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IMPORTANCE Despite the efficacy of immune checkpoint inhibitors (ICIs), cutaneous immune-related adverse events (cirAEs) occur in 20% to 40% of all treated patients. To our knowledge, little is known about the predictive value of these cutaneous eruptions and their subtypes regarding cancer survival.OBJECTIVE To determine the association of developing cirAEs following treatment with anti-programmed cell death 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) therapy with patient survival. DESIGN, SETTING, AND PARTICIPANTSThis retrospective cohort study used data from the TriNetX Diamond Network, a database of health records and claims data from more than 200 million US and European patients, to conduct a population-level cohort analysis. The study included 7008 eligible patients who developed cirAEs after treatment with anti-PD-1 or anti-PD-L1 therapy for malignant neoplasms of digestive organs, bronchus or lung, melanoma of skin, and urinary tract who were identified through the TriNetX Diamond Network along with 7008 matched controls.EXPOSURES Development of cirAEs within 6 months following anti-PD-1 or anti-PD-L1 therapy. MAIN OUTCOMES AND MEASURESA 6-month analysis using a Cox proportional hazards model was performed to determine the association of cirAEs with overall survival after adjusting for demographic characteristics, cancer type, and cancer stage. RESULTS A total of 7008 patients (3036 women [43.3%]; mean [SD] age, 68.2 [11.2] years) were matched to 7008 (3044 women [43.4%]; mean [SD] age, 68.3 [11.1] years) controls.

Knowledge of microbial gene functions comes from manipulating the DNA of individual species in isolation from their natural communities. While this approach to microbial genetics has been foundational, its requirement for culturable microorganisms has left the majority of microbes and their interactions genetically unexplored. Here we describe a generalizable methodology for editing the genomes of specific organisms within a complex microbial community. First, we identified genetically tractable bacteria within a community using a new approach, Environmental Transformation Sequencing (ET-Seq), in which non-targeted transposon integrations were mapped and quantified following community delivery. ET-Seq was repeated with multiple delivery strategies for both a nine-member synthetic bacterial community and a ~200-member microbial bioremediation community. We achieved insertions in 10 species not previously isolated and identified natural competence for foreign DNA integration that depends on the presence of the community. Second, we developed and used DNA-editing All-in-one RNA-guided CRISPR-Cas Transposase (DART) systems for targeted DNA insertion into organisms identified as tractable by ET-Seq, enabling organism- and locus-specific genetic manipulation within the community context. These results demonstrate a strategy for targeted genome editing of specific organisms within microbial communities, establishing a new paradigm for microbial manipulation relevant to research and applications in human, environmental, and industrial microbiomes.

BackgroundImmune checkpoint inhibitors (ICIs) have improved survival and are increasingly used for non-small cell lung cancer. However, use may be limited by immune-related adverse events such as checkpoint-inhibitor pneumonitis (CIP). Literature estimates for CIP incidence are inconsistent. Real-world adherence to guidelines, clinical course, and healthcare utilization in the treatment of CIP has not been described in large cohorts.MethodsA combined claims and electronic health record database (TriNetX) was used to identify 13,113 patients with lung cancer treated with programmed cell death receptor/ligand 1 (PD-1/PD-L1) inhibitors, and a propensity score-matched control cohort treated with chemotherapy or targeted therapies. The attributable risk of CIP was calculated in the first 12 months after therapy by comparing the incidence of diagnosis codes for pneumonitis/pneumonia between cohorts. Cases of CIP, identified by the most specific code for drug-induced respiratory conditions, were further analyzed for medication usage, rates of diagnostic bronchoscopy, ICI discontinuation rates, and usage of hospital services compared with patients receiving PD-1/PD-L1 inhibitors who did not develop CIP.ResultsThe attributable risk of pneumonitis to PD-1/PD-L1 inhibitors was 2.49% (95% CI, 1.50% to 3.47%). Median time to onset in the CIP subcohort was 3.9 months (IQR, 2.1–7.3 months). Steroid and antibiotic use increased dramatically after a pneumonitis diagnosis, and 70.2% of patients permanently discontinued ICI therapy. Compared with controls, patients with CIP had more than a threefold increased risk of needing critical care (relative risk 3.59, 95% CI, 2.31 to 5.57) and an increased risk of mortality (HR 2.34, 95% CI, 1.47 to 3.71).ConclusionsIn a large claims-based analysis, PD-1/PD-L1 inhibitors increase the risk of pneumonitis in patients with lung cancer by 2.49%. Cases of CIP are associated with high healthcare utilization, discontinuation of ICIs, and mortality.