Bilateral visual improvement with unilateral gene therapy injection for Leber hereditary optic neuropathy.

REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A (MT-ND4) mutation and with duration of vision loss between 6 to 12 months were treated. Each subject's right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2-ND4 (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At week 96, rAAV2/2-ND4-treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of -0.308 LogMAR (+15 ETDRS letters). A mean improvement of -0.259 LogMAR (+13 ETDRS letters) was observed in the sham-treated eyes. Consequently, the primary end point, defined as the difference in the change in BCVA from baseline to week 48 between the two treatment groups, was not met (P = 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye, and 29 subjects (78%) had an improvement in vision in both eyes. A nonhuman primate study was conducted to investigate this bilateral improvement. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection.

Integrative molecular profiling of autoreactive CD4 T cells in autoimmune hepatitis.

BACKGROUND & AIMS: In most autoimmune disorders, crosstalk of B cells and CD4 T cells results in the accumulation of autoantibodies. In autoimmune hepatitis (AIH), the presence of anti-soluble liver antigen (SLA) autoantibodies is associated with reduced overall survival, but the associated autoreactive CD4 T cells have not yet been characterised. Herein, we isolated and deeply characterised SLA-specific CD4 T cells in patients with AIH. METHODS: We used brief ex vivo restimulation with overlapping SLA peptides to isolate and phenotype circulating SLA-specific CD4 T cells, and integrative single-cell RNA-seq (scRNA-seq) to characterise their transcriptome and T-cell receptor (TCR) repertoire. Autoreactive TCRs were cloned and used to identify dominant SLA-derived epitopes. SLA-specific CD4 T cells were tracked in peripheral blood through TCR sequencing to identify their phenotypic niche. We further characterised disease-associated peripheral blood T cells by high-content flow cytometry in 42 patients with AIH and 17 controls with non-alcoholic steatohepatitis. RESULTS: Autoreactive SLA-specific CD4 T cells were only detected in patients with anti-SLA autoantibodies and had a memory PD-1+CXCR5-CCR6-CD27+ phenotype. ScRNA-seq revealed their pro-inflammatory/B-helper profile. SLA81-100 and SLA177-204 contain dominant T-cell epitopes. Autoreactive TCR clonotypes were predominantly found in the memory PD-1+CXCR5-CD4 T cells, which were significantly increased in the blood of patients with AIH and supported B-cell differentiation through IL-21. Finally, we identified specific T-cell phenotypes linked to disease activity and IgG level during AIH. CONCLUSIONS: We provide a deep characterisation of rare circulating autoreactive CD4 T cells and identify their peripheral reservoir in AIH. We also propose a specific phenotype of autoreactive T cells related to AIH disease activity, which will be essential to track, delineate, and potentially target these pathogenic cells. LAY SUMMARY: One principal characteristic of autoimmune hepatitis (AIH), like for many other autoimmune diseases, is the accumulation of autoantibodies produced by B lymphocytes following their interaction with autoreactive CD4 T lymphocytes. In this study, we identified and characterised with high resolution these CD4 T cells. This will be essential to track, delineate, and potentially target them during AIH.

Psychopathy Checklist-Revised Use and Reporting Practices in Sexually Violent Predator Evaluations.

We surveyed evaluators who conduct sexually violent predator evaluations ( N = 95) regarding the frequency with which they use the Psychopathy Checklist-Revised (PCL-R), their rationale for use, and scoring practices. Findings suggest that evaluators use the PCL-R in sexually violent predator cases because of its perceived versatility, providing information about both mental disorder and risk. Several findings suggested gaps between research and routine practice. For example, relatively few evaluators reported providing the factor and facet scores that may be the strongest predictors of future offending, and many assessed the combination of PCL-R scores and sexual deviance using deviance measures (e.g., paraphilia diagnoses) that have not been examined in available studies. There was evidence of adversarial allegiance in PCL-R score interpretation, as well as a "bias blind spot" in PCL-R and other risk measure (Static-99R) scoring; evaluators tended to acknowledge the possibility of bias in other evaluators but not in themselves. Findings suggest the need for evaluators to carefully consider the extent to which their practices are consistent with emerging research and to be attuned to the possibility that working in adversarial settings may influence their scoring and interpretation practices.

Static-99R reporting practices in sexually violent predator cases: Does norm selection reflect adversarial allegiance?

We surveyed experts (N = 109) who conduct sexually violent predator (SVP) evaluations to obtain information about their Static-99R score reporting and interpretation practices. Although most evaluators reported providing at least 1 normative sample recidivism rate estimate, there were few other areas of consensus. Instead, reporting practices differed depending on the side for which evaluators typically performed evaluations. Defense evaluators were more likely to endorse reporting practices that convey the lowest possible level of risk (e.g., routine sample recidivism rates, 5-year recidivism rates) and the highest level of uncertainty (e.g., confidence intervals, classification accuracy), whereas prosecution evaluators were more likely to endorse practices suggesting the highest possible level of risk (e.g., high risk/need sample recidivism rates, 10-year recidivism rates). Reporting practices from state-agency evaluators tended to be more consistent with those of prosecution evaluators than defense evaluators, although state-agency evaluators were more likely than other evaluators to report that it was at least somewhat difficult to choose an appropriate normative comparison group. Overall, findings provide evidence for adversarial allegiance in Static-99R score reporting and interpretation practices.

Development of a geographic information-driven real-time surveillance system for disease surveillance.

To respond to emerging public health threats such as West Nile virus, an advanced geographic information systems (GIS) -driven Web-based real-time surveillance system was developed to serve the National West Nile virus dead bird surveillance programme in Canada. The development of this system uses real-time Web GIS technologies and services to enhance conventional real-time surveillance systems based on real-time GIS requirements. The system has three modules: QuickTrack, QuickMap and QuickManage. QuickTrack is the real-time surveillance module that supports data collection, edit and transfer. QuickMap is the real-time Web GIS module that provides comprehensive real-time GIS supports and services in public health surveillance and information sharing. The QuickManage module is a Web-based system management package used to manage the entire system. This system offers an effective approach to enhance real-time public health surveillance systems by integrating real-time Web GIS technologies and services. The system demonstrates that real-time Web GIS technologies can play an important role in enhancing public health surveillance systems.