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International Journal of Molecular... Oct 2021Sublethal dosages of imidacloprid cause long-term destructive effects on honey bees at the individual and colony levels. In this review, the molecular effects of... (Review)
Review
Sublethal dosages of imidacloprid cause long-term destructive effects on honey bees at the individual and colony levels. In this review, the molecular effects of sublethal imidacloprid were integrated and reported. Several general effects have been observed among different reports using different approaches. Quantitative PCR approaches revealed that imidacloprid treatments during the adult stage are expressed as changes in immuneresponse, detoxification, and oxidation-reduction response in both workers and queens. In addition, transcriptomic approaches suggested that phototransduction, behavior, and somatic muscle development also were affected. Although worker larvae show a higher tolerance to imidacloprid than adults, molecular evidence reveals its potential impacts. Sublethal imidacloprid treatment during the larval stage causes gene expression changes in larvae, pupae, and adults. Transcriptome profiles suggest that the population and functions of affected differentially expressed genes, DEGs, vary among different worker ages. Furthermore, an early transcriptomic switch from nurse bees to foragers was observed, suggesting that precocious foraging activity may occur. This report comprehensively describes the molecular effects of sublethal dosages of imidacloprid on the honey bee . The corresponding molecular pathways for physiological and neurological responses in imidacloprid-exposed honey bees were validated. Transcriptomic evidence suggests a global and sustained sublethal impact of imidacloprid on honey bee development.
Topics: Animals; Bees; Larva; Neonicotinoids; Nitro Compounds; Transcriptome
PubMed: 34769266
DOI: 10.3390/ijms222111835 -
Journal of the American Heart... May 2024Hypertension and hypercholesterolemia are important risk factors for cardiovascular disease, and treatment with fixed-dose combination (FDC) regimens is recommended by...
BACKGROUND
Hypertension and hypercholesterolemia are important risk factors for cardiovascular disease, and treatment with fixed-dose combination (FDC) regimens is recommended by current guidelines. However, the clinical outcomes of different FDC dosages remain unknown. This study aimed to examine the clinical outcomes of FDC regimens and the free combination of amlodipine and atorvastatin at different dosages.
METHODS AND RESULTS
Patients with concurrent hypertension and hypercholesterolemia treated daily with an FDC of 5 mg amlodipine and 10 mg atorvastatin (5/10 fixed group), and FDC of 5 mg amlodipine and 20 mg atorvastatin (5/20 fixed group), or free combination of 5 mg amlodipine and 20 mg atorvastatin (5/20 free group) were identified from the National Health Insurance Research Database of Taiwan. The primary outcome was the composite cardiovascular outcomes, including cardiovascular death, acute myocardial infarction, stroke, and coronary intervention. A total of 9095 patients were eligible for inclusion. The incidence of primary outcome per 1000 person-years was 16.6 in the 5/10 fixed group, 12.6 in the 5/20 fixed group, and 16.5 in the 5/20 free group (5/20 fixed versus 5/20 free: hazard ratio [HR], 0.76 [95% CI, 0.64-0.91]; 5/20 fixed versus 5/10 fixed: HR, 0.76 [95% CI, 0.63-0.90]).
CONCLUSIONS
Among patients with concomitant hypertension and hypercholesterolemia, treatment with an FDC of amlodipine and high-dose atorvastatin led to a lower risk of a composite of cardiovascular outcomes than treatment with the free combination or a similar FDC with a lower dose of atorvastatin.
Topics: Humans; Amlodipine; Male; Hypercholesterolemia; Hypertension; Female; Middle Aged; Atorvastatin; Aged; Taiwan; Drug Combinations; Treatment Outcome; Antihypertensive Agents; Retrospective Studies; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Anticholesteremic Agents; Calcium Channel Blockers; Blood Pressure; Heptanoic Acids; Pyrroles
PubMed: 38686894
DOI: 10.1161/JAHA.123.033780 -
Briefings in Bioinformatics Nov 2023Large-scale imputation reference panels are currently available and have contributed to efficient genome-wide association studies through genotype imputation. However,...
