Identification of homologs of the Chlamydia trachomatis effector CteG reveals a family of Chlamydiaceae type III secreted proteins that can be delivered into host cells.

Chlamydiae are a large group of obligate endosymbionts of eukaryotes that includes the Chlamydiaceae family, comprising several animal pathogens. Among Chlamydiaceae, Chlamydia trachomatis causes widespread ocular and urogenital infections in humans. Like many bacterial pathogens, all Chlamydiae manipulate host cells by injecting them with type III secretion effector proteins. We previously characterized the C. trachomatis effector CteG, which localizes at the host cell Golgi and plasma membrane during distinct phases of the chlamydial infectious cycle. Here, we show that CteG is a Chlamydiaceae-specific effector with over 60 homologs phylogenetically categorized into two distinct clades (CteG I and CteG II) and exhibiting several inparalogs and outparalogs. Notably, cteG I homologs are syntenic to C. trachomatis cteG, whereas cteG II homologs are syntenic among themselves but not with C. trachomatis cteG. This indicates a complex evolution of cteG homologs, which is unique among C. trachomatis effectors, marked by numerous events of gene duplication and loss. Despite relatively modest sequence conservation, nearly all tested CteG I and CteG II proteins were identified as type III secretion substrates using Yersinia as a heterologous bacterial host. Moreover, most of the type III secreted CteG I and CteG II homologs were delivered by C. trachomatis into host cells, where they localized at the Golgi region and cell periphery. Overall, this provided insights into the evolution of bacterial effectors and revealed a Chlamydiaceae family of type III secreted proteins that underwent substantial divergence during evolution while conserving the capacity to localize at specific host cell compartments.

Epidemiological Profile of Human Papillomavirus in a Healthcare Center in Portugal: Implications for Public Health Policies.

Introduction Human papillomavirus (HPV) infection, a prevalent sexually transmitted disease, affects the majority of sexually active individuals at least once in their lifetime. Cervical cancer stands as a significant contributor to mortality among women. Cervical cancer screening (CCS) and HPV vaccination are recent, with few studies about their impact on the prevalence of HPV types. The emergence of novel predominant pathogen strains can be driven by vaccine-induced pathogen strain replacement, thereby enhancing and altering selection. Objective The aim of the study was to characterize the high-risk (HR) HPV infection in two Portuguese primary care units (PCUs). Materials and methods In this observational, cross-sectional, and descriptive study, we included women aged 25-64 years and registered in two PCUs, who were screened by SiiMA Rastreios (population-based screening management application), and were HR-HPV positive, between August 2015 and May 2018. The results of cervical cancer screening (CCS) can be accessed through the SiiMA Rastreios information system. For data treatment, we used MS Excel (Microsoft Corporation, Redmond, Washington, USA), IBM SPSS Statistics for Windows, Version 20 (Released 2011; IBM Corp., Armonk, New York, USA), and non-parametric tests. Results In our study, we included 4,614 women aged between 25 and 64 years old. CCS was performed on 24.47%, of whom 39.95% were tested for HR-HPV. The infection rate was 18.85%, and all 14 types of infection were identified. The most common HPV type was 31, followed by 16 and 68. We found HPV other than 16/18 in 84.43%. We found coinfections in 34.1%, with no statistically significant difference by age group. In the 25-34 age group, the incidence of infection was 33.7% vs. 17.54% in the 35-54 age group and 4.55% in the 55-64 age group. HPV16 was the most common infection in the 25-34 age group. In nulliparous women, the most common was HPV31. The relationship between smoking habits and HR-HPV infection was statistically significant, but economic insufficiency was not. Conclusion The infection incidence in this study was slightly higher than in the 2011 national study. Statistically, the infection rate was significantly higher in the younger age groups. The most frequent type varied from the national and international study results. This may be due to regional differences in HPV infection, changes in the pattern of incidence, or the effect of vaccination. The HPV pattern may be changing, so the scientific community must keep updated to develop increasingly efficient screening and vaccination programs.

