Nonalcoholic fatty liver disease (NAFLD) is one of the most common and increasing liver diseases worldwide with a prevalence of 20-33%. NAFLD may progress to fibrosis, compensated cirrhosis, advanced ...cirrhosis, or hepatocellular carcinoma. Despite the increasing prevalence of NAFLD, definitive medical treatment has not been established, with the exception of lifestyle modification with exercise. Because of the direct connection via portal vein between the intestines and the liver (gut-gut microbiota-liver axis), gut microbiota and associated dysbiosis have been known as regulators in the pathophysiology of NAFLD. Area covered: New therapeutic approaches for modulation of gut microbiota have been proposed and the effectiveness of new therapies including probiotics, prebiotics, synbiotics, bile acid regulation, absorbent, and fecal microbiota transplantation have been demonstrated in recent several studies. This review focuses on the available evidences for new therapies modulating gut microbiota in the management and the prevention of NAFLD. Expert commentary: Gut-gut microbiota-liver axis may play an important role in the etiology of many liver diseases, including NAFLD. It is logical to seek the manipulation of this axis, and further studies are required to understand the underlying precise mechanisms of microbiota-modulation on NAFLD.
The pseudorapidity density of charged particles, dNch / d η , at midrapidity in Pb-Pb collisions has been measured at a center-of-mass energy per nucleon pair of √ s N N = 5.02 TeV . For the 5% ...most central collisions, we measure a value of 1943 ± 54 . The rise in dNch / d η as a function of √ s N N is steeper than that observed in proton-proton collisions and follows the trend established by measurements at lower energy. The increase of dNch / d η as a function of the average number of participant nucleons, ⟨ N part ⟩ , calculated in a Glauber model, is compared with the previous measurement at √ s N N = 2.76 TeV . A constant factor of about 1.2 describes the increase in dNch / d η from √ s N N = 2.76 to 5.02 TeV for all centrality classes, within the measured range of 0%–80% centrality. The results are also compared to models based on different mechanisms for particle production in nuclear collisions.
Randomized trials demonstrated a lower risk of cardiovascular (CV) events with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes (T2D) at high CV risk. Prior ...real-world data suggested similar SGLT-2i effects in T2D patients with a broader risk profile, but these studies focused on heart failure and death and were limited to the United States and Europe.
The purpose of this study was to examine a broad range of CV outcomes in patients initiated on SGLT-2i versus other glucose-lowering drugs (oGLDs) across 6 countries in the Asia Pacific, the Middle East, and North American regions.
New users of SGLT-2i and oGLDs were identified via claims, medical records, and national registries in South Korea, Japan, Singapore, Israel, Australia, and Canada. Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching. Hazard ratios (HRs) for death, hospitalization for heart failure (HHF), death or HHF, MI, and stroke were assessed by country and pooled using weighted meta-analysis.
After propensity-matching, there were 235,064 episodes of treatment initiation in each group; ∼27% had established CV disease. Patient characteristics were well-balanced between groups. Dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, tofogliflozin, and luseogliflozin accounted for 75%, 9%, 8%, 4%, 3%, and 1% of exposure time in the SGLT-2i group, respectively. Use of SGLT-2i versus oGLDs was associated with a lower risk of death (HR: 0.51; 95% confidence interval CI: 0.37 to 0.70; p < 0.001), HHF (HR: 0.64; 95% CI: 0.50 to 0.82; p = 0.001), death or HHF (HR: 0.60; 95% CI: 0.47 to 0.76; p < 0.001), MI (HR: 0.81; 95% CI: 0.74 to 0.88; p < 0.001), and stroke (HR: 0.68; 95% CI: 0.55 to 0.84; p < 0.001). Results were directionally consistent across both countries and patient subgroups, including those with and without CV disease.
In this large, international study of patients with T2D from the Asia Pacific, the Middle East, and North America, initiation of SGLT-2i was associated with a lower risk of CV events across a broad range of outcomes and patient characteristics. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors CVD-REAL; NCT02993614).
Continual monitoring of secreted biomarkers from organ-on-a-chip models is desired to understand their responses to drug exposure in a noninvasive manner. To achieve this goal, analytical methods ...capable of monitoring trace amounts of secreted biomarkers are of particular interest. However, a majority of existing biosensing techniques suffer from limited sensitivity, selectivity, stability, and require large working volumes, especially when cell culture medium is involved, which usually contains a plethora of nonspecific binding proteins and interfering compounds. Hence, novel analytical platforms are needed to provide noninvasive, accurate information on the status of organoids at low working volumes. Here, we report a novel microfluidic aptamer-based electrochemical biosensing platform for monitoring damage to cardiac organoids. The system is scalable, low-cost, and compatible with microfluidic platforms easing its integration with microfluidic bioreactors. To create the creatine kinase (CK)-MB biosensor, the microelectrode was functionalized with aptamers that are specific to CK-MB biomarker secreted from a damaged cardiac tissue. Compared to antibody-based sensors, the proposed aptamer-based system was highly sensitive, selective, and stable. The performance of the sensors was assessed using a heart-on-a-chip system constructed from human embryonic stem cell-derived cardiomyocytes following exposure to a cardiotoxic drug, doxorubicin. The aptamer-based biosensor was capable of measuring trace amounts of CK-MB secreted by the cardiac organoids upon drug treatments in a dose-dependent manner, which was in agreement with the beating behavior and cell viability analyses. We believe that, our microfluidic electrochemical biosensor using aptamer-based capture mechanism will find widespread applications in integration with organ-on-a-chip platforms for in situ detection of biomarkers at low abundance and high sensitivity.