Large-scale imputation reference panels are currently available and have contributed to efficient genome-wide association studies through genotype imputation. However, whether large-size multi-ancestry or small-size population-specific reference panels are the optimal choices for under-represented populations continues to be debated. We imputed genotypes of East Asian (180k Japanese) subjects using the Trans-Omics for Precision Medicine reference panel and found that the standard imputation quality metric (Rsq) overestimated dosage r2 (squared correlation between imputed dosage and true genotype) particularly in marginal-quality bins. Variance component analysis of Rsq revealed that the increased imputed-genotype certainty (dosages closer to 0, 1 or 2) caused upward bias, indicating some systemic bias in the imputation. Through systematic simulations using different template switching rates (θ value) in the hidden Markov model, we revealed that the lower θ value increased the imputed-genotype certainty and Rsq; however, dosage r2 was insensitive to the θ value, thereby causing a deviation. In simulated reference panels with different sizes and ancestral diversities, the θ value estimates from Minimac decreased with the size of a single ancestry and increased with the ancestral diversity. Thus, Rsq could be deviated from dosage r2 for a subpopulation in the multi-ancestry panel, and the deviation represents different imputed-dosage distributions. Finally, despite the impact of the θ value, distant ancestries in the reference panel contributed only a few additional variants passing a predefined Rsq threshold. We conclude that the θ value substantially impacts the imputed dosage and the imputation quality metric value.
Topics: Humans; Genome-Wide Association Study; Gene Frequency; Polymorphism, Single Nucleotide; Genotype
PubMed: 38221906
DOI: 10.1093/bib/bbad509 -
The American Journal of Clinical... Jan 2022There remains a lack of evidence demonstrating a potential relationship between vitamin D and cardiometabolic risk among children. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
There remains a lack of evidence demonstrating a potential relationship between vitamin D and cardiometabolic risk among children.
OBJECTIVES
We examined the effect of 3 different dosages of vitamin D on cardiometabolic risk factors among children at risk of deficiency.
METHODS
Racially diverse schoolchildren aged 8-15 y were randomly assigned in a double-blind fashion to supplementation with 600, 1000, or 2000 IU vitamin D3/d for 6 mo. Changes in HDL cholesterol, triglycerides, LDL cholesterol, total cholesterol, and blood glucose over 6 mo and at 12 mo (6 mo post-supplementation) were assessed. Subgroup analyses were also performed by weight status and race.
RESULTS
Among 604 children, 40.9% were vitamin D-inadequate at baseline (<20 ng/mL; mean ± SD: 22.0 ± 6.8 ng/mL), 46.4% were overweight/obese, and 60.9% had ≥1 suboptimal blood lipids or glucose. Over 6 mo, serum 25-hydroxyvitamin D increased in all 3 dosage groups from baseline (mean ± SE change: 4.4 ± 0.6 ng/mL, 5.7 ± 0.7 ng/mL, and 10.7 ± 0.6 ng/mL for 600, 1000, and 2000 IU/d, respectively; P < 0.001). Whereas HDL cholesterol and triglycerides increased in the 600 IU group (P = 0.002 and P = 0.02, respectively), LDL cholesterol and total cholesterol decreased across dosage groups. At 6 mo post-supplementation, HDL cholesterol remained elevated in the 600 and 1000 IU groups ( P < 0.001 and P = 0.02, respectively) whereas triglycerides remained elevated in the 1000 and 2000 IU groups (P = 0.04 and P = 0.006, respectively). The suppression of LDL cholesterol and total cholesterol persisted in the 2000 IU group only (P = 0.04 and P < 0.001, respectively). There were no significant changes in blood glucose and similar responses were observed overall by weight status and racial groups across dosages.
CONCLUSIONS
Vitamin D supplementation demonstrated generally positive effects on HDL cholesterol, LDL cholesterol, and total cholesterol, especially at the lower dosage of 600 IU/d, with several significant changes persisting during the post-supplementation period. Increases in triglycerides across dosage groups may be due to natural changes during adolescence warranting further study.This trial was registered at clinicaltrials.gov as NCT01537809.
Topics: Adolescent; Blood Glucose; Cardiometabolic Risk Factors; Child; Child Nutritional Physiological Phenomena; Cholecalciferol; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dietary Supplements; Double-Blind Method; Female; Humans; Male; Pediatric Obesity; Triglycerides; Vitamin D; Vitamin D Deficiency
PubMed: 34550329
DOI: 10.1093/ajcn/nqab319 -
International Journal of General... 2021Droxidopa is approved for the treatment of neurogenic orthostatic hypotension (nOH) symptoms and requires patients to be titrated to individualized effective doses...
