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Inflammation Aug 2023Sepsis is a disease with a very high mortality rate, mainly involving an immune-dysregulated response due to bacterial infection. Most studies are currently limited to...
Sepsis is a disease with a very high mortality rate, mainly involving an immune-dysregulated response due to bacterial infection. Most studies are currently limited to the whole blood transcriptome level; however, at the single cell level, there is still a great deal unknown about specific cell subsets and disease markers. We obtained 29 peripheral blood single-cell sequencing data, including 66,283 cells from 10 confirmed samples of sepsis infection and 19 healthy samples. Cells related to the sepsis phenotype were identified and characterized by the "scissor" method. The regulatory relationships of sepsis-related phenotype cells in the cellular communication network were clarified using the "cell chat" method. The least absolute shrinkage and selection operator (LASSO), support vector machine (SVM), and random forest (RF) were used to identify sepsis signature genes of diagnostic value. External validation was performed using multiple datasets from the GEO database (GSE28750, GSE185263, GSE57065) and 40 clinical samples. Bayesian algorithm was used to calculate the regulatory network of LILRA5 co-expressed genes. The stability of atenolol-targeting LILRA5 was determined by molecular docking techniques. Ultimately, action trajectory and survival analyses demonstrate the effectiveness of atenolol-targeted LILRA5 in treating patients with sepsis. We successfully identified 1215 healthy phenotypic cells and 462 sepsis phenotypic cells. We focused on 447 monocytes of the sepsis phenotype. Among the cellular communications, there were a large number of differences between these cells and other immune cells showing a significant inflammatory phenotype compared to the healthy phenotypic cells. Together, the three machine learning algorithms identified the LILRA5 marker gene in sepsis patients, and validation results from multiple external datasets as well as real-world clinical samples demonstrated the robust diagnostic performance of LILRA5. The AUC values of LILRA5 in the external datasets GSE28750, GSE185263, and GSE57065 could reach 0.875, 0.940, and 0.980, in that order. Bayesian networks identified a large number of unknown regulatory relationships for LILRA5 co-expression. Molecular docking results demonstrated the possibility of atenolol targeting LILRA5 for the treatment of sepsis. Behavioral trajectory analysis and survival analysis demonstrate that atenolol has a desirable therapeutic effect. LILRA5 is a marker gene in sepsis patients, and atenolol can stably target LILRA5.
Topics: Humans; Atenolol; Bayes Theorem; Molecular Docking Simulation; Sepsis; Machine Learning
PubMed: 36920635
DOI: 10.1007/s10753-023-01803-8 -
The Lancet. Neurology Nov 2023Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial.
BACKGROUND
Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease.
METHODS
We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated.
FINDINGS
Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years [SD 9·9]) and 26 with CADASIL (53·1 years [7·0]) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10%/mm Hg [SE 20·1; 95% CI -37·6 to 41·2] for amlodipine; 16·7 × 10%/mm Hg [20·0; -22·3 to 55·8] for losartan; -7·1 × 10%/mm Hg [19·6; -45·5 to 31·1] for atenolol; p=0·39) but did differ in patients with CADASIL (15·7 × 10%/mm Hg [SE 27·5; 95% CI -38·3 to 69·7] for amlodipine; 19·4 × 10%/mm Hg [27·9; -35·3 to 74·2] for losartan; -23·9 × 10%/mm Hg [27·5; -77·7 to 30·0] for atenolol; p=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (-39·6 × 10%/mm Hg [95% CI -72·5 to -6·6; p=0·019) and with losartan compared with atenolol (-43·3 × 10%/mm Hg [-74·3 to -12·3]; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake.
INTERPRETATION
4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research.
FUNDING
EU Horizon 2020 programme.