Design and Development of a Web-Based Prospective Nationwide Registry for Ocular Inflammatory Diseases: UVEITE.PT - The Portuguese Ocular Inflammation Registry.

Uveitis is a heterogeneous collection of infrequent diseases, which poses significant challenges to cost-effective research in the field. Medical registries are being increasingly recognized as crucial tools to provide high-quality data, thus enabling prospective clinical research. This paper describes the design and technical structure development of an innovative countrywide electronic medical record for uveitis, Uveite.pt, and gives an overview of the cohort registered since its foundation, March 2020.Uveite.pt is an electronic medical record platform developed by the Portuguese Ocular Inflammation Group (POIG), a scientific committee of the Portuguese Ophthalmology Society. This is a nationwide customized web-based platform for uveitis patients useful for both clinical practice and real-world-based research, working as a central repository and reporting tool for uveitis. This paper describes the technical principles, the design and the development of a web-based interoperable registry for uveitis in Portugal and provides an overview of more than 400 patients registered in the first 18 months since inception.In infrequent diseases, the existence of registries enables to gather evidence and increase research possibilities to clinicians. The adoption of this platform enables standardization and improvement of clinical practice in uveitis. It is useful to apprehend the repercussion of medical and surgical treatments in uveitis and scleritis, supporting clinicians in the strict monitoring of drug adverse reactions and surgical outcomes.

Update on the systemic management of noninfectious uveitis in children and adolescents.

Noninfectious uveitis (NIU) in children and adolescents is a rare but treatable cause of visual impairment in children. Treatments for pediatric NIU and their side effects, along with the risks of vision loss and the need for long-term disease monitoring, pose significant challenges for young patients and their families. Treatment includes local and systemic approaches and this review will focus on systemic therapies that encompass corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARD), and biological disease-modifying antirheumatic drugs (bDMARD). Treatment is generally planned in a stepwise approach. Methotrexate is well-established as the preferential csDMARD in pediatric NIU. Adalimumab, an antitumor necrosis factor (TNF) agent, is the only bDMARD formally approved for pediatric NIU and has a good safety and efficacy profile. Biosimilars are gaining increasing visibility in the treatment of pediatric NIU. Other bDMARD with some evidence in literature for the treatment of pediatric NIU include infliximab, tocilizumab, abatacept, rituximab and, more recently, Janus kinase inhibitors. Important aspects of managing children on these systemic therapies include vaccination issues, risk of infection, and psychological distress. Also, strategies need to address regarding primary nonresponse/secondary loss of response to anti-TNF treatment, biological switching, and monitoring regimens for these drugs. Optimal management of pediatric uveitis involves a multidisciplinary team, including specialist pediatric uveitis and rheumatology nurses, pediatric rheumatologists, psychological support, orthoptic and optometry support, and play specialists.

EULAR study group on 'MHC-I-opathy': identifying disease-overarching mechanisms across disciplines and borders.

The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.

Bull's Eye Maculopathy in Near-Infrared Reflectance as An Early Sign of Hydroxychloroquine Toxicity.

Hydroxychloroquine (HCQ) ocular toxicity is rare but severe, and progression can occur even after termination of therapy. Case reports have suggested that a bull's eye maculopathy detected by near-infrared reflectance (NIR) may indicate early HCQ toxicity. This retrospective cross-sectional study evaluated patients treated with HCQ who underwent routine screening with optical coherence tomography (OCT), fundus autofluorescence (FAF) and 10-2 perimetry. NIR images captured alongside OCT were subsequently graded independently by 2 masked graders for the presence of bull's eye maculopathy, and the result was compared to the outcome of the screening. A total of 123 participants (246 eyes) were included, and 101 (90%) were female. The patients' mean age was 55.2 ± 13.8 years. The mean time of HCQ usage was 84.0 ± 72.3 months, and the mean weekly dose was 2327 ± 650 mg. Two eyes showed toxicity in all 3 routine screening exams, with one patient suspending HCQ. The prevalence of bull´s eye lesions in NIR was 13% (33 eyes) with substantial intergrader agreement, a 71.3% specificity and 88.0% negative predictive value for HCQ toxicity. We suggest that NIR changes may be a sign of early HCQ toxicity. The detection of NIR bull´s eye lesions may warrant an increased screening frequency.