When does a reigning great power of the international system supplement military containment of a challenging power by restricting its economic exchanges with that state? Scholars of great power ...politics have traditionally focused on examining a reigning power’s military containment of a challenging power. In direct contrast, Compound Containment demonstrates that these conventional studies are flawed without a sound understanding of the multilayered aspects of containment strategy in great power politics. Since economic capacity and military power are intimately linked to one another, countering a challenging power requires addressing both economic and military dimensions. Nonetheless, this nexus of security and economy in a reigning power’s response to a challenging power cannot be explained by traditional theories that dominate research in international security. Author Dong Jung Kim fills a gap in the scholarship on great power competition by investigating when a reigning power will make its military containment of a challenging power “compound” by simultaneously employing restrictive economic measures. Its main theoretical claims are corroborated by an analysis of key historical cases of reigning power-challenging power competition. This book also offers policy prescriptions for the United States by examining whether the United States is in a position to complement military containment of China with restrictive economic measures.
Congenital anomalies of the central nervous system (CNS) often demonstrate aberrant white matter connections, which may be better characterized with diffusion-tensor imaging (DTI) and fiber ...tractography (FT) than with conventional magnetic resonance (MR) imaging. DTI-FT demonstrates abnormal hemispheric fiber connections in callosal agenesis or acquired disease of the corpus callosum. Decreased anisotropy of white matter adjacent to the malformed cortex and an aberrant course of major fiber pathways due to dysplastic white matter are common findings in cortical dysplasia. Increased anisotropy of dysplastic gray matter in heterotopia supports the hypothesis that developing neurons migrate from the ependyma to the cortex with a radial growth pattern. In periventricular leukomalacia, DTI-FT demonstrates an intact corticospinal tract and decreased thalamocortical sensory connections, which are responsible for the spasticity of cerebral palsy owing to impairment of inhibitory function. Joubert syndrome comprises malformation of the cerebellar vermis and an aberrant connection between the cerebellum and the cerebral cortex via an elongated and abnormally shaped superior cerebellar peduncle, which are well visualized with DTI-FT. In developmental CNS disease, DTI-FT demonstrates additional findings beyond those seen with conventional MR imaging. Future studies will focus on determining the significance of the aberrant fiber connections and their relationships to the clinical manifestations of CNS anomalies.
Background & Aims Both corticosteroid and pentoxifylline reduce short-term mortality in severe alcoholic hepatitis. However, few studies have directly compared the efficacy of pentoxifylline and ...corticosteroid in patients with this condition. Methods In this multicentre, open-labelled, randomised non-inferiority trial, we assigned 121 patients with severe alcoholic hepatitis (Maddrey’s discriminant function ⩾32) to receive either pentoxifylline (400 mg, 3 times daily, in 62 subjects) or prednisolone (40 mg daily, in 59 subjects). The primary end point was non-inferiority in survival at the 1 month time point for the pentoxifylline treatment compared with prednisolone. Results The 1-month survival rate of patients receiving pentoxifylline was 75.8% (15 deaths) compared with 88.1% (7 deaths) in those, taking prednisolone, for a treatment difference of 12.3% (95% confidence interval, −4.2% to 28.7%; p = 0.08). The 95% confidence interval for the observed difference exceeded the predefined margin of non-inferiority (Δ15%) and included zero. The 6-month survival rate was not significantly different between the pentoxifylline and prednisolone groups (64.5% vs. 72.9%; p = 0.23). At 7 days, the response to therapy assessed by the Lille model was significantly lower in the prednisolone group (n = 58) than in the pentoxifylline group (n = 59): 0.35 vs. 0.50 ( p = 0.012). Hepatitis complications, including hepatorenal syndrome and side effects, such as infection and gastrointestinal bleeding, were similar in the two groups. Conclusions The findings demonstrate that the efficacy of the pentoxifylline is not statistically equivalent to the efficacy of prednisolone, supporting the use of prednisolone as a preferred treatment option in patients with severe alcoholic hepatitis.
