Causal identification of single-cell experimental perturbation effects with CINEMA-OT.

Recent advancements in single-cell technologies allow characterization of experimental perturbations at single-cell resolution. While methods have been developed to analyze such experiments, the application of a strict causal framework has not yet been explored for the inference of treatment effects at the single-cell level. Here we present a causal-inference-based approach to single-cell perturbation analysis, termed CINEMA-OT (causal independent effect module attribution + optimal transport). CINEMA-OT separates confounding sources of variation from perturbation effects to obtain an optimal transport matching that reflects counterfactual cell pairs. These cell pairs represent causal perturbation responses permitting a number of novel analyses, such as individual treatment-effect analysis, response clustering, attribution analysis, and synergy analysis. We benchmark CINEMA-OT on an array of treatment-effect estimation tasks for several simulated and real datasets and show that it outperforms other single-cell perturbation analysis methods. Finally, we perform CINEMA-OT analysis of two newly generated datasets: (1) rhinovirus and cigarette-smoke-exposed airway organoids, and (2) combinatorial cytokine stimulation of immune cells. In these experiments, CINEMA-OT reveals potential mechanisms by which cigarette-smoke exposure dulls the airway antiviral response, as well as the logic that governs chemokine secretion and peripheral immune cell recruitment.

Distinguishing features of long COVID identified through immune profiling.

Post-acute infection syndromes may develop after acute viral disease1. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions2-4. However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein-Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers.

NK/T-cell Lymphoma With Orbital Involvement: A Case Report and Systematic Review of the Literature.

PURPOSE: To present the clinical course of a patient with recurrent NK/T-cell lymphoma (NKTL) involving the orbit and to review the literature on patients with NKTL involving the orbit. METHODS: The PubMed database was searched for all cases of NKTL involving orbital, intraocular, or adnexal ocular structures. RESULTS: Ninety-six patients were included in the final analysis. The mean age of diagnosis was 48.1 ± 16.8 years. The patients were 53/96 (55.2%) male and 43/96 (44.8%) female. Tumor location varied and included the orbit in 80/96 (83.3%), nasosinus in 56/96 (58.3%), uvea in 11/96 (11.5%), lacrimal gland in 9/96 (9.4%), lacrimal drainage system in 11/96 (11.5%), and conjunctiva in 7/96 (7.3%) cases. Management included surgical debulking in 29/96 (30.2%) cases, radiotherapy in 52/96 (54.2%) cases, and chemotherapy in 82/96 (85.4%) cases. Median survival was 6 months (95% CI: 5-9). Chemotherapy (hazard ratio = 0.80, 95% CI: 0.67-0.95, p = 0.013), radiotherapy (hazard ratio = 0.75, 95% CI: 0.64-0.87, p < 0.001), and orbital involvement being a recurrence of disease (hazard ratio = 0.79, 95% CI: 0.67-0.95, p = 0.009) were associated with improved survival. Advanced Ann Arbor stage (III-IV) at diagnosis (hazard ratio = 1.22, 95% CI: 1.08-1.38, p = 0.001), vision loss (hazard ratio = 1.18, 95% CI: 1.04-1.34, p = 0.009), proptosis (hazard ratio = 1.15, 95% CI: 1.01-1.30, p = 0.035) and periorbital swelling (hazard ratio = 1.15, 95% CI: 1.00-1.33, p = 0.048) were associated with poor survival. CONCLUSIONS: NK/T-cell lymphoma involving the orbit, globe, or ocular adnexa heralds a poor prognosis where early diagnosis and therapy are critical. The use of radiotherapy and chemotherapy is associated with improved survival.