Tromboendarterectomía pulmonar en hipertensión pulmonar tromboembólica crónica. Experiencia binacional Uruguay-Argentina / Pulmonary thromboendarterectomy in chronic thromboembolic pulmonary hypertension. Binational experience Uruguay-Argentina / Tromboendarterectomia pulmonar na hipertensão pulmonar tromboembólica crônica. Experiência binacional Uruguai-Argentina

Introducción: La tromboendarterectomía pulmonar (TEA) es la principal herramienta terapéutica en hipertensión pulmonar tromboembólica crónica (HPTEC), potencialmente curativa. Se analiza la experiencia de 13 años de TEAs de pacientes uruguayos en el marco del convenio con el Hospital Universitario Fundación Favaloro (HUFF-Argentina). Metodología: Estudio analítico, observacional y retrospectivo de todas las TEAs realizadas entre 2011 y 2023. Resultados: Se realizaron 15 TEAs. 46 ± 17 años, 67% hombres. Diez pacientes tenían antecedentes de enfermedad tromboembólica previa y 8 hipercoagulabilidad. El tiempo desde el inicio de los síntomas al diagnóstico fue de 36 (22-78) meses. Ochenta por ciento se encontraba en CF III, con una distancia total recorrida en la prueba de la marcha de 6 minutos de 375 (272-458) metros, severidad ecocardiográfica (TAPSE/PAPs 0,22 ± 0,08 mm/mmHg) y hemodinámica (RVP 11 ± 5 UW) que mejoraron significativamente en el posoperatorio temprano. La mortalidad intrahospitalaria fue del 20% que se mantuvo en el seguimiento de 34 (7-97) meses excepto un paciente que murió por una nueva embolia de pulmón a los 3 años. Todos los fallecidos tenían una hemodinamia preoperatoria significativamente más grave (RVP 19 ± 6 UW, índice cardíaco 1,5 ± 0,4 L/min/m2). Seis sobrevivientes (50%) presentaron HP residual asociada a una mayor PAPm y RVP preoperatorias y menor recuperación funcional y ecocardiográfica a corto plazo (P <0,05), dos de los cuales recibieron terapia específica posterior al procedimiento. Conclusiones: La TEA determinó mejoría clínica, ecocardiográfica y hemodinámica. Seis supervivientes (50%) normalizaron la hemodinamia de reposo. La severidad hemodinámica preoperatoria dado por las lesiones obstructivas y microangiopatía distales se asoció con una alta tasa de complicaciones y mortalidad perioperatorias. La reducción del retardo en el diagnóstico y tratamiento junto con una mayor tasa de TEAs/año podrían reducir las complicaciones y mejorar el pronóstico.

Summary Introduction: Pulmonary thromboendarterectomy (PTE) is the main therapeutic tool for chronic thromboembolic pulmonary hypertension (CTEPH), and is potentially curative. The experience of 13 years of PTEs on Uruguayan patients under the agreement with the University Hospital Fundación Favaloro (HUFF-Argentina) is analyzed. Methodology: Analytical, observational, and retrospective study of all PTEs performed between 2011 and 2023. Results: Fifteen PTEs were performed. Age was 46 ± 17 years, 67% male. Ten patients had a history of prior thromboembolic disease, and 8 had hypercoagulability. The time from symptom onset to diagnosis was 36 (22-78) months. Eighty percent were in NYHA Functional Class III, with a total distance walked in the 6-minute walk test of 375 (272-458) meters, echocardiographic severity (TAPSE/sPAP 0,22 ± 0,08 mm/mmHg), and hemodynamic severity (PVR 11 ± 5 WU) which significantly improved in the early postoperative period. In-hospital mortality was 20% and remained at a follow-up of 34 (7-97) months, except for one patient who died from a new pulmonary embolism at 3 years. All deceased patients had significantly more severe preoperative hemodynamics (PVR 19 ± 6 WU, cardiac index 1,5 ± 0,4 L/min/m²). Six survivors (50%) presented with residual PH associated with higher preoperative mPAP and PVR and lower short-term functional and echocardiographic recovery (P <0,05), two of whom received specific therapy post-procedure. Conclusions: PTE resulted in clinical, echocardiographic, and hemodynamic improvement. Six survivors (50%) normalized resting hemodynamics. Preoperative hemodynamic severity due to distal obstructive lesions and microangiopathy was associated with a high rate of perioperative complications and mortality. Reducing the delay in diagnosis and treatment and a higher rate of PTEs/year could reduce complications and improve prognosis.

Introdução: A tromboendarterectomia pulmonar (TEP) é a principal ferramenta terapêutica na hipertensão pulmonar tromboembólica crônica (HPTEC), potencialmente curativa. Analisa-se a experiência de 13 anos de TEPs em pacientes uruguaios no âmbito do convênio com o Hospital Universitário Fundação Favaloro (HUFF-Argentina). Metodologia: Estudo analítico, observacional e retrospectivo de todas as TEPs realizadas entre 2011 e 2023. Resultados: Foram realizadas 15 TEPs. Idade de 46 ± 17 anos, 67% homens. Dez pacientes tinham antecedentes de doença tromboembólica prévia e 8 hipercoagulabilidade. O tempo desde o início dos sintomas até o diagnóstico foi de 36 (22-78) meses. Oitenta por cento encontravam-se em Classe Funcional III, com uma distância total percorrida no teste de caminhada de 6 minutos de 375 (272-458) metros, gravidade ecocardiográfica (TAPSE/sPAP 0,22 ± 0,08 mm/mmHg) e hemodinâmica (RVP 11 ± 5 UW) que melhoraram significativamente no pós-operatório precoce. A mortalidade intra-hospitalar foi de 20% e manteve-se no seguimento de 34 (7-97) meses, exceto um paciente que faleceu por uma nova embolia pulmonar aos 3 anos. Todos os falecidos apresentavam hemodinâmica pré-operatória significativamente mais grave (RVP 19 ± 6 UW, índice cardíaco 1,5 ± 0,4 L/min/m²). Seis sobreviventes (50%) apresentaram HP residual associada a maior PAPm e RVP pré-operatórias e menor recuperação funcional e ecocardiográfica a curto prazo (P <0,05), dois dos quais receberam terapia específica pós-procedimento. Conclusões: A TEP resultou em melhora clínica, ecocardiográfica e hemodinâmica. Seis sobreviventes (50%) normalizaram a hemodinâmica de repouso. A gravidade hemodinâmica pré-operatória devido a lesões obstrutivas e microangiopatia distal foi associada a uma alta taxa de complicações e mortalidade perioperatória. A redução do atraso no diagnóstico e tratamento juntamente com uma maior taxa de TEPs/ano poderia reduzir as complicações e melhorar o prognóstico.

