Angiotensin Analogs with Divergent Bias Stabilize Distinct Receptor Conformations.

"Biased" G protein-coupled receptor (GPCR) agonists preferentially activate pathways mediated by G proteins or ß-arrestins. Here, we use double electron-electron resonance spectroscopy to probe the changes that ligands induce in the conformational distribution of the angiotensin II type I receptor. Monitoring distances between 10 pairs of nitroxide labels distributed across the intracellular regions enabled mapping of four underlying sets of conformations. Ligands from different functional classes have distinct, characteristic effects on the conformational heterogeneity of the receptor. Compared to angiotensin II, the endogenous agonist, agonists with enhanced Gq coupling more strongly stabilize an "open" conformation with an accessible transducer-binding site. ß-arrestin-biased agonists deficient in Gq coupling do not stabilize this open conformation but instead favor two more occluded conformations. These data suggest a structural mechanism for biased ligand action at the angiotensin receptor that can be exploited to rationally design GPCR-targeting drugs with greater specificity of action.

Assessment of nucleic acid extraction protocols for antibiotic resistance genes (ARGs) quantification in aircraft wastewater.

This study evaluated ten nucleic acid extraction protocols (EP1 to EP10) for measuring five endogenous antibiotic resistance genes (ARGs) in four aircraft wastewater samples (AWW1 to AWW4). The targeted ARGs, including blaCTX-M, blaNDM-1, ermB, qnrS, and tetA, encompassed highly and minimally abundant ARGs. TetA and ermB were consistently detected across four aircraft wastewater samples using the DNeasy Blood and Tissue Kit and the AllPrep PowerViral DNA/RNA kit. QnrS displayed high detection rates with specific extraction protocols and aliquot volumes. Concentrations of ARGs varied across aircraft wastewater samples, with differing extraction protocols influencing quantitative results. The concentrations of tetA, ermB, and qnrS in AWW1 were distinct, while AWW2 to AWW4 exhibited a broader range for tetA, ermB, qnrS, blaCTX-M, and blaNDM-1. EP1 consistently produced the highest concentrations for several ARGs. Collective data analysis revealed varying ARG concentrations across the ten extraction protocols, suggesting the importance of careful extraction protocol selection in ARG monitoring in aircraft wastewater samples. Based on the results, we suggest that a small sample volume (as low as 0.2 mL) may be sufficient for ARG characterization in aircraft wastewater samples. The findings also emphasize the need for considering toilet paper removal without compromising nucleic acid extraction efficiency. The study highlights promising prospects for aircraft wastewater monitoring of ARGs, calling for further investigation into the import and spread of unique ARGs through transport hubs.

Combined applications of UV and chlorine on antibiotic resistance control: A critical review.

Environmental health problems caused by antibiotic-resistant bacteria (ARB) and antibiotic-resistant genes (ARGs) have become a global concern. ARB and ARGs have been continuously detected in various water environments, which pose a new challenge for water quality safety assurance. Disinfection is a key water treatment process to eliminate pathogenic microorganisms in water, and combined chlorine and UV processes (the UV/Cl2 process, the UV-Cl2 process, and the Cl2-UV process) are considered potential disinfection methods to control antibiotic resistance. This review documented the efficacy and mechanism of combined UV and chlorine processes for the control of antibiotic resistance, as well as the effects of chlorine dose, solution pH, UV wavelength, and water matrix on the effectiveness of the processes. There are knowledge gaps in research on the combined chlorine and UV processes for antibiotic resistance control, in particular the UV-Cl2 process and the Cl2-UV process. In addition, changes in the structure of microbial communities and the distribution of ARGs, which are closely related to the spread of antibiotic resistance in the water, induced by combined processes were also addressed. Whether these changes could lead to the re-transmission of antibiotic resistance and harm human health may need to be further evaluated.

Low-Dose Erythropoietin Amplifies Beneficial Effects of Angiotensin II Blockade on Glomerulosclerosis.

