Use of 6-minute walk distance to predict lung transplant-free survival in fibrosing non-IPF interstitial lung diseases.

BACKGROUND AND OBJECTIVE: The identification of progression in patients with fibrosing non-idiopathic pulmonary fibrosis (IPF) interstitial lung diseases (ILDs) represents an ongoing clinical challenge. Lung function decline alone may have significant limitations in the detection of clinically significant progression. We hypothesized that longitudinal changes of 6-min walk distance (6MWD) from baseline, simultaneously considered with measures of lung function, may independently predict survival and identifying clinically significant progression of disease. METHODS: Forced vital capacity (FVC), diffusing lung capacity (DLCO) and 6MWD were considered both at baseline and at 1 year in a discovery cohort (n = 105) and in a validation cohort (n = 138) from different centres. The primary endpoint was lung transplant (LTx)-free survival. RESULTS: Average follow-up was 3 years in both cohorts. Combined incidence of deaths and LTx was 29% and 21%, respectively. No collinearity and no strong correlations were observed among FVC, DLCO and 6MWD longitudinal changes. While age, gender and BMI were not significant, 6MWD decline ≥24 m predicted LTx-free-survival significantly and independently from FVC and DLCO declines, with high sensitivity and specificity, in both the discovery and the validation cohorts. Although FVC and DLCO declines remained significant predictors of LTx-free survival, 6MWD decline was more accurate than the proposed ATS/ERS/JRS/ALAT functional criteria. Results were confirmed after stratifying patients by baseline FVC. CONCLUSION: Longitudinal declines of 6MWD are associated with poor survival in fibrosing ILDs across a wide range of baseline severity, with high accuracy. 6MWD longitudinal decline is largely independent from lung function decline and may be integrated into the routine assessment of progression.

Effects of cannabis smoking on the respiratory system: A state-of-the-art review.

The diminished perception of the health risks associated with the consumption of cannabis (marijuana) lead to a progressive increase in its inhalational use in many countries. Cannabis can be smoked through the use of joints, spliffs and blunts, and it can be vaporised with the use of hookah or e-cigarettes. Delta-9 tetrahydrocannabinol (THC) is the main psychoactive component of cannabis smoke but contains numerous other substances. While the recreational use of cannabis smoking has been legalised in several countries, its health consequences have been underestimated and undervalued. The purpose of this review is to critically review the impact of cannabis smoke on the respiratory system. Cannabis smoke irritates the bronchial tree and is strongly associated with symptoms of chronic bronchitis, with histological signs of airway inflammation and remodelling. Altered fungicidal and antibacterial activity of alveolar macrophages, with greater susceptibility to respiratory infections, is also reported. The association with invasive pulmonary aspergillosis in immunocompromised subjects is particularly concerning. Although cannabis has been shown to produce a rapid bronchodilator effect, its chronic use is associated with poor control of asthma by numerous studies. Cannabis smoking also represents a risk factor for the development of bullous lung disease, spontaneous pneumothorax and hypersensitivity pneumonitis. On the other hand, no association with the development of chronic obstructive pulmonary disease was found. Finally, a growing number of studies report an independent association of cannabis smoking with the development of lung cancer. In conclusion, unequivocal evidence established that cannabis smoking is harmful to the respiratory system. Cannabis smoking has a wide range of negative effects on respiratory symptoms in both healthy subjects and patients with chronic lung disease. Given that the most common and cheapest way of assumption of cannabis is by smoking, healthcare providers should be prepared to provide counselling on cannabis smoking cessation and inform the public and decision-makers.

Intravitreal Aflibercept for the Treatment of Diabetic Macular Edema in Routine Clinical Practice: Results from the 24-Month AURIGA Observational Study.

