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Background: Sphingosine-1-phosphate (S1P) is a signalling molecule that has an inhibitory role in atherosclerosis, inflammation, cell proliferation, and immunity. Cenerimod is a selective S1P 1 receptor modulator under investigation for the treatment of systemic lupus erythematosus (SLE). We aimed to determine the efficacy, safety, and tolerability of four doses of cenerimod in adults with moderate-to-severe SLE receiving standard of care background therapy., Methods: CARE was a double-blind, randomised, placebo-controlled, phase 2 trial, in adults (aged 18-75 years) with moderate-to-severe SLE (a score of at least 6 out of 105 on the SLE disease activity index-2000, modified to exclude leukopenia [mSLEDAI-2K] score). Participants were recruited from 189 hospitals, specialist centres, and outpatient clinics in 22 countries in Asia Pacific, Latin America, Europe, and the USA. Participants were randomly assigned (1:1:1:1:1), using an interactive response technology via balanced block randomisation (block size of 5) and stratified by oral glucocorticoid dose at randomisation and disease activity at screening, to once-daily oral cenerimod at 0·5 mg, 1·0 mg, 2·0 mg, or 4·0 mg or placebo, in addition to stable background SLE therapy, and followed up for 12 months. After 6 months, participants assigned to cenerimod 4·0 mg were randomly assigned again (1:1) to either cenerimod 2.0 mg or placebo for a further 6 months. The primary endpoint was change from baseline to month 6 in mSLEDAI-2K score, assessed in all participants randomly assigned to treatment (full analysis set). To meet the primary endpoint, the doses had to show a significant improvement over placebo, when adjusting for multiplicity, considering the hierarchical testing strategy, per a prespecified plan. Safety analyses included all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03742037, and is complete., Findings: Between Dec 21, 2018, and Aug 25, 2022, 810 patients were screened and 427 were randomly assigned to 0·5 mg (n=85), 1·0 mg (n=85), 2·0 mg (n=86), and 4·0 mg (n=85) cenerimod or placebo (n=86). Median age was 42 years (IQR 33-51), 406 (95%) of 427 participants were women, 21 (5%) were men, and 337 (79%) were White. At month 6, the least squares mean change from baseline in mSLEDAI-2K score was -2·85 (95% CI -3·60 to -2·10) for the placebo group and -3·24 (-3·98 to -2·49; difference vs placebo -0·39 [95% CI -1·45 to 0·68]; p=0·47) for the cenerimod 0·5 mg group, -3·41 (-4·16 to -2·67; difference vs placebo -0·57 [-1·62 to 0·49]; p=0·29) for the 1·0 mg group, -2·84 (-3·58 to -2·09; difference vs placebo 0·01 [-1·05 to 1·08]; p=0·98) for the 2·0 mg group, and -4·04 (-4·79 to -3·28; difference vs placebo -1·19 [-2·25 to -0·12]; p=0·029) for the 4·0 mg group; hence, the primary endpoint was not met. Treatment-emergent adverse events up to 12 months had no clear treatment-related or dose-related pattern across the groups. At month 6, treatment-emergent lymphopenia was reported in one (1%) of 85 patients who received cenerimod 0·5 mg, five (6%) of 85 patients who received 1·0 mg, nine (10%) of 86 patients who received 2·0 mg, 12 (14%) of 84 patients who received 4·0 mg, and no patients who received placebo. Two deaths due to adverse events occurred (both in the cenerimod 1·0 mg group; one due to acute coronary syndrome and the other due to upper gastrointestinal haemorrhage), and were determined to be unrelated to study treatment., Interpretation: The primary endpoint was not met. Cenerimod was well tolerated over 12 months. Cenerimod 4·0 mg is being investigated for the treatment of SLE in two ongoing phase 3 trials (NCT05648500, NCT05672576)., Funding: Idorsia Pharmaceuticals., Competing Interests: Declaration of interests ADA is a consultant for Amgen, AstraZeneca, Aurinia, Biogen, Bristol Myers Squibb, Cabaletta, Celgene, Eli Lilly, Idorsia, Janssen, Genentech, GSK, Sana, Sanofi, and UCB; has received grants from AstraZeneca, Biogen, BMS, Cabaletta, Idorsia, Genentech, NKARTA, Pfizer, Sana, Sanofi, and UCB; and has been a participant on advisory boards for Amgen and BMS. DD is a consultant advisor for GSK, UCB, and CSL Vifor; has received speaker fees from GSK and UCB; and has received support from CSL Vifor for attending European Alliance of Associations for Rheumatology 2023. CC was an employee of Idorsia Pharmaceuticals at the time the work was performed. KK is a consultant for BMS, GSK, Genentech/Roche, Equillium, AstraZeneca, Biogen, Eli Lilly, Amgen, Aurinia, Cabaletta, Shoreline, Ventyx, and Mirador; has been a participant on an advisory board for Genentech/Roche; holds a leadership or fiduciary role in Lupus Therapeutics and Lupus Foundation of America; and hold stocks in Artiva Bio and Bento Bio. JTM is a consultant for AbbVie, Alexion, Alumis, Amgen, Astra Zeneca, Aurinia, BMS, EMD Serono, Genentech, Gilead, GSK, Lilly, Merck, Pfizer, Provention, Remegen, Sanofi, UCB, and Zenas; has received grants from BMS, GSK, and AstraZeneca; has received speaker fees from AbbVie, BMS, Merck, and Remegen; and is Chief Advisor for Clinical Development for Lupus Foundation of America. SVN is aconsultant for Biogen, Idorsia, and AstraZeneca; has received speaker fees from Astellas, AstraZeneca, Aurinia, Pfizer, GSK, and Roche; has participated on advisory boards and data safety monitoring boards for Roche; and is President and Chief Executive Officer of Rheumatology Educational Trust Foundation. PC, MJM, DSS and OB are employees of Idorsia Pharmaceuticals and shareholders in the company. LT was an employee of Idorsia Pharmaceuticals