Droxidopa is approved for the treatment of neurogenic orthostatic hypotension (nOH) symptoms and requires patients to be titrated to individualized effective doses (100-600 mg, three times daily) based on symptomatic response. As per the product label, droxidopa should be titrated every 24-48 hours to an optimum maintenance dose (maximum daily dosage 1,800 mg). In an examination of patients with nOH treated in clinical practice settings (n=4,506) using data from the central Northera specialty-pharmacy hub, titration schedules, daily titration dosage (ie, dosage during first dispensation, the assumed titration period), and daily maintenance dosage (dosage during subsequent dispensations) were characterized. It was found that customized titration schedules (ie, different from the product-label recommendation) had been used in 53% of patients, and these patients had had an average daily titration dosage of 567 mg. In contrast, patients who were titrated as per the label schedule (48 hours, 37%; 24 hours, 10%) had daily titration dosages of 1,500-1,650 mg. A relationship between treatment persistence (measured by number of refills) and maintenance dosage was identified. Average daily maintenance doses in patients who received 2, 3-6, 7-24, and >25 dispensations were 938, 969, 1,069, and 1,167 mg, respectively (<0.0001). In summary, our data suggest that more than half the patients treated with droxidopa in clinical practice settings are not titrated using the schedule recommended on the product label (ie, not 24-48 hours), and as a result receive lower daily dosages of droxidopa than those treated using the recommended titration schedules. Lower daily maintenance dosages of droxidopa were associated with shorter treatment persistence (ie, fewer dispensations). Reasons for discontinuation could not be examined in this study, but further investigation of these persistence data is warranted.
PubMed: 34421309
DOI: 10.2147/IJGM.S304012 -
Cureus Oct 2022Vitamin A deficiency is an epidemiologically significant concern in all age groups, especially in preterm and term infants. Its deficiency causes various developmental... (Review)
Review
Vitamin A deficiency is an epidemiologically significant concern in all age groups, especially in preterm and term infants. Its deficiency causes various developmental malformations. Vitamin A supplementation has been a practiced alternative for many decades, but its effectiveness is debatable in the medical system. The bioavailability of beta-carotenes varies greatly and ranges from 2% to 30%, depending on how it is present in the plant's cellular composition. Vitamin A has a bioavailability of up to 75%. The bioavailability of beta-carotenes is positively impacted by several activities but mainly by mechanical ones that allow cellular interaction. These include enough chewing, mincing, and pureeing. The bioavailability of beta-carotene can be increased by moderate cooking and combining high-quality lipids. The WHO recommends waiting for a minimum of one month between vitamin A dosages. Six months is the maximum amount of time between dosages. For instance, giving the optimum dosage to a child who has not had vitamin A in two months is preferable to skipping the dose and making the child wait eight months (i.e., two months plus six months) before receiving the following amount. There were no discernible variations in the occurrence of momentarily increased aspartate aminotransferase (AST), alanine transaminase (ALT), or alkaline phosphatase between the leading group and the trace group. However, patients in the top group experienced high blood triacylglycerol levels more frequently than those in the trace group, suggesting that hypertriacylglycerolemia may be a side effect of vitamin A administration. It is imperative to memo that neonatal vitamin A supplementation negatively affects subsequent diphtheria-pertussis-tetanus (DPT) vaccination in females. Since many children are delayed in obtaining their initial DPT series, several nations prescribe DPT boosters, so older children may be affected if vitamin A supplementation negatively interacts with DPT in such children.
PubMed: 36381685
DOI: 10.7759/cureus.30242 -
Therapeutic Innovation & Regulatory... Nov 20223d printing is capable of providing dose individualization for pediatric medicines and translating the precision medicine approach into practical application. In... (Review)
Review
3d printing is capable of providing dose individualization for pediatric medicines and translating the precision medicine approach into practical application. In pediatrics, dose individualization and preparation of small dosage forms is a requirement for successful therapy, which is frequently not possible due to the lack of suitable dosage forms. For precision medicine, individual characteristics of patients are considered for the selection of the best possible API in the most suitable dose with the most effective release profile to improve therapeutic outcome. 3d printing is inherently suitable for manufacturing of individualized medicines with varying dosages, sizes, release profiles and drug combinations in small batch sizes, which cannot be manufactured with traditional technologies. However, understanding of critical quality attributes and process parameters still needs to be significantly improved for this new technology. To ensure health and safety of patients, cleaning and process validation needs to be established. Additionally, adequate analytical methods for the in-process control of intermediates, regarding their printability as well as control of the final 3d printed tablets considering any risk of this new technology will be required. The PolyPrint consortium is actively working on developing novel polymers for fused deposition modeling (FDM) 3d printing, filament formulation and manufacturing development as well as optimization of the printing process, and the design of a GMP-capable FDM 3d printer. In this manuscript, the consortium shares its views on quality aspects and measures for 3d printing from drug-loaded filaments, including formulation development, the printing process, and the printed dosage forms. Additionally, engineering approaches for quality assurance during the printing process and for the final dosage form will be presented together with considerations for a GMP-capable printer design.