INTRODUCTION: AURIGA is the largest real-world study to date to evaluate intravitreal aflibercept (IVT-AFL) in the treatment of diabetic macular edema (DME) or macular edema secondary to retinal vein occlusion in routine clinical practice. The 24-month outcomes in the DME cohort from across 11 participating countries are reported here. METHODS: AURIGA (NCT03161912) was a prospective observational study. The study enrolled eligible patients with DME for whom the decision to treat with IVT-AFL had previously been made by the attending physician. Patients were treated with IVT-AFL for up to 24 months at physician discretion according to local practice. The primary endpoint was mean change in visual acuity (VA; Early Treatment Diabetic Retinopathy Study [ETDRS] letters) from baseline to month 12 (M12). All statistical analyses were descriptive. RESULTS: In 1478 treatment-naïve and 384 previously treated patients with DME, the mean (95% confidence interval) change in VA from baseline was +6.7 (5.7, 7.6) and +7.4 (5.5, 9.4) letters by M12 and +5.9 (4.9, 6.9) and +8.1 (6.1, 10.1) letters by M24 (baseline [mean ± standard deviation]: 56.0 ± 19.8 and 50.8 ± 19.5 letters), respectively; 25.9% of treatment-naïve and 32.8% of previously treated patients achieved ≥ 15-letter gains by M24. The mean change in central retinal thickness from baseline to M24 was -110 (-119, -102) µm in treatment-naïve patients and -169 (-188, -151) µm in previously treated patients. By M6, M12, and M24, treatment-naïve patients had received 3.8 ± 1.7, 4.9 ± 2.8, and 5.7 ± 3.9 injections, respectively, and previously treated patients had received 3.9 ± 1.5, 4.9 ± 2.4, and 6.2 ± 3.6 injections, respectively. The safety profile of IVT-AFL was consistent with previous studies. CONCLUSION: In AURIGA, treatment-naïve and previously treated patients with DME achieved clinically relevant functional and anatomic improvements following IVT-AFL treatment for up to 24 months in routine clinical practice. Even with the decreasing injection frequency observed, these gains were largely maintained throughout the study, suggesting long-term durability of the positive effects of IVT-AFL treatment. Infographic available for this article. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03161912 (May 19, 2017). INFOGRAPHIC.

Why the SAFE-S Strategy for Trachoma? Are Musca sorbens or Scatophaga stercoraria Really the Culprit?-A Brief Historical Review from an Italian Point of View.

The biological history of Chlamydia trachomatis is intertwined with the evolution of the man. Infecting Elemental Bodies (EBs), having penetrated mucosal epithelial cells, wrap themselves in a cloak (ĸλαµÎ¹ς) of glycogen that ensures their obligatory intracellular survival and protects this differentiation into Reticulate Bodies (RBs) that feed on cellular ATP. Multiple chemokines and cytokines are involved under the direction of IL-6 in the florid phase and IL-17A in the scar phase. The WHO has successfully identified the SAFE strategy against trachoma (Surgery, Antibiotics, Facial cleansing, Environment) as the blueprint to eliminate the disease by 2020. Recently, interest has been increasingly focused on changing sexual attitudes in different areas of the world, leaving Musca sorbens, Scatophaga stercoraria, and stepsisters fairly blameless, but extolling the role of Chlamydia trachomatis in apparently "sterile" chronic prostatitis or conjunctivitis or, less frequently, in oropharyngitis and proctitis. The addition of an S (SAFE-S) standing for "sexual behavior" was then proposed to also attract the interest and attention not only of Ophthalmologists and Obstetricians/Gynecologists, Urologists/Andrologists, and the School Authorities for information on the prevention of sexually transmitted diseases, but also of Social Physicians and Pediatricians. This means that sexually transmitted infections should be screened in asymptomatic patients with risky sexual behavior or sexual contact with people diagnosed with a transmitted infection.

The State of Intraoperative OCT in Vitreoretinal Surgery: Recent Advances and Future Challenges.