Exogenous erythropoietin (EPO) is used to treat anemia in patients with chronic kidney disease (CKD). Concerns about the possible adverse effect of EPO on the progression of CKD have been raised owing to nonerythroid cell effects. We investigated the effects of low-dose EPO, independent of correcting anemia, on existing glomerulosclerosis. Adult mice underwent 5/6 nephrectomy and were randomized into the following 4 groups at week 8 after surgery: vehicle (VEH), losartan (angiotensin II type 1 receptor blocker [ARB]), darbepoetin-α (DA), or combination (DA+ARB). Four weeks later, mice were euthanized, followed by evaluation of renal structure and function. Glomerular endothelial cells and podocytes were cultured to evaluate the effects of DA on cell migration, apoptosis, and Akt signaling. ARB reduced blood pressure, albuminuria, and the level of serum creatinine and increased hematocrit compared with VEH, whereas low-dose DA only reduced the level of serum creatinine. Combination treatment showed a trend to increase hematocrit and survival compared with ARB alone. Combination treatment but not ARB alone significantly reduced the progression of glomerulosclerosis compared with VEH. Low-dose DA resulted in more preserved glomerular and peritubular capillary endothelial cells with increased p-Akt and even further endothelial cell preservation in combination with ARB. In cultured glomerular endothelial cells, angiotensin II induced more apoptosis, reduced migration, and decreased p-Flk1, a receptor for the proangiogenic vascular endothelial growth factor. DA counteracted these injuries and increased p-Akt, a key factor in angiogenesis and cell survival. DA also protected cultured podocytes against transforming growth factor ß-induced apoptosis and synaptopodin loss. Low-dose EPO directly protects glomerular and peritubular endothelial cells via Akt phosphorylation. Therefore, treatment using a combination of low-dose EPO and ARB results in less progression of glomerulosclerosis in an experimental CKD model.

Association of ACEI/ARB and statin prescribing patterns with mortality after Transcatheter Aortic Valve Replacement (TAVR): Findings from real-world claims data.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has become the standard of care for most patients with severe aortic stenosis (AS), but the impact of medical therapy prescribing patterns on post-TAVR patients has not been thoroughly investigated. METHODS: We analyzed Optum claims data from 9,012 adults who received TAVR for AS (January 2014-December 2018). Pharmacy claims data were used to identify patients who filled ACEI/ARB and/or statin prescriptions during the study's 90-day landmark period post-TAVR. Kaplan-Meier and adjusted Cox Proportional Hazards models were used to evaluate the association of prescribing patterns with mortality during the 3-year follow-up period. Subgroup analyses were performed to examine the impact of 11 potential confounders on the observed associations. RESULTS: A significantly lower adjusted 3-year mortality was observed for patients with post-TAVR prescription for ACEI/ARBs (hazard ratio [HR] = 0.82, 95% confidence interval [CI] 0.74-0.91, P = .0003) and statins (HR = 0.85, 95% CI 0.77-0.94, P = .0018) compared to patients who did not fill prescriptions for these medications post-TAVR. Subgroup analyses revealed that the survival benefit associated with ACEI/ARB prescription was not affected by any of the potential confounding variables, except preoperative ACEI/ARB prescription was associated with significantly lower risk of mortality vs postoperative prescription only. No other subgroup variables had significant interactions associated with survival benefits, including preoperative use of statins. CONCLUSIONS: In this large-scale, real-world analysis of patients undergoing TAVR, the prescription of ACEI/ARB and statins was associated with a significantly lower risk of mortality at 3-years, especially in those where the medications were initiated preoperatively.

Developmental regulation of the male urogenital papilla in the male marine teleost black rockfish, Sebastes schlegelii (Hilgendorf, 1880)†.

The male external genitalia of the black rockfish (Sebastes schlegelii Hilgendorf, 1880) is a fleshy protrusion known as the urogenital papilla (UGP), which functions to deliver sperm into the female reproductive tract for internal fertilization. It is not known which genes regulate the development of the UGP. The aim of this study was to identify key genes that regulate the development of the UGP in black rockfish and to determine the distribution of androgen receptor gene (ar) in the UGP. A total of 26 adult males and 560 juvenile fish were used in the experiment, in which we divided all normally developing juveniles into normal development and androgen groups. We added methyltestosterone solution (100 µg/l) to the androgen group-treated fish tank, soaked for 2 h per day for 38 days, and sampled 5~10 samples each time every 5 days during the culture process. Gene expression changes related to UGP were analyzed with tissue specificity between control and androgen groups during sex differentiation, adult male maturation, and the copulation stage (September to December) using real-time quantitative polymerase chain reaction. The expression of ar was also localized by two-color in situ hybridization in the UGP region of juvenile fish. Androgen treatment enhanced ar expression levels and the ar signal was stronger in the UGP region of both adult breeding fish and androgen-treated juvenile fish. This study provides insights into the regulation of the external genitalia of black rockfish and presents vital information for the artificial breeding of viviparous fish.

ACEI/ARB and beta-blocker therapies for preventing cardiotoxicity of antineoplastic agents in breast cancer: a systematic review and meta-analysis.

