitivity, InflammaDry® tear immunoassay, and tear cytokine profiles using a bead-based multiplex assay. RESULTS: A total of ten consecutive patients were enrolled between January and August 2018 and evaluated after one-month treatment with 20% autologous serum eye drops. Significant improvement was observed in symptoms (OSDI scores from 25.5 ± 20.9 to 10.5 ± 12.0; P = .039), TFBUT (from 3.1 ± 1.8 s to 5.4 ± 2.3 s; P = .025), corneoconjunctival staining scores (from 7.7 ± 1.8 to 1.8 ± 1.9 NEI scale; P = .005), corneal sensitivity (from 4.6 ± .9 cm to 5.8 ± .5 cm; P = .013), and metalloproteinase-9 levels (P = .013). There were no significant changes in Schirmer I values and tear cytokine levels on multiplex assays. Treatment-related side effects were not detected. CONCLUSIONS: Topical instillation of 20% autologous serum is an effective treatment for toxic corneal epitheliopathy associated with anti-glaucoma eye drops. TRIAL REGISTRATION NUMBER: KCT0003827.

Predictive biomarkers for graft rejection in pig-to-non-human primate corneal xenotransplantation.

We investigated the predictive biomarkers for graft rejection in pig-to-non-human primate (NHP) full-thickness corneal xenotransplantation (n = 34). The graft score (0-12) was calculated based on opacity, edema, and vascularization. Scores ≥ 6 were defined as rejection. NHPs were divided into two groups: (a) graft rejection within 6 months; and (b) graft survival until 6 months. In the evaluation of 2-week biomarkers, none of the NHPs showed rejection within 2 weeks and the 34 NHPs were divided into two groups: (a) entire rejection group (n = 16); and (b) survival group (n = 18). In the evaluation of 4-week biomarkers, four NHPs showing rejection within 4 weeks were excluded and the remaining 30 NHPs were divided into two groups: (a) late rejection group (n = 12); and (b) survival group (n = 18). Analysis of biomarker candidates included T/B-cell subsets, levels of anti-αGal IgG/M, donor-specific IgG/M from blood, and C3a from plasma and aqueous humor (AH). CD8+ IFNγ+ cells at week 2 and AH C3a at week 4 were significantly elevated in the rejection group. Receiver operating characteristic areas under the curve was highest for AH C3a (0.847) followed by CD8+ IFNγ+ cells (both the concentration and percentage: 0.715), indicating excellent or acceptable discrimination ability, which suggests that CD8+ IFNγ+ cells at week 2 and AH C3a at week 4 are reliable biomarkers for predicting rejection in pig-to-NHP corneal xenotransplantation.

Protocol for the first clinical trial to investigate safety and efficacy of corneal xenotransplantation in patients with corneal opacity, corneal perforation, or impending corneal perforation.

BACKGROUND: Xenotransplantation using fresh porcine corneas has been suggested as a feasible alternative to overcome the shortage of human donor corneas. Successful long-term survival of grafts without evidence of xenozoonosis in clinically applicable pig-to-non-human primate corneal transplantation model has brought researchers close to human clinical trials. Accordingly, we aimed to prepare a clinical trial protocol to conduct the first corneal xenotransplantation. METHODS: We developed the clinical trial protocol based on international consensus statement on conditions for undertaking clinical trials of corneal xenotransplantation developed by the International Xenotransplantation Society. Detailed contents of the protocol have been modified with reference to comments provided by ophthalmologists and multidisciplinary experts, including an infectionist, an organ transplantation specialist, a clinical pharmacologist, a neuropsychiatrist, a laboratory medicine doctor, and a microbiologist. RESULTS: Two patients with bilateral legal corneal blindness (best-corrected visual acuity ≤20/200 in the better eye and ≤20/1000 in the candidate eye) or with (impending) corneal perforation will be enrolled. During the screening period, participants and their family members will have two separate deep consideration periods before signing informed consent forms. Each patient will undergo corneal xenotransplantation using fresh corneas from Seoul National University miniature pigs. Commercially available immunosuppressants will be administered and systemic infection prophylaxis will be performed according to the program schedule. After transplantation, each patient will be monitored at a specialized clinic to investigate safety up to 2 years and efficacy up to 1 year. CONCLUSIONS: A detailed clinical trial protocol for the first corneal xenotransplantation reflecting the global guidelines is provided.

Mesenchymal Stromal Cells Inhibit Inflammatory Lymphangiogenesis in the Cornea by Suppressing Macrophage in a TSG-6-Dependent Manner.

