Optimal Dose Range Research Articles

Palmitoylethanolamide as a Supplement: The Importance of Dose-Dependent Effects for Improving Nervous Tissue Health in an In Vitro Model.

Palmitoylethanolamide (PEA) is a highly lipophilic molecule with low solubility, making absorption difficult. Recent techniques like micronisation, ultra-micronisation and combining PEA with solvents have improved their bioavailability and stability. Our study analysed particle size differences and absorption kinetics using specific solvents (PEAΩ and PEA DynoΩ) over time (0.5 h-6 h) in a dose-dependent manner (200 mg-1800 mg). The results showed that PEAΩ and PEA DynoΩ achieved 82-63% absorption at 3 h, compared to 30-60% for micronised, ultra-micronised PEA and a commercial product, highlighting the optimal dose range of 300 mg-600 mg. In addition, a 3D model of the peripheral nerve was utilised to explain the efficacy after gut passage and support the most effective dose (300 mg or 600 mg) achieved at the gut level. PEAΩ and PEA DynoΩ, which are associated with better intestinal bioavailability compared to PEA-micronised, PEA ultra-micronised and a commercial product, have allowed not only a reduction in the inflammatory context but also an improvement of peripheral nerve well-being by increasing specific markers like MPZ (26-36% vs. 8-15%), p75 (25-32% vs. 13-16%) and NRG1 (22-29.5% vs. 11-14%). These results highlight the potential of advanced PEA formulations to overcome solubility challenges and maintain in vitro efficacy, modulating peripheral nerve well-being.

Abstract We079: Program Macrophage Phenotypes and Cardiac Remodeling After Myocardial Infarction with Interleukin-10

Introduction: Macrophages (Mφ) and their phenotypic polarization play essential roles in modulating cardiac inflammation and recovery after myocardial infarction (MI). Interleukin-10 (IL-10) is a potent immunomodulatory cytokine that directs Mφ polarization to beneficial reparative phenotypes and is widely investigated in diseases involving extensive inflammation. However, high-dose IL-10 treatment may not lead to the expected therapeutic outcome, raising the question of whether IL-10 has dose-dependent effects on Mφ polarization and cardiac remodeling post-MI. Hypothesis: IL-10 can program Mφ phenotypes under inflammation and has functional impact in cardiac remodeling post-MI in dose-dependent manner. Goals: We use RAW264.7 Mφ and mouse permanent MI models to test our hypothesis. Approach: We applied 25-1000 ng/mL IL-10 in vitro before or after inducing M1 (with interferon-g) and M2 (with interleukin-4) polarization for pro-inflammatory and anti-inflammatory phenotypes, respectively. We intramyocardially administered 25-2000 ng IL-10 in vivo immediately after inducing MI and examined cardiac function, inflammatory responses, fibrosis and revascularization for 6 weeks (n=5/group). Results: IL-10 at 100-250 ng/mL directed Mφ phenotype shift from M1 to M2 most effectively after inducing polarization in vitro (both p <0.01); groups with ≥500 ng/mL IL-10 exhibited high M1/low M2 phenotypes, similar to no IL-10 controls. Cells treated with ≥100 ng/mL IL-10 before polarization exhibited a notable reduction in M1 phenotype after induction (all p <0.05). Echocardiography showed that with single IL-10 administration, only 250 ng IL-10 notaly improved left ventricular (LV) function and reduced LV chamber size compared with the saline control ( p <0.05) whilst ≥1000 ng caused a transient negative impact in LV function at 5 days post-MI ( p <0.05), Phagocyte infiltration at MI was notably diminished in ≥100 ng groups at 6 weeks post-MI (all p <0.05). Only 250 ng IL-10 led to a notable 53% reduction in LV fibrosis ( p =0.05) and nearly 200% increase in CD31+ cell counts at MI ( p =0.013). Conclusion: Our results suggest an optimal range of IL-10 doses for macrophage polarization and cardiac benefits post-MI, with risks of side effects from IL-10 overdose.

