Immediate and long-term effects of COVID-19 on antibiotic dispensing: increasing use of Watch antibiotics.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic affected antibiotic usage worldwide. However, there is limited data from Serbia. Dispensing of oral antibiotics in Serbian pharmacies was analyzed to calculate monthly and yearly changes between 2018-2021, and to explore immediate and long-term effects of COVID-19 on antibiotic dispensing during this period. METHODOLOGY: The number of antibiotic packages dispensed from pharmacies during the study period was analyzed with a Chi-square test to assess the average change in annual dispensing, and an interrupted time-series analysis was used to evaluate the impact of the pandemic on antibiotic dispensing. The data from 2018-2021 were retrieved from the database of a large community pharmacy chain in Serbia. RESULTS: The average number of antibiotic packages dispensed per day and per pharmacy was higher in 2021 compared to 2018 by one package. However, the dispensing of macrolides increased significantly; 17.7% (2018) vs. 22.5% (2021) (p < 0.05). In general, an increase in antibiotic dispensing was detected during COVID-19 for total antibiotics (16.4%), Watch antibiotics (44.8%), third-generation cephalosporins (80.4%), macrolides (45.5%) and azithromycin (83.7%). However, the immediate effect of COVID-19 was a decrease in the dispensing of Watch antibiotics, penicillin, and third-generation cephalosporins (p < 0.05); and a notable long-term COVID-19 effect was an increase in the dispensing of azithromycin (p < 0.05). CONCLUSIONS: In spite of a relatively stable trend of total antibiotic dispensing before and during COVID-19 pandemic, the use of Watch antibiotics, third-generation cephalosporins, and macrolides (particularly azithromycin) showed an increasing trend in dispensing that should be optimized.

Clinical Significance and Expression Pattern of RIP5 and VGLL4 in Clear Cell Renal Cell Carcinoma Patients Treated with Sunitinib.

While clear cell renal cell carcinoma (ccRCC) is curable, advanced metastatic (mRCC) remains a clinical challenge. We analyzed clinical, pathohistological, and molecular data (Receptor Interacting Protein 5-RIP5 and Vestigial Like Family Member 4-VGLL4 expression) of 55 mRCC patients treated with first-line treatment with sunitinib. The trend of linear increase in the protein expression of RIP5 was observed with the progression of tumor grade. Overall, 80% of RIP5-positive cells were in the control kidneys and high-grade mRCC. On the contrary, RIP5 displayed low expression in grade 2 mRCC (5.63%). The trend of linear decrease in the expression of VGLL4 was observed with the progression of tumor grade. The highest protein expression of VGLL4 was observed in grade 2 (87.82%) in comparison to grade 3 and 4 and control. High expression of RIP5 mRNA was associated with longer first-line overall survival and longer progression-free survival in mRCC. In addition, a high VGLL4 mRNA expression showed better overall survival in patients with ccRCC. In conclusion, high mRNA expression of RIP5 and VGLL4 are important markers of better survival rates in mRCC patients.

Association of MTHFR polymorphism, folic acid and vitamin B12 with serum homocysteine levels in pregnant women.

Homocysteine is known to be associated with adverse vascular and metabolic effects, as well as pregnancy complications. Its serum levels are influenced by the function of the enzyme methylenetetrahydrofolate reductase (MTHFR) and the dietary intake of folic acid, vitamin B12, and methionine. In this cross-sectional study, we investigated the association of genetic polymorphisms of the MTHFR gene with vitamin status in pregnant women during mandatory folic acid supplementation. The study included 102 pregnant women between 24 and 28 weeks of gestation who were attending regular outpatient examinations at the maternity clinic. Homocysteine, folic acid, vitamin B12 levels, and MTHFR gene polymorphisms (C677T and A1298C) were analyzed. Significant associations were found between vitamin B12 and folic acid levels with homocysteine (P < 0.001), with lower serum levels of these vitamins being associated with higher homocysteine levels. Surprisingly, there was no significant association between MTHFR genetic polymorphisms and serum homocysteine levels, likely attributed to the supplementation of folic acid and vitamin B12 in vitamin supplements for pregnant women, which counteracts the effect of the mutation. Remarkably, a high prevalence of MTHFR gene mutations was found, with the C677T polymorphism present in 56.9% and the A1298C polymorphism in 87.2% of pregnant women. These findings emphasize the importance of adequate folic acid and vitamin B12 intake during pregnancy to regulate homocysteine levels. Although the MTHFR gene mutations were highly prevalent, their influence on homocysteine levels in this population appears to be mitigated by vitamin supplementation. Further research is warranted to explore the impact of these mutations on other aspects of pregnancy outcomes. The trial is registrated at Clinicaltrail.gov (NCT04952324).

Antimicrobial utilization and resistance in Pseudomonas aeruginosa using segmented regression analysis: a comparative study between Serbia and eight European Countries.