Topics: Humans; Middle Aged; Aged; Antihypertensive Agents; Blood Pressure; Losartan; Atenolol; CADASIL; Cross-Over Studies; Treatment Outcome; Hypertension; Amlodipine; Double-Blind Method
PubMed: 37863608
DOI: 10.1016/S1474-4422(23)00293-4 -
The Medical Letter on Drugs and... May 2024
Review
Topics: Humans; Hypertension; Antihypertensive Agents; Blood Pressure
PubMed: 38771738
DOI: 10.58347/tml.2024.1703a -
Materials (Basel, Switzerland) Mar 2024Adsorptive, catalytic, and antibacterial properties of clinoptilolite-rich tuffs (ZT) are presented here. ZT transformed into Fe-containing ZT (Fe-ZT) removes various... (Review)
Review
Adsorptive, catalytic, and antibacterial properties of clinoptilolite-rich tuffs (ZT) are presented here. ZT transformed into Fe-containing ZT (Fe-ZT) removes various organic and inorganic anions from water. Fe-ZT, which contains selenium, is beneficial for growing mushrooms. The fungi convert inorganic Se from Fe-ZT into a more useful organically bonded form. ZT and Fe-ZT as supplements retain nitrogen and potassium in sandy, silty loam and silty clay soils. ZT shows an affinity toward toxic metal cations, which are essential for cleaning contaminated water. The adsorption of atenolol, acetylsalicylic, and salicylic acid onto M-ZT (M-Cu, Mn, Ni, or Zn) from water solutions suggests that both the natures of M and pharmaceuticals have a significant impact on the adsorption mechanism and determine the adsorption capability of the ZT. ZT is an excellent carrier for ultrafine (2-5 nm) nano oxide particles, which have been shown to have catalytic activity in different chemical processes and photodegradation reactions of organic pollutants. ZT can also be transformed into SO-SnO-ZT, which is catalytically active as a solid acid. M-ZT is an effective carrier of valuable bacteria. Ag-ZT possesses beneficial bactericidal activity in disinfecting water and soil remediation.
PubMed: 38541460
DOI: 10.3390/ma17061306 -
The Medical Letter on Drugs and... Jan 2024
Topics: Humans; Atrial Fibrillation
PubMed: 38180321
DOI: 10.58347/tml.2024.1693a -
Environmental Toxicology and... Sep 2023Blood pressure medications like atenolol are detected in aquatic ecosystems. The objectives here were to (1) map the global presence of atenolol in surface water and... (Review)
Review
Blood pressure medications like atenolol are detected in aquatic ecosystems. The objectives here were to (1) map the global presence of atenolol in surface water and sewage; (2) present current knowledge regarding removal efficiency and degradation of atenolol; (3) identify biological endpoints sensitive to exposure; (4) reveal molecular biomarkers that may be useful for exposure studies in fish; (5) determine whether toxicology studies are within environmental relevance. In fish, atenolol exposure affects endocrine and immune systems, metabolism, and epigenetics. Fewer than half of all studies measuring biological responses use environmentally-relevant concentrations. Heart rate appeared most sensitive to atenolol exposure relative to other endpoints. Data are lacking for behavioral responses to atenolol. Molecular biomarkers for atenolol may include those associated with acute kidney injury, cholestasis, and hypertriglyceridemia. Head kidney and liver may therefore be useful for detecting atenolol-induced effects. This review synthesizes knowledge regarding atenolol-induced toxicity in fish.
Topics: Animals; Atenolol; Ecosystem; Fishes; Biomarkers
PubMed: 37481051
DOI: 10.1016/j.etap.2023.104236 -
The Science of the Total Environment Dec 2023The presence of pharmaceuticals in surface water and wastewater has been an increasing area of research since they can represent a possible route for human exposure when...
The presence of pharmaceuticals in surface water and wastewater has been an increasing area of research since they can represent a possible route for human exposure when these waters are used to irrigate crops. The concentration of these drugs in crops depends on their uptake and translocation within plants. A less recognized question is that over 50 % of pharmaceuticals are chiral compounds, but there is little knowledge about their enantioselectivity in plants. In this study, we evaluated the uptake, bioconcentration, and translocation of enantiomers of atenolol, a commonly used beta-blocker, in Arabidopsis thaliana cells and Lactuca sativa plants under hydroponic conditions. Atenolol was taken up by Arabidopsis thaliana cells during 120 h of exposure to solutions with 1 mg/L of R/S-(±)-atenolol. A moderate preference for R-(+)-atenolol over S-(-)-atenolol was observed, with the enantiomeric fraction (EF) reaching 0.532 ± 0.002 for the R enantiomer. Atenolol was also taken up and translocated by Lactuca sativa after hydroponic cultivation in nutrient solutions containing 1 or 10 μg/L R/S-(±)-atenolol. Moderate enantioselectivity was detected in the treatment with 10 μg/L, and the EF after 168 h was 0.42 ± 0.01, suggesting that S-(-)-atenolol was preferentially accumulated. Selectivity was also observed in the translocation factor (TF), calculated as the ratio of the concentration in the leaves over that in the roots. As many emerging contaminants are chiral, our findings highlight the importance to consider their fate and risks in terrestrial ecosystems at the enantiomer scale.
