Single-cell landscape of functionally cured chronic hepatitis B patients reveals activation of innate and altered CD4-CTL-driven adaptive immunity.

BACKGROUND & AIMS: Hepatitis B surface antigen (HBsAg) loss or functional cure (FC) is considered the optimal therapeutic outcome for patients with chronic hepatitis B (CHB). However, the immune-pathological biomarkers and underlying mechanisms of FC remain unclear. In this study we comprehensively interrogate disease-associated cell states identified within intrahepatic tissue and matched PBMCs (peripheral blood mononuclear cells) from patients with CHB or after FC, at the resolution of single cells, to provide novel insights into putative mechanisms underlying FC. METHODS: We combined single-cell transcriptomics (single-cell RNA sequencing) with multiparametric flow cytometry-based immune phenotyping, and multiplexed immunofluorescence to elucidate the immunopathological cell states associated with CHB vs. FC. RESULTS: We found that the intrahepatic environment in CHB and FC displays specific cell identities and molecular signatures that are distinct from those found in matched PBMCs. FC is associated with the emergence of an altered adaptive immune response marked by CD4 cytotoxic T lymphocytes, and an activated innate response represented by liver-resident natural killer cells, specific Kupffer cell subtypes and marginated neutrophils. Surprisingly, we found MHC class II-expressing hepatocytes in patients achieving FC, as well as low but persistent levels of covalently closed circular DNA and pregenomic RNA, which may play an important role in FC. CONCLUSIONS: Our study provides conceptually novel insights into the immuno-pathological control of HBV cure, and opens exciting new avenues for clinical management, biomarker discovery and therapeutic development. We believe that the discoveries from this study, as it relates to the activation of an innate and altered immune response that may facilitate sustained, low-grade inflammation, may have broader implications in the resolution of chronic viral hepatitis. IMPACT AND IMPLICATIONS: This study dissects the immuno-pathological cell states associated with functionally cured chronic hepatitis B (defined by the loss of HBV surface antigen or HBsAg). We identified the sustained presence of very low viral load, accessory antigen-presenting hepatocytes, adaptive-memory-like natural killer cells, and the emergence of helper CD4 T cells with cytotoxic or effector-like signatures associated with functional cure, suggesting previously unsuspected alterations in the adaptive immune response, as well as a key role for the innate immune response in achieving or maintaining functional cure. Overall, the insights generated from this study may provide new avenues for the development of alternative therapies as well as patient surveillance for better clinical management of chronic hepatitis B.

Predictive neural computations in the cerebellum contribute to motor planning and faster behavioral responses in larval zebrafish.

The ability to predict the future based on past experience lies at the core of the brain's ability to adapt behavior. However, the neural mechanisms that participate in generating and updating predictions are not clearly understood. Further, the evolutionary antecedents and the prevalence of predictive processing among vertebrates are even less explored. Here, we show evidence of predictive processing via the involvement of cerebellar circuits in larval zebrafish. We presented stereotyped optic flow stimuli to larval zebrafish to evoke swims and discovered that lesioning the cerebellum abolished prediction-dependent modulation of swim latency. When expectations of optic flow direction did not match with reality, error signals arrive at Purkinje cells via the olivary climbing fibers, whereas granule cells and Purkinje cells encode signals of expectation. Strong neural representations of expectation correlate with faster swim responses and vice versa. In sum, our results show evidence for predictive processing in nonmammalian vertebrates with the involvement of cerebellum, an evolutionarily conserved brain structure.

Identification of outcomes in clinical studies for pelvic venous disorders.

OBJECTIVE: There is increasing recognition that health systems need to measure and improve the value of patient care by measuring outcomes. Chronic pelvic pain secondary to pelvic venous insufficiency can have a significant impact on the quality of life (QOL) of women affected. Despite growing recognition, pelvic venous disorders (PeVDs), an important cause of chronic pelvic pain, remain underdiagnosed. Developing a core outcome set (COS) for benchmarking care delivery enhances the standardization of care. However, there is no consensus regarding a standardized minimum set of outcomes for PeVD. We aimed to generate a list of outcomes reported in previous PeVD treatment studies to lay the foundation for developing a COS for PeVD. METHODS: This scoping review was undertaken according to the PRISMA-ScR guidelines. Initially, screening, full-text review and extraction was conducted on studies published between 2018 and 2023. Subsequently, the search was expanded using 1-year intervals, until, over a 1-year interval, no new outcomes were recorded. Closely related outcomes were classified into domains, and domains into three core areas: disease-specific, treatment-related, and QOL-related outcomes. RESULTS: Of the 1579 records identified, 51 publications were included. From these studies, 108 different outcomes were identified. The median number of outcomes per study was 8 (interquartile range, 6-13). Closely related outcomes were organized into 42 outcome domains, which were then categorized into 3 core outcome areas; 47.6% (20/42) were disease specific, 35.7% (15/42) treatment related, and 16.7% (7/42) were QOL related. Of the 51 included studies, disease-specific outcomes were identified in 96.1% of the studies (49/51), treatment-related outcomes in 94.1% (48/51), and QOL outcomes in only 13.7% (7/51). CONCLUSIONS: There was significant heterogeneity in outcomes reported in PeVD studies. Most PeVD treatment studies evaluated disease-specific and treatment-related outcomes of PeVD, but few reported outcomes that measured the impact on QOL. These findings will inform the next steps in developing a COS for PeVD.

A scoping review of scores or grading systems for pelvic venous disorders.

BACKGROUND: Pelvic venous disorders (PeVD) encompass a variety of conditions linked to chronic pelvic pain in women. However, PeVD remain underdiagnosed due to the absence of universally accepted diagnostic criteria. The complexity of PeVD classifications across specialties leads to delays in treatment. This scoping review aims to fill a gap in PeVD diagnosis and management by identifying all existing scoring or grading systems to lay the foundation for standardized clinical scoring tools for PeVD. METHODS: This scoping review was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping reviews. Online databases were searched up to April 2023. Studies implementing a scoring or grading system for patients with confirmed or suspected PeVD were included. Scores or grading systems were classified into four main categories based on their use in the study: screening, diagnosis, measure of disease severity, and measure of response to treatment. RESULTS: Of the 2976 unique records identified, 82 were reviewed in full, and 20 were included in this study. The publication dates ranged from 1984 to 2023 (median, 2018; interquartile range, 2003-2022). A total of 21 scores and/or grading systems were identified. Of these 21 scores, 10 (47.6%) were clinical scores, and 10 (47.6%) were scores based on radiological findings; one study included a score that used both clinical and radiological findings. The identified scores were used in various settings. Of the 21 scores, 2 (9.52%) were used for screening in a tertiary care setting; 3 (14.3%) were used to establish the PeVD diagnosis; 8 (38.1%) were used to assess disease severity; and 8 (38.1%) were used as measures of response to treatment. Of the eight scores assessing disease severity, four (50.0%) assessed the degree of dilatation of pelvic veins and four (50%) assessed the severity of reflux. Only three of the scores were validated. CONCLUSIONS: This scoping review identified a range of scoring and grading systems for PeVD. We note a lack of a validated scoring system, both clinical and radiological, for screening and assessment of disease severity. This is an important first step in developing validated disease-specific scoring systems for patient screening, appropriate referral, assessment of symptom severity, and assessment of the response to treatment.