Omadacycline, Eravacycline, and Tigecycline Express Anti-Mycobacterium abscessus Activity In Vitro.

Mycobacterium abscessus infections are increasing worldwide necessitating the development of new antibiotics and treatment regimens. The utility of third-generation tetracycline antibiotics was reestablished; their anti-M. abscessus activity needs further study. The activities of omadacycline (OMC), eravacycline (ERC), tigecycline (TGC), and sarecycline (SAC) were tested against two reference strains and 193 clinical M. abscessus isolates at different temperatures (30°C and 37°C). The minimum bactericidal concentrations (MBCs) of the four drugs were determined to distinguish between their bactericidal and bacteriostatic activities. The MICs of OMC, ERC, and TGC for the reference strains and clinical isolates were summarized and compared. OMC, ERC, and TGC exhibited a high level of bacteriostatic activity against M. abscessus. The MICs of OMC and ERC for M. abscess remained stable, while the MICs of TGC for the isolates/strains increased with increasing temperature. Notably, the MICs of OMC for M. abscessus isolates obtained in the United States are lower than for those obtained in China. IMPORTANCE The antimicrobial activities of four third-generation tetracycline-class drugs, omadacycline (OMC), eravacycline (ERC), tigecycline (TGC), and sarecycline (SAC), were determined for 193 M. abscessus isolates. The activities of the four drugs at two different temperatures (30°C and 37°C) were also tested. OMC, ERC, and TGC exhibited significant activity against M. abscessus. The anti-M. abscessus activity of TGC increased when the temperature was increased from 30°C to 37°C; the activities of OMC and ERC, on the other hand, remained the same. We found that in vitro MICs of OMC against Chinese and American isolates were distinct. Evaluations in in vivo models of M. abscessus disease or in the clinical setting will provide more accurate insight into potency of OMC against distinct isolates.

Automated feature-based grading and progression analysis of diabetic retinopathy.

BACKGROUND: In diabetic retinopathy (DR) screening programmes feature-based grading guidelines are used by human graders. However, recent deep learning approaches have focused on end to end learning, based on labelled data at the whole image level. Most predictions from such software offer a direct grading output without information about the retinal features responsible for the grade. In this work, we demonstrate a feature based retinal image analysis system, which aims to support flexible grading and monitor progression. METHODS: The system was evaluated against images that had been graded according to two different grading systems; The International Clinical Diabetic Retinopathy and Diabetic Macular Oedema Severity Scale and the UK's National Screening Committee guidelines. RESULTS: External evaluation on large datasets collected from three nations (Kenya, Saudi Arabia and China) was carried out. On a DR referable level, sensitivity did not vary significantly between different DR grading schemes (91.2-94.2.0%) and there were excellent specificity values above 93% in all image sets. More importantly, no cases of severe non-proliferative DR, proliferative DR or DMO were missed. CONCLUSIONS: We demonstrate the potential of an AI feature-based DR grading system that is not constrained to any specific grading scheme.

Comparison of two regimens for patients with thyroid-associated ophthalmopathy receiving intravenous methyl prednisolone: A single center prospective randomized trial.

