The renoprotective activity of amikacin-gamma-amino butyric acid-chitosan nanoparticles: a comparative study.

The development of nanoparticles (NPs) with active components with upgraded stability, and prolonged release helps in enhanced tissue regeneration. In addition, NPs are feasible strategy to boost antibiotic effectiveness and reduce drug side effects. Our study focuses on the use of amikacin (AMK) and gamma amino butyric acid (GABA) unloaded combinations or loaded on chitosan nanoparticles (CSNPs) for kidney protection. The AMK-GABA-CSNPs were prepared with the ionic gelation method, the morphology was studied using transmission electron microscopy (TEM), zetasizer and the Fourier transform-infrared spectroscopy (FT-IR) spectrum of the synthesized NPs was observed. The average size of AMK-GABA-CSNPs was 77.5 ± 16.5 nm. Zeta potential was + 38.94 ± 2.65 mV. AMK-GABA-CSNPs revealed significant in vitro antioxidant, anti-coagulation, non-hemolytic properties and good cell compatibility. To compare the effects of the unloaded AMK-GABA combination and AMK-GABA-CSNPs on the renal tissue, 42 healthy Sprague-Dawley rats were divided into seven groups. G1: normal control (NC), normal saline; G2: low-dose nephrotoxic group (LDN), AMK (20 mg/kg/day; i.p.); G3: unloaded AMK (20 mg/kg/day; i.p.) and GABA (50 mg/kg/day; i.p.); G4: AMK-GABA-CSNPs (20 mg/kg/day; i.p.); G5: high-dose nephrotoxic group (HDN), AMK (30 mg/kg/day; i.p.); G6: unloaded AMK (30 mg/kg/day; i.p.) and GABA (50 mg/kg/day; i.p.) and G7: AMK-GABA-CSNPs (30 mg/kg/day; i.p.). The results showed that AMK-GABA-CSNPs formulation is superior to unloaded AMK-GABA combination as it ameliorated kidney functions, oxidative stress and displayed a significant homeostatic role via suppression of inflammatory cytokines of Th1, Th2 and Th17 types. Hence, AMK-GABA-CSNPs could afford a potential nano-based therapeutic formula for the management of AMK-nephrotoxicity.

The effect of urethane and MS-222 anesthesia on the electric organ discharge of the weakly electric fish Apteronotus leptorhynchus.

Urethane and MS-222 are agents widely employed for general anesthesia, yet, besides inducing a state of unconsciousness, little is known about their neurophysiological effects. To investigate these effects, we developed an in vivo assay using the electric organ discharge (EOD) of the weakly electric fish Apteronotus leptorhynchus as a proxy for the neural output of the pacemaker nucleus. The oscillatory neural activity of this brainstem nucleus drives the fish's EOD in a one-to-one fashion. Anesthesia induced by urethane or MS-222 resulted in pronounced decreases of the EOD frequency, which lasted for up to 3 h. In addition, each of the two agents caused a manifold increase in the generation of transient modulations of the EOD known as chirps. The reduction in EOD frequency can be explained by the modulatory effect of urethane on neurotransmission, and by the blocking of voltage-gated sodium channels by MS-222, both within the circuitry controlling the neural oscillations of the pacemaker nucleus. The present study demonstrates a marked effect of urethane and MS-222 on neural activity within the central nervous system and on the associated animal's behavior. This calls for caution when conducting neurophysiological experiments under general anesthesia and interpreting their results.

Eobania vermiculata whole-body muscle extract-loaded chitosan nanoparticles enhanced skin regeneration and decreased pro-inflammatory cytokines in vivo.

BACKGROUND: Usually, wounds recover in four to six weeks. Wounds that take longer time than this to heal are referred to as chronic wounds. Impaired healing can be caused by several circumstances like hypoxia, microbial colonization, deficiency of blood flow, reperfusion damage, abnormal cellular reaction and deficiencies in collagen production. Treatment of wounds can be enhanced through systemic injection of the antibacterial drugs and/or other topical applications of medications. However, there are a number of disadvantages to these techniques, including the limited or insufficient medication penetration into the underlying skin tissue and the development of bacterial resistance with repeated antibiotic treatment. One of the more recent treatment options may involve using nanotherapeutics in combination with naturally occurring biological components, such as snail extracts (SE). In this investigation, chitosan nanoparticles (CS NPs) were loaded with an Eobania vermiculata whole-body muscle extract. The safety of the synthesized NPs was investigated in vitro to determine if these NPs might be utilized to treat full-skin induced wounds in vivo. RESULTS: SEM and TEM images showed uniformly distributed, spherical, smooth prepared CS NPs and snail extract-loaded chitosan nanoparticles (SE-CS NPs) with size ranges of 76-81 and 91-95 nm, respectively. The zeta potential of the synthesized SE-CS NPs was - 24.5 mV, while that of the CS NPs was 25 mV. SE-CS NPs showed a remarkable, in vitro, antioxidant, anti-inflammatory and antimicrobial activities. Successfully, SE-CS NPs (50 mg/kg) reduced the oxidative stress marker (malondialdehyde), reduced inflammation, increased the levels of the antioxidant enzymes (superoxide dismutase and glutathione), and assisted the healing of induced wounds. SE-CS NPs (50 mg/kg) can be recommended to treat induced wounds safely. SE was composed of a collection of several wound healing bioactive components [fatty acids, amino acids, minerals and vitamins) that were loaded on CS NPs. CONCLUSIONS: The nanostructure enabled bioactive SE components to pass through cell membranes and exhibit their antioxidant and anti-inflammatory actions, accelerating the healing process of wounds. Finally, it is advised to treat rats' wounds with SE-CS NPs.