Since its first introduction more than 30 years ago, optical coherence tomography (OCT) has revolutionized ophthalmology practice, providing a non-invasive in vivo cross-sectional view of the structures of the eye. Mostly employed in the clinical setting due to its tabletop configuration requiring an upright patient positioning, the recent advent of microscope-integrated systems now allows ophthalmologists to perform real-time intraoperative OCT (iOCT) during vitreoretinal surgical procedures. Numerous studies described various applications of this tool, such as offering surgeons feedback on tissue-instrument interactions in membrane peeling, providing structural images in macular hole repair, and showing residual subretinal fluid or perfluorocarbon in retinal detachment surgery. This narrative review aims at describing the state of the art of iOCT in vitreoretinal procedures, highlighting its modern role and applications in posterior segment surgery, its current limitations, and the future perspectives that may improve the widespread adoption of this technology.

Macrophage Activation in Follicular Conjunctivitis during the COVID-19 Pandemic.

Among the symptoms of SARS-CoV-2, follicular conjunctivitis has become relevant. The conjunctiva acts as an open lymph node, reacting to the viral antigen that binds the epithelial cells, forming follicles of B cells with activated T cells and NK cells on its surface, which, in turn, talk to monocyte-derived inflammatory infected macrophages. Here, the NLRP3 inflammasome is a major driver in releasing pro-inflammatory factors such as IL-6 and caspase-1, leading to follicular conjunctivitis and bulbar congestion, even as isolated signs in the 'asymptomatic' patient.

Long-term functional and structural outcomes after large chorioretinectomy for ruptured globe following blunt trauma.

BACKGROUND: The purpose of this study was to present a modified surgical technique involving pars plana vitrectomy with large chorioretinectomy for eyes with rupture of the globe due to severe ocular blunt trauma. METHODS: This retrospective study included consecutive patients with rupture of the globe due to blunt trauma who were treated at the King Khaled Eye Specialist Hospital (Riyadh, Saudi Arabia). All patients underwent 25-gauge pars plana vitrectomy with large chorioretinectomies involving all the tissue around the posterior scleral wounds. Outcome measures included best-corrected visual acuity (BCVA), anatomical success and globe survival, rates of complications. RESULTS: 15 eyes of 15 patients were included. Mean BCVA was 2.88 ± 0.13 logMAR at presentation, and significantly improved to 0.83 ± 0.28 logMAR (P < 0.001), with 10 patients (67%) achieving a final BCVA ≥ 20/200. Anatomical success and globe survival were achieved in 11 (73%) and 15 (100%) of eyes, respectively. Postoperative complications included retinal detachment in 6 eyes (40%), epiretinal membrane in 6 (40%), hypotony in 4 (26%), PVR in 2 (13%). CONCLUSIONS: Pars plana vitrectomy with large chorioretinectomy is an effective treatment for globe rupture following severe blunt trauma, yielding good visual outcomes and anatomical success rates.

Cone dystrophy associated with autoimmune polyglandular syndrome type 1.

To report the association of autoimmune polyglandular syndrome type 1 (APS1) with cone dystrophy in a large Saudi family. This is a Retrospective chart review and prospective genetic testing and ophthalmic examination of a large multiplex consanguineous family. Genetic testing was performed on 14 family members, seven of whom had detailed ophthalmic examinations. Medical history, ocular history and evaluation, visual field testing, full-field electroretinogram (ERG), and Whole Exome Sequencing (WES) results were analyzed. Three family members were homozygous for c.205_208dupCAGG;p.(Asp70Alafs*148) in AIRE and homozygous for c.481-1G>A in PDE6C. One additional family member was homozygous for only the AIRE variant and another additional family member was homozygous for only the PDE6C variant. All patients with homozygosity for the PDE6C variant had cone dystrophy, and all patients with homozygosity for the AIRE variant had APS1. In addition, two of the family members who were homozygous for the PDE6C and AIRE variants had reduced rod function on ERG. We report the co-inheritance for APS1 and PDE6C-related cone dystrophy, an unusual example of two seemingly independent recessive conditions coinciding within a family. Dual molecular diagnosis must be taken into account by ophthalmologists facing unusual constellations of findings, especially in consanguineous families.