Epithelial Immune Cell Response to Initial Soft Contact Lens Wear in the Human Corneal and Conjunctival Epithelium.

Purpose: The purpose of this study was to assess the immediate ocular immune response to soft contact lens (CL) wear by examining presumed epithelial immune cell (EIC) density and morphology at the central, peripheral, limbal cornea, and conjunctiva. Methods: Fifty-four participants naïve to CL wear (mean age = 24.8 ± 9.8 years, 44% female participants), were examined using in vivo confocal microscopy at baseline and after 2 hours of CL wear (1-Day ACUVUE MOIST). Images were captured at the central, temporal far peripheral and limbal cornea, and bulbar conjunctiva. EIC density was counted manually and morphology was graded. Differences in EIC parameters pre- and post-CL wear were examined using a generalized estimating equation model with appropriate post hoc analyses. Results: After 2 hours of soft CL wear, there was a significant increase in EIC density in all regions other than the central cornea (all P < 0.001). Cell body size was significantly larger, and a higher proportion of participants exhibited EIC with long dendrites after lens wear at the central and peripheral cornea (both P < 0.001). There was a significant increase in the number of participants displaying EIC with thick dendrites at the peripheral (P = 0.04) and limbal cornea (P < 0.001) after lens wear. Conclusions: EICs were primarily recruited to the peripheral regions, whereas the central cornea shows no significant recruitment after short-term CL wear. Both central and peripheral corneas exhibited an enhanced antigen capture capacity, whereas migratory capacity was increased in the peripheral corneal regions suggesting EIC activation following a short period of CL wear.

Soft toric contact lens wear improves digital performance and vision-A randomised clinical trial.

PURPOSE: To compare objective and subjective digital near visual performance and comfort in low to moderate astigmatic participants fitted with toric versus spherical equivalent silicone hydrogel daily disposable contact lenses. METHODS: This was a double-masked, randomised, crossover study. Participants aged 18 to 39 years with astigmatism of -0.75 to -1.50 D were recruited and fitted with toric and spherical contact lenses, in random order. Outcomes were measured at baseline and after 1 week of wear with each contact lens type after the follow-up visits. High- and low-contrast near logMAR visual acuity, automated visual acuity, zoom (%), contrast (%), reading distance (cm), critical print size (logMAR) and reading speed were assessed. Participants also completed the validated Near Activity Visual Questionnaire (NAVQ) and Contact Lens Dry Eye Questionnaire 8 (CLDEQ-8) for each correction type. RESULTS: Twenty-three participants completed the study (74% female, average age 24.4 ± 4.2 years). When participants wore toric contact lenses, near high- and low-contrast visual acuity and automated visual acuity improved by 3-4 letters (all p < 0.03) and participants were able to read faster on an iPad (p = 0.02). Participants were also able to read with 8% less contrast on the iPad with toric lenses (p = 0.01). Participants reported better subjective vision on the overall NAVQ (p = 0.001) and better comfort on the CLDEQ-8 (p = 0.02) with toric lenses. Fewer participants reported difficulty with maintaining focus at near, reading small print, reading labels/instructions, reading the computer display/keyboard and reading post/mail with toric correction. CONCLUSIONS: Toric contact lenses improve comfort, subjective and objective visual performance with digital devices and other near tasks compared with the spherical equivalent correction in participants with low to moderate astigmatism.

Corneal epithelial dendritic cells, tear neuropeptides and corneal nerves continue to be affected more than 12 months after LASIK.

PURPOSE: LASIK causes corneal nerve damage and may affect the neuro-immune crosstalk. This study examined the effects of LASIK on corneal epithelial dendritic cells (CEDC) density and morphology and explored their relationships with corneal nerves and tear neuropeptides. A grading system was developed to assess CEDC morphology. METHODS: Intra- and inter-observer repeatability of the CEDC morphology grading system was established using kappa (κ). In vivo confocal microscope images of the central cornea were captured from 20 participants who had undergone LASIK 12-16 months earlier and 20 controls (age 18-32 years, 55%F). CEDC density was counted manually, and CEDC morphology was assessed using a new grading system. CEDC sub-types (contacting nerves [CEDCc] and not contacting nerves [CEDCnc]) were also assessed. Differences in CEDC density and morphology were examined using mixed models and chi-squared test. Relationships between CEDC and corneal nerve parameters and tear substance P were explored using Spearman's correlation. RESULTS: Excellent intra- and inter-observer repeatability was demonstrated for the grading system (κ = 0.82-0.97). In post-LASIK participants, CEDC density was lower compared with controls (5 [0-34] vs. 21 [7-77] cells/mm2 ; p = 0.01), and the proportion of CEDC with thick dendrites was higher (55%-73% vs. 11%-21%, p < 0.003). Higher tear substance P levels were associated with higher CEDC density (rho = 0.48, p = 0.003). Fewer nerve interconnections were observed in participants in whom CEDC had dendrites (p = 0.03). CEDC sub-types followed a similar pattern to CEDC. CONCLUSIONS: The findings suggest that CEDC may remain altered more than 12 months post-LASIK. The association with substance P suggests a role for CEDC in corneal neurogenic inflammation.