Anthracyclines and trastuzumab are widely used to treat breast cancer but increase the risk of cardiomyopathy and heart failure. With the use of trastuzumab and anthracycline-containing medications, this study intends to evaluate the effectiveness and security of current treatments against cardiotoxicity. We conducted a systematic review of randomized controlled trials (RCTs), which used at least one angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), or beta-blocker (BB) to prevent cardiotoxicity of antineoplastic agents for breast cancer, in 4 databases (PubMed, Cochrane Library, EMBASE, Web of Science) from inception to 11 May 2022, without language restrictions. The outcome of interest was left ventricular ejection fraction (LVEF) and adverse events. Stata 15 and R software 4.2.1 were used to perform all statistical analyses. The Cochrane version 2 of the risk of bias tool was used to assess the risk of bias, and the grading of recommendations assessment, development, and evaluation (GRADE) assessment was used to appraise the quality of the evidence. Fifteen randomized clinical studies with a total of 1977 patients were included in the analysis. The included studies demonstrated statistically significant LVEF in the ACEI/ARB and BB treatment groups (χ2 = 184.75, I2 = 88.6%, p = 0.000; SMD 0.556, 95% CI 0.299 to 0.813). In an exploratory subgroup analysis, the benefit of experimental agents on LVEF, whether anthracyclines or trastuzumab, was prominent in patients treated with ACEIs, ARBs, and BBs. Compared to placebo, ACEI/ARB and BB treatments in breast cancer patients protect against cardiotoxicity after trastuzumab and anthracycline-containing medication treatment, indicating a benefit for both.

A Real-World Analysis of Post-Marketing Surveillance Data Assessing the Incidence of Hyperkalemia or Acute Kidney Injury in Patients on Angiotensin-Converting Enzyme Inhibitors Versus Angiotensin-Receptor Blockers.

Background: The widely used Renin-angiotensin-aldosterone system inhibitor (RASI) may increase the risk of hyperkalemia and acute kidney injury (AKI). We aimed to analyze the RASI-related AKI or hyperkalemia reported in the Food and Drug Administration's Adverse Event Reporting System (FAERS) database to optimize patients' treatment and provide a reference for a clinically safe and rational prescription. Methods: We obtained data in FAERS recorded from January 2004 to December 2020. Disproportionality analysis and Bayesian analysis were used in data mining to screen the suspected AKI or hyperkalemia after RASI. The time to onset, hospitalization, and prognosis of RASI-associated AKI or hyperkalemia were also investigated. Results: We identified 11,301 RASI-related adverse events (AEs) of hyperkalemia and AKI in the FAERS database; 4997 were due to Angiotensin-converting enzyme inhibitors (ACEIs), 5658 were due to angiotensin receptor blockers (ARBs), and 646 were due to the combination of ACEI and ARB. AKI was more commonly reported in patients with ARB (78.42%) than ACEI users (57.27%). Hyperkalemia cases were reported more in ACEI users (28.70%) than ARB users (14.14%). The median time to onset of RAS-associated AKI was 135.0 (17.0-620.0) days. RASI-associated hyperkalemia occurred relatively later in ACEI users, with a median onset time of 261.0 (43.0-1097.7) days, compared with that of 200.5 (52.0-636.0) days in ARB users (p < 0.001). Among all AEs, 72.39% of cases received hospitalization. Death occurred in 6.3% of the renal AE cases. The elderly and heart failure were potential risk factors for death in patients who developed RASI-associated renal AEs, with an increased Odds Ratio (OR) compared with younger age (OR = 1.32) and hypertension patients (OR = 2.55). Based on the criteria of the four algorithms, the ACEI and ARB combination further increased the incidence of AKI and hyperkalemia, demonstrating the highest Reporting Odds Ratios (RORs), Proportional Reporting Ratios (PRRs) and Empirical Bayesian Geometric Average (EBGMs). Conclusions: Patients who indicated RASI for heart failure demonstrated a higher death risk when AEs occurred. ACEI combined with ARB can increase the incidence of hyperkalemia and AKI. Careful and individualized management is necessary.

