Preliminary evidence suggests that the glutamate–serine–glycine (GSG) index, which combines three amino acids involved in glutathione synthesis, may be used as a potential biomarker of non-alcoholic fatty liver disease (NAFLD). We investigated whether the GSG index is associated with NAFLD in youth, independent of other risk factors. Intrahepatic fat content (HFF%) and abdominal fat distribution were measured by magnetic resonance imaging (MRI) in a multiethnic cohort of obese adolescents, including Caucasians, African Americans, and Hispanics. NAFLD was defined as HFF% ≥ 5.5%. Plasma amino acids were measured by mass spectrometry. The GSG index was calculated as glutamate/(serine + glycine). The GSG index was higher in NAFLD patients (p = 0.03) and positively correlated with HFF% (r = 0.26, p = 0.02), alanine aminotransferase (r = 0.39, p = 0.0006), and aspartate aminotransferase (r = 0.26, p = 0.03). Adolescents with a high GSG index had a twofold higher prevalence of NAFLD than those with a low GSG index, despite similar adiposity, abdominal fat distribution, and liver insulin resistance. NAFLD prevalence remained significantly different between groups after adjustment for age, sex, race/ethnicity, and body mass index (OR 3.07, 95% confidence interval 1.09–8.61, p = 0.03). This study demonstrates the ability of the GSG index to detect NAFLD in at-risk pediatric populations with different genetically determined susceptibilities to intrahepatic fat accumulation, independent of traditional risk factors.

Aims: To establish the long-term prognostic value of abnormal circadian blood pressure (BP) patterns in diabetes. Materials and Methods:We retrospectively examined a cohort of 349 outpatients with diabetes who were screened for microvascular complications and followed up for 21 years. Dipping, nondipping and reverse-dipping status were defined based on 24-hour ambulatory BP monitoring (ABPM) as ≥10% reduction, <10% reduction, and any increase in average nighttime versus daytime systolic BP (SBP), respectively.Results: After 6251 person-years of follow-up (median [range] follow-up 21.0 [1.1-22.0] years, 52% women, age 57.1 ± 11.9 years, 81.4% type 2 diabetes and 18.6% type 1 diabetes), a total of 136 deaths (39%) occurred. Compared with dippers, the nondippers and reverse dippers showed progressively higher prevalence of chronic kidney disease (CKD), cardiac autonomic neuropathy (CAN) and postural hypotension. Reverse dippers showed a 13.4% (2.5-year) reduction in mean overall survival and a twofold increased risk of all-cause mortality after adjustment for traditional risk factors (hazard ratio 2.2 [95% confidence interval 1.3-3.8]). Each 1% decrease in nighttime versus daytime SBP ratio was independently associated with a 4% reduction in 20-year mortality risk. Conclusions:In patients with diabetes, reverse dipping is associated with a higher prevalence of CKD and CAN and more than doubled the adjusted risk of all-cause mortality over a 21-year observation.

Background The prognostic value of common and frequently associated diabetic microvascular complications (MVC), namely chronic kidney disease (CKD), cardiac autonomic neuropathy (CAN), peripheral neuropathy (DPN), and retinopathy (DR), is well established. However, the impact of their different combinations on long-term mortality has not been adequately assessed. Methods We retrospectively analyzed 21-year longitudinal data from 303 patients with long-standing type 1 (T1D) or type 2 diabetes (T2D), who were thoroughly characterized at baseline for the presence of MVC using 99mTc-DTPA dynamic renal scintigraphy, overnight urine collection, cardiovascular autonomic tests, monofilament testing, and dilated fundus oculi examination. Results After a 5,244 person-years follow-up, a total of 133 (43.9%) deaths occurred. The presence of CKD and CAN, regardless of other MVC, increased the adjusted all-cause mortality risk by 117% (HR 2.17 [1.45–3.26]) and 54% (HR 1.54 [1.01–2.36]), respectively. Concomitant CKD&CAN at baseline were associated with the highest mortality risk (HR 5.08 [2.52–10.26]), followed by CKD&DR (HR 2.95 [1.63–5.32]), and CAN&DR (HR 2.07 [1.11–3.85]). Compared with patients free from MVC, the mortality risk was only numerically higher in those with any isolated MVC (HR 1.52 [0.87–2.67]), while increased by 203% (HR 3.03 [1.62–5.68]) and 692% (HR 7.92 [2.93–21.37]) in patients with two and three concomitant MVC, respectively. Conclusions Our study demonstrates the long-term, synergistic, negative effects of single and concomitant diabetic MVC on all-cause mortality, which should encourage comprehensive screenings for MCV in both T1D and T2D to improve risk stratification and treatment.

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Background: AtezoTRIBE phase II randomized study demonstrated that adding atezolizumab to first-line FOLFOXIRI (5fluoruracil, oxaliplatin, irinotecan) plus bevacizumab prolongs progression-free survival (PFS) of metastatic colorectal cancer (mCRC) patients, with a modest benefit among proficient mismatch repair (pMMR). DetermaIO is an immune-related 27-gene expression signature able to predict benefit from immune-checkpoint inhibition in triple-negative breast cancer. In this analysis of AtezoTRIBE, we investigated the predictive impact of DetermaIO in mCRC. Methods: mCRC patients unselected for MMR status were randomized(1:2) to FOLFOXIRI plus bevacizumab (control arm) or the same regimen with atezolizumab (atezolizumab arm). RT-qPCR by DetermaIO was performed on RNA purified from pre-treatment tumours of 132(61%) out of 218 enrolled patients. A binary result (IOpos versus IOneg) adopting the pre-established DetermaIO cut-point (0.09) was obtained, and an exploratory optimized cut-point (IOOPT) was computed in the overall population and in pMMR subgroup (IOOPTpos versus IOOPTneg). Results: DetermaIO was successfully determined in 122 (92%) cases, and 23 (27%) tumours were IOpos. IOpos tumours achieved higher PFS benefit from atezolizumab arm than IOneg (HR:0.39 versus 0.83, P interaction=0.066). In pMMR tumours (N=110), a similar trend was observed (HR:0.47 versus 0.93, P interaction=0.139). In the overall population, with the computed IOOPT cut-point (0.277), 16 (13%) tumours were IOOPTpos and they derived higher PFS benefit from atezolizumab than IOOPTneg(HR:0.10 versus 0.85, P interaction=0.004). Similar results were found in the pMMR subgroup. Conclusions :DetermaIO may be useful to predict benefit of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in mCRC. The exploratory IOOPT cut-point should be validated in independent mCRC cohorts.