BACKGROUND: In Europe, Serbia occupies a high position in antibiotic utilization and antimicrobial resistance (AMR). AIM: The aim was to analyse utilization trends of meropenem, ceftazidime, aminoglycosides, piperacillin/tazobactam and fluoroquinolones (2006-2020), and the reported AMR in Pseudomonas aeruginosa (2013-2020) in Serbia and to compare with data from eight European countries (2015-2020). METHOD: Joinpoint regression was used to analyse antibiotic utilization data (2006-2020) and the reported AMR in Pseudomonas aeruginosa (2013-2020). Data sources were relevant national and international institutions. Antibiotic utilization and AMR in Pseudomonas aeruginosa data in Serbia were compared with eight European countries. RESULTS: There was a significantly increased trend for ceftazidime utilization and reported resistance in Pseudomonas aeruginosa, Serbia (p < 0.05) (2018-2020). For ceftazidime, piperacillin/tazobactam, and fluoroquinolones resistances in Pseudomonas aeruginosa an increased trend was observed, Serbia (2013-2020). A decrease in both the utilization of aminoglycosides, Serbia (p < 0.05) (2006-2018) and contemporaneous Pseudomonas aeruginosa resistance (p > 0.05) was detected. Fluoroquinolone utilization (2015-2020) was highest in Serbia compared to Netherlands and Finland, 310 and 305% higher, similar compared to Romania, and 2% less compared to Montenegro. Aminoglycosides (2015-2020) were 2550 and 783% more used in Serbia compared to Finland and Netherlands, and 38% less regarding Montenegro. The highest percentage of Pseudomonas aeruginosa resistance was in Romania and Serbia (2015-2020). CONCLUSION: The use of piperacillin/tazobactam, ceftazidime and fluoroquinolones should be carefully monitored in clinical practice due to increased Pseudomonas aeruginosa resistance. The level of utilization and AMR in Pseudomonas aeruginosa is still high in Serbia compared to other European countries.

Effects of the technical ingredient clomazone and its two formulated products on aquatic macrophytes.

One active ingredient can be a component of different types of formulations of pesticides, while the toxicity of its formulations may vary depending on various constituents used in the mixture. The present study focuses on evaluating the effects of the active ingredient clomazone and its formulations (Rampa® EC and GAT Cenit 36 CS, both containing 360 g a.i./l of clomazone) on non-target aquatic macrophytes. The two formulation types differ in their active ingredient release and presumed environmental impact. In order to cover different ecological traits, two species of aquatic macrophytes - the floating monocot Lemna minor and the rooted dicot Myriophyllum aquaticum, were used as test models. The results of this study revealed differences in the sensitivity of tested plants to clomazone. Based on the most sensitive parameters, M. aquaticum proved to be more sensitive than L. minor to the technical ingredient and both formulations. The species sensitivity distribution (SSD) approach that was tried out in an attempt to create a higher tier step of risk assessment of clomazone for primary producers indicates that tests on rooted macrophytes can add value in risk assessment of plant protection products. The capsule formulation of clomazone was less toxic than the emulsion for L. minor, but more toxic for M. aquaticum. The most toxic for L. minor was the emulsifiable concentrate formulation Rampa® EC, followed by technical clomazone (EC50 33.3 and 54.0 mg a.i./l, respectively), while the aqueous capsule suspension formulation GAT Cenit 36 CS did not cause adverse effects. On the other hand, the most toxic for M. aquaticum was the formulation GAT Cenit 36 CS, followed by technical clomazone and the formulation Rampa® EC, demonstrating a greater effect of the capsule formulation.

The impact of humic acid on toxicity of individual herbicides and their mixtures to aquatic macrophytes.

This study investigates the impact of humic acid (HA) on the toxicity of selected herbicides and their binary mixtures to aquatic plants. The focus was on two auxin simulators (2,4-D and dicamba) and two photosynthetic inhibitors (atrazine and isoproturon). The results suggested that the addition of HA to the standard synthetic medium does not affect Lemna minor growth nor the toxicity of atrazine, but increases the toxicity of 2,4-D and the binary mixture of atrazine and 2,4-D. The addition of HA to the standard synthetic medium reversibly decreased the growth (biomass) of Myriophyllum aquaticum and enhanced the toxicity of individually tested herbicides (isoproturon and dicamba) as well as their binary mixture. The results showed delayed toxic effects of auxin simulators, especially 2,4-D in the Lemna test. The recovery after the exposure to individual photosystem II inhibitors (atrazine and isoproturon) is fast in both plant species, regardless of the presence of HA. In the case of selected mixtures (atrazine + 2,4-D and isoproturon + dicamba), recovery of both plant species was noted, while the efficiency depended on the herbicide concentration in the mixture rather than the presence or absence of HA.

Non-aspirin non-steroidal anti-inflammatory drugs in prevention of colorectal cancer in people aged 40 or older: A systematic review and meta-analysis.

There is still insufficient data about the risk-benefit profile about recommending non-aspirin, non-steroidal anti-inflammatory drugs (NA-NSAIDs) for colorectal cancer (CRC) prevention, especially in people aged 40 years or older. This study specifically addressed the association between regular NA-NSAIDs use and CRC risk in the population aged 40 years or older, performing a comprehensive systematic review and meta-analysis of all published studies on this topic until April 2018, by a search of PubMed, Scopus and Web of science databases and clinical trial registries. Two reviewers independently selected studies based on predefined inclusion criteria and assessed study quality using the Newcastle-Otawa scale. The data was combined with the random effects model. Potential heterogeneity was calculated as Q statistic and I2 value. A total of 23 studies involving more than 1 million subjects contributed to the analysis. Pooled odds ratio (OR) of NA-NSAIDs effects on CRC risk was 0.74 (0.67-0.81), I2 = 75.9%, p < 0.001. Heterogeneity was explained by a number of variables including the quality of the studies. Significant protective effects of NA-NSAIDs use were found for women (risk reduction of 19%), higher doses (risk reduction of 18%), distal colon cancer (risk reduction of 22%) and white people (risk reduction from 31% to 41%). From the results NA-NSAIDs use appears to be CRC chemopreventive for a specific subgroup of the population.