The association between dual RAAS inhibition and risk of acute kidney injury and hyperkalemia in patients with diabetic kidney disease: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Dual renin-angiotensin-aldosterone system (RAAS) blockade involves dual therapy with a combination of angiotensin-converting enzyme inhibitors (ACEis), angiotensin-receptor blockers (ARBs), direct renin inhibitors (DRIs), or mineralocorticoid receptor antagonists (MRAs). It is hypothesized that dual RAAS blockade would result in a more complete inhibition of the RAAS cascade. However, large clinical trials on dual RAAS inhibition have shown increased risk of acute kidney injury (AKI) and hyperkalemia without additional benefit on mortality, cardiovascular events, or chronic kidney disease (CKD) progression compared to RAAS inhibitor monotherapy in patients with diabetic kidney disease (DKD). The development of newer, more selective non-steroidal MRAs as cardiorenal protective therapies has created a new opportunity for dual RAAS inhibition. We conducted a systematic review and meta-analysis of the risks of AKI and hyperkalemia with dual RAAS blockade in patients with DKD. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This is a systematic review and meta-analysis of the randomized controlled trials (RCT) published from 1 January 2006 to 30 May 2022. The study population included adult patients with DKD receiving dual RAAS blockade. A total of 31 RCTs and 33 048 patients were included in the systematic review. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using random effects. RESULTS: There were 208 AKI events in 2690 patients on ACEi + ARB versus 170 in 4264 patients with ACEi or ARB monotherapy (pooled RR 1.48, 95% CI: 1.23-1.39). There were 304 hyperkalemia events in 2818 patients on ACEi + ARB versus 208 in 4396 patients with ACEi or ARB monotherapy (pooled RR 1.97, 95% CI: 1.32-2.94). A non-steroidal MRA + ACEi or ARB showed no increase in the risk of AKI (pooled RR 0.97, 95% CI: 0.81-1.16) compared to ACEi or ARB monotherapy but had a 2-fold higher risk of hyperkalemia with 953 events in 7837 patients in dual therapy versus 454 events in 6895 patients in monotherapy (pooled RR 2.05, 95% CI: 1.84-2.28). A steroidal MRA + ACEi or ARB had a 5-fold higher risk of hyperkalemia with 28 events in 245 at risk in dual therapy versus five events in 248 at risk in monotherapy (pooled RR 5.42 95% CI: 2.15-13.67). CONCLUSION: Dual therapy with RAASi is associated with an increased risk of AKI and hyperkalemia compared to RAASi monotherapy. Conversely, dual therapy with RAAS inhibitors and non-steroidal MRAs have no additional risk of AKI but a similar risk of hyperkalemia, which is lower than dual therapy with RAAS inhibitors and steroidal MRAs.

Deciphering the Role of WWTPs in Cold Environments as Hotspots for the Dissemination of Antibiotic Resistance Genes.

Cold environments are the most widespread extreme habitats in the world. However, the role of wastewater treatment plants (WWTPs) in the cryosphere as hotspots in antibiotic resistance dissemination has not been well established. Hence, a snapshot of the resistomes of WWTPs in cold environments, below 5 °C, was provided to elucidate their role in disseminating antibiotic resistance genes (ARGs) to the receiving waterbodies. The resistomes of two natural environments from the cold biosphere were also determined. Quantitative PCR analysis of the aadA, aadB, ampC, blaSHV, blaTEM, dfrA1, ermB, fosA, mecA, qnrS, and tetA(A) genes indicated strong prevalences of these genetic determinants in the selected environments, except for the mecA gene, which was not found in any of the samples. Notably, high abundances of the aadA, ermB, and tetA(A) genes were found in the influents and activated sludge, highlighting that WWTPs of the cryosphere are critical hotspots for disseminating ARGs, potentially worsening the resistance of bacteria to some of the most commonly prescribed antibiotics. Besides, the samples from non-disturbed cold environments had large quantities of ARGs, although their ARG profiles were highly dissimilar. Hence, the high prevalences of ARGs lend support to the fact that antibiotic resistance is a common issue worldwide, including environmentally fragile cold ecosystems.

Beneficial Effects of Angiotensin II Receptor Blockers on Mortality in Patients with COVID-19: A Retrospective Study from 2019 to 2020 in China.

