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The transmission of antimicrobial resistance (AMR) between food‐producing animals (poultry, cattle and pigs) during short journeys (< 8 h) and long journeys (> 8 h) directed to other farms or to the slaughterhouse lairage (directly or with intermediate stops at assembly centres or control posts, mainly transported by road) was assessed. Among the identified risk factors contributing to the probability of transmission of antimicrobial‐resistant bacteria (ARB) and antimicrobial resistance genes (ARGs), the ones considered more important are the resistance status (presence of ARB/ARGs) of the animals pre‐transport, increased faecal shedding, hygiene of the areas and vehicles, exposure to other animals carrying and/or shedding ARB/ARGs (especially between animals of different AMR loads and/or ARB/ARG types), exposure to contaminated lairage areas and duration of transport. There are nevertheless no data whereby differences between journeys shorter or longer than 8 h can be assessed. Strategies that would reduce the probability of AMR transmission, for all animal categories include minimising the duration of transport, proper cleaning and disinfection, appropriate transport planning, organising the transport in relation to AMR criteria (transport logistics), improving animal health and welfare and/or biosecurity immediately prior to and during transport, ensuring the thermal comfort of the animals and animal segregation. Most of the aforementioned measures have similar validity if applied at lairage, assembly centres and control posts. Data gaps relating to the risk factors and the effectiveness of mitigation measures have been identified, with consequent research needs in both the short and longer term listed. Quantification of the impact of animal transportation compared to the contribution of other stages of the food‐production chain, and the interplay of duration with all risk factors on the transmission of ARB/ARGs during transport and journey breaks, were identified as urgent research needs.

Environmental aquatic pollution with antibiotics is a global challenge that affects even pristine mountain environments. Monitoring the concentration of antibiotics in water is critical to water resource management. In this review, we present the sources and degradation routes of antibiotics polluting surface waters, with particular focus on mountain environments and pristine areas. This pollution is strongly related to anthropopressure resulting from intensive tourism. An important aspect of the threat to the environment is water containing antibiotics at sub-inhibitory concentrations, which affects bacterial populations. Antibiotics are ecological factors driving microbial evolution by changing the bacterial community composition, inhibiting or promoting their ecological functions, and enriching and maintaining drug resistance. We paid attention to the stability of antibiotics and their half-lives in water related to biotic and abiotic degradation, which results from the structures of molecules and environmental conditions. Wastewater treatment combined with advanced treatment techniques significantly increase the efficiency of antibiotic removal from wastewater. Modern methods of wastewater treatment are crucial in reducing the supply of antibiotics to aquatic environments and enhancing the possibility of economic and safe reuse of wastewater for technical purposes. We provide a perspective on current research investigating antibiotic emergence in mountain areas and identify knowledge gaps in this field.

Antibiotics are commonly used to prevent and control diseases in aquaculture. However, long-term/overuse of antibiotics not only leaves residues but results in the development of antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs). Antibiotics, ARB, and ARGs are widespread in aquaculture ecosystems. However, their impacts and interaction mechanisms in biotic and abiotic media remain to be clarified. In this paper, we summarized the detection methods, present status, and transfer mechanisms of antibiotics, ARB, and ARGs in water, sediment, and aquaculture organisms. Currently, the dominant methods of detecting antibiotics, ARB, and ARGs are UPLC−MS/MS, 16S rRNA sequencing, and metagenomics, respectively. Tetracyclines, macrolides, fluoroquinolones, and sulfonamides are most frequently detected in aquaculture. Generally, antibiotic concentrations and ARG abundance in sediment are much higher than those in water. Yet, no obvious patterns in the category of antibiotics or ARB are present in organisms or the environment. The key mechanisms of resistance to antibiotics in bacteria include reducing the cell membrane permeability, enhancing antibiotic efflux, and structural changes in antibiotic target proteins. Moreover, horizontal transfer is a major pathway for ARGs transfer, including conjugation, transformation, transduction, and vesiculation. Identifying, quantifying, and summarizing the interactions and transmission mechanisms of antibiotics, ARGs, and ARB would provide useful information for future disease diagnosis and scientific management in aquaculture.

