Long-term variability of human health-related solar ultraviolet-B radiation doses for the 1980s to the end of the 21st century.

Solar ultraviolet-B (UV-B) radiation has played a crucial role in the evolution of life on Earth, and potential changes in its levels could affect the health and functionality of humans and the ecosystems. UV exposure presents both risks and benefits to humans. However, optimal UV-B radiation exposure depends on several environmental and physiological factors and cannot be easily determined. The present document provides a review of the current state of knowledge relative to the effects of UV-B radiation on human health. A brief description of the physical mechanisms that control the levels of solar UV-B radiation at the Earth's surface is provided, with special emphasis on the role of ozone and the importance of the Montreal Protocol. A comprehensive review of studies reporting current trends in levels of surface solar UV-B radiation and projections of future levels reveals the dominant role of climatic changes in the long-term variability of UV-B radiation and its impact on the development of melanomas as well as eye disorders. The review provides strong evidence that despite the success of the Montreal Protocol and the expected ozone recovery, the future evolution of the levels of solar UV-B radiation at the Earth's surface is not certain.

Evaluation of the impact of repeated intravenous phage doses on mammalian host-phage interactions.

Phage therapy has shown great promise for the treatment of multidrug-resistant bacterial infections. However, the lack of a thorough and organized understanding of phage-body interactions has limited its clinical application. Here, we administered different purified phages (Salmonella phage SE_SZW1, Acinetobacter phage AB_SZ6, and Pseudomonas phage PA_LZ7) intravenously to healthy animals (rats and monkeys) to evaluate the phage-induced host responses and phage pharmacokinetics with different intravenous (IV) doses in healthy animals. The plasma and the organs were sampled after different IV doses to determine the phage biodistribution, phage-induced cytokines, and antibodies. The potential side effects of phages on animals were assessed. A non-compartment model revealed that the plasma phage titer gradually decreased over time following a single dose. Repeated doses resulted in a 2-3 Log10 decline of the plasma phage titer at 5 min compared to the first dose, regardless of the type of phage administered in rats. Host innate immune responses were activated including splenic enlargement following repeated doses. Phage-specific neutralization antibodies in animals receiving phages were detected. Similar results were obtained from monkeys. In conclusion, the mammalian bodies were well-tolerant to the administered phages. The animal responses to the phages and the phage biodistribution profiles could have a significant impact on the efficacy of phage therapy.IMPORTANCEPhage therapy has demonstrated potential in addressing multidrug-resistant bacterial infections. However, an insufficient understanding of phage-host interactions has impeded its broader clinical application. In our study, specific phages were administered intravenously (IV) to both rats and monkeys to elucidate phage-host interactions and evaluate phage pharmacokinetics (PK). Results revealed that with successive IV administrations, there was a decrease in plasma phage concentrations. Concurrently, these administrations elicited both innate and adaptive immune responses in the subjects. Notably, the observed immune responses and PK profiles exhibited variation contingent upon the phage type and the mammalian host. Despite these variations, the tested mammals exhibited a favorable tolerance to the IV-administered phages. This underscores the significance of comprehending these interactions for the optimization of phage therapy outcomes.

An exploratory study of community violence and HIV care engagement among Black gay and bisexual men.

This study examined the relationship between exposure to community violence and HIV care engagement among 107 Black gay or bisexual men living with HIV in Chicago. Measures assessed the importance of demographic covariates (age, annual income, health insurance status, and years living with HIV), community violence exposures, mental health, social support, in explaining variations in missed doses of antiretroviral therapy (ART) medication and missed HIV care appointments. Results showed that participants who reported higher rates of exposure to community violence were two times more likely to have missed ART doses and HIV care appointments. Participants who reported depression scores were two times more likely to have greater non-ART adherence. Finally, older participants were more likely to report fewer missed ART doses. More research is needed to clarify the mechanisms between age or depression and ART adherence given community violence exposure. Health care providers should screen for depression when attempting to promote better ART adherence and keeping HIV care appointments for Black gay and bisexual men living with HIV. Younger Black gay and bisexual men living with HIV may be more vulnerable than older men for missed ART doses and may require additional screening and follow-up.

