The impact of modified incision height and surgical procedure on trichiasis surgery outcomes: Results of the maximizing trichiasis surgery success (MTSS) randomized trial.

BACKGROUND: Poor surgical outcomes remain a problem in trachoma-endemic countries working to reach elimination thresholds. Methods to improve outcomes could positively impact programmatic success. METHODS: This parallel, three-armed clinical trial conducted in Ethiopia randomized individuals with previously unoperated trachomatous trichiasis (TT) to receive surgery utilizing one of three approaches: bilamellar tarsal rotation with a 3 mm incision height (BLTR-3), BLTR with 5 mm incision height (BLTR-5) and posterior lamellar tarsal rotation (PLTR). We followed participants for one year. The primary outcome was post-operative trichiasis (PTT). Secondary outcomes were eyelid contour abnormalities (ECA) and pyogenic granulomata. FINDINGS: We randomized and operated on 4,914 individuals with previously unoperated TT (6,940 eyes). Primary analyses include 6,815 eyes with follow-up. Overall, 1,149 (16.9%) eyes developed PTT. The risk difference for PTT was minimal comparing BLTR-3 and PLTR (adjusted risk difference [aRD] 1.8% (98.3%CI: -0.5-4.2%)), but significantly higher for BLTR-5 surgeries compared to BLTR-3 (aRD: 6.7% (3.9-9.4%)) and PLTR (aRD: 8.6% (5.9-11.3%)). BLTR-5 had the lowest ECA (6.1% versus 9.6% BLTR-3, 11.2% PLTR) and granuloma rates (5.2% versus 6.5% BLTR-3 and 7.5% PLTR). One eyelid operated with PLTR experienced an eyelid margin division; four BLTR-3 and eight BLTR-5 eyelids experienced excessive bleeding. INTERPRETATION: We do not recommend modifying the BLTR incision height of 3 mm. Overall, we did not find a significant difference in PTT between BLTR-3 and PLTR in terms of PTT or ECA. TRIAL REGISTRATION: Registration number: NCT03100747; ClinicalTrials.gov Full study protocol available at (https://doi.org/10.15139/S3/QHZXWD).

Gender differences in the surgical management of trachomatous trichiasis: an exploratory analysis of global trachoma survey data, 2015-2019.

BACKGROUND: Trachomatous trichiasis (TT) is a painful, potentially blinding eye condition that can be managed through epilation or surgery. Women are affected by TT approximately twice as often as men and are believed to face gendered barriers to receiving surgical care to prevent vision loss. METHODS: We used data from 817 cross-sectional surveys conducted during 2015-2019 in 20 African countries to estimate the prevalence difference (PD) between female and male eyes for four outcomes potentially indicating gender-related differences in TT management: (1) received surgery and developed postoperative TT (PTT), (2) never offered surgery, (3) offered surgery but declined it, and (4) offered epilation but never offered surgery. RESULTS: The prevalence was modestly elevated among female eyes compared with male eyes for having PTT (PD:1.8 [95% confidence limits (CL): 0.6, 3.0]) and having declined surgery for the eye (PD: 6.2 [95% CL: 1.8, 10.7]). The proportion offered epilation was similar by gender (PD:0.5 [95% CL: -0.4, 1.3]), while never having been offered surgery was somewhat more prevalent among male eyes (PD: -2.1 [95% CL: -3.5, -0.7]). CONCLUSIONS: Our results suggest potential gender differences in TT management. More research is needed to determine the causes and implications of the observed differences.

Maximising trichiasis surgery success (MTSS) trial: rationale and design of a randomised controlled trial to improve trachomatous trichiasis surgical outcomes.

INTRODUCTION: Trachomatous trichiasis (TT) is a condition in which the eyelid turns inward and eyelashes abrade the front part of the eye. To prevent eventual blindness, surgery is recommended. Two surgical procedures are commonly used, bilamellar tarsal rotation (BLTR) and posterior lamellar tarsal rotation (PLTR). Evidence suggests that incision height and surgery type may affect the risk of postoperative TT (PTT) and other surgical outcomes. However, these studies have not prospectively compared the impact of incision height on surgical outcomes. METHODS AND ANALYSIS: Maximising trichiasis surgery Success (MTSS) is a three-arm, randomised clinical trial being conducted in Ethiopia. Participants will be randomly assigned on a 1:1:1 basis to BLTR with a 3 mm incision height, BLTR with a 5 mm incision height, or PLTR 3 mm incision height. Patients are eligible for the trial if they have previously unoperated upper eyelid TT. Follow-up visits will be conducted by trained eye examiners at 1 day, 2 weeks, 6 weeks and 12 months after surgery. The primary outcome is incident PTT within 1 year following surgery. Logistic regression will be used in an intention-to-treat analysis to assess outcome incidence by surgical approach. ETHICS AND DISSEMINATION: The University of North Carolina and Johns Hopkins School of Medicine institution review boards, Ethiopian National Research Ethics Review Committee and Ethiopian Food, Medicine, Healthcare and Administration and Control Authority provided ethics approval for the trial. On completion, trial results will be disseminated at local and international meetings and in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03100747.