Background While the renin-angiotensin-aldosterone system (RAAS) is critically involved in pathomechanisms related to SARS-CoV-2 infection, the role of ongoing therapy with angiotensin-converting enzyme 1 inhibitors (ACEi) or Angiotensin-II type 1 receptor (AT 1 R) blockers (ARB) is much less clear. We evaluated the effects of the ACEi enalapril (ENA) and the ARB losartan (LOS) on SARS-CoV-2 infection in human ex vivo-cultured, precision-cut lung slices (PCLS) obtained from normal human lung tissue. Methods PCLS were pre-treated for 5d with vehicle, LOS or ENA (300 µM), followed by mock infection or infection with SARS-CoV-2 and incubation with vehicle, LOS or ENA for 1d or 2d. Thereafter, PCLS were harvested for analysis of viral replication, inflammatory responses, endoplasmic reticulum (ER) stress and apoptosis pathways. Results Both LOS and ENA significantly reduced viral replication in PCLS, with ENA being more potent. LOS was more efficient than ENA in reducing the expression of IL1B , CCL2 , CXCL2 and TNFA , but not of IL6 , whereas ENA preferentially caused a reduction of IL6 and CCL2 in SARS-CoV-2-infected PCLS. Further, ENA, but not LOS, significantly decreased the expression of viral entry factors, ACE2 and transmembrane serine protease 2 (TMPRSS2), in infected PCLS. Importantly, LOS or ENA did not exert cytotoxic effects. Conclusions RAAS-antagonizing drugs do not seem to exert detrimental effects during SARS-CoV-2 infection. In opposite, in an ex-vivo model of human PCLS, such treatment was found to dampen SARS-CoV-2 infection and consecutive inflammation.

Angiotensin receptor blockers (ARBs) used in the treatment of hypertension and potentially in SARS-CoV-2 infection exhibit inverse agonist effects at angiotensin AR1 receptors, suggesting the receptor may have evolved to accommodate naturally occurring angiotensin ‘antipeptides’. Screening of the human genome has identified a peptide (EGVYVHPV) encoded by mRNA, complementary to that encoding ANG II itself, which is an inverse agonist. Thus, opposite strands of DNA encode peptides with opposite effects at AR1 receptors. Agonism and inverse agonism at AR1 receptors can be explained by a receptor ‘switching’ between an activated state invoking receptor dimerization/G protein coupling and an inverse agonist state mediated by an alternative/second messenger that is slow to reverse. Both receptor states appear to be driven by the formation of the ANG II charge-relay system involving TyrOH-His/imidazole-Carboxylate (analogous to serine proteases). In this system, tyrosinate species formed are essential for activating AT1 and AT2 receptors. ANGII is also known to bind to the zinc-coordinated metalloprotease angiotensin converting enzyme 2 (ACE2) used by the COVID-19 virus to enter cells. Here we report in silico results demonstrating the binding of a new class of anionic biphenyl-tetrazole sartans (‘Bisartans’) to the active site zinc atom of the endopeptidase Neprilysin (NEP) involved in regulating hypertension, by modulating humoral levels of beneficial vasoactive peptides in the RAS such as vasodilator angiotensin (1–7). In vivo and modeling evidence further suggest Bisartans can inhibit ANG II-induced pulmonary edema and may be useful in combatting SARS-CoV-2 infection by inhibiting ACE2-mediated viral entry to cells.

Few millions of new cancer cases are diagnosed worldwide every year. Due to significant progress in understanding cancer biology and developing new therapies, the mortality rates are decreasing with many of patients that can be completely cured. However, vast majority of them require chemotherapy which comes with high medical costs in terms of adverse events, of which cardiotoxicity is one of the most serious and challenging. Anthracyclines (doxorubicin, epirubicin) are a class of cytotoxic agents used in treatment of breast cancer, sarcomas, or hematological malignancies that are associated with high risk of cardiotoxicity that is observed in even up to 30% of patients and can be diagnosed years after the therapy. The mechanism, in which anthracyclines cause cardiotoxicity are not well known, but it is proposed that dysregulation of renin-angiotensin-aldosterone system (RAAS), one of main humoral regulators of cardiovascular system, may play a significant role. There is increasing evidence that drugs targeting this system can be effective in the prevention and treatment of anthracycline-induced cardiotoxicity what has recently found reflection in the recommendation of some scientific societies. In this review, we comprehensively describe possible mechanisms how anthracyclines affect RAAS and lead to cardiotoxicity. Moreover, we critically review available preclinical and clinical data on use of RAAS inhibitors in the primary and secondary prevention and treatment of cardiac adverse events associated with anthracycline-based chemotherapy.

The disposal of municipal solid waste (MSW) directly at landfills or open dump areas, without segregation and treatment, is a significant concern due to its hazardous contents of antibiotic-resistant bacteria (ARB), antibiotic resistance genes (ARGs), and metal resistance genes (MGEs). The released leachate from landfills greatly effects the soil physicochemical, biological, and groundwater properties associated with agricultural activity and human health. The abundance of ARB, ARGs, and MGEs have been reported worldwide, including MSW landfill sites, animal husbandry, wastewater, groundwater, soil, and aerosol. This review elucidates the occurrence and abundance of ARB, ARGs, and MRGs, which are regarded as emerging contaminants (ECs). Recently, ECs have received global attention because of their prevalence in leachate as a substantial threat to environmental and public health, including an economic burden for developing nations. The present review exclusively discusses the demands to develop a novel eco-friendly management strategy to combat these global issues. This review also gives an intrinsic discussion about the insights of different aspects of environmental and public health concerns caused due to massive leachate generation, the abundance of antibiotics resistance (AR), and the effects of released leachate on the various environmental reservoirs and human health. Furthermore, the current review throws light on the source and fate of different ECs of landfill leachate and their possible impact on the nearby environments (groundwater, surface water, and soil) affecting human health. The present review strongly suggests the demand for future research focuses on the advancement of the removal efficiency of contaminants with the improvement of relevant landfill management to reduce the potential effects of disposable waste. We propose the necessity of the identification and monitoring of potential environmental and human health risks associated with landfill leachate contaminants.