Evaluation of a Pharmacist-Led Implementation of Standardized Medication Administration Times for Inpatients Receiving Hemodialysis.

BACKGROUND: Missed medication doses are a common and often preventable medication-related error that have been associated with an increased length of stay and mortality. Hemodialysis is a common, relatively predictable reason that patients are unavailable, resulting in missed doses. OBJECTIVE: To evaluate the implications of a pharmacist-led intervention to standardize the medication administration times for patients requiring hemodialysis who were prescribed antihypertensives, antiepileptics, apixaban, and/or antimicrobials. METHODS: A retrospective preanalysis and postanalysis of a pharmacist-led intervention were performed at a single-center, safety net hospital. Patients receiving dialysis and prescribed one of the targeted medications were included. The primary endpoint was the composite of missed and delayed doses. RESULTS: A total of 25 patients receiving 126 dialysis sessions in the preintervention group and 29 patients receiving 80 dialysis sessions in the postintervention group were included for analysis. For the primary endpoint, 118 (18%) versus 57 (9.3%) doses were missed or delayed in the preintervention versus postintervention group, respectively (P < 0.001). The primary endpoint was driven by fewer delayed doses in the postgroup. The number of antimicrobials given on a correct schedule increased in the postintervention group (98.3% vs 99.1%, P = 0.044). CONCLUSION AND RELEVANCE: A pharmacist-led intervention for standard medication administration times in patients requiring hemodialysis increased the number of prescribed medication doses given and given on time. The intervention also led to more antimicrobials administered at appropriate times relative to dialysis sessions.

ACD856, a novel positive allosteric modulator of Trk receptors, single ascending doses in healthy subjects: Safety and pharmacokinetics.

PURPOSE: AlzeCure Pharma AB is developing novel positive allosteric modulators of Trk-receptors for treatment of Alzheimer's disease, depression, other psychiatric conditions and other disorders where cognition is impaired. The preceding candidate drug ACD855 was shown to have a too long half-life in humans to allow further development. To de-risk the development of the follow-up compound ACD856, the oral single ascending dose study of ACD856 in humans was preceded by an intravenous microdose study, assessing the elimination half-life in plasma. METHODS: A phase 0 study with a microdose of ACD856 (0.100 mg), was conducted in six healthy male subjects all receiving ACD856. Sequentially, a randomized, placebo-controlled, double-blind Phase I single ascending oral dose study (1 - 150 mg) was conducted, including 56 healthy subjects. Both studies assessed the safety and tolerability, as well as the PK properties of ACD856 after single dose intravenous and oral administration. RESULTS: ACD856 was well tolerated with no treatment emergent, or dose related adverse events or other safety assessments. In the microdose study, ACD856 exhibited a bi-exponential plasma decline, low distribution volume, low plasma clearance with a half-life of approximately 20 hours. Orally, ACD856 exhibited rapid absorption, an almost complete bioavailability and a dose proportional increase in exposure. While the Cmax was lowered and delayed by food intake, the effect on plasma half-life and the overall bioavailability was low. No renal elimination of ACD856 was detected. CONCLUSION: The prediction proved accurate demonstrating the value of conducting a microdose study prior to ascending dose studies. TRIAL REGISTRATION: NCT05783830 March 24, 2023 (microdose study, retrospectively registered) and NCT05077631 October 14, 2021 (single ascending dose study).

Sublethal pesticide exposure in non-target terrestrial ecosystems: From known effects on individuals to potential consequences on trophic interactions and network functioning.