Fluctuations of functionally distinct CD8+ T-cell clonotypes demonstrate flexibility of the HIV-specific TCR repertoire.

T-cell receptor (TCR) diversity of virus-specific CD8+ T cells likely helps prevent escape mutations in chronic viral infections. To understand the dynamics of the virus-specific T cells in more detail, we followed the evolution of the TCR repertoire specific for a dominant HLA-B*08-restricted epitope in Nef (FLKEKGGL) in a cohort of subjects infected with HIV. Epitope-specific CD8+ T cells used structurally diverse TCR repertoires, with different TCRbeta variable regions and with high amino acid diversity within antigen recognition sites. In a longitudinal study, distinct Vbeta populations within the HIV-specific TCR repertoire expanded simultaneously with changes in plasma viremia, whereas other Vbeta populations remained stable or even decreased. Despite antigenic variation in some subjects, all subjects had the consensus sequence present during the study period. Functional analysis of distinct Vbeta populations revealed differences in HIV-specific IFN-gamma secretion ex vivo as well as differences in tetramer binding, indicating functional heterogeneity among these populations. This contrasts with findings in a subject on antiretroviral therapy with suppression of viremia to less than 50 copies/mL, where we observed long-term persistence of a single clonotype. Our findings illustrate the flexibility of a heterogeneous HIV-1-specific CD8+ TCR repertoire in subjects with partial control of viremia.

Selection, transmission, and reversion of an antigen-processing cytotoxic T-lymphocyte escape mutation in human immunodeficiency virus type 1 infection.

Numerous studies now support that human immunodeficiency virus type 1 (HIV-1) evolution is influenced by immune selection pressure, with population studies showing an association between specific HLA alleles and mutations within defined cytotoxic T-lymphocyte epitopes. Here we combine sequence data and functional studies of CD8 T-cell responses to demonstrate that allele-specific immune pressures also select for mutations flanking CD8 epitopes that impair antigen processing. In persons expressing HLA-A3, we demonstrate consistent selection for a mutation in a C-terminal flanking residue of the normally immunodominant Gag KK9 epitope that prevents its processing and presentation, resulting in a rapid decline in the CD8 T-cell response. This single amino acid substitution also lies within a second HLA-A3-restricted epitope, with the mutation directly impairing recognition by CD8 T cells. Transmission of the mutation to subjects expressing HLA-A3 was shown to prevent the induction of normally immunodominant acute-phase responses to both epitopes. However, subsequent in vivo reversion of the mutation was coincident with delayed induction of new CD8 T-cell responses to both epitopes. These data demonstrate that mutations within the flanking region of an HIV-1 epitope can impair recognition by an established CD8 T-cell response and that transmission of these mutations alters the acute-phase CD8(+) T-cell response. Moreover, reversion of these mutations in the absence of the original immune pressure reveals the potential plasticity of immunologically selected evolutionary changes.

Fine specificity and cross-clade reactivity of HIV type 1 Gag-specific CD4+ T cells.

Despite growing evidence that HIV-1-specific CD4(+) T helper (Th) cells may play a role in the control of viremia, discrete Th cell epitopes remain poorly defined. Furthermore, it is not known whether Th cell responses generated using vaccines based on clade B virus sequences will elicit immune responses that are effective in regions of the world where non-clade B viruses predominate. To address these issues we isolated CD4(+) T cell clones from individuals with vigorous HIV-1-specific Th cell responses and identified the minimum epitopes recognized. The minimum peptide length required for induction of CD4(+) T cell proliferation, IFN-gamma secretion, and cytolytic activity ranged from 9 to 16 amino acids in the five epitopes studied. Cross-clade recognition of the defined epitopes was examined for variant peptides from clades A, B, C, D, and AE. Over half the variant epitopes (17 of 32) exhibited impaired recognition, defined as less than 50% of the IFN-gamma secretion elicited by B clade consensus sequence. There was no evidence for antagonistic activity mediated by the variant peptides, and despite strong responses there was no escape of autologous virus from Th responses in the epitopes we studied. Abrogated recognition of variant CD4(+) T cell epitopes presents a potential obstacle to vaccine development.