Gamma irradiation-induced crosslinking and enhanced functionality of fish gelatin-agar edible films

Fish gelatin-agar edible films have potential for sustainable food packaging, but their limitations particularly water sensitivity require improvement. In this research, the effects of radiation from gamma rays at rates ranging from 0 to 40 kGy on the films' mechanical characteristics, microstructure, color, opacity, and water resistance were examined. Overall, gamma irradiation at doses of up to 30 kGy substantially improved the water resistance of the gelatin-agar film, as demonstrated by decreased water solubility, water absorption, and film vapor permeability. This could be due to crosslinking within the biopolymer network. However, at doses of 40 kGy, potential chain scission in the film's polymeric structure might occur, which counteracts further improvement and consequently starts degrading its water resistance. Similarly, the improvement of film's tensile strength and modulus of elasticity peaked at an optimal dose of 30 kGy, and then decreased at higher doses, while the film's elongation at break remained unaffected. FTIR and SEM analysis supported changes in functional group and structural morphology in these observations. Although irradiation caused some yellowing, an optimal dose range (at around 20–30 kGy) was identified to achieve improved functionality without degrading film integrity. These findings highlight the potential of gamma irradiation as a viable technique for modifying fish gelatin-agar films for enhanced performance in food packaging applications.

Effect of caffeine ingestion on time trial performance in cyclists: a systematic review and meta-analysis.

Caffeine, widely recognized as an ergogenic aid, has undergone extensive research, demonstrating its effectiveness to enhance endurance performance. However, there remains a significant gap in systematically evaluating its effects on time trial (TT) performance in cyclists. This meta-analysis aimed to determine the efficacy of caffeine ingestion to increase cycling TT performance in cyclists and to evaluate the optimal dosage range for maximum effect. A search of four databases was completed on 1 December 2023. The selected studies comprised crossover, placebo-controlled investigations into the effects of caffeine ingestion on cycling TT performance. Completion time (Time) and mean power output (MPO) were used as performance measures for TT. Meta-analyses were performed using a random-effects model to assess the standardized mean differences (SMD) in individual studies. Fifteen studies met the inclusion criteria for the meta-analyses. Subgroup analysis showed that moderate doses of caffeine intake (4-6 mg/kg) significantly improved cycling performance (SMD Time = -0.55, 95% confidence interval (CI) = -0.84 ~ -0.26, p < 0.01, I2 = 35%; SMD MPO = 0.44, 95% CI = 0.09 ~ 0.79, p < 0.05, I2 = 39%), while the effects of low doses (1-3 mg/kg) of caffeine were not significant (SMD Time = -0.34, 95% CI = -0.84 ~ 0.17, p = 0.19, I2 = 0%; SMD MPO = 0.31, 95% CI = -0.02 ~ 0.65, p = 0.07, I2 = 0%). A moderate dosage (4-6 mg/kg) of caffeine, identified as the optimal dose range, can significantly improve the time trial performance of cyclists, while a low dose (1-3 mg/kg) does not yield improvement. In addition, the improvements in completion time and mean power output resulting from a moderate dose of caffeine are essentially the same in cycling time trails.

The Effect of SkQ1 on the Oxidative Stress and Inflammatory Responses in Corneal Endothelial Cells During Ex Vivo Expansion

Purpose: The purpose of this study was to characterize the oxidative stress and inflammatory responses in ex vivo corneal endothelial cells (evCEnC) during expansion and assess the impact of SkQ1, an antioxidant and anti-inflammatory compound, on measures of oxidative stress and inflammation. Methods: A CEnC line (HCEnC-21T) was cultured in media supplemented with varying SkQ1 concentrations to determine the optimal SkQ1 dose range of toxicity and protective effect on CEnC exposed to acute oxidative stress. The impact of SkQ1 treatment on intracellular free radical (IFR) levels, NRF2-mediated oxidative stress response, and NFkB-mediated inflammatory response was determined at each passage of evCEnC isolated from donor corneas and cultured in SkQ1-supplemented and untreated media. Results: HCEnC-21T cultured in media supplemented with ≤250 nM SkQ1 retained over 95% cell viability compared with untreated cells. SkQ1 provided oxidative stress protection to HCEnC-21T in a dose-dependent manner up to 500 nM. In evCEnC, 50 nM and 250 nM SkQ1 supplementation significantly reduced IFR levels across passages 0 to 3 (P-values of 0.015 and 0.023, respectively) and 50 nM SkQ1 supplementation led to decreased levels of active NRF2 in evCEnC at passage 2. However, media supplementation with SkQ1 (50 nM and 250 nM) did not alter NFkB activation at any passage. Conclusions: SkQ1 media supplementation provides oxidative stress protection to HCEnC-21T in a dose-dependent manner and decreases IFR levels and NRF2 activation in evCEnC during expansion at concentrations that do not negatively affect CEnC viability. These findings indicate that SkQ1 supplementation may increase the expansion potential of evCEnC.

