The long-term safety of chronic azithromycin use in adult patients with cystic fibrosis, evaluating biomarkers for renal function, hepatic function and electrical properties of the heart

Background: Azithromycin maintenance therapy is widely used in cystic fibrosis (CF), but little is known about its long-term safety. We investigated whether chronic azithromycin use is safe regarding renal function, hepatic cell toxicity and QTc-interval prolongation. Methods: Adult CF patients (72 patients using azithromycin for a cumulative period of 364.8 years and 19 controls, 108.8 years) from two CF-centers in the Netherlands with azithromycin (non)-use for at least three uninterrupted years were studied retrospectively. Results: There was no difference in mean decline of estimated glomerular filtration rate (eGFR), nor in occurrence of eGFR-events. No drug-induced liver injury could be attributed to azithromycin. Of the 39 azithromycin users of whom an ECG was available, 4/39 (10.3%) had borderline and 4/39 (10.3%) prolonged QTc-intervals, with 7/8 patients using other QTc-prolonging medication. Of the control patients 1/6 (16.7%) had a borderline QTc-interval, without using other QTc-prolonging medication. No cardiac arrhythmias were observed. Conclusion: We observed no renal or hepatic toxicity, nor cardiac arrythmias during azithromycin use in CF patients for a mean study duration of more than 5 years. One should be aware of possible QTc-interval prolongation, in particular in patients using other QTc-interval prolonging medication

Distinct fermentation of human milk oligosaccharides 3-FL and LNT2 and GOS/inulin by infant gut microbiota and impact on adhesion of Lactobacillus plantarum WCFS1 to gut epithelial cells

Human milk oligosaccharides (hMOs) are unique bioactive components in human milk. 3-Fucosyllactose (3-FL) is an abundantly present hMO that can be produced in sufficient amounts to allow application in infant formula. Lacto-N-triaose II (LNT2) can be obtained by acid hydrolysis of lacto-N-neotetraose (LNnT). Both 3-FL and LNT2 have been shown to have health benefits, but their impact on infant microbiota composition and microbial metabolic products such as short-chain fatty acids (SCFAs) is unknown. To gain more insight in fermentability, we performed in vitro fermentation studies of 3-FL and LNT2 using pooled fecal microbiota from 12-week-old infants. The commonly investigated galacto-oligosaccharides (GOS)/inulin (9 : 1) served as control. Compared to GOS/inulin, we observed a delayed utilization of 3-FL, which was utilized at 60.3% after 36 h of fermentation, and induced the gradual production of acetic acid and lactic acid. 3-FL specifically enriched bacteria of Bacteroides and Enterococcus genus. LNT2 was fermented much faster. After 14 h of fermentation, 90.1% was already utilized, and production of acetic acid, succinic acid, lactic acid and butyric acid was observed. LNT2 specifically increased the abundance of Collinsella, as well as Bifidobacterium. The GOS present in the GOS/inulin mixture was completely fermented after 14 h, while for inulin, only low DP was rapidly utilized after 14 h. To determine whether the fermentation might lead to enhanced colonization of commensal bacteria to gut epithelial cells, we investigated adhesion of the commensal Lactobacillus plantarum WCFS1 to Caco-2 cells. The fermentation digesta of LNT2 collected after 14 h, 24 h, and 36 h, and GOS/inulin after 24 h of fermentation significantly increased the adhesion of L. plantarum WCFS1 to Caco-2 cells, while 3-FL had no such effect. Our findings illustrate that fermentation of hMOs is very structure-dependent and different from the commonly applied GOS/inulin, which might lead to differential potencies to stimulate adhesion of commensal cells to gut epithelium and consequent microbial colonization. This knowledge might contribute to the design of tailored infant formulas containing specific hMO molecules to meet the need of infants during the transition from breastfeeding to formula

Evidence for Quantum Interference in SAMs of Arylethynylene Thiolates in Tunneling Junctions with Eutectic Ga-In (EGaIn) Top-Contacts

This paper compares the current density (J) versus applied bias (V) of self-assembled monolayers (SAMs) of three different ethynylthiophenol-functionalized anthracene derivatives of approximately the same thickness with linear-conjugation (AC), cross-conjugation (AQ), and broken-conjugation (AH) using liquid eutectic Ga-In (EGaIn) supporting a native skin (~1 nm thick) of Ga2O3 as a nondamaging, conformal top-contact. This skin imparts non-Newtonian rheological properties that distinguish EGaIn from other top-contacts; however, it may also have limited the maximum values of J observed for AC. The measured values of J for AH and AQ are not significantly different (J ≈ 10-1 A/cm2 at V = 0.4 V). For AC, however, J is 1 (using log averages) or 2 (using Gaussian fits) orders of magnitude higher than for AH and AQ. These values are in good qualitative agreement with gDFTB calculations on single AC, AQ, and AH molecules chemisorbed between Au contacts that predict currents, I, that are 2 orders of magnitude higher for AC than for AH at 0 < |V| < 0.4 V. The calculations predict a higher value of I for AQ than for AH; however, the magnitude is highly dependent on the position of the Fermi energy, which cannot be calculated precisely. In this sense, the theoretical predictions and experimental conclusions agree that linearly conjugated AC is significantly more conductive than either cross-conjugated AQ or broken conjugate AH and that AQ and AH cannot necessarily be easily differentiated from each other. These observations are ascribed to quantum interference effects. The agreement between the theoretical predictions on single molecules and the measurements on SAMs suggest that molecule-molecule interactions do not play a significant role in the transport properties of AC, AQ, and AH.