Intravitreal Fluocinolone 0.19mg Implant in the Management of Chronic Non-Infectious Uveitis: 12-Month Outcomes from a Single Tertiary Centre.

AIM: To present efficacy and safety of 0.19 mg fluocinolone acetonide insert (FAi) to treat chronic noninfectious uveitis (NIU) in a single referral center. METHODS: A retrospective observational clinical study of 11 eyes with NIU complicated by chronic cystoid macular edema (CMO). RESULTS: The main indication for treatment was chronic CMO in all 11 eyes. The mean central retinal thickness (CRT) at baseline was 435 µm ± 176, improving to 296 µm ± 67 at 12 months. Raised intraocular pressure (IOP) was the commonest adverse event. An IOP >21 mmHg was observed in three eyes, and >30 mmHg in one eye, managed with topical therapy. The mean best corrected visual acuity (BCVA) was stable at 12 months. There were no observed recurrences of uveitis. Two eyes received adjunctive treatment for worsening CRT. CONCLUSIONS: Our results suggest FAi is an effective maintenance treatment for NIU with favorable functional and anatomical outcomes.

The 2021 Portuguese Society of Ophthalmology joint guidelines with Paediatric Rheumatology on the screening, monitoring and medical treatment of juvenile idiopathic arthritis-associated uveitis.

AIM: To develop the first Ophthalmology joint guidelines with Paediatric Rheumatology with recommendations on the screening, monitoring and medical treatment of juvenile idiopathic arthritis-associated uveitis (JIA-U), endorsed by the Portuguese Society of Ophthalmology (SPO). METHODS: A systematic literature review was conducted to include publications up to July 14th 2020, with no language restrictions, in order to include all the international position papers/guidelines concerning the medical management of JIA-U and randomised clinical trials assessing the efficacy and safety of medical treatment in this field. We searched through MEDLINE (PubMed), Scopus, Web of Science and Cochrane Library. The Delphi modified technique to generate consensus was used. Preliminary evidence statements were subject to an anonymous agreement assessment and discussion process using an online survey, followed by further discussion and update at a national meeting. A draft of the manuscript with all recommendations was then circulated among all participants and suggestions were incorporated. The final version was again circulated before publication. RESULTS: Twenty-six recommendations were developed focusing on the following topics: general management (3), screening and follow-up of uveitis (4), treatment (17) and health education in JIA-U among patients and families (2). CONCLUSION: These guidelines were designed to support the shared medical management of patients with JIA-U and emphasize the need for a multidisciplinary approach between Ophthalmology and Paediatric Rheumatology regarding the comprehensive care of JIA-U. We acknowledge that updating these recommendations will be warranted in the future, as more evidence becomes available. KEY-WORDS: juvenile idiopathic arthritis, uveitis, biological treatment, conventional immunosuppressive treatment, multidisciplinary management, guidelines, consensus, review, Delphi Technique.

Topical corticosteroids with topical cyclosporine A versus topical corticosteroids alone for immunological corneal graft rejection.