Over the last decades, the intensification of agriculture has resulted in an increasing use of pesticides, which has led to widespread contamination of non-target ecosystems in agricultural landscapes. Plants and arthropods inhabiting these systems are therefore chronically exposed to, at least, low levels of pesticides through direct pesticide drift, but also through the contamination of their nutrient sources (e.g. soil water or host/prey tissues). Pesticides (herbicides, acaricides/insecticides and fungicides) are chemical substances used to control pests, such as weeds, phytophagous arthropods and pathogenic microorganisms. These molecules are designed to disturb specific physiological mechanisms and induce mortality in targeted organisms. However, under sublethal exposure, pesticides also affect biological processes including metabolism, development, reproduction or inter-specific interactions even in organisms that do not possess the molecular target of the pesticide. Despite the broad current knowledge on sublethal effects of pesticides on organisms, their adverse effects on trophic interactions are less investigated, especially within terrestrial trophic networks. In this review, we provide an overview of the effects, both target and non-target, of sublethal exposures to pesticides on traits involved in trophic interactions between plants, phytophagous insects and their natural enemies. We also discuss how these effects may impact ecosystem functioning by analyzing studies investigating the responses of Plant-Phytophage-Natural enemy trophic networks to pesticides. Finally, we highlight the current challenges and research prospects in the understanding of the effects of pesticides on trophic interactions and networks in non-target terrestrial ecosystems.

Antimicrobial Stewardship of Oral Third-Generation Cephalosporins in Community Pharmacy: A Single-Center Quasi-Experimental Study.

Proper use of antimicrobials in hospital and outpatient settings is critical for minimizing the occurrence of antimicrobial resistance. Some hospitals have intervened in the inappropriate use of third-generation oral cephalosporins. However, there have been no such studies in community pharmacy settings. This study aimed to investigate how the use of oral third-generation cephalosporins in community pharmacies affects the amount of antimicrobials used. Patients who visited Nakanomaru Pharmacy after being prescribed antimicrobials at target medical institutions between February 2021 and January 2023 were identified. The number of oral antimicrobials used, duration of use, number of prescriptions, patient age and sex, and infectious diseases in the target patients before and after the intervention for the proper use of oral third-generation cephalosporins were retrospectively investigated based on the patients' medication history and prescription receipts. Through efforts to ensure the proper use of oral third-generation cephalosporins, the amount of oral third-generation cephalosporins used has decreased, and the use of penicillins and oral first-generation cephalosporins has increased. There was no increase in the antimicrobial change or relapse rates associated with treatment failure before and after the initiation of appropriate antimicrobial use. By working toward the proper use of oral third-generation cephalosporins in community pharmacies, we were able to reduce the doses of oral third-generation cephalosporins without compromising their therapeutic efficacy. We believe that recommending the selection of narrow-spectrum antimicrobials based on these guidelines will contribute to their proper use.

Effect of cancer cachexia on first-line chemotherapy in patients with advanced pancreatic cancer: a claims database study in Japan.

BACKGROUND: Cancer cachexia is a multifactorial syndrome leading to progressive functional impairment. How cachexia affects the treatment course of chemotherapy in patients with pancreatic cancer has not been well understood. METHODS: This is an exploratory, retrospective, observational cohort study using the Japanese medical claims database from Medical Data Vision Co., Ltd. The study population included patients diagnosed with pancreatic cancer in whom first-line FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (GnP) was initiated between October 1, 2018, and September 30, 2020. In this study, we defined patients with cancer cachexia as those who had a weight loss of ≥ 5% in the preceding 6 months. The primary outcome was time-to-treatment failure (TTF). The observation period was six months from the initiation of first-line FFX or GnP treatment. RESULTS: A total of 1897 patients (421 patients into the cachexia group; 1476 patients into the non-cachexia group) were analyzed in this study. The median TTF was 121 days (95% confidence interval [CI] 94-146) in the cachexia group and 143 days (95% CI 134-152) in the non-cachexia group. The hazard ratio for TTF of the cachexia versus non-cachexia group was 1.136 (95% CI 0.979-1.319). The median number of doses was two doses fewer in the cachexia group than in the non-cachexia group for both FFX and GnP. CONCLUSION: Cancer cachexia was suggested to be associated with shorter TTF and a reduced number of doses in patients with pancreatic cancer who received first-line FFX or GnP treatment. Clinical Trial Registration clinicaltrials.jp: UMIN000045820.

