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OBJECTIVE Basal insulin Fc (BIF) (insulin efsitora alfa; LY3209590), a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for once-weekly basal insulin administration. This phase 2 study assessed the safety and efficacy of BIF versus degludec in insulin-naive patients with type 2 diabetes (T2D) previously treated with oral antihyperglycemic medications. RESEARCH DESIGN AND METHODS During this randomized, parallel, open-label study, 278 insulin-naive patients with T2D were randomly assigned (1:1) to receive BIF once weekly or degludec once daily over the 26-week treatment period. Both groups were titrated to fasting glucose of 80–100 mg/dL (4.4 to RESULTS After 26 weeks of treatment, BIF demonstrated a noninferior HbA1c change from baseline versus degludec, with a treatment difference of 0.06% (90% CI −0.11, 0.24; P = 0.56). Both BIF and degludec treatment led to significant reductions in FBG from baseline. At week 26, the between-treatment difference for BIF versus degludec was 4.7 mg/dL (90% CI 0.1, 9.3; P = 0.09). The rate of level 2 hypoglycemia was low and not significantly different between treatment groups (BIF 0.22 events/patient/year, degludec 0.15 events/patient/year; P = 0.64); there was no severe hypoglycemia. The occurrence of treatment-emergent adverse events was also similar between BIF and degludec. CONCLUSIONS Once-weekly BIF achieved excellent glycemic control similar to degludec, with no concerning hypoglycemia or other safety findings.

OBJECTIVE Basal Insulin Fc (BIF; insulin efsitora alfa; LY3209590), a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for once-weekly basal insulin administration. This phase 2 study assessed safety and efficacy of BIF versus degludec in 265 patients with type 1 diabetes (T1D) using multiple daily injections. RESEARCH DESIGN AND METHODS During this randomized, parallel, open-label study, patients with T1D were randomized (1:1) to receive BIF once weekly or degludec once daily over the 26-week treatment period. Both groups were titrated to a fasting glucose level of 80–100 mg/dL. The primary end point was HbA1c change from baseline to week 26 (noninferiority margin, 0.4%). Secondary end points included percent time in range (TIR) (70–180 mg/dL), continuous glucose monitoring (CGM) fasting glucose (FG) level, and rate of hypoglycemia. RESULTS After 26 weeks, patients receiving BIF had noninferior HbA1c change from baseline versus those receiving degludec, with a statistically significant treatment difference of 0.17% (90% CI 0.01, 0.32; P = 0.07) favoring the comparator. Percent TIR was similar for patients in the BIF (56.1%) and degludec (58.9%; P = 0.112) groups at week 26. FG values were significantly higher for patients receiving BIF (158.8 mg/dL) versus degludec (143.2 mg/dL; P = 0.003). Rates of CGM-derived hypoglycemia were not statistically significantly different for BIF and degludec over 24 h for level 1 (P = 0.960) or level 2 (P = 0.517) hypoglycemia during the treatment period. Occurrence of serious adverse events was similar between the BIF and degludec groups. CONCLUSIONS Once-weekly BIF demonstrated noninferior glycemic control to once-daily degludec (treatment difference: 0.17% favoring degludec) and no difference in hypoglycemia or other safety findings in patients with T1D.

Objective Basal Insulin Fc (BIF; insulin efsitora alfa; LY3209590), a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for once weekly basal insulin administration. This Phase 2 study assessed safety and efficacy of BIF versus degludec in insulin-naïve patients with type 2 diabetes (T2D) previously treated with oral antihyperglycemic medications. Research Design and Methods During this randomized, parallel, open-label study, 278 insulin-naïve patients with T2D were randomized (1:1) to receive BIF once weekly or degludec once daily over the 26-week treatment period. Both groups were titrated to fasting glucose of 80-100 mg/dL (4.4 to Results After 26 weeks of treatment, BIF demonstrated non-inferior HbA1c change from baseline versus degludec with a treatment difference of 0.06% (90% CI= -0.11, 0.24; p=0.56).. Both BIF and degludec treatment led to significant reductions in FBG from baseline; at Week 26 the between treatment difference for BIF versus degludec was 4.7 mg/dL [90% CI=0.1, 9.3]; p=0.09). The rate of Level 2 hypoglycemia was low and not significantly different between treatment groups (BIF=0.22; degludec=0.15 events/pt/yr; p=0.64); there was no severe hypoglycemia. The occurrence of treatment-emergent adverse events was also similar between BIF and degludec. Conclusions Once weekly BIF achieved excellent glycemic control similar to degludec with no concerning hypoglycemia or other safety findings.