Beneficial effects of oleanolic acid on hepatopancreas oxidative stress and intestinal microbiota structure of red swamp crayfish (Procambarus clarkia)

This study aimed to evaluate the beneficial effects of oleanolic acid (OA) in the culture of red swamp crayfish (Procambarus clarkia) by investigating the impact of dietary OA on growth performance, hepatopancreas antioxidant activity, innate immunity, and intestinal microbiota structure. An eight-week feeding trial was conducted using different dietary OA concentrations: 0, 250, 500, 750, and 1000 mg·kg–1. The results revealed that the groups with 500–1000 mg·kg–1 OA exhibited increased final body weight, weight gain rate, and specific growth rate, as well as decreased feed conversion ratio compared to those in the control group (P < 0.05). Serum alanine transaminase (ALT) and aspartate transaminase (AST) activities showed a linear decrease with increasing dietary OA concentration. OA demonstrated hypolipidemic effects by reducing serum glucose, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels, while increasing serum high-density lipoprotein cholesterol levels (P < 0.05). OA500 to OA1000 groups exhibited significantly higher trypsin activity compared to that of the control, while lipase activity linearly decreased with increasing dietary OA concentration. The antioxidant capacity, as indicated by glutathione level in the hepatopancreas, showed significant differences between the OA treatment group and the control group. However, dietary OA did not significantly alter the structure of the intestinal microbiota. These findings suggest that dietary OA supplementation effectively improves the growth performance and enhanced the innate immunity of crayfish. Furthermore, OA significantly promotes the antioxidant capacity, thereby protecting the hepatopancreas from oxidative damage. The optimal dose range of dietary OA for application in crustacean culture is recommended to be between 500 and 1000 mg·kg−1.

Effects of Interfraction Dose Variations of Target and Organs at Risk on Clinical Outcomes in High Dose Rate Brachytherapy for Cervical Cancer.

Meeting dose prescription is critical to control tumors in radiation therapy. Interfraction dose variations (IDVs) from the prescribed dose in high dose rate brachytherapy (HDR) would cause the target dose to deviate from the prescription but their clinical effect has not been widely discussed in the literature. Our previous study found that IDVs followed a left-skewed distribution. The clinical effect of the IDVs in 100 cervical cancer HDR patients will be addressed in this paper. An in-house Monte Carlo (MC) program was used to simulate clinical outcomes by convolving published tumor dose response curves with IDV distributions. The optimal dose and probability of risk-free local control (RFLC) were calculated using the utility model. The IDVs were well-fitted by the left-skewed Beta distribution, which caused a 3.99% decrease in local control probability and a 1.80% increase in treatment failure. Utility with respect to IDV uncertainty increased the RFLC probability by 6.70% and predicted an optimal dose range of 83 Gy-91 Gy EQD2. It was also found that a 10 Gy dose escalation would not affect toxicity. In conclusion, HRCTV IDV uncertainty reduced LC probabilities and increased treatment failure rates. A dose escalation may help mitigate such effects.