Denuded Descemet's membrane supports human embryonic stem cell-derived retinal pigment epithelial cell culture.

Recent clinical studies suggest that retinal pigment epithelial (RPE) cell replacement therapy may preserve vision in retinal degenerative diseases. Scaffold-based methods are being tested in ongoing clinical trials for delivering pluripotent-derived RPE cells to the back of the eye. The aim of this study was to investigate human embryonic stem cell-derived retinal pigment epithelial (hESC-RPE) cells survival and behaviour on a decellularized Descemet's Membrane (DM), which may be of clinical relevance in retinal transplantation. DMs were isolated from human donor corneas and treated with thermolysin. The DM surface topology and the efficiency of the denudation method were evaluated by atomic force microscope, scanning electron microscopy and histology. hESC-RPE cells were seeded onto the endothelial-side surface of decellularized DM in order to determine the potential of the membrane to support hESC-RPE cell culture, alongside maintaining their viability. Integrity of the hESC-RPE monolayer was assessed by measuring transepithelial resistance. RPE-specific gene expression and growth factors secretion were assessed to confirm maturation and functionality of the cells over the new substrate. Thermolysin treatment did not affect the integrity of the tissue, thus ensuring a reliable method to standardize the preparation of decellularized DM. 24 hours post-seeding, hESC-RPE cell attachment and initial proliferation rate over the denuded DM were higher than hESC-RPE cells cultured on tissue culture inserts. On the new matrix, hESC-RPE cells succeeded in forming an intact monolayer with mature tight junctions. The resulting cell culture showed characteristic RPE cell morphology and proper protein localization. Gene expression analysis and VEGF secretion demonstrate DM provides supportive scaffolding and inductive properties to enhance hESC-RPE cells maturation. Decellularized DM was shown to be capable of sustaining hESC-RPE cells culture, thus confirming to be potentially a suitable candidate for retinal cell therapy.

Risk of retinal vein occlusion following COVID-19 vaccination: a self-controlled case series.

BACKGROUND: To evaluate the association between COVID-19 vaccination and retinal vein occlusion (RVO). METHODS: This multicentre self-controlled case series included patients with RVO seen in five tertiary referral centres in Italy. All adults who received at least one dose of the BNT162b2, ChAdOx1 nCoV-19, mRNA-1273 or Ad26.COV2.S vaccine and had a first diagnosis of RVO between January 01, 2021, and December 31, 2021 were included. Incidence rate ratios (IRRs) of RVO were estimated using Poisson regression, comparing rates of events in a 28-day period following each dose of vaccination and in the unexposed control periods. RESULTS: 210 patients were included in the study. No increased risk of RVO was observed after the first dose (1-14 days IRR: 0.87, 95% CI: 0.41-1.85; 15-28 days IRR: 1.01, 95% CI: 0.50-2.04; 1-28 days IRR: 0.94, 95% CI: 0.55-1.58) and second dose of vaccination (1-14 days IRR: 1.21, 95% CI: 0.62-2.37; 15-28 days IRR: 1.08, 95% CI: 0.53-2.20; 1-28 days IRR: 1.16, 95% CI: 0.70-1.90). No association between RVO and vaccination was found in subgroup analyses by type of vaccine, gender and age. CONCLUSIONS: This self-controlled case series found no evidence of an association between RVO and COVID-19 vaccination.

Cluster analysis of transcriptomic datasets to identify endotypes of idiopathic pulmonary fibrosis.