PURPOSE: To assess the efficacy and safety of supplementing topical cyclosporine A (CsA) to topical corticosteroids (CS), in the prophylaxis and treatment of corneal graft rejection following penetrating keratoplasty (PK). METHODS: Meta-analysis. Search was performed in PubMed, CENTRAL, ClinicalTrials.gov, reference lists of articles and conference proceedings. Primary outcomes: 1-year rejection-free survival rate (prophylaxis); resolution rate of rejection episodes (treatment). Secondary outcomes: 6- and 24-month rejection-free graft survival rate, number of rejection episodes during follow-up, time-to-resolution of rejection episode, 12- and 24-months graft survival rate, adverse events. Subgroup analyses were planned for high-risk grafts; primary vs. secondary prophylaxis of graft rejection episodes; and CsA concentrations of 0.05%, 1%, and 2%. RESULTS: Five studies of moderate methodological quality were included (one retrospective, four RCT), assessing 459 eyes (CS + CsA 226, CS 233). In the prophylaxis setting, supplemental CsA was associated with a higher rejection-free survival rate at 12-months (RR 1.25, 95% CI: 1.00-1.56, p = 0.05) and 24-months post-PK (RR 1.56, 95% CI: 1.15-2.11, p < 0.01), though no differences were found at the 6-months timepoint (p = 0.93). This effect was mostly verified using CsA 2% in the high-risk subset of patients. In the treatment setting, no differences were found in the resolution rate of rejection episodes (p = 0.23). No differences existed on drug-related adverse events. CONCLUSION: In the prophylaxis of rejection episodes post-PK, the combined regimen of CS + CsA was associated with a higher 1- and 2-year rejection-free graft survival rate. Subgroup analysis mostly supported the use of CsA 2% for high-risk grafts. Further studies are needed to validate these results.

A Non-Infectious Uveitis Multidisciplinary Clinic in a Tertiary Referral Center: Clinical Impact and Added Value.

Non-infectious uveitis (NIU) is a group of sight-threatening diseases that generates significant burden for the healthcare systems due to its adverse outcomes, irreversible structural complications in the eye with loss of visual function, limited clinical expertise and low-grade evidence for best practice. The usefulness of multidisciplinary care, specifically close collaboration between Rheumatologists and Ophthalmologists in NIU, has been emphasized in the literature. In this paper, the assessment tools and protocols used in our clinic are depicted and an overview of our activity with a brief description of the patients included in our registry, between 2018 and 2020 is provided. The cohort of 290 patients assessed in our NIU clinic, their demographics, sources of referral, details about immunosuppression treatment, and internal and external collaborations is described. This experience-based manuscript aims to describe the general functioning of our multidisciplinary NIU clinic, highlighting the benefits and drawbacks of multidisciplinary team management in patients with NIU, ultimately initiating a dialogue on what an NIU clinic should be and providing information for newly NIU clinics start-up. In conclusion, establishing a standardized and multidisciplinary clinic in NIU allows to systematically observe and follow-up this infrequent disease at a tertiary hospital level, thus improving quality of care delivery and research avenues.

Evaluating the Safety, Efficacy and Patient Acceptability of Intravitreal Fluocinolone Acetonide (0.2mcg/Day) Implant in the Treatment of Non-Infectious Uveitis Affecting the Posterior Segment.

Long-acting, slow-release injectable fluocinolone intravitreal implants have been approved for the treatment of non-infectious uveitis affecting the posterior segment. We summarise the development of intravitreal fluocinolone implants and discuss the technology including pharmacokinetics. We conducted a systematic review of evidence for the efficacy, safety and patient acceptability of fluocinolone 0.18 mg and 0.19 mg injectable implants. We summarise evidence from the pivotal phase 3 studies that lead to the approval of these implants and evaluate real-world including disease-specific evidence. Safety including injection-related events and long-term adverse events is presented.

Retinal Vascular Reactivity in Type 1 Diabetes Patients Without Retinopathy Using Optical Coherence Tomography Angiography.