BACKGROUND: The COVID-19 pandemic has become a serious global public health problem. Although the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor type 1 blockers (ARBs) has been recommended in patients with COVID-19 and cardiovascular diseases (CVDs), according to the results of some small-sample retrospective analyses, there remains a lack of sufficient evidence to validate their efficacy. This multicenter retrospective study investigated whether ACEI/ARB administration was beneficial in patients with COVID-19 and CVDs. METHODS: A total of 11,231 patients with confirmed COVID-19 and CVDs, from 138 hospitals in Hubei Province, were included in this multicenter retrospective study. We compared the clinical characteristics and outcomes between the ARB and non-ARB groups and analyzed the risk factors for in-hospital death using univariate and multivariate Cox regression analyses and Kaplan-Meier curves. RESULTS: In the multivariate Cox regression model, after adjusting for age, gender, comorbidities, and in-hospital medications, ARB use was associated with lower all-cause mortality (adjusted HR, 0.53; 95% CI, 0.38-0.73; P < 0.001). After propensity score-matched analysis, the adjusted HR for the use of ARB associated with all-cause mortality was 0.62 (95% CI, 0.40-0.88; P = 0.02). Further subgroup analyses found that the adjusted HRs for the use of ARB associated with all-cause mortality were 0.52 (95% CI, 0.30-0.89; P = 0.016), 0.37 (95% CI, 0.21-0.64; P < 0.001), 0.42 (95% CI, 0.28-0.64; P < 0.001), and 0.55 (95% CI, 0.37-0.84; P = 0.005) in patients with heart failure, diabetes, and hypercholesterolemia, and severe COVID-19, respectively. CONCLUSIONS: ARB administration was significantly associated with a lower risk of all-cause mortality in patients with COVID-19 and CVDs. TRIAL REGISTRATION: ClinicalTrials.gov NCT05615792. https://www. CLINICALTRIALS: gov/ct2/show/NCT05615792.

Emerging soil contamination of antibiotics resistance bacteria (ARB) carrying genes (ARGs): New challenges for soil remediation and conservation.

Soil plays a vital role as a nutrient source for microflora and plants in ecosystems. The accumulation and proliferation of antibiotics resistance bacteria (ARB) and antibiotics resistance genes (ARGs) causes emerging soil contamination and pollution, posing new challenges for soil remediation, recovery, and conservation. Fertilizer application in agriculture is one of the most important sources of ARB and ARGs contamination in soils. The recent existing techniques for the remediation of soil polluted with ARB and ARGs are very limited in terms of ARB and ARGs removal in soil. Bioelectrochemical remediation using bioelectrochemical systems such as microbial fuel cells and microbial electrolysis cells are promising technologies for the removal of ARB and ARGs in soil. Herein, diverse sources of ARB and ARGs in soil have been reviewed, their effects on soil microbial diversity have been analyzed, and the causes of ARB and ARGs rapid proliferation in soil are explained. Bioelectrochemical systems used for the remediation of soil contaminated with ARB and ARGs is still in its infancy stage and presents serious disadvantage and limits, therefore it needs to be well understood and implemented. In general, merging soil contamination of ARB and ARGs is an increasing concern threatening the soil ecosystem while the remediation technologies are still challenging. Efforts need to be made to develop new, effective, and efficient technologies for soil remediation and conservation to tackle the spread of ARB and ARGs and overcome the new challenges posed by ARB and ARGs contamination in soil.

The use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers may relate to the survival and walking ability in geriatric patients with hip fractures: a 1-year follow-up study.

BACKGROUND: Many elder patients with hip fractures also suffered from hypertension. This study aims to explore the relationship between the use of ACEI or ARB and the outcomes of geriatric hip fractures. METHODS: All the patients were divided into four groups: non-users without hypertension, non-users with hypertension, ACEI users, and ARB users. The outcomes of patients in different groups were compared. LASSO regression and univariable Cox analysis were used for variable screening. Then Cox models and Logistics models were established to identify the relationships between the use of RAAS inhibitors and outcomes. RESULTS: ACER users (p = 0.016) and ARB users (p = 0.027) had a significantly lower survival probability than the non-users with hypertension. Non-users without hypertension, ACEI users, and ARB users may face lower 6-month and 1-year mortalities and higher 6-month and 1-year free walking rates compared with non-users with hypertension. CONCLUSION: Patients with the use of ACEI or ARB may face a better prognosis of hip fractures.

Dual Blockade of TGF-ß Receptor and Endothelin Receptor Synergistically Inhibits Angiotensin II-Induced Myofibroblast Differentiation: Role of AT1R/Gαq-Mediated TGF-ß1 and ET-1 Signaling.