Analgesic and Antipyretic Activity of Sweet Orange Peel Methanol Extract

An analgesic-antipyretic drug widely used is paracetamol, which has various health benefits and several adverse effects. Therefore, various natural products have been extensively studied as alternative analgesic-antipyretics, one of which is sweet orange peel. This study aimed to investigate sweet orange peel's analgesic and antipyretic activity by in vivo methods. This experimental study evaluated the analgesic and antipyretic effects of sweet orange peel extract extracted by the maceration method. The analgesic effect was evaluated by tail immersion (Maximum Possible Analgesia) and acetic acid-induced writhing method (total abdominal writhing). Meanwhile, the antipyretic effect was evaluated by the brewer yeast-induced hyperpyrexia (body temperature) method. This study showed that sweet orange peel methanol extract significantly increased the maximum possible analgesia value (132.79%) and reduced the number of abdominal writhing (44.05%) at the highest dose of 750 mg/kg BW. It indicated analgesic activity from sweet orange peels. Meanwhile, the antipyretic effect of sweet orange peel methanol extract was observed from 1-4 hours after administration, and the highest percentage inhibition of body temperature 4 hours after administration was found in a moderate dose, that was 5.98% (P value: 0.042). Therefore, it can be concluded that sweet orange peel methanol extract has analgesic and antipyretic effects with an optimal dose range of 500-750 mg/kg BW.

Effects of monensin supplementation on rumen fermentation, methane emissions, nitrogen balance, and metabolic responses of dairy cows: A systematic review and dose-response meta-analysis

To investigate the effects of supplemental monensin administration on the metabolic responses of dairy cows, a systematic review and dose-response meta-analysis were conducted. Initially, 604 studies were identified through comprehensive database searches, including Google Scholar, Scopus, Science Direct, and PubMed, using key words related to dairy cows, monensin, and metabolic outcomes. After a 2-stage screening process, 51 articles with a total of 60 experiments were selected for meta-analysis based on criteria such as study implementation date between 2001 and 2022, presence of a control group that did not receive monensin supplementation, reporting of at least 1 outcome variable, and presentation of means and corresponding errors. The meta-analysis used the 1-stage random-effects method, and sensitivity analyses were performed to assess the robustness of the results. The results showed that the administration of monensin at a dosage of 19 to 26 mg/kg was inversely related to methane emissions and that the administration of monensin at a dosage of 18 to 50 mg/kg resulted in a significant decrease in dry matter intake. Administration of monensin at doses of 13 to 28 and 15 to 24 mg/kg also resulted in a significant decrease in ruminal acetate proportion and an increase in propionate proportion, respectively, with no effects on ruminal butyrate, NH3, or pH levels. We found no effects on blood parameters or nitrogen retention, but a significant negative correlation was observed between monensin supplementation and fecal nitrogen excretion. Based on the analysis of all variables evaluated, the optimal dose range of monensin was estimated to be 19 to 24 mg/kg.

β-Glucans in particulate and solubilized forms elicit varied immunomodulatory and apoptosis effects in teleost macrophages in a dosedependent manner.

β-Glucans are a group of heterogeneous glucose polymers that possess immunomodulatory activities. The complex nature of their structures, uncertainty regarding the doses, and variable immune effects pose a challenge to comprehensive understanding. In this study, we investigated the immune responses and apoptosis effects in Nile tilapia (Oreochromis niloticus) head kidney macrophages (MФ) upon exposure to two β-Glucans (Paramylon and Laminarin) at low and high doses. Our results demonstrate that Paramylon elicits more robust immune responses than Laminarin, albeit with a dose-limiting effect. We also observed that the high-dose Paramylon induces apoptosis, whereas no such effect was detected in Laminarin treatment. Mechanistically, high-dose Paramylon activates the intrinsic apoptosis pathway, with significantly up-regulation of intrinsic apoptosis-related genes and impaired mitochondrial function. On the other hand, Laminarin triggers metabolic reprogramming in MФ, resulting in the enrichment of the metabolite α-Ketoglutarate, which protects the MФ from apoptosis. Overall, our findings highlight the importance of identifying the optimal dose range for β-Glucans, based on sources or structures, to achieve maximal immunomodulatory effects. These results have important implications for the design and optimization of β-Glucans-based drugs or adjuvants in immunotherapies.