Comparison between a single dose of PEG G-CSF and multiple doses of non-PEG G-CSF: a systematic review and meta-analysis from Clinical Practice Guidelines for the use of G-CSF 2022.

BACKGROUD: Granulocyte colony-stimulating factor (G-CSF) is widely used for the primary prophylaxis of febrile neutropenia (FN). Two types of G-CSF are available in Japan, namely G-CSF chemically bound to polyethylene glycol (PEG G-CSF), which provides long-lasting effects with a single dose, and non-polyethylene glycol-bound G-CSF (non-PEG G-CSF), which must be sequentially administrated for several days. METHODS: This current study investigated the utility of these treatments for the primary prophylaxis of FN through a systematic review of the literature. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis or meta-analysis was conducted to evaluate six outcomes. RESULTS: Through the first and second screenings, 23 and 18 articles were extracted for qualitative synthesis and meta-analysis, respectively. The incidence of FN was significantly lower in the PEG G-CSF group than in the non-PEG G-CSF group with a strong quality/certainty of evidence. The differences in other outcomes, such as overall survival, infection-related mortality, the duration of neutropenia (less than 500/µL), quality of life, and pain, were not apparent. CONCLUSIONS: A single dose of PEG G-CSF is strongly recommended over multiple-dose non-PEG G-CSF therapy for the primary prophylaxis of FN.

Dietary risk assessment of drinking water and fish from cultivated wetlands of Ndop.

This study evaluated pesticide exposure practices, and the potential health risks of drinking water and consuming fish from the cultivated wetlands of Ndop, Cameroon. Six hundred and twenty-six questionnaires were conveniently administered to farmers (≥ 26 years old) in a cross-sectional study to assess exposure practices and dietary risks. The Chi-square and Pearson correlation coefficients were used to establish relationships between variables. The PRIMET model was used to predict a worst-case dietary risk. The pesticide handling practices of 90% of farmers were inadequate. Chlorpyriphos, lambda-cyhalothrin, fipronil, and paraquat dichloride posed a possible dietary risk at recommended and applied doses, with chlorpyrifos having the highest exposure toxicity ratio (ETRdiet = 36.72). Paraquat dichloride, fipronil, and lambda-cyhalothrin posed a possible dietary risk at 26.3%, 58.3%, and 62.2% of their recommended concentrations, respectively. Remarkably, the dietary risk for cypermethrin was acceptable at 5.8 times its recommended dose (ETRdietR = 0.29). The significant positive correlation (p = 0.000) between PECfish and ETRdiet, suggests a possible health risk of consuming fish and drinking water harvested from the wetlands, thus the need for replacing pesticides posing possible risks at lower or recommended concentrations with less toxic alternatives and to train farmers on pesticide application practices.

Radiation doses and diagnostic reference levels for common CT scans in adults in Northwest region of Iran.

This study aims to estimate organ dose and cancer risks, establish region-specific diagnostic reference levels (DRLs), and determine achievable doses (ADs) for common CT procedures in adults in the northwest of Iran. Effective and organ doses were estimated using VirtualDoseCT software in a sample of 480 adult patients who underwent head, sinus, chest, and abdomen-pelvis (AP) CT scans. The guidelines provided by the BEIR VII report were utilized to estimate cancer risks. Effective and organ doses for specific procedures were determined, with the highest mean organ dose being observed in the brain during head CT examinations, with a value of 54.02 mGy. It was observed that the lungs in chest examinations and the colon in AP examinations had the highest risk of cancer, with rates of 30.72 and 21.37 per 100,000 persons, respectively. Higher cancer risk values were generally exhibited by females compared to males. The DRLs for common CT examinations were established as follows: Head CT (CTDIvol 41 mGy, DLP 760 mGy cm), Sinus CT (CTDIvol 16 mGy, DLP 261 mGy cm), Chest CT (CTDIvol 8 mGy, DLP 287 mGy cm), and AP CT (CTDIvol 9 mGy, DLP 508 mGy cm). Significant variations in dose distribution among facilities were identified, indicating the need for optimization. The study highlights the importance of minimizing radiation exposure to critical organs and promoting patient safety in CT examinations. The establishment of region-specific DRLs and ADs can help optimize radiation doses and reduce cancer risks for patients.