Angiotensin II (Ang II) upregulates transforming growth factor-beta1 (TGF-ß1) and endothelin-1 (ET-1) in various types of cells, and all of them act as profibrotic mediators. However, the signal transduction of angiotensin II receptor (ATR) for upregulation of TGF-ß1 and ET-1, and their effectors that play an essential role in myofibroblast differentiation, are not fully understood. Therefore, we investigated the ATR networking with TGF-ß1 and ET-1 and identified the signal transduction of these mediators by measuring the mRNA expression of alpha-smooth muscle actin (α-SMA) and collagen I using qRT-PCR. Myofibroblast phenotypes were monitored by α-SMA and stress fiber formation with fluorescence microscopy. Our findings suggested that Ang II induced collagen I and α-SMA synthesis and stress fiber formation through the AT1R/Gαq axis in adult human cardiac fibroblasts (HCFs). Following AT1R stimulation, Gαq protein, not Gßγ subunit, was required for upregulation of TGF-ß1 and ET-1. Moreover, dual inhibition of TGF-ß and ET-1 signaling completely inhibited Ang II-induced myofibroblast differentiation. The AT1R/Gαq cascade transduced signals to TGF-ß1, which in turn upregulated ET-1 via the Smad- and ERK1/2-dependent pathways. ET-1 consecutively bound to and activated endothelin receptor type A (ETAR), leading to increases in collagen I and α-SMA synthesis and stress fiber formation. Remarkably, dual blockade of TGF-ß receptor and ETR exhibited the restorative effects to reverse the myofibroblast phenotype induced by Ang II. Collectively, TGF-ß1 and ET-1 are major effectors of AT1R/Gαq cascade, and therefore, negative regulation of TGF-ß and ET-1 signaling represents a targeted therapeutic strategy for the prevention and restoration of cardiac fibrosis.

Anaerobic sludge digestion elevates dissemination risks of bacterial antibiotic resistance in effluent supernatant.

Anaerobic digestion following a variety of pretreatments is a promising technique for the reduction of excess sludge in municipal wastewater treatment plants (MWWTPs), and eliminations of possible pathogens, viruses, protozoa, and other disease-causing organisms. Notwithstanding a rapidly increasing health concern of antibiotic resistant bacteria (ARB) in MWWTPs, dissemination risks of ARB in anaerobic digestion processes are still poorly understood, especially in the digested supernatant. Taking the representative ARB with respect to the common tetracycline-, sulfamethoxazole-, clindamycin- and ciprofloxacin resistance, we investigated the compositions of ARB in the sludge and supernatant, and quantified their variations along the entire anaerobic sludge digestion process following ultrasonication-, alkali-hydrolysis- and alkali-ultrasonication pretreatments, respectively. Results showed that the abundance of ARB was diminished by up to 90% from the sludge along anaerobic digestion coupling with the pretreatments. Surprisingly, pretreatments clearly boosted the abundance of specific ARB (e.g., 2.3 × 102 CFU/mL of tetracycline-resistant bacteria) in the supernatant that otherwise remained relatively low value of 0.6 × 102 CFU/mL from the direct digestion. Measurements of the soluble-, loosely-bound- and tightly-bound extracellular polymeric substances components revealed a gradually intensified destruction of the sludge aggregates along the entire anaerobic digestion processes, which could be likely responsible to the increase of the ARB abundance in the supernatant. Furthermore, analysis of the bacterial community components showed that the ARB populations were strongly correlated with the occurrence of Bacteroidetes, Patescibacteria, and Tenericutes. Interestingly, intensified conjugal transfer (0.015) of antibiotic resistance genes (ARGs) was observed upon returning of the digested supernatant to the biological treatment system. It implies the likelihood of ARGs spreading and subsequent ecological risks upon anaerobic digestion towards reducing excess sludge, and therefore requires further attentions for the excess sludge treatments especially of supernatant.

Effects of Melaleuca alternifolia Chell (Tea Tree) and Eucalyptus globulus Labill. Essential Oils on Antibiotic-Resistant Bacterial Biofilms.

In the present investigation, the anti-biofilm potential of two essential oils (EOs), Melaleuca alternifolia Chell (Tea-Tree) (TTO) and Eucalyptus globulus Labill. (EEO) was characterized and tested "in vitro" against both mature biofilms and biofilms in the process of formation, produced by strains belonging to three main categories of antibiotic resistant bacteria (ARB): Vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA) and broad-spectrum ß-lactamase-producing Escherichia coli (ESBL). The study was carried out in 96-well microtiter-plates using EOs alone, in association with each other and in combination with antibiotics against both single and multi-species biofilm. The study demonstrated the ability of TTO and EEO to counteract the ARB strains in sessile form, with promising results in particular against the biofilm in formation. Mature biofilm by ESBL E. coli was the most sensitive in the results from the quantification study of viable cells performed in multi-species biofilms. Lastly, in all tests, carried out using TTO/EEO associations and EOs/antibiotic combinations, the synergistic effect which emerged from the FIC-index has been confirmed, and both the reduction of biofilm in formation, and the removal of mature structure was obtained at very low concentrations, with values from 4 to >512-fold lower than the minimum inhibitory concentration (MIC) of the single compounds.

Comparison of cardiocerebrovascular disease incidence between angiotensin converting enzyme inhibitor and angiotensin receptor blocker users in a real-world cohort.