Tear proteomic analysis of young glasses, orthokeratology, and soft contact lens wearers.

Contact lens-related ocular surface complications occur more often in teenagers and young adults. The purpose of this study was to determine changes in tear proteome of young patients wearing glasses (GL), orthokeratology lenses (OK), and soft contact lenses (SCL). Twenty-two young subjects (10-26 years of age) who were established GL, OK, and SCL wearers were recruited. Proteomic data were collected using a data-independent acquisition-parallel accumulation serial fragmentation workflow. In total, 3406 protein groups were identified, the highest number of proteins identified in Schirmer strip tears to date. Eight protein groups showed higher abundance, and 11 protein groups showed lower abundance in the SCL group compared to the OK group. In addition, the abundance of 82 proteins significantly differed in children compared to young adult GL wearers, among which 67 proteins were higher, and 15 proteins were lower in children. These 82 proteins were involved in inflammation, immune, and glycoprotein metabolic biological processes. In summary, this work identified over 3000 proteins in Schirmer Strip tears. The results indicated that tear proteomes were altered by orthokeratology and soft contact wear and age, which warrants further larger-scale study on the ocular surface responses of teenagers and young adults separately to contact lens wear. SIGNIFICANCE: In this work, we examined the tear proteomes of young patients wearing glasses, orthokeratology lenses, and soft contact lenses using a data-independent acquisition-parallel accumulation serial fragmentation (diaPASEF) workflow and identified 3406 protein groups in Schirmer strip tears. Nineteen protein groups showed significant abundance changes between orthokeratology and soft contact lens wearers. Moreover, eighty-two protein groups significantly differed in abundance in children and young adult glasses wearers. As a pilot study, this work provides a deep coverage of tear proteome and suggests the need to investigate ocular responses to contact lens wear separately for children and young adults.

Changes in tear glucose and insulin concentrations following an oral glucose tolerance test.

CLINICAL RELEVANCE: Tear glucose and insulin are responsible for the health of the ocular surface; thus, it is important for clinicians to detect the tear glucose and insulin using point-of-care methods. AIM: To determine if changes in blood glucose and insulin levels following an oral glucose tolerance test are reflected in the tears and to test the association between gene expression and tear insulin and glucose. METHODS: Twenty healthy young adults were enrolled. Basal tears and peripheral blood samples were collected to assess glucose and insulin using a point-of-care glucometer and ELISA assays in fasted subjects, and 1.5 and 3 h after an oral glucose challenge. Conjunctival impression cytology was collected to determine gene expression of insulin receptor (INSR) and glucose transporters (GLUT1 and GLUT4). Changes were examined using non-parametric one-way ANOVA. Spearman tests were conducted to examine associations between variables. RESULTS: Glucose and insulin levels increased 1.5 h after oral glucose in both blood (P < 0.001) and tears (P < 0.049) and returned to near baseline values after 3 h. There was a positive correlation between glucose levels in the blood and tears (rho = 0.57, P < 0.001), but not between blood and tear insulin levels (P = 0.18). Glucose and insulin levels in tears were correlated (rho = 0.32, P = 0.048). Tear glucose concentration at 1.5 h after oral glucose was associated with INSR expression (rho = 0.49, P = 0.03), and there was a trend with GLUT1 (P = 0.06) but not GLUT4. CONCLUSION: Tear glucose reflected blood glucose levels but this correspondence was not observed for insulin. Further studies are required to determine the role of glucose and insulin on the ocular surface in both health and diabetes.

Patient and parent perceptions of myopia modalities.

PURPOSE: This study compared quality of life (QoL) of myopic adults and children who were established spectacle, soft contact lens (SCL), or orthokeratology (OK) wearers as well as parent/child responses using Pediatric Refractive Error Profile 2 (PREP2). METHODS: Forty-eight adults (aged 18-26 years), 49 children (aged 9-17 years), and the children's parent, completed PREP2, with 7 subscales (symptoms, vision, activities, appearance, peer perception, handling, and overall). Adults and children must have worn their correction for at least three years. Parents were asked to answer how they thought their child would answer. Scores were compared between age groups, among correction groups, and between children and their parents using non-parametric ANOVA, Mann-Whitney U and Wilcoxon Signed-Rank tests, as appropriate. Post-hoc pairwise comparisons among correction groups were conducted with Bonferroni adjustment. RESULTS: Average age of adults was 22 ± 2 and children was 14 ± 2 years, and duration of correction use was 8 ± 3 for adults and 5 ± 2 years for children (both p < 0.01). Adult OK wearers were more satisfied with vision (p = 0.04), activities (p < 0.001) and overall (p = 0.03) compared to spectacle wearers. Children OK wearers reported higher scores for activities than SCL (p = 0.048) and spectacle wearers (p < 0.001). Parents of contact lens wearers reported higher perceived QoL for activities (OK p < 0.001; SCL p = 0.02), handling (OK p = 0.02; SCL p < 0.001), appearance (SCL p = 0.001), and overall (OK p = 0.001; SCL p < 0.001) subscales than parents of child spectacle wearers. CONCLUSION: Activity-driven children and adults perceive significant benefits from OK over spectacles. Parents' perceptions did not align with their children's perceptions of their correction.

Tear Proteomics of Children and Young Adult Soft Contact Lens, Orthokeratology and Spectacle Wearers - A Pilot Study.