Quantifying noise limitations of neural network segmentations in high-resolution transmission electron microscopy

Motivated by the need for low electron dose transmission electron microscopy imaging, we report the optimal frame dose (i.e.e−/Å2) range for object detection and segmentation tasks with neural networks. The MSD-net architecture shows promising abilities over the industry standard U-net architecture in generalising to frame doses below the range included in the training set, for both simulated and experimental images. It also presents a heightened ability to learn from lower dose images. The MSD-net displays mild visibility of a Au nanoparticle at 20–30 e−/Å2, and converges at 200 e−/Å2 where a full segmentation of the nanoparticle is achieved. Between 30 and 200 e−/Å2 object detection applications are still possible. This work also highlights the importance of modelling the modulation transfer function when training with simulated images for applications on images acquired with scintillator based detectors such as the Gatan Oneview camera. A parametric form of the modulation transfer function is applied with varying ranges of parameters, and the effects on low electron dose segmentation is presented.

The Intensity of the Biological Effect and Stress of Extracts of the Aerial Parts of Artemisia herba-alba-on Algae (Klisinema persicum)

Inhibitory impact of Artemisia herba-alba extract on Klisinema persicum growth was investigated. This study looked at the effects of different concentrations of A. herba-alba extracts on the growth and antioxidant enzyme (superoxide dismutase and Catalase) activity of K. persicum in order to determine the optimal dose range for the good anti-algal action. Concentrations were used (2.5,5, 10, 20, 40,80 and 160) mg. L-1 as well as control. Results showed that both crude extracted, alcoholic extract, and aqueous extract of A. herba-alba had an obvious inhibitory effect on K. persicum growth, as such the obtained results demonstrated A. herba-alba crude extracted inhibited algal growth more efficiently than alcoholic extract and aqueous extract of A. herba-alba. This investigation found that a dose of 10 mg. L-1 with above 50% of IR of extracted crude, alcoholic extractand aqueous of A. herba-alba was best, based on changes in algal cell density and inhibitory ratio (IR). Additionally, after 4 days, the extracted A. herba-alba group saw a significant decline in Chlorophyll-a concentration and antioxidant enzymes activity, falling below the detection threshold. Our findings may pave the way for further investigation into the mechanisms underlying inhibitory effects on dangerous algae, which in turn could lead to the creation of novel anti-algal materials.

Multi-generation study of heavy ion beam-induced mutations and agronomic trait variations to accelerate rice breeding.

Heavy ion beam (HIB) is an effective physical mutagen that has been widely used in plant mutational breeding. Systemic knowledge of the effects caused by different HIB doses at developmental and genomic levels will facilitate efficient breeding for crops. Here we examined the effects of HIB systematically. Kitaake rice seeds were irradiated by ten doses of carbon ion beams (CIB, 25 - 300 Gy), which is the most widely used HIB. We initially examined the growth, development and photosynthetic parameters of the M1 population and found that doses exceeding 125 Gy caused significant physiological damages to rice. Subsequently, we analyzed the genomic variations in 179 M2 individuals from six treatments (25 - 150 Gy) via whole-genome sequencing (WGS). The mutation rate peaks at 100 Gy (2.66×10-7/bp). Importantly, we found that mutations shared among different panicles of the same M1 individual are at low ratios, validating the hypothesis that different panicles may be derived from different progenitor cells. Furthermore, we isolated 129 mutants with distinct phenotypic variations, including changes in agronomic traits, from 11,720 M2 plants, accounting for a 1.1% mutation rate. Among them, about 50% possess stable inheritance in M3. WGS data of 11 stable M4 mutants, including three lines with higher yields, reveal their genomic mutational profiles and candidate genes. Our results demonstrate that HIB is an effective tool that facilitates breeding, that the optimal dose range for rice is 67 - 90% median lethal dose (LD50), and that the mutants isolated here can be further used for functional genomic research, genetic analysis, and breeding.

Effectiveness, safety, initial optimal dose, and optimal maintenance dose range of basal insulin regimens for type 2 diabetes: A systematic review with meta-analysis.