Objective Basal Insulin Fc (BIF; insulin efsitora alfa; LY3209590), a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for once weekly basal insulin administration. This Phase 2 study assessed safety and efficacy of BIF versus degludec in N=265 patients with type 1 diabetes (T1D) using multiple daily injections. Research Design and Methods During this randomized, parallel, open-label study, patients with T1D were randomized (1:1) to receive BIF once weekly or degludec once daily over the 26-week treatment period. Both groups were titrated to fasting glucose 80-100 mg/dL. Primary endpoint was HbA1c change from baseline to Week 26 (non-inferiority margin=0.4%). Secondary endpoints included percent time in range (TIR, 70-180 mg/dL), CGM fasting glucose (FG), and rate of hypoglycemia. Results After 26 weeks, BIF demonstrated non-inferior HbA1c change from baseline versus degludec with a statistically significant treatment difference of 0.17% (90% CI=0.01, 0.32; p=0.07) favoring the comparator. Percent TIR was similar for BIF (56.1%) and degludec (58.9%; p=0.112) at Week 26. FG values were significantly higher for BIF (158.8 mg/dL) versus degludec (143.2 mg/dL; p=0.003). Rates of CGM-derived hypoglycemia were not statistically significantly different for BIF and degludec over 24 hours for Level 1 (p=0.960) or Level 2 (p=0.517) during the treatment period. Occurrence of serious adverse events was similar between BIF and degludec. Conclusions Once weekly BIF demonstrated non-inferior glycemic control to once daily degludec (treatment difference: 0.17% favoring degludec) and no difference in hypoglycemia or other safety findings in patients with T1D.

Biogas (methane) as a source of renewable energy, was produced in the anaerobic co-digestion of blackwater (BW, municipal toilet wastewater) and organic kitchen waste (KW). The impact on methane production of various BW to KW mixing ratios, with and without the addition of granular activated carbon (GAC), were studied under thermophilic (55 °C) temperatures. GAC is reported to enhance methane production in such digestions through direct interspecies electron transfer. The results showed that the co-digestion of BW and KW under the 1:2 VS ratio significantly improved the biomethane potential (BMP). In the absence of GAC, an optimal BW:KW ratio was found to be 1:2, achieving a BMP of 0.76 g CH4-COD/g feed-COD. With GAC addition, the BMP increased to 0.81 g CH4-COD/g feed-COD, the lag phase in the digestion was significantly reduced, and the methane production rate increased. Microbial communities in the BW-KW anaerobic digestion were analyzed with and without the addition of GAC. Methanothermobacter and Methanosarcina were predominant archaea in BW-KW digests, with and without GAC amendment, while a third methanogen, Methanomassiliicoccus, was enriched with the addition of GAC to the digest. Further, through SEM image, the enrichment of pili-like stucture was observed in GAC surface.

Objective We expanded the previous assessment of a mortality variable suited for real‐world evidence‐focused oncology research. Data source We used a nationwide electronic health record (EHR)‐derived de‐identified database. Data collection We included patients with at least 1 of 18 cancer types between January 1, 2011 and December 31, 2017. Patient‐level structured data (EHRs, obituaries, and Social Security Death Index) and unstructured EHR data (abstracted) were linked to generate a composite mortality variable. Study design We benchmarked sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and ±15‐day agreement against the National Death Index (NDI). Real‐world overall survival (rwOS) was estimated using the Kaplan‐Meier method. We performed sensitivity analyses using a smaller patient cohort that underwent next‐generation sequencing testing. Principal findings Compared with the NDI across 18 cancer types (overall N = 160 436): sensitivity, 83.9%‐91.5% (17/18 cancer types had sensitivity ≥85.0%); specificity, 93.5%‐99.7%; PPV, 96.3%‐98.3%; NPV, 75.0%‐98.7%; ±15‐day agreement, 95.6%‐97.6%; and median rwOS estimates ranging from 2.8% to 12.7% greater. Sensitivity analysis results (n = 17 540) were consistent with the main analysis. Conclusions Across all cancer types analyzed, this composite mortality variable showed high sensitivity, specificity, PPV, NPV, and ±15‐day agreement, and yielded median rwOS values modestly overestimated when compared to NDI‐based results.

Circular RNAs (circRNAs) are emerging as novel regulators in the biological development of various diseases, but their expression profiles, functions and mechanisms in silicosis and pulmonary fibrosis remain largely unexplored. In this study, we constructed a mouse model of pulmonary fibrosis by intratracheal injection of silica particles and then performed transcriptome RNA sequencing of lung tissues. The results showed that 78 circRNAs, 39 miRNAs and 262 mRNAs were differentially expressed. Among them, five circRNAs, three miRNAs and four mRNAs were further selected, and their abnormal expression was verified in mouse fibrotic lung tissues by RT-qPCR assay. The circRNA-associated ceRNA network including 206 ceRNA triplets was constructed based on abnormally expressed circRNAs, miRNAs and mRNAs, and miR-199b-5p, miR-296-5p and miR-708-5p were identified as hub miRNAs connected to circRNAs and mRNAs. Subsequently, GO and KEGG pathway enrichment analyses were performed to detect the potential roles of differentially expressed mRNAs in pulmonary fibrosis, which were mainly involved in immune response, Th17 cell differentiation, NF-κB signaling pathway and PI3K-Akt signaling pathway. Furthermore, we identified that hsa_circ_0006916 was up-regulated in pulmonary fibrosis. To characterize the potential role of hsa_circ_0006916, we transfected siRNA targeting hsa_circ_0006916 into alveolar macrophages and found that knockdown of hsa_circ_0006916 significantly increased the expression levels of M1 molecules IL-1β and TNF-α and reduced the expression level of M2 molecule TGF-β1, indicating that hsa_circ_0006916 may play an important role in the activation of M1-M2 polarization effect in macrophages. Our results provided important evidence on the possible contribution of these abnormal circRNAs to the development of silicosis and pulmonary fibrosis.