PURPOSE: Contact lens complications occur more often in older teenagers and young adults compared to children. This study explored differences in tear proteomics between children and young adults wearing soft contact lens (SCL), orthokeratology or spectacles for >3 years. METHODS: Twelve children and 12 sex- and correction-matched young adults were enrolled. Tears were collected via Schirmer strips for tear proteomic analysis using mass spectrometry. Proteome Discoverer was used for protein identification. Label-Free Quantitation was generated using Scaffold software; Fisher's Exact tests were used to compare proteins by age and correction groups. Generalized linear models were used to assess differences in overall protein levels by age and correction groups. A secondary analysis of proteins presented in >50% of samples of each group was conducted using the R/Bioconductor limma package. RESULTS: There were 385 proteins present only in young adults while 183 were unique in children. There were 528 unique proteins to SCL, 96 to orthokeratology and 149 to spectacle wearers. Based on Fisher's Exact analyses, 126 proteins were higher in young adults than children (all P < 0.048). Forty-seven protein levels were higher in SCL compared to orthokeratology (all P < 0.01), 33 protein levels were higher in SCL compared to spectacles (all P < 0.01), 15 protein levels were higher in orthokeratology compared to spectacle wearers (all P < 0.01). Based on generalized linear models, young adults had higher overall protein levels than children (P = 0.001), SCL had higher protein levels than spectacle wearers (P < 0.001) but no differences were found between orthokeratology and spectacle wearers (P = 0.79). Based on the secondary analysis, only Antileukoproteinase was higher in the young adult orthokeratology group compared to other groups (P < 0.01). CONCLUSIONS: Tear protein type and abundance differ by age and correction. Further research is needed to understand the effects of contact lens correction in children and young adults on the tear proteome.

The structural and functional corneal reinnervation mechanism at different regions after LASIK-an in vivo confocal microscopy study.

PURPOSE: To determine the recovery of structural and functional corneal sensory nerves within the LASIK flap in order to provide insight to more proximal corneal reinnervation and symptoms post-LASIK. METHODS: Twenty participants underwent femtosecond LASIK with a superior flap hinge. Ocular Comfort Index in Chinese (OCI-C), Cochet-Bonnet esthesiometry, and in vivo confocal microscopy were conducted before surgery and 1 week, 1-, 3-, and 6-months post-LASIK to measure symptoms, corneal sensitivity, nerve fiber density, width, and the number of interconnections within the flap (central and mid-temporal regions), and next to the superior flap hinge. Linear mixed models were used to compare differences between corneal regions at each time point post-LASIK and changes over time post-LASIK. Spearman's correlation tests were used to examine the associations between variables post-LASIK. RESULTS: The least reduction in sensitivity (P < 0.03) and in nerve fiber density (P < 0.02) was found near the flap hinge compared to other regions, but no regional differences were found in nerve fiber width and interconnections. Nerve fiber density and the number of interconnections at all regions within the flap recovered over time (P < 0.02). The recovery of corneal sensitivity and nerve fiber width was only seen at the central and temporal regions (P < 0.04). No association was found between sensitivity and nerve parameters, but a higher OCI-C score was associated with a lower nerve fiber density near the hinge (r = - 0.43, P = 0.003) over time post-LASIK. CONCLUSION: Corneal sensitivity and density are preserved in the hinge, but this preservation of the corneal nerve damage does not affect the nerve morphology.

The Relationship Between Corneal Nerve Density and Hemoglobin A1c in Patients With Prediabetes and Type 2 Diabetes.

Purpose: Decreased corneal nerve fiber density and higher corneal epithelial dendritic cells have been reported in established patients with type 2 diabetes; however, alterations in the subbasal nerve plexus in prediabetes with healthy subjects or subjects with diabetes is limited. The study aimed to determine corneal nerve fiber density and morphology and dendritic cell density between healthy subjects and those with prediabetes or type 2 diabetes. Methods: Fifty-two subjects (aged 30-70 years) were recruited. Blood samples and body metrics were taken. Subjects were grouped as: healthy controls (hemoglobin A1c [HbA1c] < 5.7%), prediabetes (5.7-6.4%), and type 2 diabetes (> 6.4% or physician diagnosis). Central corneal subbasal nerve plexus was imaged using in vivo confocal microscopy. Corneal nerve fiber density and morphology, including interconnections and tortuosity, and dendritic cell density were assessed. Kruskal-Wallis tests were carried out to compare differences in the examined variables between groups. Spearman correlations were carried out to examine the associations between body metrics with HbA1c and corneal findings. Results: Seventeen healthy controls, 20 subjects with prediabetes, and 15 subjects with type 2 diabetes completed this study. Central corneal nerve fiber density was significantly lower in type 2 diabetes compared to prediabetes (P = 0.045) and healthy controls (P = 0.001). No differences were found in central corneal nerve fiber interconnections, tortuosity, or dendritic cell density between groups. There was a significant association between HbA1c and corneal nerve fiber density (rho = -0.45, P = 0.001) and body mass index (BMI; rho = -0.30, P = 0.04). Conclusions: Increased HbA1c values are associated with decreased corneal nerve fiber density across the spectrum of type 2 diabetes.

Effect of Dry Eye Disease on the Kinetics of Lacrimal Gland Dendritic Cells as Visualized by Intravital Multi-Photon Microscopy.

The lacrimal gland (LG) is the main source of the tear film aqueous layer and its dysfunction results in dry eye disease (DED), a chronic immune-mediated disorder of the ocular surface. The desiccating stress (DS) murine model that mimics human DED, results in LG dysfunction, immune cell infiltration, and consequently insufficient tear production. To date, the immune cell kinetics in DED are poorly understood. The purpose of this study was to develop a murine model of intravital multi-photon microscopy (IV-MPM) for the LG, and to investigate the migratory kinetics and 3D morphological properties of conventional dendritic cells (cDCs), the professional antigen presenting cells of the ocular surface, in DED. Mice were placed in a controlled environmental chamber with low humidity and increased airflow rate for 2 and 4 weeks to induce DED, while control naïve transgenic mice were housed under standard conditions. DED mice had significantly decreased tear secretion and increased fluorescein staining (p < 0.01) compared to naïve controls. Histological analysis of the LG exhibited infiltrating mononuclear and polymorphonuclear cells (p < 0.05), as well as increased LG swelling (p < 0.001) in DED mice compared to controls. Immunofluorescence staining revealed increased density of cDCs in DED mice (p < 0.001). IV-MPM of the LG demonstrated increased density of cDCs in the LGs of DED mice, compared with controls (p < 0.001). cDCs were more spherical in DED at both time points compared to controls (p < 0.001); however, differences in surface area were found at 2 weeks in DED compared with naïve controls (p < 0.001). Similarly, 3D cell volume was significantly lower at 2 weeks in DED vs. the naïve controls (p < 0.001). 3D instantaneous velocity and mean track speed were significantly higher in DED compared to naïve mice (p < 0.001). Finally, the meandering index, an index for directionality, was significant increased at 4 weeks after DED compared with controls and 2 weeks of DED (p < 0.001). Our IV-MPM study sheds light into the 3D morphological alterations and cDC kinetics in the LG during DED. While in naïve LGs, cDCs exhibit a more dendritic morphology and are less motile, they became more spherical with enhanced motility during DED. This study shows that IV-MPM represents a robust tool to study immune cell trafficking and kinetics in the LG, which might elucidate cellular alterations in immunological diseases, such as DED.