BACKGROUND: Both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are known to be effective in managing cardiovascular diseases, but more evidence supports the use of an ACEI. This study investigated the difference in cardiovascular disease incidence between relatively low-compliance ACEIs and high-compliance ARBs in the clinical setting. METHODS: Patients who were first prescribed ACEIs or ARBs at two tertiary university hospitals in Korea were observed in this retrospective cohort study for the incidence of heart failure, angina, acute myocardial infarction, cerebrovascular disease, ischemic heart disease, and major adverse cardiovascular events for 5 years after the first prescription. Additionally, 5-year Kaplan-Meier survival curves were used based on the presence or absence of statins. RESULTS: Overall, 2,945 and 9,189 patients were prescribed ACEIs and ARBs, respectively. When compared to ACEIs, the incidence of heart failure decreased by 52% in those taking ARBs (HR [95% CI] = 0.48 [0.39-0.60], P < 0.001), and the incidence of cerebrovascular disease increased by 62% (HR [95% CI] = 1.62 [1.26-2.07], P < 0.001). The incidence of ischemic heart disease (P = 0.223) and major adverse cardiovascular events (P = 0.374) did not differ significantly between the two groups. CONCLUSIONS: ARBs were not inferior to ACEIs in relation to reducing the incidence of cardiocerebrovascular disease in the clinical setting; however, there were slight differences for each disease. The greatest strength of real-world evidence is that it allows the follow-up of specific drug use, including drug compliance. Large-scale studies on the effects of relatively low-compliance ACEIs and high-compliance ARBs on cardiocerebrovascular disease are warranted in the future.

Longitudinal Plasma Proteomics Analysis Reveals Novel Candidate Biomarkers in Acute COVID-19.

The host response to COVID-19 pathophysiology over the first few days of infection remains largely unclear, especially the mechanisms in the blood compartment. We report on a longitudinal proteomic analysis of acute-phase COVID-19 patients, for which we used blood plasma, multiple reaction monitoring with internal standards, and data-independent acquisition. We measured samples on admission for 49 patients, of which 21 had additional samples on days 2, 4, 7, and 14 after admission. We also measured 30 externally obtained samples from healthy individuals for comparison at baseline. The 31 proteins differentiated in abundance between acute COVID-19 patients and healthy controls belonged to acute inflammatory response, complement activation, regulation of inflammatory response, and regulation of protein activation cascade. The longitudinal analysis showed distinct profiles revealing increased levels of multiple lipid-associated functions, a rapid decrease followed by recovery for complement activation, humoral immune response, and acute inflammatory response-related proteins, and level fluctuation in the regulation of smooth muscle cell proliferation, secretory mechanisms, and platelet degranulation. Three proteins were differentiated between survivors and nonsurvivors. Finally, increased levels of fructose-bisphosphate aldolase B were determined in patients with exposure to angiotensin receptor blockers versus decreased levels in those exposed to angiotensin-converting enzyme inhibitors. Data are available via ProteomeXchange PXD029437.