The impact of Renin-Angiotensin System Inhibitors on bone fracture risk: a nationwide nested case-control study.

BACKGROUND: The therapeutic efficacy of renin-angiotensin system inhibitors (RASi) in elderly patients with hypertension and at risk of fractures has been in the limelight because of accumulating evidence that localized RAS activation in bone tissue leads to osteoclastic bone resorption, resulting in osteoporosis. This study set out to investigate the association between RASi use and fracture incidence in a large cohort. METHODS: We employed a nested case-control design to investigate the association between RASi use and newly developed fractures. A case was defined as a patient newly diagnosed with a fracture between January 2004 and December 2015. We selected 1,049 cases and controls using 1:1 propensity score matching. Conditional logistic regression analysis was conducted to estimate the association between RASi exposure and fracture incidence. RESULTS: Overall, RASi usage was significantly associated with lower odds for fracture incidence (ever-users vs never-users: OR, 0.73; 95% CI, 0.59-0.91). We found that ARB-only users experienced fewer fractures than RASi-never users (OR, 0.65; 95% CI, 0.49-0.86), whereas ACEi-only users or ARB/ACEi-ever users did not. In subgroup analysis, RASi-ever users without cerebrovascular disease, those with a BMI exceeding 23, and statin exposure had significantly lower ORs. CONCLUSIONS: The present study established a significant association between RASi use and reduced fracture incidence, thus highlighting the potential clinical utility of RASi use as a preventive strategy in elderly patients at risk for osteoporotic fractures.

Effect of a dairy farmworker stewardship training program on antimicrobial drug usage in dairy cows.

Antimicrobial use (AMU) is critical to preserving animal health and welfare. However, the development of antimicrobial resistance (AMR) represents a public health threat. Although most antimicrobials used on the farm require a veterinarian prescription, farmworkers make daily on-farm treatment decisions. Therefore, farmworker training is vital to promote responsible AMU. This research project aimed to evaluate the effect of farmworker antimicrobial stewardship (AMS) training on the quantity of AMU on dairy farms in Ohio and California. We hypothesized that farms receiving AMS training would have reduced AMU in dairy cattle compared with farms where training wasn't administered. We designed a quasiexperimental study with 18 conventional dairy farms enrolled in Ohio and California. Twelve farms received AMS training, and 6 farms did not. The AMS program included a 12-wk training focused on accurate identification of cows requiring antimicrobial treatment. We quantified AMU by collecting used drug containers, manually counted by researchers during farm visits. Treatment incidence (TI) was calculated using animal daily doses (ADD), and Poisson regression models were used to analyze the TI data. Disease incidence rate (DIR) in lactating cows was 2.2, 1.5, 1.0, 0.4, 0.3, 0.2, and 0.03/1,000 cow-days for mastitis, lameness, metritis, pneumonia, retained placenta, diarrheas, and other diseases (e.g., conjunctivitis, injuries), respectively. The highest TI by antimicrobial class (provided in ADD/1,000 cow-days) was cephalosporin (5.9), penicillin (5.2), tetracyclines (0.4), lincosamides (0.2), and sulfonamides (0.1). Among the trained farms using a within-treatment group analysis, no significant differences were observed in TI pre-intervention (10.9 ADD/1,000 cow-days) compared with TI postintervention (10.3 ADD/1,000 cow-days). Treatment incidence from the training group was 10.8 ADD/1,000 cow-days and although numerically lower, it was not significantly different compared with TI in the control groups at 13.9 ADD/1,000 cow-days (rate ratio = 0.77, CI = 0.25-2.38). Future research on AMS should incorporate farmworker training with social science approaches to overcome barriers and promote on-farm responsible use.