Purpose: We hypothesize that patients with type 1 diabetes (T1D) may have abnormal retinal vascular responses before diabetic retinopathy (DR) is clinically evident. Optical coherence tomography angiography (OCTA) was used to dynamically assess the retinal microvasculature of diabetic patients with no clinically visible retinopathy. Methods: Controlled nonrandomized interventional study. The studied population included 48 eyes of 24 T1D patients and 24 demographically similar healthy volunteers. A commercial OCTA device (AngioVue) was used, and two tests were applied: (1) the hypoxia challenge test (HCT) and (2) the handgrip test to induce a vasodilatory or vasoconstrictive response, respectively. The HCT is a standardized test that creates a mild hypoxic environment equivalent to a flight cabin. The handgrip test (i.e., isometric exercise) induces a sympathetic autonomic response. Changes in the parafoveal superficial and deep capillary plexuses in both tests were compared in each group. Systemic cardiovascular responses were also comparatively evaluated. Results: In the control cohort, the vessel density of the median parafoveal superficial and deep plexuses increased during hypoxia (F1,23 = 15.69, P < 0.001 and F1,23 = 16.26, P < 0.001, respectively). In the T1D group, this physiological response was not observed in either the superficial or the deep retinal plexuses. Isometric exercise elicited a significant decrease in vessel density in both superficial and deep plexuses in the control group (F1,23 = 27.37, P < 0.0001 and F1,23 = 27.90, P < 0.0001, respectively). In the T1D group, this response was noted only in the deep plexus (F1,23 = 11.04, P < 0.01). Conclusions: Our work suggests there is an early impairment of the physiological retinal vascular response in patients with T1D without clinical diabetic retinopathy.

Intraocular Pressure Reduction After Real-world Cataract Surgery.

PRéCIS:: A large cohort undergoing cataract extraction was retrospectively analyzed to ascertain the degree of real-world intraocular pressure (IOP) reduction in normal eyes and those with glaucoma, and a predictive formula was developed. PURPOSE: The purpose of this study was to define the real-world degree of IOP reduction after cataract extraction to guide its role as an isolated intervention for glaucoma. MATERIALS AND METHODS: A retrospective analysis was carried out of clinical data collected in 8 clinical sites in the United Kingdom from an electronic medical record system between January 2006 and May 2015. A total of 20,508 eyes without known pathology and 2251 eyes from patients with glaucoma undergoing phacoemulsification and intraocular lens insertion were included. Eyes with intraoperative complications, undergoing additional procedures, axial lengths outside 22 to 26.5 mm, preoperative IOP under 6 mm Hg or over 30 mm Hg, and copathology, except for amblyopia or glaucoma, were excluded. The main outcome measure was the change in preoperative IOP compared with the next recorded visit for up to 12 weeks. RESULTS: In eyes without pathology, the mean reduction in IOP was 1.40 mm Hg (±3.74) compared with 1.03 (±5.02), P-value <0.001, in eyes with a diagnosis of glaucoma. A multiple linear regression model identified preoperative IOP, a glaucoma diagnosis, preoperative corrected visual acuity, age, and axial length as determinants of IOP reduction. The model was validated against an independent cohort. CONCLUSIONS: We quantify mean IOP reduction achieved in a real-world setting from cataract surgery alone. In glaucomatous eyes where angle closure is not differentiated, phacoemulsification alone yields only a modest reduction of IOP.

Complete ILM Peeling Versus Inverted Flap Technique for Macular Hole Surgery: A Meta-Analysis.

BACKGROUND AND OBJECTIVE: To compare complete internal limiting membrane (ILM) peeling with the inverted flap technique for macular hole (MH) surgery. PATIENTS AND METHODS: An electronic database search on PubMed, CENTRAL, and ClinicalTrials.gov was performed. Inclusion criteria were comparative prospective/retrospective studies including patients with MH of any size with at least 6 months of follow-up. The primary outcome was MH closure rate. Secondary outcomes were best-corrected visual acuity improvement and surgery-related adverse events. RESULTS: Sixteen papers enrolling 1,403 eyes were included (733 ILM peeling, 670 inverted flap). MH mean minimum diameter and time of symptomatic evolution were higher in the inverted flap group (531.1 µm ± 188.8 µm vs. 602.8 µm ± 223.8 µm; 10.4 ± 20.2 months vs. 12.0 ± 18.4 months; P < .01). Overall, MH closure rate was superior with the inverted flap technique (risk-ratio [RR]: 1.25; 95% confidence interval [CI], 1.14-1.38; P < .0001), as well as in all subgroups: idiopathic large MH (n = 362; RR: 1.12; 95% CI, 1.05-1.20; P < .001), myopic MH without retinal detachment (n = 133; RR: 1.35; 95% CI, 1.14-1.59; P < .001), and MH retinal detachment (n = 198; RR: 1.89; 95% CI, 1.31-2.73; P < .001). CONCLUSION: This meta-analysis suggests the inverted flap technique is more effective in achieving MH closure. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:187-195.].