Alteration of the pattern of regenerative corneal subbasal nerves after laser in-situ keratomileusis surgery.

PURPOSE: Corneal nerves exhibit high plasticity, which allows successful reinnervation after nerve damage caused by laser in-situ keratomileusis (LASIK) surgery. This study aimed to examine corneal subbasal nerve orientation during regeneration after LASIK. METHODS: This study involved 20 healthy, myopic subjects who had undergone bilateral Femto-LASIK 12-16 months prior with a superior hinge position. The corneal subbasal nerve plexus at the central, mid-temporal and mid-superior cornea on the right eye were imaged using in vivo confocal microscopy. Global nerve fibre orientation (indicating the overall pattern) and variation of nerve fibre orientation (indicating the consistency of the orientation) was determined using customised MATLAB™ software (www.mathworks.com/products/matlab.html). Differences in nerve orientation variables between groups were examined using the Mann-Whitney U test. Linear mixed models with Bonferroni adjustment were conducted to examine differences between corneal regions, and over time, after LASIK. RESULTS: There were no differences between post-LASIK and control groups in global nerve orientation at any of the examined corneal regions. The post-LASIK subjects had a greater variation of nerve orientation at the central (p = 0.007) and temporal (p = 0.049) cornea than the controls. There was a difference in global nerve fibre orientation between corneal regions (p < 0.001) in the controls but not in the post-LASIK group. The variation of nerve fibre orientation was higher at the central, compared to the temporal and superior cornea after LASIK (p < 0.001), although there were no differences between corneal regions in controls. CONCLUSIONS: Our results demonstrate that there was an increased variability in the corneal subbasal innervation patterns following LASIK when compared to controls.

Intravital Multiphoton Microscopy of the Ocular Surface: Alterations in Conventional Dendritic Cell Morphology and Kinetics in Dry Eye Disease.

Dry eye disease (DED) is a multifactorial disease of the ocular surface, characterized by loss of tear film homeostasis and ocular symptoms, in which neurosensory abnormalities have recently been shown to play an etiological role. Although the role of inflammation has been widely studied in DED, the kinetics of immune cells of the ocular surface in this complex disease are hereto unclear. Herein, we utilized intravital multiphoton imaging on transgenic mice to investigate the 3D morphology and kinetics of conventional dendritic cells (cDCs) and the role of ocular surface sensory nerves in regulating them in both the naïve state and experimental DED. Mice with DED had significantly lower tear secretion (p < 0.01), greater corneal fluorescein staining (p < 0.001), and higher cDC density in the ocular surface (p < 0.05), compared to naïve mice. cDCs in DED mice showed morphological alterations in the limbus, exhibiting smaller surface area (p < 0.001) and volume (p < 0.001) compared to naïve mice. Furthermore, corneal cDCs showed greater sphericity in DED mice compared to naïve mice (p < 0.01). In addition, limbal cDCs displayed significantly increased migratory kinetics in DED, including mean track speed, 3D instantaneous velocity, track length, and displacement, compared to naïve mice (all p < 0.05). In mice with DED, cDCs showed a higher meandering index in the limbus compared to central cornea (p < 0.05). In DED, cDCs were less frequently found in contact with nerves in the limbus, peripheral, and central cornea (p < 0.05). cDCs in contact with nerves demonstrated a larger surface area (p < 0.001) and volume (p < 0.001), however, they exhibited less sphericity (p < 0.05) as compared to cDCs not in contact with nerves in naïve mice. Importantly, cDCs in contact with nerves during DED had a decreased track length, displacement, mean track speed, and 3D instantaneous velocity compared to those not in contact with nerves (all p < 0.05). Taken together, we present in vivo evidence of altered cDC kinetics and 3D morphology in DED. Furthermore, apparent neuronal contact significantly alters cDC kinetics and morphological characteristics, suggesting that ocular surface nerves may play a direct role in mediating immune responses in DED.

Eye care providers' emerging roles in early detection of diabetes and management of diabetic changes to the ocular surface: a review.

US adults visit eye care providers more often than primary healthcare providers, placing these doctors in a prime position to help identify and manage patients with prediabetes and diabetes. Currently, diabetes is identified in eye clinics in an advanced stage, only after visible signs of diabetic retinopathy. Recent ophthalmic research has identified multiple subclinical and clinical changes that occur in the anterior segment of the eye with metabolic disease. The corneal epithelium exhibits increased defects and poor healing, including an increased risk of neurotrophic keratitis. Increased thickness and stiffness of the cornea artificially alters intraocular pressure. There is damage to the endothelial cells and changes to the bacterial species on the ocular surface, both of which can increase risk of complications with surgery. Decreased corneal sensitivity due to a loss of nerve density predispose patients with metabolic disease to further neurotrophic complications. Patients with diabetes have increased Meibomian gland dysfunction, blepharitis and reduced tear production, resulting in increased rates of dry eye disease and discomfort. Early detection of metabolic disease may allow eye care providers to be more proactive in recommending referral and intervention in order to reduce the risk of blindness and other diabetes-related morbidity. Continued research is needed to better understand the time course of changes to the anterior segment and what can be done to better detect and diagnose patients with prediabetes or undiagnosed diabetes and provide improved care for these patients.