BACKGROUND: Considerable clinical heterogeneity in idiopathic pulmonary fibrosis (IPF) suggests the existence of multiple disease endotypes. Identifying these endotypes would improve our understanding of the pathogenesis of IPF and could allow for a biomarker-driven personalised medicine approach. We aimed to identify clinically distinct groups of patients with IPF that could represent distinct disease endotypes. METHODS: We co-normalised, pooled and clustered three publicly available blood transcriptomic datasets (total 220 IPF cases). We compared clinical traits across clusters and used gene enrichment analysis to identify biological pathways and processes that were over-represented among the genes that were differentially expressed across clusters. A gene-based classifier was developed and validated using three additional independent datasets (total 194 IPF cases). FINDINGS: We identified three clusters of patients with IPF with statistically significant differences in lung function (p=0.009) and mortality (p=0.009) between groups. Gene enrichment analysis implicated mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in the pathogenesis underlying these groups. We developed and validated a 13-gene cluster classifier that predicted mortality in IPF (high-risk clusters vs low-risk cluster: HR 4.25, 95% CI 2.14 to 8.46, p=3.7×10-5). INTERPRETATION: We have identified blood gene expression signatures capable of discerning groups of patients with IPF with significant differences in survival. These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. Although more work must be done to confirm the existence of these endotypes, our classifier could be a useful tool in patient stratification and outcome prediction in IPF.

Retinal periphlebitis associated with branch retinal vein occlusion and complicated by subfoveal hemorrhage: a case report.

Retinal periphlebitis is a subtype of retinal vasculitis affecting the retinal veins. We report a case of bilateral branch retinal vein occlusion (BRVO) associated with idiopathic retinal periphlebitis and complicated by subfoveal hemorrhage (SFH). An 18-year-old woman presented with best-corrected visual acuity of 20/20 in the right eye and 20/30 in the left eye. Examination revealed bilateral retinal vascular sheathing predominantly involving the retinal veins and bilateral BRVO. Fundus fluorescein angiography revealed localized vascular leakage in the right eye and diffuse vascular leakage in the left eye. Spectral-domain optical coherence tomography showed mild nasal thickening with subfoveal fluid in the left eye. Oral steroids were started on a tapering dosage as well as oral methotrexate. A year later, she presented with regressed vascular sheathing in both eyes with 5/200 vision and SFH in the left eye. Pars plana vitrectomy, subretinal tissue plasminogen activator, intravitreal ranibizumab, laser photocoagulation, and gas injection were performed. The SFH resolved and the visual acuity improved to 20/100. Good vision was preserved in both eyes with no active inflammation. Timely management of SFH in idiopathic retinal periphlebitis can achieve a favorable visual outcome.

The role of the mTOR pathway in diabetic retinopathy.

The retina, the part of the eye, translates the light signal into an electric current that can be sent to the brain as visual information. To achieve this, the retina requires fine-tuned vascularization for its energy supply. Diabetic retinopathy (DR) causes alterations in the eye vascularization that reduce the oxygen supply with consequent retinal neurodegeneration. During DR, the mammalian target of rapamycin (mTOR) pathway seems to coordinate retinal neurodegeneration with multiple anabolic and catabolic processes, such as autophagy, oxidative stress, cell death, and the release of pro-inflammatory cytokines, which are closely related to chronic hyperglycemia. This review outlines the normal anatomy of the retina and how hyperglycemia can be involved in the neurodegeneration underlying this disease through over activation or inhibition of the mTOR pathway.