To investigate the effectiveness, safety, optimal starting dose, optimal maintenance dose range, and target fasting plasma glucose of five basal insulins in insulin-naïve patients with type 2 diabetes mellitus. MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched from January 2000 to February 2022. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach was adopted. The registration ID is CRD42022319078 in PROSPERO. Among 11 163 citations retrieved, 35 publications met the planned criteria. From meta-analyses and network meta-analyses, we found that when injecting basal insulin regimens at bedtime, the optimal choice in order of most to least effective might be glargine U-300 or degludec U-100, glargine U-100 or detemir, followed by neutral protamine hagedorn (NPH). Injecting glargine U-100 in the morning may be more effective (ie, more patients archiving glycated hemoglobin < 7.0%) and lead to fewer hypoglycemic events than injecting it at bedtime. The optimal starting dose for the initiation of any basal insulins can be 0.10-0.20 U/kg/day. There is no eligible evidence to investigate the optimal maintenance dose for basal insulins. The five basal insulins are effective for the target population. Glargine U-300, degludec U-100, glargine U-100, and detemir lead to fewer hypoglycemic events than NPH without compromising glycemic control.

Dosimetric response of Gafchromic™ EBT-XD film to therapeutic protons.

EBT-XD model of Gafchromic™ films has a broader optimal dynamic dose range, up to 40 Gy, compared to its predecessor models. This characteristic has made EBT-XD films suitable for high-dose applications such as stereotactic body radiotherapy and stereotactic radiosurgery, as well as ultra-high dose rate FLASH radiotherapy. The purpose of the current study was to characterize the dependence of EBT-XD film response on linear energy transfer (LET) and dose rate of therapeutic protons from a synchrotron. A clinical spot-scanning proton beam was used to study LET dependence at three dose-averaged LET (LETd) values of 1.0 keV/µm, 3.6 keV/µm, and 7.6 keV/µm. A research proton beamline was used to study dose rate dependence at 150 Gy/second in the FLASH mode and 0.3 Gy/second in the non-FLASH mode. Film response data from LETd values of 0.9 keV/µm and 9.0 keV/µm of the proton FLASH beam were also compared. Film response data from a clinical 6 MV photon beam were used as a reference. Both gray value method and optical density (OD) method were used in film calibration. Calibration results using a specific OD calculation method and a generic OD calculation method were compared. The four-parameter NIH Rodbard function and three-parameter rational function were compared in fitting the calibration curves. Experimental results showed that the response of EBT-XD film is proton LET dependent but independent of dose rate. Goodness-of-fit analysis showed that using the NIH Rodbard function is superior for both protons and photons. Using the "specific OD + NIH Rodbard function" method for EBT-XD film calibration is recommended.

Application of ionizing radiation as an elicitor to enhance the growth and metabolic activities in Chlamydomonas reinhardtii.

Chlamydomonas reinhardtii is a eukaryotic, unicellular photosynthetic organism and a potential algal platform for producing biomass and recombinant proteins for industrial use. Ionizing radiation is a potent genotoxic and mutagenic agent used for algal mutation breeding that induces various DNA damage and repair responses. In this study, however, we explored the counterintuitive bioeffects of ionizing radiation, such as X- and γ-rays, and its potential as an elicitor to facilitate batch or fed-batch cultivation of Chlamydomonas cells. A certain dose range of X- and γ-rays was shown to stimulate the growth and metabolite production of Chlamydomonas cells. X- or γ-irradiation with relatively low doses below 10 Gy substantially increased chlorophyll, protein, starch, and lipid content as well as growth and photosynthetic activity in Chlamydomonas cells without inducing apoptotic cell death. Transcriptome analysis demonstrated the radiation-induced changes in DNA damage response (DDR) and various metabolic pathways with the dose-dependent expression of some DDR genes, such as CrRPA30, CrFEN1, CrKU, CrRAD51, CrOASTL2, CrGST2, and CrRPA70A. However, the overall transcriptomic changes were not causally associated with growth stimulation and/or enhanced metabolic activities. Nevertheless, the radiation-induced growth stimulation was strongly enhanced by repetitive X-irradiation and/or subsequent cultivation with an inorganic carbon source, i.e., NaHCO3, but was significantly inhibited by treatment of ascorbic acid, a scavenger of reactive oxygen species (ROS). The optimal dose range of X-irradiation for growth stimulation differed by genotype and radiation sensitivity. Here, we suggest that ionizing radiation within a certain dose range determined by genotype-dependent radiation sensitivity could induce growth stimulation and enhance metabolic activities, including photosynthesis, chlorophyll, protein, starch, and lipid synthesis in Chlamydomonas cells via ROS signaling. The counterintuitive benefits of a genotoxic and abiotic stress factor, i.e., ionizing radiation, in a unicellular algal organism, i.e., Chlamydomonas, may be explained by epigenetic stress memory or priming effects associated with ROS-mediated metabolic remodeling.