Effect of age and contact lens wear on corneal epithelial dendritic cell distribution, density, and morphology.

PURPOSE: Contact lens wearers aged 15-25 years are at higher risk of corneal inflammation, yet little is known about corneal inflammatory state in this group. Previous investigations show density of corneal epithelial dendritic cells (CEDC) may increase with contact lens wear. However, it is not known how corneal distribution or morphology of CEDC alters with lens wear or whether these markers are affected by age. This study characterised CEDC in adolescent and young adult contact lens wearers to determine effects of contact lens wear and age on CEDC density, distribution and morphology. METHOD: Forty participants (20 contact lens wearers, 20 healthy non-wearers; age 16-36 years; 16M:24F) completed this pilot study. Corneal images were captured using in vivo confocal microscopy (HRTII, Rostock). CEDC were manually counted in a 1 mm2 area of the central and mid-peripheral cornea, and ratio of central to midperipheral density was calculated. CEDC morphology and dendrite length were graded. Differences between groups and between regions, and associations with age were examined. Significance was determined at P < 0.05. RESULTS: A lower ratio of central to mid-peripheral CEDC density was found with younger age (ρ = 0.42, P = 0.01). CEDC morphology was not associated with age or contact lens wear. CEDC density in the mid-peripheral cornea was higher in soft lens wearers than non-wearers (P = 0.04), but central density did not differ. CEDC density and morphology were not significantly different between centre (median density 11 cells/mm2, range 0-120) and mid-periphery (10 cells/mm2, 0-58). CONCLUSION: Density, distribution and morphology of CEDC do not differ in established contact lens wearers. A relatively lower density of CEDC in the central cornea of younger patients may allude to a more naive immune status in this group and warrants further study. Decreased central CEDC density identified in orthokeratology lens wear requires confirmation in a larger group.

Topical Review: Effects of Contact Lens Wear on Corneal, Conjunctival, and Lid Margin Sensitivity.

SIGNIFICANCE: Contemporary soft contact lenses do not affect mechanical sensitivity of the cornea, whereas conjunctival sensitivity is increased compared with nonwearers. Orthokeratology lens wear, however, reduces corneal sensitivity. The effects of contact lenses on lid margin sensitivity are unclear, and the link between ocular surface sensitivity and discomfort requires further exploration.Although up to 50% of contact lens wearers experience discomfort with varying severity, impact, and frequency, the relationship between ocular surface sensitivity and ocular surface discomfort experienced during contact lens wear is unclear. The purpose of this review is to examine and summarize the current evidence for the impact of both historical and contemporary contact lens wear on ocular surface sensitivity, the etiology of changes in ocular surface sensitivity, contact lens wear-related factors associated with changes in ocular surface sensitivity, and the relationship between sensitivity and discomfort. Despite minimal effects on mechanical corneal sensitivity with contemporary soft contact lens wear, orthokeratology reduces corneal sensitivity through pressure-related effects. This review addresses the relevance of conjunctival and potentially lid margin sensitivity in tolerance and discomfort with contemporary lens wear and the impact of instrument and stimulus characteristics. Less invasive techniques particularly for lid margin sensitivity measurements are required. Given the potential interactions between a contact lens and the varied types of ocular surface nociceptors, instruments that allow for exploration of cold and chemical sensitivity particularly may better allow the effects of lens wear to be elucidated compared with those that explore high-threshold mechanical sensitivity alone. A better understanding of the relationships between lens wear and ocular surface sensitivity may result in improved management of contact lens discomfort.

Diez años de experiencia de un centro de referencia en hipertensión arterial pulmonar en Uruguay / A ten year experience in a pulmonary hypertension reference center in Uruguay

Introducción: la hipertensión arterial pulmonar (HAP) es una condición clínica que conduce al fallo ventricular derecho y la muerte. Se caracterizó la epidemiología de pacientes con HAP en un centro de referencia de Uruguay. Métodos: se incluyeron 52 pacientes adultos con diagnóstico invasivo de HAP (enero 2006-diciembre 2016). Se estimó el riesgo mediante un modelo de cuatro variables (clase funcional-CF, distancia recorrida de 6 minutos -DR6M, presión auricular derecha e índice cardíaco). Se le asignó un valor de 1, 2 y 3 (bajo, intermedio y alto riesgo, respectivamente) a cada variable (European Society of Cardiology y European Respiratory Society 2015). Se categorizó el riesgo mediante el redondeo al valor entero más cercano del promedio de la suma de los valores asignados para cada variable. Resultados: edad 46±2 años, 85% femenino. Predominaron la HAP idiopática, HAP asociada a cardiopatía congénita (HAP-CPC) e HAP asociada a enfermedades del tejido conectivo (HAP-ETC). Los pacientes con HAP-CPC presentaron la mayor DR6M y la menor proporción de CF III/IV (p < 0,05). La sobrevida fue menor en HAP-ETC (p = 0,069). La mortalidad al año observada fue de 0%, 6% y 20% para pacientes con bajo (n=17), intermedio (n=28) y alto (n=7) riesgo, respectivamente, independientemente de la edad, sexo y subgrupo de HAP. El 51% de los pacientes con riesgo intermedio y alto recibieron tratamiento combinado. Conclusiones: se analizaron las características y sobrevida de pacientes con HAP de un centro de referencia uruguayo. El modelo de riesgo permitió discriminar la mortalidad de los pacientes. El 51% de los pacientes con riesgo intermedio y alto recibieron tratamiento combinado.