The cause of seasonal failure of a nitrifying municipal landfill leachate treatment plant utilizing a fixed biofilm was investigated by wastewater analyses and batch respirometric tests at every ...treatment stage. Nitrification of the leachate treatment plant was severely affected by the seasonal temperature variation. High free ammonia (NH
3-N) inhibited not only nitrite oxidizing bacteria (NOB) but also ammonia oxidizing bacteria (AOB). In addition, high pH also increased free ammonia concentration to inhibit nitrifying activity especially when the NH
4-N level was high. The effects of temperature and free ammonia of landfill leachate on nitrification and nitrite accumulation were investigated with a semi-pilot scale biofilm airlift reactor. Nitrification rate of landfill leachate increased with temperature when free ammonia in the reactor was below the inhibition level for nitrifiers. Leachate was completely nitrified up to a load of 1.5
kg NH
4-N m
−3
d
−1 at 28
°C. The activity of NOB was inhibited by NH
3-N resulting in accumulation of nitrite. NOB activity decreased more than 50% at 0.7
mg NH
3-N L
−1. Fluorescence in situ hybridization (FISH) was carried out to analyze the population of AOB and NOB in the nitrite accumulating nitrifying biofilm. NOB were located close to AOB by forming small clusters. A significant fraction of AOB identified by probe Nso1225 specifically also hybridized with the
Nitrosomonas specific probe Nsm156. The main NOB were
Nitrobacter and
Nitrospira which were present in almost equal amounts in the biofilm as identified by simultaneous hybridization with
Nitrobacter specific probe Nit3 and
Nitrospira specific probe Ntspa662.
Aims
We compared the new use of sodium‐glucose cotransporter‐2 inhibitor (SGLT2i) versus dipeptidyl peptidase‐4 inhibitor (DPP4i) and the risk of cardiorenal disease, heart failure (HF) or chronic ...kidney disease (CKD), in patients with type 2 diabetes without a history of prevalent cardiovascular and renal disease, defined as cardiovascular and renal disease (CVRD) free, managed in routine clinical practice.
Materials and methods
In this observational cohort study, patients were identified from electronic health records from England, Germany, Japan, Norway, South Korea and Sweden, during 2012‐2018. In total, 1 006 577 CVRD‐free new users of SGLT2i or DPP4i were propensity score matched 1:1. Unadjusted Cox regression was used to estimate hazard ratios (HRs) for outcomes: cardiorenal disease, HF, CKD, stroke, myocardial infarction (MI), cardiovascular and all‐cause mortality.
Results
Baseline characteristics were well balanced between the treatment groups (n = 105 130 in each group) with total follow‐up of 187 955 patient years. Patients had a mean age of 56 years, 43% were women and they were indexed between 2013 and 2018. The most commonly used agents were dapagliflozin (91.7% of exposure time) and sitagliptin/linagliptin (55.0%), in the SGLT2i and DPP4i, groups, respectively. SGLT2i was associated with lower risk of cardiorenal disease, HF, CKD, all‐cause and cardiovascular mortality; HR (95% confidence interval), 0.56 (0.42‐0.74), 0.71 (0.59‐0.86), 0.44 (0.28‐0.69), 0.67 (0.59‐0.77), and 0.61 (0.44‐0.85), respectively. No differences were observed for stroke 0.87 (0.69‐1.09) and MI 0.94 (0.80‐1.11).
Conclusion
In this multinational observational study, SGLT2i was associated with a lower risk of HF and CKD versus DPP4i in patients with type 2 diabetes otherwise free from both cardiovascular and renal disease.
Genus
Nitrospira and
Nitrobacter species are the key nitrite-oxidizing bacteria (NOB) in nitrifying wastewater treatment plants. It has been hypothesized that genus
Nitrospira are K-strategists and ...can exploit low amounts of nitrite more efficiently than
Nitrobacter. In contrast,
Nitrobacter species are r-strategists that can grow faster than
Nitrospira. To elucidate the K/r hypothesis and to analyze the effect of substrate (nitrite) concentration on the competition and distribution of the two NOB, two different reactor types were employed for nitrite oxidation (nitratation) and NOB growth. The continuous biofilm airlift reactor (CBAR) maintained low nitrite concentration due to the complete oxidation of nitrite in continuous operation while the sequencing batch reactor (SBR) was kept in a relatively high nitrite concentration environment due to a cyclic substrate concentration profile. Fluorescence in situ hybridization (FISH) and confocal laser scanning microscopy (CLSM) showed that both
Nitrobacter species and genus
Nitrospira were present in the CBAR and the SBR. Quantitative FISH analyses of the CBAR showed that
Nitrospira occupied 59% of the total bacteria while
Nitrobacter occupied only 5%. On the other hand,
Nitrobacter, occupying 64%, was the dominant NOB in the SBR, and only 3% of total bacteria belonged to genus
Nitrospira. Nitrite oxidation kinetics and quantitative FISH analyses revealed that the specific nitrite oxidation activities of
Nitrobacter and
Nitrospira are 93.8 and 10.5
mg/g NOB
h, respectively, and the specific activity of
Nitrobacter is about 9 times higher than that of
Nitrospira. In conclusion, the results confirm the K/r hypothesis and the distribution of
Nitrobacter and
Nitrospira is likely to depend mainly on nitrite concentration. It seems that nitrite load and starvation conditions do not give a direct effect on the distribution of NOB.
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