Achieving big with small: quantitative clinical pharmacology tools for drug development in pediatric rare diseases.

Pediatric populations represent a major fraction of rare diseases and compound the intrinsic challenges of pediatric drug development and drug development for rare diseases. The intertwined complexities of pediatric and rare disease populations impose unique challenges to clinical pharmacologists and require integration of novel clinical pharmacology and quantitative tools to overcome multiple hurdles during the discovery and development of new therapies. Drug development strategies for pediatric rare diseases continue to evolve to meet the inherent challenges and produce new medicines. Advances in quantitative clinical pharmacology research have been a key component in advancing pediatric rare disease research to accelerate drug development and inform regulatory decisions. This article will discuss the evolution of the regulatory landscape in pediatric rare diseases, the challenges encountered during the design of rare disease drug development programs and will highlight the use of innovative tools and potential solutions for future development programs.

Alcohol impairs recognition and uptake of Mycobacterium tuberculosis by suppressing toll-like receptor 2 expression.

BACKGROUND: Alcohol impairs pulmonary innate immune function and is associated with an increased risk of tuberculosis (TB). Toll-like receptor 2 (TLR2) is a pattern recognition receptor on alveolar macrophages that recognizes Mycobacterium tuberculosis (Mtb). The expression of TLR2 depends, in part, on granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling. Given our prior work demonstrating the suppression of GM-CSF signaling following chronic alcohol ingestion, we hypothesized that alcohol impairs TLR2 expression via the suppression of GM-CSF and thereby reduces the ability of the macrophage to recognize and phagocytose Mtb. METHODS: Primary alveolar macrophages were isolated from control-fed and alcohol-fed rats. Prior to cell isolation, some alcohol-fed rats were treated with intranasal GM-CSF and then endotracheally inoculated with an attenuated strain of Mtb. Primary macrophages were then isolated and immunofluorescence was used to determine phagocytic efficiency and TLR2 expression in the presence and absence of GM-CSF treatment and phagocytic efficiency in the presence and absence of TLR2 neutralization. RESULTS: TLR2 expression and phagocytosis of Mtb were significantly lower in the alveolar macrophages of alcohol-fed rats than control-fed rats. In parallel, blocking TLR2 signaling recapitulated this decreased phagocytosis of Mtb. In contrast, intranasal GM-CSF treatment restored TLR2 expression and Mtb phagocytosis in the alveolar macrophages of alcohol-fed rats to levels comparable to those of control-fed rats. CONCLUSIONS: Chronic alcohol ingestion reduces TLR2 protein expression and phagocytosis of Mtb, likely due to impaired GM-CSF signaling. GM-CSF restores membrane-bound TLR2 expression and phagocytic function.

Efficacy of Hibiscus sabdariffa on Reducing Blood Pressure in Patients With Mild-to-Moderate Hypertension: A Systematic Review and Meta-Analysis of Published Randomized Controlled Trials.

We aimed to assess the efficacy of Hibiscus sabdariffa in patients with mild-to-moderate hypertension or metabolic syndrome (MetS) by comparing it against placebo, antihypertensive drugs, or other herbal products. Four databases were searched for randomized clinical trials (RCTs) examining the efficacy of H. sabdariffa in patients with mild-to-moderate hypertension or hypertension associated with MetS. Data on the change in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were extracted and analyzed using Review Manager Version 5.3. A total of 13 RCTs (1205 participants) were analyzed. Hibiscus sabdariffa significantly reduced both SBP and DBP compared with placebo (mean difference -6.67, P = 0.004 and -4.35 mm Hg, P = 0.02). Subgroup analysis showed that change in SBP and DBP was statistically significant in patients with only hypertension, whereas not significant in patients with hypertension associated with MetS. When H. sabdariffa was compared with active controls (antihypertensive drugs or other herbals), the change in SBP and DBP was not statistically significant (all P > 0.05). Hibiscus sabdariffa is effective in reducing the SBP and DBP in patients with mild-to-moderate hypertension, but was neither effective in those with MetS nor superior to antihypertensive drugs. Further RCTs are required to determine the long-term efficacy of H. sabdariffa and to describe patients who would benefit most from this treatment.