Introduction: Pulmonary Arterial Hypertension (PAH) is a clinical condition that leads to failure in the right ventricle and death. The epidemiology of patients with pulmonary hypertension was characterized in a reference center in Uruguay. Method: 52 patients with a diagnose of invasive pulmonary hypertension (January 2006-December 2016) were included in the study. Risk was estimated by means of a four variable model (functional class -FC, functional capacity, 6 minutes walking distance -6MWD, right atrium pressure and cardiac output). Values of 1, 2 and 3 were allocated (low, medium and high risk respectively) to each variable (ESC/ERS 2015 PAH guidelines). Risk was categorized by rounding the average of the sum of values allocated for each variable to the nearest integer. Results: age ranged 46±2 years old, 85% of patients were women. Idiopathic hypertension, PAH associated to congenital heart disease (PAH-CHD) and PAH associated to connective tissue diseases (PAH-CTD) prevailed. Patients with PAH-CHD evidenced the greatest 6MWD and the lowest proportion of FC III/IV (p <0.05). Survival was lowet in the PAH-CTD (p =0.069). Mortality after one year was 0%, 6% and 20% for patients with low (n=17), intermediate (n=28) and high (n=7) risk, respectively, regardless of age, sex and subgroup of PAH. 51% of patients with intermediate and high risk received combined treatment. Conclusions: the characteristics and survival of patients with PAH of a reference center in Uruguay were analysed in the study. The risk model allowed discriminating patient mortality. 51% of patients with intermediate and high risk received combined treatment.

Introdução: a Hipertensão Arterial Pulmonar (HAP) é uma condição clínica que leva a insuficiência ventricular direita e à morte. Neste artigo descreve-se a epidemiologia dos pacientes com HAP de um centro de referência no Uruguai. Métodos: foram incluídos 52 pacientes adultos com diagnóstico invasivo de HAP (janeiro 2006-dezembro 2016). O risco foi estimado utilizando um modelo com quatro variáveis (classe funcional -CF, distância percorrida em 6 minutos -DR6M, pressão auricular direita e índice cardíaco). Foram atribuídos os valores 1, 2 ou 3 (risco baixo, médio e alto respectivamente) a cada variável (ESC/ERS 2015). O risco foi caracterizado arredondando o valor inteiro mais próximo à média da soma dos valores atribuídos a cada variável. Resultados: a média de Idade dos pacientes era 46±2 anos sendo 85% do sexo feminino. Predominaram a HAP idiopática, a HAP associada a cardiopatia congênita (HAP-CPC) e HAP associada a doenças do tecido conectivo (HAP-ETC). Os pacientes com HAP-CPC apresentaram a maior DR6M e a menor proporção de CF III/IV (p <0.05). A sobrevida foi menor nos portadores de HAP-ETC (p =0.069). A mortalidade observada ao ano foi de 0%, 6% e 20% respectivamente para pacientes com risco baixo (n=17), médio (n=28) e alto (n=7), independentemente da idade, sexo e subgrupo de HAP. 51% dos pacientes com risco médio e alto receberam tratamento combinado. Conclusões: as características e a sobrevida de pacientes com HAP de um centro de referência uruguaio foram analisadas. O modelo de risco permitiu discriminar a mortalidade dos pacientes. 51% de dos pacientes com RI/RA recibieron tratamento combinado.

Absorption and Extraction of Inflammatory Mediators From Contact Lens Materials.

OBJECTIVES: This report aimed to explore whether certain inflammatory mediators were absorbed, extracted, or bound by various contact lens materials. METHODS: Comfilcon A, balafilcon A, omafilcon A, and etafilcon A were soaked in 500 and 100 pg/mL of interleukin-8 (IL-8), matrix metalloproteinase-9 (MMP-9), or interleukin-1 receptor antagonist (IL-1Ra), and also in combined solutions of inflammatory mediators (500 pg/mL or 100 pg/mL) separately. Lenses were then extracted in 1:1 2% trifluoroacetic acid:acetonitrile. The extracted and residual concentrations of inflammatory mediators were determined using enzyme-linked immunosorbent assays. Absorbed (control-residual) and firmly bound (absorbed-extracted) concentrations were calculated for analysis. RESULTS: More MMP-9 was absorbed by omafilcon A (466±9 pg/mL) than balafilcon A (P=0.006; 437±11 pg/mL) or etafilcon A (P=0.001; 428±13 pg/mL) when soaked in 500 pg/mL, but no differences in 100 pg/mL. More MMP-9 remained firmly bound to omafilcon A (P=0.03; 174±3 pg/mL), comfilcon A (P=0.049; 168±34 pg/mL), and balafilcon A (P=0.01; 186±14 pg/mL) than etafilcon A (128±22 pg/mL). There were no differences in IL-8 absorption between lenses; however, more IL-8 remained firmly bound to omafilcon A (P=0.01; 336±25 pg/mL) than etafilcon A (106±133 pg/mL) when soaked in 500 pg/mL. No differences were found in concentrations of absorbed or firmly bound IL-1Ra between materials. When the mediators were combined, IL-8 was absorbed more in etafilcon A (P=0.03) than in other lens materials, but the absorbed IL-8 did not remain firmly bound. CONCLUSIONS: The uptake and extraction of inflammatory mediators from contact lenses was affected by competitive binding between the mediators.

Corneal epithelial dendritic cell density in the healthy human cornea: A meta-analysis of in-vivo confocal microscopy data.

PURPOSE: Numerous studies have reported a wide range of corneal epithelial dendritic cells (CEDC) density using in-vivo confocal microscopy in healthy participants. It is necessary to establish normal CEDC values for healthy corneas to enable differentiation from pathological corneas. This meta-analysis aimed to establish CEDC density and distribution and examine their relationship with age and sex. METHODS: A systematic review of the literature of studies using the Heidelberg Retinal Tomograph with Rostock Corneal Module and reporting CEDC density in healthy subjects up to December 2018 was conducted via Medline, Google Scholar, Scopus, PubMed, Embase and Cochrane library. A random effect modeling approach was used to obtain the results of meta-analysis and meta-regression was conducted to estimate the effect of age and sex. RESULTS: 38 studies reported central and 9 reported peripheral inferior CEDC density of 1203 participants (mean age 46.0 ±â€¯12.2, range 18-81 years). CEDC density in the central and peripheral inferior cornea was 26.4 ±â€¯13.6 cells/mm2 (95% CI:22.5-26.8) and 74.9 ±â€¯22.7 cells/mm2 (95%CI:59.8-90.0), respectively. No effect of age was found on central CEDC density (p = 0.63); whereas peripheral CEDC density decreased with increasing age (p = 0.02). CEDC density was not influenced by sex at either location (p > 0.48). CONCLUSION: This study established that the density at the peripheral inferior cornea is three-fold higher than at the central cornea. Peripheral but not central CEDC density decreased with increasing age. There are limited studies in youth (<18 years), precluding a more detailed analysis. Sex does not appear to be a significant factor in CEDC density.