Optical coherence tomography angiography study of the retinal vascular plexuses in type 1 diabetes without retinopathy.

AIM: Previous data suggest the existence of retinal vascular changes and impaired autoregulation in the very early stages of diabetic retinopathy (DR). We compared the retinal plexuses between patients with type 1 diabetes (T1D) without DR and a demographically similar healthy cohort, using optical coherence tomography angiography (OCT-A). METHODS: Patients with T1D and no signs of DR were prospectively recruited from an outpatient clinic. Using OCT-A (AngioVue®), the parafoveal superficial (SCP) and deep (DPC) capillary plexus as well as the foveal avascular zone (FAZ) and perimeter were gathered. Mean comparison tests and linear regression analysis were used as statistical tests (STATA v14). RESULTS: Studied population included 48 subjects (24 T1D). The analysis of SCP revealed an attenuation of the capillary network compared with the control group in both parafoveal (51.8 ± 4.5 vs. 55.8 ± 3.2, p < 0.001) and perifoveal (51.9 ± 3.3 vs. 53.9 ± 1.9, p = 0.01) regions. A similar finding was observed in the DCP for both parafoveal (56.4 ± 4.3 vs. 60.4 ± 2.2, p < 0.001) and perifoveal (54.7 ± 3.9 vs. 60.8 ± 3.4, p = 0.001) sectors. Also, a longer time since T1D diagnosis was associated with a larger FAZ area (p = 0.055) and perimeter (p = 0.03). CONCLUSIONS: Significant differences in the retinal microvasculature were observed between healthy subjects and T1D patients using OCT-A, even before clinically detectable disease on fundus biomicroscopy.

Automated gonioscopy photography for iridocorneal angle grading.

PURPOSE: The aim of this study is to assess the agreement between manual and automated gonioscopy for iridocorneal angle opening. METHODS: The research is a cross-sectional observational study. Manual and automated gonioscopy were performed to consecutive patients in a glaucoma clinic. Iridocorneal angle opening grading was performed according to Shaffer's classification. Automated gonioscopy was performed with NGS-1 automated gonioscope (NIDEK Co., Gamagori, Japan). The automated gonio-photos were graded by two independent observers. Agreement between automated and manual gonioscopy and also among raters was ascertained by Fleiss' kappa statistic and comparison of area under curve. RESULTS: In total, 88 eyes of 47 subjects were analysed. Mean age was 63 ± 10 years. Twenty eyes (22.7%) were excluded from grading due to poor quality images. Angle closure was detected in 23.4% with dynamic gonioscopy in comparison with 4.3% using automated image grading. The agreement for angle closure diagnosis between dynamic and automated gonioscopy was low (κ = 0.09 ± 0.10; p = 0.18). The area under curve for detecting eyes with angle closure showed poor accuracy between automated and manual methods (area under curve: 0.53 ± 0.05, 95% confidence interval: 0.44-0.62). There was modest inter-rater agreement for angle opening assessment of automated images with Fleiss' kappa of 0.17 (95% confidence interval: 0.035-0.238). CONCLUSION: Manual and automated gonioscopy showed only slight agreement for the assessment of iridocorneal angle opening status. Further improvements of the NGS-1 automated gonioscopy and technique are desired for widespread use in a real-life setting.