ABSTRACT The spread of antibiotic resistance in the water environment has been widely described. However, still many knowledge gaps exist regarding the selection pressure from antibiotics, heavy metals and other substances present in surface waters as a result of anthropogenic activities, as well as the extent and impact of this phenomenon on aquatic organisms and humans. In particular, the relationship between environmental concentrations of antibiotics and the acquisition of ARGs by antibiotic-sensitive bacteria as well as the impact of heavy metals and other selective agents on antimicrobial resistance (AMR) need to be defined. Currently, established safety values are based on the effects of antibiotic toxicity neglecting the question of AMR spread. In turn, risk assessment of antibiotics in waterbodies remains a complex question implicating multiple variables and unknowns reinforced by the lack of harmonized protocols and official guidelines. In the present review, we discussed current state-of-the-art and the knowledge gaps related to pressure exerted by antibiotics and heavy metals on aquatic environments and their relationship to the spread of AMR. Along with this latter, we reflected on (i) the risk assessment in surface waters, (ii) selective pressures contributing to its transfer and propagation and (iii) the advantages of metagenomics in investigating AMR. Furthermore, the role of microplastics in co-selection for metal and antibiotic resistance, together with the need for more studies in freshwater are highlighted. The spread of antibiotic resistance in water environments is a complex issue affected by knowledge gaps relative to the (i) selection pressures, (ii) lack of harmonized assessment and (iii) methodological approaches, which require intense research efforts to estimate and limit the risk to human health.

An association among the use of angiotensin converting enzyme (ACE) inhibitors and angiotensin‐receptor blockers (ARBs) with the clinical outcomes of coronavirus disease 2019 (COVID‐19) is unclear. PubMed, EMBASE, MedRxiv, and BioRxiv were searched for relevant studies that assessed the association between application of ACEI/ARB and risk of COVID‐19, inflammation level, severity COVID‐19 infection, and death in patients with COVID‐19. Ten studies were included with 13,944 patients. ACEI/ARB therapy might be associated with the reduced inflammatory factor (interleukin‐6) and elevated immune cells counts (CD3, CD8). Meta‐analysis showed no significant increase in the risk of COVID‐19 infection (odds ratio [OR]: 0.95, 95% CI: 0.89‐1.05) in patients receiving ACEI/ARB therapy, and ACEI/ARB therapy was associated with a decreased risk of severe COVID‐19 (OR: 0.75, 95% CI: 0.59‐0.96, p = 0.02) and mortality (OR: 0.57, 95% CI: 0.37‐0.87, p = 0.009). Subgroup analyses showed among the general population, ACEI/ARB therapy was not associated with reduced risks of severe COVID‐19 infection (OR: 0.85, 95% CI: 0.66‐1.08, p = 0.19) and all‐cause mortality (OR: 0.31, 95% CI: 0.13‐0.75), and COVID‐19 infection (OR: 0.97, 95% CI: 0.89‐1.05, p = 0.45) were not increased. Among patients with hypertension, the use of an ACEI/ARB was associated with a non‐significant lower severity of COVID‐19 (OR: 0.73, 95% CI: 0.51‐1.03, p = 0.07) and significant lower mortality (OR: 0.57, 95% CI: 0.37‐0.87, p = 0.009), without evidence of an increased risk of COVID‐19 infection (OR: 1.00, 95% CI: 0.90‐1.12, p = 1.00). On the basis of the available evidence, ACEI/ARB therapy should be continued in patients who are at risk for, or have COVID‐19, either in general population or hypertension patients. Our results need to be interpreted with caution considering the potential for residual confounders, and more well‐designed studies that control the clinical confounders are necessary to confirm our findings.

Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease (ESKD) in the United States. Risk factor modification, such as tight control of blood glucose, management of hypertension and hyperlipidemia, and the use of renin–angiotensin–aldosterone system (RAAS) blockade have been proven to help delay the progression of DKD. In recent years, new therapeutics including sodium-glucose transport protein 2 (SGLT2) inhibitors, endothelin antagonists, glucagon like peptide-1 (GLP-1) agonists, and mineralocorticoid receptor antagonists (MRA), have provided additional treatment options for patients with DKD. This review discusses the various treatment options available to treat patients with diabetic kidney disease.