Topics: Humans; Atenolol; Arabidopsis; Stereoisomerism; Ecosystem; Embryophyta; Crops, Agricultural; Pharmaceutical Preparations
PubMed: 37657535
DOI: 10.1016/j.scitotenv.2023.166720 -
American Journal of Obstetrics &... Jan 2024Risk mitigation for most teratogenic medications relies on risk communication via drug label, and prenatal exposures remain common. Information on the types of and risk...
BACKGROUND
Risk mitigation for most teratogenic medications relies on risk communication via drug label, and prenatal exposures remain common. Information on the types of and risk factors for prenatal exposures to medications with teratogenic risk can guide strategies to reduce exposure.
OBJECTIVE
This study aimed to identify medications with known or potential teratogenic risk commonly used during pregnancy among privately insured persons.
STUDY DESIGN
We used the Merative™ MarketScan® Commercial Database to identify pregnancies with live or nonlive (ectopic pregnancies, spontaneous and elective abortions, stillbirths) outcomes among persons aged 12 to 55 years from 2011 to 2018. Start/end dates of medication exposure and pregnancy outcomes were identified via an adapted algorithm based on validation studies. We required continuous health plan enrollment from 90 days before conception until 30 days after the pregnancy end date. Medications with known or potential teratogenic risk were selected from TERIS (Teratogen Information System) and drug monographs based on the level of risk and quality of evidence (138 with known and 60 with potential risk). We defined prenatal exposure on the basis of ≥1 outpatient pharmacy claim or medical encounter for medication administration during target pregnancy periods considering medication risk profiles (eg, risk only in the first trimester or at a certain dose threshold). Sex hormones and hormone analogs, and abortion and postpartum/abortion hemorrhage treatments were not considered as teratogenic medications because of challenges in separating pregnancy-related indications, nor were opioids (because of complex risk-benefit considerations) or antiobesity medications if their only teratogenic mechanism was weight loss.
RESULTS
Among all pregnancies, the 10 medications with known teratogenic risk and the highest prenatal exposures were sulfamethoxazole/trimethoprim (1988 per 100,000 pregnancy-years), high-dose fluconazole (1248), topiramate (351), lisinopril (144), warfarin (57), losartan (56), carbamazepine (50), valproate (49), vedolizumab (28 since 2015), and valsartan (25). Prevalence of exposure to sulfamethoxazole/trimethoprim decreased from 2346 to 1453 per 100,000 pregnancy-years from 2011 to 2018, but prevalence of exposure to vedolizumab increased 6-fold since its approval in 2015. Prenatal exposures in the first trimester were higher among nonlive pregnancies than among live-birth pregnancies, with the largest difference observed for warfarin (nonlive 370 vs live birth 78), followed by valproate (258 vs 86) and topiramate (1728 vs 674). Prenatal exposures to medications with potential teratogenic risk were most prevalent for low-dose fluconazole (6495), metoprolol (1325), and atenolol (448). The largest first-trimester exposure differences between nonlive and live-birth pregnancies were observed for lithium (242 vs 89), gabapentin (1639 vs 653), and duloxetine (1914 vs 860). Steady increases in hydralazine and gabapentin exposures were observed during the study years, whereas atenolol exposure decreased (561 to 280).
CONCLUSION
Several medications with teratogenic risk for which there are potentially safer alternatives continue to be used during pregnancy. The fluctuating rates of prenatal exposure observed for select teratogenic medications suggest that regular reevaluation of risk mitigation strategies is needed. Future research focusing on understanding the clinical context of medication use is necessary to develop effective strategies for reducing exposures to medications with teratogenic risk during pregnancy.
Topics: Pregnancy; Female; Humans; United States; Teratogens; Valproic Acid; Topiramate; Prenatal Exposure Delayed Effects; Gabapentin; Warfarin; Atenolol; Fluconazole; Sulfamethoxazole; Trimethoprim
PubMed: 38061552
DOI: 10.1016/j.ajogmf.2023.101245