X-ray Doses in Relation to Body Mass, Indication, and Substrate During Pediatric Electrophysiological Procedures on the Heart.

The main goal of this study is to determine typical values of dose area product (DAP) and difference in the effective dose (ED) for pediatric electrophysiological procedures on the heart in relation to patient body mass. This paper also shows DAP and ED in relation to the indication, the arrhythmia substrate determined during the procedure, and in relation to the reason for using radiation. Organ doses are described as well. The subjects were children who have had an electrophysiological study done with a 3D mapping system and X-rays in two healthcare institutions. Children with congenital heart defects were excluded. There were 347 children included. Significant difference was noted between mass groups, while heavier children had higher values of DAP and ED. Median DAP in different mass groups was between 4.00 (IQR 1.00-14.00) to 26.33 (IQR 8.77-140.84) cGycm2. ED median was between 23.18 (IQR 5.21-67.70) to 60.96 (IQR 20.64-394.04) µSv. The highest DAP and ED in relation to indication were noted for premature ventricular contractions and ventricular tachycardia-27.65 (IQR 12.91-75.0) cGycm2 and 100.73 (IQR 53.31-258.10) µSv, respectively. In arrhythmia substrate groups, results were similar, and the highest doses were in ventricular substrates with DAP 29.62 (IQR 13.81-76.0) cGycm2 and ED 103.15 (IQR 60.78-266.99) µSv. Pediatric electrophysiology can be done with very low doses of X-rays when using 3D mapping systems compared to X-rays-based electrophysiology, or when compared to pediatric interventional cardiology or adult electrophysiology.

Clinical Effect Analysis of Different Doses of Creatine Phosphate Sodium Combined with Immunoglobulin in the Treatment of Pediatric Viral Myocarditis.

The purpose of this paper was to unravel the clinical effect analysis of different doses of creatine phosphate sodium (CPS) combined with immunoglobulin in the treatment of pediatric viral myocarditis (VMC). One hundred and twenty children with VMC were recruited and randomized into three groups (40 patients each). Group I received 1.0 g of CPS dissolved in 100 mL of 5% glucose injection intravenously 1 time/day; group II received 1.25 g of CPS dissolved in 125 mL of 5% glucose injection intravenously 1 time/day; group III received 1.5 g of CPS dissolved in 150 mL of 5% glucose injection intravenously 1 time/day; then all three groups were treated with combined use of immunoglobulin (300-400 mg/day) intravenously once a day; and all three groups were treated for 14 days. The clinical efficacy, cardiac function, serum inflammatory factor levels, immune function, and the occurrence of drug toxicity and adverse effects of the children in the three groups were compared after 14 days of treatment. All three groups achieved better therapeutic effects after treatment, in which the effective rate of the Group II and Group III was notably higher versus the Group I. Lower levels of cTnI, CK-MB, LDH, AST, IL-18, IL-6, IFN-γ, and LVEDD and higher CD3+, CD4+, and CD4+/CD8+, FS, and LVEF values were noted in the Group II and Group III versus the Group I, and the results were more pronounced in the high-dose group. The liver and kidney functions of the children in the three groups before and after treatment did not show any significant changes and the incidence of adverse reactions during the treatment period was low in all three groups. Children with VMC can be treated with high-dose CPS in combination with immunoglobulin, which can improve their cardiac function and immune function and reduce the inflammatory response with good overall therapeutic efficacy and fewer adverse effects.

Bicarbonate and BSA increase the capacitation pattern and acrosomal exocytosis in boar sperm after 120 min of incubation.