Topics: Child; Drug Combinations; Drug Liberation; Humans; Polymers; Printing, Three-Dimensional; Solubility
PubMed: 34826120
DOI: 10.1007/s43441-021-00354-0 -
Iranian Journal of Pharmaceutical... Dec 2022The determination of radioiodine remnant ablation (RRA) dosage in post-operation thyroid residual tissues resection has been largely subject of discussion, yet no... (Review)
Review
The determination of radioiodine remnant ablation (RRA) dosage in post-operation thyroid residual tissues resection has been largely subject of discussion, yet no concise conclusion is released through systematic review studies. In this study, we conducted a systematic review of comparative experiments to evaluate and compare the efficacy of different prescribed dosages of radioiodine in post-op thyroid residual tissues resection among low, intermediate, and high-risk patients to approve the common method. Using automated searches, studies were collected from PubMed, Google Scholar, Elsevier, Scopus, and UpToDate, all until April 2021. Alongside the aforementioned sources, comparative experiments were added in for further investigation. Overall, 4000 patients with papillary thyroid cancer, differentiated thyroid carcinoma (DTC), metastasized and non-metastasized thyroid cancer took part in twenty-one trials are assessed. We discovered no significant difference in successful thyroid residual tissues excision between low-activity and high-activity radioiodine treatment in people with low and intermediate risk. In these individuals, there was no significant difference between the high therapeutic dose of 3700 MBq and the lesser dose of 1850 MBq for RRA. However, high-dose treatment usually yielded superior results. Low activity RRA causes fewer adverse effects in metastasis-free patients than high-activity 3.7 GBq. There was no significant therapeutic difference regarding treatment efficacy in patients with low and moderate risks. However, in patients with high-risk status, applying a high-dose regimen of RRA produced a significantly better response.
PubMed: 36060901
DOI: 10.5812/ijpr-123825 -
Pharmaceutics May 2023The effects of various dosages and treatment regimens on intravitreal aflibercept concentrations and the proportion of free vascular endothelial growth factor (VEGF) to...
BACKGROUND
The effects of various dosages and treatment regimens on intravitreal aflibercept concentrations and the proportion of free vascular endothelial growth factor (VEGF) to total VEGF were evaluated using a drug and disease assessment model. The 8 mg dosage received specific attention.
METHODS
A time-dependent mathematical model was developed and implemented using Wolfram Mathematica software v12.0. This model was used to obtain drug concentrations after multiple doses of different aflibercept dosages (0.5 mg, 2 mg, and 8 mg) and to estimate the time-dependent intravitreal free VEGF percentage levels. A series of fixed treatment regimens were modeled and evaluated as potential clinical applications.
RESULTS
The simulation results indicate that 8 mg aflibercept administered at a range of treatment intervals (between 12 and 15 weeks) would allow for the proportion of free VEGF to remain below threshold levels. Our analysis indicates that these protocols maintain the ratio of free VEGF below 0.001%.
CONCLUSIONS
Fixed q12-q15 (every 12-15 weeks) 8 mg aflibercept regimens can produce adequate intravitreal VEGF inhibition.
PubMed: 37242658
DOI: 10.3390/pharmaceutics15051416 -
European Journal of Pediatrics Mar 2022In daily paediatrics, drugs are commonly used off-label, as they are not approved for children. Approval is lacking because the required clinical studies were limited to...
In daily paediatrics, drugs are commonly used off-label, as they are not approved for children. Approval is lacking because the required clinical studies were limited to adults in the past. Without clinical studies, evidence-based recommendations for drug use in children are limited. Information on off-label drug dosing in children can be found in different handbooks, databases and scientific publications but the dosing recommendations can differ considerably. To improve safety and efficacy of drugs prescribed to children and to assist the prescribers, stakeholders in Swiss paediatrics started a pilot project, supported by the Federal Office of Public Health, with the aim to create a database, providing healthcare professionals with so called "harmonised" dosage recommendations based on the latest available scientific evidence and best clinical practice. A standardised process for dosage harmonisation between paediatric experts was defined, guided and documented in an electronic tool, developed for this purpose. As proof of principle, a total of 102 dosage recommendations for 30 different drugs have been nationally harmonised in the pilot phase considering the current scientific literature and the approval of the most experienced national experts in the field.Conclusion: This approach paved the way for unified national dosage recommendations for children. Reaching the project's milestones fulfilled the prerequisites for funding and starting regular operation of SwissPedDose in 2018. Since then, the database was extended with recommendations for 100 additional drugs. What is Known: • Prescribing off-label is a common practice among paediatricians, as many drugs are still not authorised for use in children. • Some countries developed national drug formularies providing off-label dosage recommendations. What is New: • Comparison of published dosage recommendations in known drug handbooks and online databases show substantial differences and heterogeneity, revealing the need for harmonisation. • The design of a tool for standardised harmonisation of dosage recommendations, based on information collected on currently applied dosages, latest scientific evidence and the approval of experts.
Topics: Adult; Child; Databases, Pharmaceutical; Drug Labeling; Humans; Off-Label Use; Pediatrics; Pilot Projects; Switzerland
PubMed: 34739591
DOI: 10.1007/s00431-021-04304-8