Effect of sacubitril/valsartan and ACEI/ARB on glycaemia and the development of diabetes: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Sacubitril/valsartan and angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor blocker (ARB) therapies were reported to affect glycaemic control and the development of diabetes mellitus (DM), but the findings are inconsistent. We examined the evidence for the effects of sacubitril/valsartan and ACEI/ARB in DM by conducting a meta-analysis. METHODS: The Cochrane Central Register of Controlled Trials (The Cochrane Library), Embase, PubMed, and ClinicalTrials.gov were searched for data from randomised clinical trials (RCTs) that evaluated the efficacy of sacubitril/valsartan and ACEI/ARB in patients, as of May 25, 2022. Patients were grouped by their disease background at baseline. The main outcomes were the number of new-onset DM and hypoglycaemia, elevated glycaemia, inadequate DM control, diabetes treatment, and diabetic complications, from baseline to the end of the trials. The risk of bias was assessed using the revised Cochrane risk-of-bias tool for randomized trials (ROB 2). The quality of the evidence was evaluated according to the Recommendations for Assessment, Development, and Evaluation guidelines. The meta-analysis of the incidence of various outcomes was conducted using fixed or random effects models. The results are expressed as binary risk, 95% confidence interval (CI), and relative risk (RR). The Mantel-Haenszel method and Z test were used to determine the overall results and determine the significance of the RR. RESULTS: This study included 31 RCTs and 86,809 subjects. Compared with placebo, sacubitril/valsartan treatment significantly reduced the risk of new-onset DM among all patients (RR = 0.78, 95% CI: 0.64-0.95), patients with heart failure (HF) (RR = 0.24, 95% CI: 0.12-0.48), HF with reduced ejection fraction (HFrEF) (RR = 0.24, 95% CI: 0.12-0.50), and HF with preserved ejection fraction (HFpEF) (RR = 0.54, 95% CI 0.34-0.85). In contrast, sacubitril/valsartan treatment significantly increased the risk of hypoglycaemia among all patients (RR = 1.91, 95% CI: 1.05-3.47), patients with not all-DM (defined as part of the study population having DM at baseline) (RR = 5.71, 95% CI: 2.02-16.21), and patients with HFpEF (RR = 7.06, 95% CI: 2.10-23.76). Compared with ACEI/ARB, sacubitril/valsartan treatment significantly increased the risk of hypoglycaemia among patients with HF (RR 1.85, 95% CI 1.12-3.06, p = 0.02) and HFpEF (RR 3.59, 95% CI 1.51-8.55, p = 0.004). Compared with placebo, ACEI/ARB treatment did significantly reduce the risk of new-onset DM among all patients (RR 0.85, 95% CI 0.77-0.93, p = 0.0007) and patients with not all-HF (defined as part of the study population having HF at baseline) (RR 0.87, 95% CI 0.82-0.93, p<0.0001) and HFpEF (RR 0.60, 95% CI 0.44-0.83, p = 0.002), diabetes complications among patients with non-HF (/not all-DM) (RR 0.87, 95% CI 0.76-0.99, p = 0.04), and subsequent diabetes treatment among patients with new-onset DM (RR 0.70, 95% CI 0.58-0.84, p = 0.0002) and significantly increased the risk of hypoglycaemia among patients with not all-DM (RR 2.06, 95% CI 1.172-3.61, p = 0.01). CONCLUSIONS: The results of our study, especially in reducing glycaemia and new-onset DM, revealed that sacubitril/valsartan had a positive effect on the control of glycaemia and the development of DM. ACEI/ARB also had a beneficial effect but the effect was weaker than that of sacubitril/valsartan. The above effects varied across diseases but the evidence was strongest in patients with HF. TRIAL REGISTRATION: CRD42022336311.

Hyperkalemia-Related Discontinuation of Renin-Angiotensin-Aldosterone System Inhibitors and Clinical Outcomes in CKD: A Population-Based Cohort Study.

RATIONALE & OBJECTIVE: Renin-angiotensin-aldosterone system (RAAS) inhibitors are evidence-based therapies that slow the progression of chronic kidney disease (CKD) but can cause hyperkalemia. We aimed to evaluate the association of discontinuing RAAS inhibitors after an episode of hyperkalemia and clinical outcomes in patients with CKD. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adults in Manitoba (7,200) and Ontario (n = 71,290), Canada, with an episode of de novo RAAS inhibitor-related hyperkalemia (serum potassium ≥ 5.5 mmol/L) and CKD. EXPOSURE: RAAS inhibitor prescription. OUTCOME: The primary outcome was all-cause mortality. Secondary outcomes were cardiovascular (CV) mortality, fatal and nonfatal CV events, dialysis initiation, and a negative control outcome (cataract surgery). ANALYTICAL APPROACH: Cox proportional hazards models examined the association of RAAS inhibitor continuation (vs discontinuation) and outcomes using intention to treat approach. Sensitivity analyses included time-dependent, dose-dependent, and propensity-matched analyses. RESULTS: The mean potassium and mean estimated glomerular filtration rate were 5.8 mEq/L and 41 mL/min/1.73 m2, respectively, in Manitoba; and 5.7 mEq/L and 41 mL/min/1.73 m2, respectively, in Ontario. RAAS inhibitor discontinuation was associated with a higher risk of all-cause mortality (Manitoba: HR, 1.32 [95% CI, 1.22-1.41]; Ontario: HR, 1.47 [95% CI, 1.41-1.52]) and CV mortality (Manitoba: HR, 1.28 [95% CI, 1.13-1.44]; and Ontario: HR, 1.32 [95% CI, 1.25-1.39]). RAAS inhibitor discontinuation was associated with an increased risk of dialysis initiation in both cohorts (Manitoba: HR, 1.65 [95% CI, 1.41-1.85]; Ontario: HR, 1.11 [95% CI, 1.08-1.16]). LIMITATIONS: Retrospective study and residual confounding. CONCLUSIONS: RAAS inhibitor discontinuation is associated with higher mortality and CV events compared with continuation among patients with hyperkalemia and CKD. Strategies to maintain RAAS inhibitor treatment after an episode of hyperkalemia may improve clinical outcomes in the CKD population.