The cornea is a transparent tissue devoid of blood and lymphatic vessels. However, various inflammatory conditions can cause hemangiogenesis and lymphangiogenesis in the cornea, compromising transparency and visual acuity. Mesenchymal stem/stromal cells (MSCs) have therapeutic potentials in a variety of diseases because of anti-inflammatory properties. Herein, we investigated the effects of MSCs on corneal angiogenesis using a model of suture-induced inflammatory corneal neovascularization. Data demonstrated that an intravenous administration of MSCs suppressed corneal inflammation and neovascularization, inhibiting both hemangiogenesis and lymphangiogenesis. MSCs reduced the levels of vascular endothelial growth factor (VEGF)-C, VEGF-D, Tek, MRC1, and MRC2 in the cornea, which are expressed by pro-angiogenic macrophages. Moreover, the number of CD11b+ monocytes/macrophages in the cornea, spleen, peripheral blood, and draining lymph nodes was decreased by MSCs. Depletion of circulating CD11b+ monocytes by blocking antibodies replicated the effects of MSCs. Importantly, knockdown of tumor necrosis factor alpha (TNF-α)-stimulated gene/protein 6 (TSG-6) in MSCs abrogated the effects of MSCs in inhibiting corneal hemangiogenesis and lymphangiogenesis and monocyte/macrophage infiltration. Together, the results suggest that MSCs inhibit inflammatory neovascularization in the cornea by suppressing pro-angiogenic monocyte/macrophage recruitment in a TSG-6-dependent manner.

Long-term safety outcome of systemic immunosuppression in pig-to-nonhuman primate corneal xenotransplantation.

BACKGROUND: Safety concerns exist for corneal recipients under immunosuppression. We report long-term safety results of porcine corneal xenotransplantation under immunosuppression in nonhuman primates. METHODS: Systemic monitoring data from 49 Chinese rhesus macaques that received pig corneal transplant between 2009 and 2018 were retrospectively reviewed. The recipients were divided into 4 groups depending on the systemic immunosuppressants used: (a) conventional steroid group; costimulation blockade groups ([b] anti-CD154 antibody, [c] anti-CD40 antibody); and (d) commercially available immunosuppressants (anti-CD20 antibody, tacrolimus, basiliximab) group. We compared results of general condition monitoring; hematologic, biochemical, and electrolyte tests; and Rhesus Cytomegalovirus infection monitoring. RESULTS: All recipients recovered from early weight loss. White blood cell counts significantly decreased at 6 months in the steroid and anti-CD154 groups. Abnormal liver and kidney function and electrolyte imbalance were not observed in all groups. The mean value of Rhesus Cytomegalovirus DNA copies was consistently lower than 200 copies/mL, and antibody titers did not change over time in all groups. Tacrolimus-associated thrombotic microangiopathy was developed in one case, which resolved after discontinuation of tacrolimus. In 2017, a simian varicella virus outbreak led to clinical signs in 5 that received immunosuppressive therapies, of which 3 died. CONCLUSION: Costimulatory blockade-based and anti-CD20 antibody/tacrolimus-based immunosuppressive therapies seem to be comparably safe with steroid therapy in nonhuman primates receiving corneal xenotransplantation, as they did not reactivate Rhesus Cytomegalovirus and maintained manageable systemic status. Although reactivation is rare, antiviral prophylaxis for simian varicella virus should be considered in immunocompromised hosts.

Trifocal versus Bifocal Diffractive Intraocular Lens Implantation after Cataract Surgery or Refractive Lens Exchange: a Meta-analysis.

BACKGROUND: We compared the efficacy between trifocal and bifocal diffractive intraocular lens (IOL) implantation. METHODS: Through PubMed, MEDLINE, EMBASE, and CENTRAL, we searched potentially relevant articles published from 1990 to 2018. Defocus curves, visual acuities (VAs) were measured as primary outcomes. Spectacle dependence, postoperative refraction, contrast sensitivity (CS), glare, and higher-order aberrations (HOAs) were measured as secondary outcomes. Effects were pooled using random-effects method. RESULTS: We included 11 clinical trials, with a total of 787 eyes (395 subjects). The trifocal IOL group showed better binocular distance VA corrected with defocus levels of -0.5, -1.0, -1.5, and -2.5 diopter than the bifocal IOL group (All P ≤ 0.004). The trifocal IOL group showed better monocular uncorrected distance and intermediate VAs (mean difference [MD], -0.04 logarithm of the minimum angle of resolution [logMAR]; 95% confidence interval [CI], -0.07, -0.01; P = 0.006 and MD, -0.07 logMAR; 95% CI, -0.13, -0.01; P = 0.03, respectively). Postoperative refraction, glare, CS, and HOAs were not significantly different from each other. CONCLUSION: The overall findings indicate that trifocal diffractive IOL implantation is better than the bifocal diffractive IOL in intermediate VA, and provides similar or better in distance and near VAs without any major deterioration in the visual quality.