and a shareholder in the company at the time the work was performed., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Aim: Avelumab has been approved worldwide for treatment of metastatic Merkel cell carcinoma (mMCC), a rare and aggressive skin cancer. This study evaluated outcomes in patients with mMCC in France who received avelumab as second-line or later (2L+) treatment in routine clinical practice., Methods: This retrospective, noninterventional study evaluated all patients diagnosed with mMCC using two databases: CARADERM (French national database of rare dermatological cancers) and SNDS (national healthcare database), identified via probabilistic linkage. Eligible patients initiated avelumab as 2L+ treatment between August 2016 and December 2019 and were followed for 24 months. The primary endpoint was overall survival (OS) at 24 months., Results: Overall, 180 patients who received 2L+ avelumab were identified (112 from CARADERM, 68 after SNDS linkage). Median age at diagnosis was 74.0 years and 177 (98.3 %) had received chemotherapy alone as first-line treatment. Median follow-up was 13.1 months. Median OS from start of avelumab was 14.6 months (95 % CI, 9.9-21.3) in the overall population, 15.9 months (95 % CI, 8.6-28.3) in CARADERM patients, and 13.3 months (95 % CI, 6.7-19.1) in non-CARADERM patients. OS rates at 12 and 24 months were 53.8 % (95 % CI, 46.2 %-60.8 %) and 40.5 % (95 % CI, 33.2 %-47.6 %), respectively. In evaluable patients (CARADERM database), median progression-free survival was 3.6 months (95 % CI, 2.7-7.5) and the objective response rate was 55.3 % (95 % CI, 45.3-65.4), including complete response in 31.9 %., Conclusions: Real-world outcomes with 2L+ avelumab treatment for mMCC are consistent with clinical trial findings, supporting the recommendation of avelumab as a standard of care., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

There is extensive literature addressing acceptable practices of colostrum distribution to new-born calves; however, no economic analyses are available concerning the profitability of this practice. Moreover, the health standards associated with colostrum management have been defined through the observation of reference farms without explicit reference to economic assessments. The objective of the current study was to evaluate the profitability of farm colostrum management and to define the optimal economic situations for given livestock systems and farm situations. The herd-level net value was calculated using the value of calf products, the cost of passive transfer failure and the cost of prevention. This value was determined for various beef and dairy scenarios and the various time periods spent managing colostrum. The maximal net values defined the optimal economic situations and enabled the determination of the optimal times for colostrum management and respective health standards (i.e., the prevalence of disorders at optimum). The results showed that the optimal time farmers should spend on colostrum management is approximately 15 min per calf. Furthermore, farmers should err on the side of spending too much time (> 15 min) on colostrum management rather than not enough, unless the cost of labour is high. This is all the more true that potential long term consequences of passive transfer failure on milk yields were not accounted for here due to scarcity of data, leading to consider this time threshold (15 min) as a minimal recommendation. This potential underestimation may arise from the greater nutrient content and bioactive compounds identified in colostrum although the passive immune transfer is here defined through immunoglobulins only. The present results show that for small farms that cannot hire colostrum managers, this work can be performed by the farmer after subcontracting other tasks. Moreover, the method proposed here-the definition of health standards through economic optimisation-is a promising approach to analysing health conventions in the cattle industry.

Low colostrum intake at birth results in the failure of passive transfer (FPT) due to the inadequate ingestion of colostral immunoglobulins (Ig). FPT is associated with an increased risk of mortality and decreased health and longevity. Despite the known management practices associated with low FPT, it remains an important issue in the field. Neither a quantitative analysis of FPT consequences nor an assessment of its total cost are available. To address this point, a meta-analysis on the adjusted associations between FPT and its outcomes was first performed. Then, the total costs of FPT in European systems were calculated using a stochastic method with adjusted values as the input parameters. The adjusted risks (and 95% confidence intervals) for mortality, bovine respiratory disease, diarrhoea and overall morbidity in the case of FPT were 2.12 (1.43-3.13), 1.75 (1.50-2.03), 1.51 (1.05-2.17) and 1.91 (1.63-2.24), respectively. The mean (and 95% prediction interval) total costs per calf with FPT were estimated to be €60 (€10-109) and €80 (€20-139) for dairy and beef, respectively. As a result of the double-step stochastic method, the proposed economic estimation constitutes the first estimate available for FPT. The results are presented in a way that facilitates their use in the field and, with limited effort, combines the cost of each contributor to increase the applicability of the economic assessment to the situations farm-advisors may face. The present economic estimates are also an important tool to evaluate the profitability of measures that aim to improve colostrum intake and FPT prevention.