Basal Insulin Fc (BIF; LY3209590) , a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for QW administration. This randomized, parallel, open-label Ph2 study assessed safety and efficacy of BIF vs. DEG in insulin-naïve patients with T2D previously treated with oral antihyperglycemic medication. BIF was injected QW, and DEG was injected QD. Both groups were titrated to fasting blood glucose (FBG) ≤100 mg/dL. The primary endpoint was HbA1c change from baseline (CFBL) to Wk 26 (non-inferiority margin=0.4%) . Patients randomized to BIF (N=129) and DEG (N=135) had a mean age of 58.4 yrs and baseline HbA1c of 8.0%. After 26 wks, BIF showed non-inferiority vs. DEG for HbA1c CFBL with a treatment difference of 0.06% (90% CI = -0.11, 0.24; p = .56) , and both groups had >75% time in range (70-180 mg/dL) on average at Wk 26 (Figure) . BIF and DEG significantly reduced FBG from baseline (treatment difference BIF vs. DEG = 4.7 mg/dL [90% CI = 0.1, 9.3]; p = .09) . Rate of Level 2 hypoglycemia was low and not significantly different (BIF = 0.22; DEG = 0.15 events/pt/yr; p = 0.64) . Occurrence of treatment-emergent adverse events was similar between BIF and DEG. QW BIF achieved excellent glycemic control similar to DEG with no concerning hypoglycemia or other safety findings, supporting continued development of BIF in Ph3. Disclosure J.M. Bue-Valleskey: None. C.M. Kazda: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. C. Ma: None. J. Chien: Employee; Eli Lilly and Company. Q. Zhang: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. E. Chigutsa: Employee; Eli Lilly and Company. W. Landschulz: Employee; Eli Lilly and Company. J. Swan: Employee; Eli Lilly and Company. A. Haupt: Employee; Lilly. Stock/Shareholder; Lilly. J. Frias: Advisory Panel; Altimmune, Becton, Dickinson and Company, Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi. Consultant; 89bio, Inc., Akero Therapeutics, Inc., Altimmune, Becton, Dickinson and Company, Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk, Pfizer Inc., Sanofi. Research Support; Afimmune Limited, Akero Therapeutics, Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Carmot Therapeutics, Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Ionis Pharmaceuticals, Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi. Speaker's Bureau; Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. Funding Funded by Eli Lilly and Company.

ObjectiveEarly gastric cardia adenocarcinoma (EGCA) is a highly heterogeneous cancer, and the understanding of its classification and malignant progression is limited. This study explored the cellular and molecular heterogeneity in EGCA using single-cell RNA sequencing (scRNA-seq).DesignscRNA-seq was conducted on 95 551 cells from endoscopic biopsies of low-grade intraepithelial neoplasia, well/moderately/poorly differentiated EGCA and their paired adjacent nonmalignant biopsy samples. Large-scale clinical samples and functional experiments were employed.ResultsIntegrative analysis of epithelial cells revealed that chief cells, parietal cells and enteroendocrine cells were rarely detected in the malignant epithelial subpopulation, whereas gland and pit mucous cells and AQP5+stem cells were predominant during malignant progression. Pseudotime and functional enrichment analyses showed that the WNT and NF-κB signalling pathways were activated during the transition. Cluster analysis of heterogeneous malignant cells revealed that NNMT-mediated nicotinamide metabolism was enriched in gastric mucin phenotype cell population, which was associated with tumour initiation and inflammation-induced angiogenesis. Furthermore, the expression level of NNMT was gradually increased during the malignant progression and associated with poor prognosis in cardia adenocarcinoma. Mechanistically, NNMT catalysed the conversion of nicotinamide to 1-methyl nicotinamide via depleting S-adenosyl methionine, which led to a reduction in H3K27 trimethylation (H3K27me3) and then activated the WNT signalling pathway to maintain the stemness of AQP5+stem cells during EGCA malignant progression.ConclusionOur study extends the understanding of the heterogeneity of EGCA and identifies a functional NNMT+/AQP5+population that may drive malignant progression in EGCA and could be used for early diagnosis and therapy.

A graph-based particle filter bathymetric simultaneous localization and mapping (BSLAM) method is proposed to solve the oscillation problem of the trajectories estimated by particles when using a low precise vehicle motion model and obtain accurate navigation results for autonomous underwater vehicles (AUVs). A graph-based trajectory update method is proposed to update the trajectories stored in particles before particle weighting to weaken the influence of the low precise odometer model on the particle trajectories. A particle weighting method based on submap matching is proposed to improve the robustness of the particle filter. Besides, a graph-based map generation method is proposed to solve the map selection problem of the particle filtering theory. The performance of the proposed method is demonstrated using a simulated dataset and a field dataset collected from a sea trial. The results show that the proposed method is more accurate and effective compared with a state-of-art particle filter BSLAM method.