Trasplante pulmonar en Uruguay: avances en curso para la consolidación del programa / Lung transplant in Uruguay: progress in motion for the consolidation of the program / Transplante pulmonar no Uruguai: avanços atuais para a consolidação del programa

Introducción: en Uruguay funciona desde el año 2003 un programa de trasplante pulmonar (TP) mediante un convenio binacional con la República Argentina, con Fundación Favaloro, centro regional de referencia. Objetivos: describir los resultados del programa y herramientas en curso para mejorar la procuración pulmonar en Uruguay. Material y método: estudio descriptivo, retrospectivo, entre 2003 y 2017. Recopilación de datos del registro electrónico y análisis mediante SPSS. Resultados: ingresaron a lista 70 pacientes, 27 fueron trasplantados, 95% se reinsertaron a actividades sociales o laborales. Las etiologías fueron enfisema (33%), fibrosis quística (26%) y fibrosis pulmonar idiopática (11%). Las complicaciones más frecuentes fueron infecciones respiratorias y alteraciones de la vía aérea. La mortalidad postrasplante es 34% y la supervivencia mediana condicional supera los ocho años. La elevada mortalidad en lista (32%) impulsó el establecimiento de nuevas estrategias de procuración pulmonar. Destacamos: seguimiento longitudinal de pacientes, modificación de umbral de convocatoria, realización de maniobras de reclutamiento alveolar, realización sistemática de fibrobroncoscopía; minimización de tiempos de traslado y entrenamiento de equipo quirúrgico uruguayo para ablación. La procuración pulmonar pasó de 0 por millón de población (pmp) en 2014 y 2015 a 1,8 pmp en 2017. Conclusiones: el Programa Uruguayo de Trasplante Pulmonar ha tenido importantes avances. Los últimos dos años han sido claves para el crecimiento de la procuración pulmonar. Los resultados, la sobrevida y la morbimortalidad son comparables a los descritos internacionalmente. Las perspectivas a futuro serán consolidar el programa en un centro de referencia y realización de ablación e implante en nuestro territorio. (AU)

Introduction: a program for Lung Transplant (LT) has been operative in Uruguay since 2003, by means of a bi-national agreement with Fundación Favaloro, a regional reference center in Argentina. Method: descriptive, retrospective study performed between 2003 and 2017. Data in the electronic register was compiled and analyzed using SPSS (Statistical Package for the Social Sciences). Results: 70 patients were entered in the list, 27 of which underwent transplant surgery, 95% of them resumed social like and/or work. Etiologies included emphysema (33%), cystic fibrosis (26%) and idiopathic pulmonary fibrosis (11%). The most frequent complications were respiratory infections and alterations in the airway. Post-transplant mortality is 34% and conditional median survival is higher than 8 years. The increased mortality in the list (32%) encouraged development of new strategies for lung procurement. The following facts are pointed out: longitudinal follow-up of patients, modification of the calling threshold, the performance of alveolar recruitments maneuvers, the systematic performance of fibrobroncoscopy, minimization of transport times and training of the Uruguayan surgical team for ablation. Lung procurement increased from 0 per million of population (pm) in 2014 to 1.8 pmp in 2017. Conclusions: the Uruguayan program for LT has evidenced significant progress. The last two years have been essential for the increase of lung procurement. Results, survival and morbi-mortality are comparable to those described globally. Future perspectives will focus on consolidating the program in a reference center and performing ablation and implants in our country.

Introdução: desde 2003 funciona no Uruguai um programa de Transplante Pulmonar (TP) através de um convenio binacional com Argentina, com Fundación Favaloro, centro regional de referência. Objetivos: descrever os resultados do programa e as ferramentas que estão sendo utilizadas para melhorar a procuração pulmonar no Uruguai. Materiais e métodos: estudo descritivo, retrospectivo do período 2003-2017. Coleta de dados do registro eletrônico e análise com o programa SPSS. Resultados: ingressaram à lista 70 pacientes; 27 foram transplantados dos quais 95% voltaram a atividades sociais e/ou de trabalho. As etiologias foram enfisema (33%), fibrose cística (26%) e fibrose pulmonar idiopática (11%). As complicações mais frequentes foram as infecções respiratórias e alterações da via aérea. A mortalidade pós-transplante foi de 34% e a sobrevida mediana condicional foi superior a 8 anos. Dada la elevada mortalidade na lista de espera (32%) novas estratégias de procuração pulmonar foram estabelecidas. Destacamos: seguimento longitudinal dos pacientes, modificação do umbral de convocatória, realização de manobras de recrutamento alveolar, realização sistemática de fibrobroncoscopia, minimização dos tempos de traslado e capacitação da equipe uruguaia de cirurgia em ablação. A procuração pulmonar passou de 0 por milhão de habitantes (pmp) em 2014 e 2015 a 1.8 pmp em 2017. Conclusões: o Programa Uruguaio de TP mostrou importantes avanços. Os últimos 2 anos foram fundamentais para o crescimento da procuração pulmonar. Os resultados, a sobrevida e a morbimortalidade são comparáveis aos descritos na literatura internacional. As perspectivas para o futuro são consolidar o programa em um centro de referência e a realização de ablação e implante no nosso território.