AIT in pediatric allergology: Opportunities and difficulties on the home stretch of the Therapy Allergen Ordinance.

Allergen immunotherapy (AIT) is the only causal therapy for allergic diseases and therefore particularly important. Allergen preparations have been classified as medicinal products since 1989 (Directive 89/342/EEC) and were taken over into Directive 2001/83/EC in 2001. In addition, in 2008 the Therapy Allergen Ordinance (TAO) came into force to stricter regulate the exception for named patient products (NPP) by exclusion of common therapy allergens from the exception to be marketed as NPP. The TAO regulates the requirements for testing safety and efficacy for these common therapy allergens. Due to the long transitional provisions, the last deadlines for solving clinical shortcomings will end in 2026. The advantage of this regulation is that the market for common allergens has been cleared of products without proof of efficacy, and new preparations with an optimal dose range are developed through dose-finding studies. The demand for long-term pediatric studies has been outlined by the standard Pediatric Investigation Plan (PIP) on allergen products from the Pediatric Committee of the EMA (PDCO). This is particularly problematic, as it is foreseeable that recruitment of patients will be limited and ethical problems arise from the prolonged use of placebo. Furthermore, many newly approved preparations will not be used in pediatrics for the foreseeable future, as no marketing authorization has yet been granted for this age group. This will result in a serious supply gap for children.

Effects of supplementation with Saccharomyces cerevisiae products on dairy calves: A meta-analysis.

Saccharomyces cerevisiae products (SCP) have the potential to promote the growth and development of the gastrointestinal tract and immunity in young livestock animals. However, the effects of SCP supplementation on calves are inconsistent among the reported studies in the literature. Hence, we performed a meta-analysis to comprehensively assess the effects of SCP on the growth performance, ruminal fermentation parameters, nutrients digestibility, ruminal histological morphology, serum immune response, and fecal pathogen colony counts in calves. We searched the Web of Science, ScienceDirect, PubMed, and China National Knowledge Infrastructure for relevant studies published up to October 1, 2021. After screening against a set of criteria, the data of 36 studies were included in our meta-analysis (2,126 calves in total). We evaluated the quality of the data using sensitivity analysis and assessed publication bias. Our meta-analysis revealed several important findings. First, SCP supplementation increased the ruminal short-chain fatty acid concentration, ruminal papilla height, and fiber digestibility, pointing toward stimulation of the development of the rumen in calves. Second, SCP supplementation increased the serum concentrations of total protein, IgA, and IgG but decreased fecal pathogen colony counts, suggesting that SCP could help calves to promote immunity (especially maintaining circulating concentrations of immunoglobulins in preweaning calves) and resistance to pathogens. Third, a subgroup analysis between preweaning and postweaning calves showed that SCP increased average daily gain and dry matter intake preweaning but not postweaning, suggesting that SCP is better supplemented to preweaning calves to achieve the best results. Forth, based on the dose-response curve, 24 to 25 g/d might be the optimal dose range of SCP supplementation (into starter feed) preweaning to achieve the best overall effect, meanwhile, we need more studies to improve the consistency and accuracy of the dose-response curve prediction. Overall, SCP supplementation improved growth performance, rumen development, and immunocompetence in calves, particularly in preweaning calves.

