BackgroundEffects of extreme sleep duration on risk of mortality and cardiovascular outcomes remain controversial. We aimed to quantify the dose‐response relationships of sleep duration with risk of all‐cause mortality, total cardiovascular disease, coronary heart disease, and stroke.Methods and ResultsPubMed and Embase were systematically searched for prospective cohort studies published before December 1, 2016, that examined the associations between sleep duration and at least 1 of the 4 outcomes in generally healthy populations. U‐shaped associations were indicated between sleep duration and risk of all outcomes, with the lowest risk observed for ≈7‐hour sleep duration per day, which was varied little by sex. For all‐cause mortality, when sleep duration was <7 hours per day, the pooled relative risk (RR) was 1.06 (95% CI, 1.04–1.07) per 1‐hour reduction; when sleep duration was >7 hours per day, the pooled RR was 1.13 (95% CI, 1.11–1.15) per 1‐hour increment. For total cardiovascular disease, the pooled RR was 1.06 (95% CI, 1.03–1.08) per 1‐hour reduction and 1.12 (95% CI, 1.08–1.16) per 1‐hour increment of sleep duration. For coronary heart disease, the pooled RR was 1.07 (95% CI, 1.03–1.12) per 1‐hour reduction and 1.05 (95% CI, 1.00–1.10) per 1‐hour increment of sleep duration. For stroke, the pooled RR was 1.05 (95% CI, 1.01–1.09) per 1‐hour reduction and 1.18 (95% CI, 1.14–1.21) per 1‐hour increment of sleep duration.ConclusionsOur findings indicate that both short and long sleep duration is associated with an increased risk of all‐cause mortality and cardiovascular events.

2509 Background: As a promising approach for some cancers, chimeric antigen receptor T cell therapy has limited success in solid tumors. Claudin18.2 (CLDN 18.2) is a stomach-specific isoform of Claudin-18, and highly expressed in gastric and pancreatic adenocarcinoma, the advanced form of both of which have urgent unmet medical needs. We previously developed and demonstrated ability of CLDN 18.2-specific CAR (CAR-CLDN18.2) T cells to eradicate CLDN 18.2-positive gastric cancer xenografts without obvious on-target off-tumor toxicity (Huang J. JNCI 2018). Methods: In this single-arm, open-label, first-in-human phase I pilot study (NCT03159819) to investigate the safety and explore the efficacy of the autologous CAR-CLDN18.2 T cells, patients with confirmed CLDN 18.2 positive advanced gastric or pancreatic adenocarcinoma aged 18 to 70 years received 1 or more cycles of CAR-CLDN18.2 T cell infusion(s) after lymphodepletion pretreatment (fludarabine and cyclophosphamide, with or without nab-paclitaxel) until disease progression or presence of intolerable toxicity. Adverse Event (AE) grade categorization is according to CTCAE 4.0, and tumor response was assessed per RECIST 1.1. Results: As of November 30th, 2018, 12 subjects with metastatic adenocarcinoma (7 gastric and 5 pancreatic) were treated with 1–5 cycles (total of 0.5 - 55 X 108) of CAR-positive T cells infusions. There were no serious adverse events, treatment-related death or severe neurotoxicity occurred in the study. No grade 4 AEs except for decreased lymphocytes, neutrophils and white blood cells. All cytokine release syndromes observed were grade 1 or 2. Among the 11 evaluable subjects, 1 achieved a complete response (gastric adenocarcinoma), 3 had partial responses (2 gastric adenocarcinomas and 1 pancreatic adenocarcinoma), 5 had stable disease and 2 had progression of disease. The total objective response rate was 33.3%, with median PFS of 130 days estimated using Kaplan-Meier method [95% CI (38, 230)]. Conclusions: This clinical study indicated that CAR-CLDN18.2 T cell therapy were safe and well tolerated and may have promising therapeutic efficacy in patients with advanced gastric and pancreatic adenocarcinoma. Clinical trial information: NCT03159819.

Background The microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) has been reported as a novel and independent risk factor for the development of cardiovascular and metabolic diseases, but the association with gestational diabetes mellitus (GDM) remains unclear. Objective The aim of this study was to investigate the association between plasma TMAO concentration and GDM in a 2-phase study. Design A 2-phase design was used in the current study. An initial phase included 866 participants (433 GDM cases and 433 matched controls) with fasting blood samples collected at the time of GDM screening (24–32 wk of gestation). An independent-phase study, with 276 GDM cases and 552 matched controls who provided fasting blood samples before 20 wk of gestation and who had GDM screened during 24–32 wk of gestation, was nested within a prospective cohort study. These 2 studies were both conducted in Wuhan, China, and the incidence of GDM in the cohort study was 10.8%. Plasma TMAO concentrations were determined by stable isotope dilution liquid chromatography–tandem mass spectrometry. GDM was diagnosed according to the American Diabetes Association criteria by using an oral-glucose-tolerance test. Results In the initial case-control study, the adjusted OR of GDM comparing the highest TMAO quartile with the lowest quartile was 1.94 (95% CI: 1.28, 2.93). Each SD increment of ln-transformed plasma TMAO was associated with 22% (95% CI: 5%, 41%) higher odds of GDM. In the nested case-control study, women in the highest quartile also had increased odds of GDM (adjusted OR: 2.06; 95% CI: 1.28, 3.31) compared with women in the lowest quartile, and the adjusted OR for GDM per SD increment of ln-transformed plasma TMAO was 1.26 (95% CI: 1.08, 1.47). Conclusions Consistent findings from this 2-phase study indicate a positive association between plasma TMAO concentrations and GDM. Future studies are warranted to elucidate the underlying mechanisms. This trial was registered at www.clinicaltrials.gov as NCT03415295.