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A growing body of evidence suggests that the human gut microbiota plays a role in the development of obesity and related metabolic diseases. However, there is little consensus between studies, which could be due to biological as well as technical variation. In addition, little human data are available to investigate whether tissue-specific insulin sensitivity is related to specific microbial patterns. We examined this relation in two independent cohorts of overweight and obese pre-diabetic men, using phylogenetic microarray data and hepatic, peripheral and adipose tissue insulin sensitivity that were determined by a two-step hyperinsulinemic-euglycemic clamp with [6,6-2H2]-glucose tracer infusion. Despite a prominent subject-specific microbiota, we found significant associations of microbial taxa with tissue-specific insulin sensitivity using regression analysis. Using random forests we found moderate associations with other measures of glucose homeostasis in only one of the cohorts (fasting glucose concentrations AUC = 0.66 and HbA1c AUC = 0.65). However, all findings were cohort-specific due to pronounced variation in microbiota between cohorts, suggesting the existence of alternative states for dysbiosis in metabolic syndrome patients. Our findings suggest individual or group related dynamics, instead of universal microbiota signals, related to the host when the overweight or obese state has already developed and argue that care should be taken with extrapolating significant correlations from single cohorts, into generalized biological relevance. [ABSTRACT FROM AUTHOR]

Objectives: Blocking the interleukin-6 pathway by tocilizumab (TCZ) has been associated with changes in the lipoprotein profile, which could adversely impact cardiovascular (CV) risk in patients with rheumatoid arthritis (RA). In the present study, we addressed the effect of TCZ on lipoproteins in both fasting and non-fasting state in RA patients and tested the effect of TCZ on LDL receptor (LDLr) expression in vitro. Methods: Twenty patients with active RA and an inadequate response to TNF blockers received monthly TCZ intravenously. On week 0, 1 and 6 blood was drawn before and after an oral fat load, the lipid profiles and HDL antioxidative capacity were measured. Effects of TCZ on LDLr expression in transfected HepG2 cells were subjected. Results: After 6 weeks of TCZ, total cholesterol increased by 22% (4.8 ± 0.9 to 5.9 ± 1.3 mmol/L; p < 0.001), LDLc by 22% (3.0 ± 0.6 to 3.6 ± 0.8 mmol/L; p < 0.001) and HDLc by 17% (1.4 ± 0.4 to 1.7 ± 0.7 mmol/L; p < 0.016). Fasting triglycerides (TG) increased by 48% (1.0 ± 0.4 to 1.4 ± 0.8 mmol/L; p = 0.011), whereas postprandial incremental area under the curve TG increased by 62% (p = 0.002). Lipid changes were unrelated to the change in disease activity or inflammatory markers. No difference in HDL antioxidative capacity was found. In vitro, LDLr expression in cultured liver cells was significantly decreased following TCZ incubation (P < 0.001). Conclusions: TCZ adversely impacts on both LDLc as well as fasting and postprandial TG in patients with RA. The changes in hepatic LDLr expression following TCZ imply that adverse lipid changes may be a direct hepatic effect of TCZ. The net effect of TCZ on CV-morbidity has to be confirmed in future clinical trials. [ABSTRACT FROM AUTHOR]

Background: CT is thought to play a key role in coronavirus disease 2019 (COVID-19) diagnostic workup. The possibility of comparing data across different settings depends on the systematic and reproducible manner in which the scans are analyzed and reported. The COVID-19 Reporting and Data System (CO-RADS) and the corresponding CT severity score (CTSS) introduced by the Radiological Society of the Netherlands (NVvR) attempt to do so. However, this system has not been externally validated.Research Question: We aimed to prospectively validate the CO-RADS as a COVID-19 diagnostic tool at the ED and to evaluate whether the CTSS is associated with prognosis.Study Design and Methods: We conducted a prospective, observational study in two tertiary centers in The Netherlands, between March 19 and May 28, 2020. We consecutively included 741 adult patients at the ED with suspected COVID-19, who received a chest CT and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR (PCR). Diagnostic accuracy measures were calculated for CO-RADS, using PCR as reference. Logistic regression was performed for CTSS in relation to hospital admission, ICU admission, and 30-day mortality.Results: Seven hundred forty-one patients were included. We found an area under the curve (AUC) of 0.91 (CI, 0.89-0.94) for CO-RADS using PCR as reference. The optimal CO-RADS cutoff was 4, with a sensitivity of 89.4% (CI, 84.7-93.0) and specificity of 87.2% (CI, 83.9-89.9). We found a significant association between CTSS and hospital admission, ICU admission, and 30-day mortality; adjusted ORs per point increase in CTSS were 1.19 (CI, 1.09-1.28), 1.23 (1.15-1.32), 1.14 (1.07-1.22), respectively. Intraclass correlation coefficients for CO-RADS and CTSS were 0.94 (0.91-0.96) and 0.82 (0.70-0.90).Interpretation: Our findings support the use of CO-RADS and CTSS in triage, diagnosis, and management decisions for patients presenting with possible COVID-19 at the ED. [ABSTRACT FROM AUTHOR]

Background & Aims: Obesity has been associated with changes in the composition and function of the intestinal microbiota. Modulation of the microbiota by antibiotics also alters bile acid and glucose metabolism in mice. Hence, we hypothesized that short term administration of oral antibiotics in humans would affect fecal microbiota composition and subsequently bile acid and glucose metabolism. Methods: In this single blinded randomized controlled trial, 20 male obese subjects with metabolic syndrome were randomized to 7days of amoxicillin 500mg t.i.d. or 7days of vancomycin 500mg t.i.d. At baseline and after 1week of therapy, fecal microbiota composition (Human Intestinal Tract Chip phylogenetic microarray), fecal and plasma bile acid concentrations as well as insulin sensitivity (hyperinsulinemic euglycemic clamp using [6,6-2H2]-glucose tracer) were measured. Results: Vancomycin reduced fecal microbial diversity with a decrease of gram-positive bacteria (mainly Firmicutes) and a compensatory increase in gram-negative bacteria (mainly Proteobacteria). Concomitantly, vancomycin decreased fecal secondary bile acids with a simultaneous postprandial increase in primary bile acids in plasma (p <0.05). Moreover, changes in fecal bile acid concentrations were predominantly associated with altered Firmicutes. Finally, administration of vancomycin decreased peripheral insulin sensitivity (p <0.05). Amoxicillin did not affect any of these parameters. Conclusions: Oral administration of vancomycin significantly impacts host physiology by decreasing intestinal microbiota diversity, bile acid dehydroxylation and peripheral insulin sensitivity in subjects with metabolic syndrome. These data show that intestinal microbiota, particularly of the Firmicutes phylum contributes to bile acid and glucose metabolism in humans. This trial is registered at the Dutch Trial Register (NTR2566). [Copyright &y& Elsevier]