Radiographic Progression and Survival of the Different HRCT Patterns of Idiopathic Pulmonary Fibrosis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic disease with a peculiar (typical) HRCT pattern, but biopsy can demonstrate usual interstitial pneumonia in patients with atypical patterns. It is unknown how progression pattern varies among different radiographic presentations of IPF. We sought to investigate the longitudinal radiographic evolution and survival of typical and non-typical patterns. Materials and Methods: One-hundred-twenty-three patients diagnosed with IPF in 2 tertiary referral hospitals were included in the study. Longitudinal evolution of non-typical patterns was considered. The HRCT visual fibrosis score was used as a reliable evaluation tool of disease progression. HRCTs were scored by 2 senior chest radiologists with ILD expertise. The primary endpoint was the evolution of the presentation pattern to probable or typical. The secondary endpoint was lung transplant (LTx)-free survival from the time of diagnosis. Results: Average interval between HRCTs was 16±5 months; average follow-up after the 2nd HRCT was 17±11 months. Four out of 45 (8.9%) patients with probable pattern "evolved" to a typical pattern of IPF, while 5 out of 31 (16.1%) with indeterminate/alternative pattern "evolved" to probable pattern. An average HRCT fibrosis score increase of 9±11% was observed with typical (n=49), 6±5% with probable (n=43) and 7±8% (n=31) with indeterminate/alternative presentation pattern. LTx-free survival and lung function declines did not show any difference related to presentation HRCT patterns. Conclusions: The evolution of a non-typical UIP pattern to a typical one is infrequent. All presentation HRCT patterns of IPF evolve in similar way and are associated with comparable survival time.[/sc].

Management of complicated proliferative diabetic retinopathy in a patient with oculocutaneous albinism.

Purpose: To describe the management and outcome of a patient with oculocutaneous albinism and complicated proliferative diabetic retinopathy, as well as to discuss treatment challenges and strategies in this patient population. Observation: A 52-year-old patient with oculocutaneous albinism and diabetes presented with light perception vision in her right eye and 20/300 vision in her left eye. Examination showed a diabetic tractional retinal detachment in the right eye and high-risk proliferative diabetic retinopathy (PDR) in the left eye. In the right eye, the patient underwent pars plana vitrectomy, membrane delamination, endolaser therapy, and silicone oil tamponade, with follow-up evaluations showing a flat retina under silicone oil with regressed retinopathy in this eye. In her left eye, pan-retinal photocoagulation was attempted without success, with persistent PDR and absence of laser marks in this eye. Subsequently, the patient underwent six intravitreal anti-VEGF injections, after which she developed a tractional retinal detachment necessitating treatment cessation and a planned surgical intervention. Conclusion and Importance: This case highlights the difficulty of using standard medical and surgical treatment strategies when caring for patients with oculocutaneous albinism and complicated proliferative diabetic retinopathy. If medical treatments fail in these patients, surgical approaches should be planned with extreme care due to the risks and challenges posed by hypopigmented fundi. Method: Interventional case report.

Immunomodulatory treatment of interstitial lung disease.

Interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) have an array of immunomodulatory treatment options compared with IPF, due to their inflammatory component. However, there is a relative paucity of guidance on the management of this heterogeneous group of diseases. In ILDs other than IPF, immunosuppression is the cornerstone of therapy, with varying levels of evidence for different immunomodulatory agents and for each specific ILD. Classification of ILDs is important for guiding treatment decisions. Immunomodulatory agents mainly include corticosteroids, mycophenolate mofetil (MMF), azathioprine, methotrexate, cyclophosphamide and rituximab. In this review, the available evidence for single agents in the most common ILDs is first discussed. We then reviewed practical therapeutic approaches in connective tissue disease-related ILD and interstitial pneumonia with autoimmune features, scleroderma-related ILD, vasculitis and dermatomyositis with hypoxemic respiratory failure, idiopathic non-specific interstitial pneumonia, hypersensitivity pneumonitis sarcoidosis, fibrosing organizing pneumonia and eosinophilic pneumonia. The treatment of acute exacerbations of ILD is also discussed. Therapy augmentation in ILD is dictated by the recognition of progression of disease. Criteria for the evaluation of progression of disease are then discussed. Finally, specific protocol and measures to increase patients' safety are reviewed as well, including general monitoring and serologic surveillance, Pneumocystis jirovecii prophylaxis, patients' education, genetic testing for azathioprine, MMF serum levels and cyclophosphamide administration protocols. Immunomodulatory therapies are largely successful in the management of ILDs and can be safely managed with the application of specific protocols, precautions and monitoring.