Intravenous (i.v.) glucocorticoid is recommended for active moderate-to-severe thyroid-associated ophthalmopathy (TAO). However, the details of the treatment schedule are still debatable. The present prospective randomized trial was performed to compare clinical outcomes and serum cytokines between the two regimens. A cohort of 90 patients with active moderate-to-severe TAO was randomized to receive i.v. methyl prednisolone on a weekly protocol or daily scheme. The response rate was evaluated at the 12-week follow-up visit. Serum interleukin (IL)-2, IL-6 and IL-17 levels were measured in 160 patients with TAO, 60 patients with isolated Graves' disease (GD) and 60 normal control (NC) at baseline, as well as patients with active moderate-to-severe TAO at the 12th week after treatment. The daily scheme had a higher response rate than the weekly protocol without a significant difference (77.8 vs. 63.6%, P>0.05). No major adverse events were recorded under either regimen. Overall, minor events were more common on the daily scheme (11.36 vs. 4.35%, P<0.05)than on the weekly protocol, whereas the deterioration of eye symptoms (two patients) was only reported on the weekly protocol. At baseline, the IL-17 level in the TAO group was higher than that in the isolated GD and NC groups (P<0.05). In addition, the IL-17 level in the active TAO group was higher than that in the inactive TAO group (P<0.05). Furthermore, the IL-17 level had significantly decreased under the two regimens at the 12-week visit (P<0.05). In conclusion, for patients with active moderate-to-severe TAO, daily i.v. glucocorticoid therapy has a relative higher response rate than the weekly protocol with a few more minor adverse events. These two regimens have their own merits with regard to adverse effects. IL-17 has the potential to be a biomarker for evaluating TAO activity and treatment effects.

Evidence Based Prediction and Progression Monitoring on Retinal Images from Three Nations.

Purpose: The aim of this work is to demonstrate how a retinal image analysis system, DAPHNE, supports the optimization of diabetic retinopathy (DR) screening programs for grading color fundus photography. Method: Retinal image sets, graded by trained and certified human graders, were acquired from Saudi Arabia, China, and Kenya. Each image was subsequently analyzed by the DAPHNE automated software. The sensitivity, specificity, and positive and negative predictive values for the detection of referable DR or diabetic macular edema were evaluated, taking human grading or clinical assessment outcomes to be the gold standard. The automated software's ability to identify co-pathology and to correctly label DR lesions was also assessed. Results: In all three datasets the agreement between the automated software and human grading was between 0.84 to 0.88. Sensitivity did not vary significantly between populations (94.28%-97.1%) with specificity ranging between 90.33% to 92.12%. There were excellent negative predictive values above 93% in all image sets. The software was able to monitor DR progression between baseline and follow-up images with the changes visualized. No cases of proliferative DR or DME were missed in the referable recommendations. Conclusions: The DAPHNE automated software demonstrated its ability not only to grade images but also to reliably monitor and visualize progression. Therefore it has the potential to assist timely image analysis in patients with diabetes in varied populations and also help to discover subtle signs of sight-threatening disease onset. Translational Relevance: This article takes research on machine vision and evaluates its readiness for clinical use.

1,25-Dihydroxyvitamin D3 Ameliorates Collagen-Induced Arthritis via Suppression of Th17 Cells Through miR-124 Mediated Inhibition of IL-6 Signaling.

Objectives: To explore the molecular mechanisms in which vitamin D (VD) regulates T cells, especially Th17 cells in collagen-induced arthritis (CIA). Methods: DBA1/J mice induced for CIA were intraperitoneally treated with VD. CIA clinical symptoms and inflammatory responses including Th1/Th17/Tregs percentages were determined and compared. Mouse naïve CD4+ T cells transduced with miR-124 inhibitor or not were polarized to Th17 cells with or without VD. Subsequently, cellular differentiation and IL-6 signaling moleculars were analyzed. Results: VD treatment significantly delayed CIA onset, decreased incidence and clinical scores of arthritis, downregulated serum IgG levels and ameliorated bone erosion. VD downregulated IL-17A production in CD4+ T cells while increased CD4+Foxp3+Nrp-1+ cells both in draining lymph nodes and synovial fluid in arthritic mice. VD inhibited Th17 cells differentiation in vivo and in vitro and potentially functioning directly on T cells to restrain Th17 cells through limiting IL-6R expression and its downstream signaling including STAT3 phosphorylation, while these effects were blocked when naïve CD4+ T cells were transduced with miR-124 inhibitor. Conclusions: VD treatment ameliorates CIA via suppression of Th17 cells and enhancement of Tregs. miR-124-mediated inhibition of IL-6 signaling, provides a novel explanation for VD's role on T cells in CIA mice or RA patients and suggests that VD may have treatment implications in rheumatoid arthritis.