Sperm capacitation is a crucial step towards the acquisition of fertilizing capacity. Despite the attempts to mimic the in vivo situation, there is still a lack of standardization in vitro techniques. Bicarbonate and serum albumin (BSA) are routinely used, although controversial results are reported regarding the optimal concentration of each compound. In addition, whether caffeine is needed on in vitro capacitation media in boar sperm remains to be elucidated. Here, 18 boar commercial artificial insemination doses were used to test different concentrations of bicarbonate (19, 37 or 56 mM) in experiment 1, BSA (1.5, 3, 4.5 mg/mL) in experiment 2 and the presence or absence of caffeine (5.15 mM) experiment 3. We analysed at 0, 30 and 120 min of incubation at 38.5°C, 5% CO2 : Total motility (TMOT), membrane integrity (VIAB), acrosomal exocytosis (rAcro; H33342/PI/PNA), capacitation status (chlortetracycline staining CTC) and mitochondrial membrane potential (JC-1). The higher concentrations of bicarbonate (37 and 56 mM) decreased TM and VIAB (p < .01) but increased rAcro (p < .01) after 120 min of incubation compared to the fresh control. In contrast, only the BSA concentration of 3 mg/mL reduced the VIAB at 120 min, but all the concentrations tested increased the average of JC-1 and decreased TM (p < .01) throughout incubation compared to the fresh control. Finally, in experiment 3, when boar sperm were incubated in the capacitating media with bicarbonate, BSA and with or without caffeine, the capacitated pattern measured by the CTC technique and rAcro increased after 120 min of incubation (p < .01) compared to fresh control, either in the presence or in the absence of caffeine. In summary, our results suggested that the combination of capacitating components, like bicarbonate and BSA, contributed to increasing the proportion of capacitated boar spermatozoa, mitochondrial membrane potential as well as acrosomal exocytosis. However, caffeine did not significantly influence in vitro sperm capacitation in this species.

The association between trajectory of serum cholesterol, statin dosage, and the risk of recurrent biliary stone diseases.

BACKGROUND: Statins may reduce the risk of recurrent gallstone disease by decreasing bile cholesterol saturation and pathogenicity. However, limited studies have investigated this issue. This study aimed to assess whether statin doses and serum cholesterol levels were associated with a decreased risk of recurrent biliary stone diseases after the first event index, with a follow-up time of 15 years. METHODS: Based on the Chang Gung Research Database (CGRD) between January 1, 2001, and December 31, 2020, we enrolled 68,384 patients with the International Classification of Diseases, Ninth and Tenth Revision codes of choledocholithiasis. After exclusions, 32,696 patients were divided into non-statin (<28 cDDD, cumulative defined daily doses) (n = 27,929) and statin (≥28 cDDD) (n = 4767) user groups for analysis. Serum cholesterol trajectories were estimated using group-based trajectory modeling (n = 8410). RESULTS: The statin users had higher Charlson Comorbidity Index (CCI) scores than the non-statin users. Time-dependent Cox regression analysis showed that statin use >365 cDDD was associated with a significantly lower risk of recurrent biliary stones (adjusted hazard ratio [aHR] = 0.28, 95% CI, 0.24-0.34; p < 00.0001), acute pancreatitis (aHR = 0.24, 95% CI, 0.17-0.32, p < 00.0001), and cholangitis (aHR = 0.28, 95% CI, 0.25-0.32, p < 00.0001). Cholecystectomy was also a protective factor for recurrent biliary stones (aHR = 0.41, 95% CI, 0.37-0.46; p < 00.0001). The higher trajectory serum cholesterol group (Group 3) had a lower risk trend for recurrent biliary stones (aHR = 0.79, p = 0.0700) and a lower risk of cholangitis (aHR = 0.79, p = 0.0071). CONCLUSION: This study supports the potential benefits of statin use and the role of cholecystectomy in reducing the risk of recurrent biliary stone diseases.

Current Insights into Sublethal Effects of Pesticides on Insects.