Artemisia annua L. Aqueous Extract Promotes Intestine Immunity and Antioxidant Function in Broilers.

This study was conducted to investigate the effects of Artemisia annua L. aqueous extract (AAE) on intestinal immune and antioxidative function of broilers. A total of 200 one-day-old Arbor Acre broilers were randomly allotted into five dietary treatment groups, with five replicates per treatment and eight broilers per replicate. The five treatment diets were formulated by adding, respectively, 0 (control group), 0.5, 1.0, 1.5, and 2.0 g/kg AAE in the basal diet. The results showed that dietary inclusion of AAE quadratically decreased interleukin (IL)-1β content, linearly decreased IL-6 content in the small intestine through regulating the nuclear factor-kappa B signal pathway, and quadratically increased immunoglobulin (Ig)M and sIgA content in ileum and jejunum. Besides, there was a quadratic decrease in the gene expression of IL-1β, IL-6, and toll like receptor 4 (TLR4) in ileum on day 21, and the gene expression of IL-6 and TLR4 in duodenum on day 42, thereby improving small intestinal immune function in broilers. Additionally, dietary inclusion of AAE improves antioxidative function through the nuclear factor-erythroid 2-related factor 2 (Nrf2) signal pathway in the small intestinal mucosa of broilers, especially, quadratically increased catalase (CAT) and superoxidase dismutase activity in ileum, and total antioxidant capacity and glutathione peroxidase activity in duodenum, and quadratically decreased malondialdehyde concentration in ileum, besides, linearly increased heme oxygenase-1 and Nrf2 gene expression in jejunum and ileum on day 42, quadratically increased CAT gene expression in the small intestine. Furthermore, regression analyses of the above parameters showed that the optimal dose range of AAE in the diet of broilers was 1.12–1.38 g/kg.

The Optimal Dose of Intraoperative Dexmedetomidine for Antiemetic Effects of Post-operative Nausea and Vomiting in Patients Undergoing Elective Thoracic Surgery: A Retrospective Cohort Study.

BackgroundDexmedetomidine (DEX) administration decreases post-operative nausea and vomiting (PONV), but it is a lack of large-scale retrospective cohort study and is unclear whether there is a dose-relationship and optimal dose for antiemetic effects between DEX and PONV. We performed a large-scale retrospective cohort study to explore the optimal dose of intraoperative DEX for antiemetic effects of PONV.MethodsA total of 5,310 patients aged ≥18 who underwent elective thoracic surgery from January 2016 to March 2020 under total intravenous anesthesia (TIVA) or combined intravenous and inhalation anesthesia in Henan Provincial People's Hospital. Patients were divided into two groups, those who received DEX intraoperatively and those who did not receive DEX. Patients who received DEX after surgery were excluded. Our primary outcomes were the association, the dose-response relationship, and the optimal dose for antiemetic effects between intraoperative DEX and PONV.ResultsAmong the 3,878 patients enrolled, 2,553 patients received DEX and 1,325 patients did not receive DEX. The incidence of PONV in patients who received DEX was 21.3%, and the incidence of PONV in patients who did not receive DEX was 46.5% (P = 0.001). After the matched-pairs cohort consisted of 1,325 patients, the incidence of PONV in patients who received DEX was 23.6%, and the incidence of PONV in patients who did not receive DEX was 46.5% (P = 0.001). We analyzed three different models after propensity matching to validate the stability of the prediction model between intraoperative DEX and PONV. A dose-response relationship between intraoperative DEX and PONV was observed. The optimal dose range of intraoperative DEX for antiemetic effects of PONV is 50–100 μg in elective thoracic surgery.ConclusionsIntraoperative DEX was associated with a decreased incidence of PONV in the large-scale retrospective cohort study. A dose-response relationship between intraoperative DEX and PONV was observed. The optimal dose range of intraoperative DEX for antiemetic effects of PONV is 50–100 μg in elective thoracic surgery.