The effect of pesticides on insects is often discussed in terms of acute and chronic toxicity, but an important and often overlooked aspect is the impact of sublethal doses on insect physiology and behavior. Pesticides can influence various physiological parameters of insects, including the innate immune system, development, and reproduction, through a combination of direct effects on specific exposed tissues and the modification of behaviors that contribute to health and reproductive success. Such behaviors include mobility, feeding, oviposition, navigation, and the ability to detect pheromones. Pesticides also have a profound effect on insect learning and memory. The precise effects depend on many different factors, including the insect species, age, sex, caste, physiological condition, as well as the type and concentration of the active ingredients and the exposure route. More studies are needed to assess the effects of different active ingredients (and combinations thereof) on a wider range of species to understand how sublethal doses of pesticides can contribute to insect decline. This review reflects our current knowledge about sublethal effects of pesticides on insects and advancements in the development of innovative methods to detect them.

Radiation Hormesis in Barley Manifests as Changes in Growth Dynamics Coordinated with the Expression of PM19L-like, CML31-like, and AOS2-like.

The stimulation of growth and development of crops using ionising radiation (radiation hormesis) has been reported by many research groups. However, specific genes contributing to the radiation stimulation of plant growth are largely unknown. In this work, we studied the impact of the low-dose γ-irradiation of barley seeds on the growth dynamics and gene expression of eight barley cultivars in a greenhouse experiment. Our findings confirmed that candidate genes of the radiation growth stimulation, previously established in barley seedlings (PM19L-like, CML31-like, and AOS2-like), are significant in radiation hormesis throughout ontogeny. In γ-stimulated cultivars, the expression of these genes was aligned with the growth dynamics, yield parameters, and physiological conditions of plants. We identified contrasting cultivars for future gene editing and found that the γ-stimulated cultivar possessed some specific abiotic stress-responsive elements in the promotors of candidate genes, possibly revealing a new level of radiation hormesis effect execution. These results can be used in creating new productive barley cultivars, ecological toxicology of radionuclides, and eustress biology studies.

Effective doses of midazolam oral solution for the prevention of preoperative anxiety in paediatric patients.

BACKGROUND: More than 60% children exhibit anxiety before undergoing an anesthetic-surgical procedure, particularly among pre-school paediatric patients. Oral midazolam can provide procedural sedation for children prior to anesthesia. However, extemporaneous solutions of midazolam are usually prepared from injectable drug solutions, leading to inconsistent efficacy due to variable preparation methods. Xiaoerjing® is the first commercially available oral formulation of midazolam for procedural sedation in children in China. Despite the recommended dosage range of 0.25-0.5 mg/kg, its effective dose is still largely unknown. AIM: To determine the 95% effective dose (ED95) of midazolam oral solution (Xiaoerjing®) for alleviating preoperative anxiety in children prior to mask induction of general anesthesia. DESIGN: The study included 61 children between the ages of 1 and 6 years undergoing elective surgery under general anesthesia. The first patient received a single dose of 0.5 mg/kg midazolam oral solution, which was adjusted for subsequent patients using the biased coin design method based on their response to the previous dose. Doses were increased or decreased at the rate of 0.1 mg/kg. An effective response was defined as having a modified Ramsay sedation score ≥3a, separation anxiety score ≤2, and mask acceptance score ≤2 during inhalational anesthesia induction. RESULTS: Fifty-six children were included in the final analysis. Of those, sedation was successful in 50 patients, with a median separation time of 15 (IQR: 25) min. Midazolam oral solution has an ED95 of 0.8254 mg/kg (95% CI: 0.6915-0.8700 mg/kg) for relieving preoperative anxiety in children. No adverse events occurred following drug administration. CONCLUSION: Midazolam oral solution is a safe and effective medication for relieving preoperative anxiety in children. The ED95 of a single oral dose of midazolam oral solution is 0.8254 mg/kg (95% CI: 0.6915-0.8700 mg/kg).