Potential of selected plant extracts to control severe subacute ruminal acidosis in vitro as compared with monensin.

BACKGROUND: In recent years, researchers have become increasingly interested in developing natural feed additives that can stabilize ruminal pH and thus prevent or eliminate the risk of severe subacute rumen acidosis. Herein, 3 experiments were conducted using a semi-automated in vitro gas production technique. In the experiment (Exp.) 1, the efficacy of 9 plant extracts (1.5 mg/ml), compared to monensin (MON; 12 µg/ml), to counteract ruminal acidosis stimulated by adding glucose (0.1 g/ml) as a fermentable carbohydrate without buffer was assessed for 6 h. In Exp. 2, cinnamon extract (CIN) and MON were evaluated to combat glucose-induced acidosis with buffer use for 24 h. In Exp. 3, the effect of CIN and MON on preventing acidosis when corn or barley grains were used as substrate was examined. RESULTS: In Exp. 1, cinnamon, grape seeds, orange, pomegranate peels, propolis, and guava extracts significantly increased (P < 0.05) pH compared to control (CON). Both CIN and MON significantly increased the pH (P < 0.001) but reduced cumulated gas production (P < 0.01) compared to the other treatments. In Exp. 2, the addition of CIN extract increased (P < 0.01) pH value compared to CON at the first 6 h of incubation. However, no significant differences in pH values between CIN and CON at 24 h of incubation were observed. The addition of CIN extract and MON decreased (P < 0.001) lactic acid concentration and TVFA compared to CON at 24 h. The CIN significantly (P < 0.01) increased acetate: propionate ratio while MON reduced it. In Exp. 3, both CIN and MON significantly increased (P < 0.05) ruminal pH at 6 and 24 h and reduced lactic acid concentration at 24 h compared to CON with corn as substrate. However, CIN had no effect on pH with barley substrate at all incubation times. CONCLUSIONS: It can be concluded that CIN can be used effectively as an alternative antibiotic to MON to control ruminal acidosis when corn is used as a basal diet.

An integrated PK-PD model for cortisol and the 17-hydroxyprogesterone and androstenedione biomarkers in children with congenital adrenal hyperplasia.

AIMS: The aim of this study was to characterize the pharmacokinetic/pharmacodynamic relationships of cortisol and the adrenal biomarkers 17-hydroxyprogesterone and androstenedione in children with congenital adrenal hyperplasia (CAH). METHODS: A nonlinear mixed-effect modelling approach was used to analyse cortisol, 17-hydroxyprogesterone and androstenedione concentrations obtained over 6 hours from children with CAH (n = 50). A circadian rhythm was evident and the model leveraged literature information on circadian rhythm in untreated children with CAH. Indirect response models were applied in which cortisol inhibited the production rate of all three compounds using an Imax model. RESULTS: Cortisol was characterized by a one-compartment model with apparent clearance and volume of distribution estimated at 22.9 L/h/70 kg and 41.1 L/70 kg, respectively. The IC50 values of cortisol concentrations for cortisol, 17-hydroxyprogesterone and androstenedione were estimated to be 1.36, 0.45 and 0.75 µg/dL, respectively. The inhibitory effect was found to be more potent on 17OHP than D4A, and the IC50 values were higher in salt-wasting subjects than simple virilizers. Production rates of cortisol, 17-hydroxyprogesterone and androstenedione were higher in simple-virilizer subjects. Half-lives of cortisol, 17-hydroxyprogesterone and androstenedione were 60, 47 and 77 minutes, respectively. CONCLUSION: Rapidly changing biomarker responses to cortisol concentrations highlight that single measurements provide volatile information about a child's disease control. Our model closely captured observed cortisol, 17-hydroxyprogesterone and androstenedione concentrations. It can be used to predict concentrations over 24 hours and allows many novel exposure metrics to be calculated, e.g., AUC, AUC-above-threshold, time-within-range, etc. Our long-range goal is to uncover dose-exposure-outcome relationships that clinicians can use in adjusting hydrocortisone dose and timing.

Twelve tips for designing assignments that foster independence in learning.

Independent learning refers to opportunities in which responsibility for learning shifts to learners. Providing health professions learners with independent learning opportunities can be challenging because of the often highly structured curricula of health professions education. Structured independent learning assignments that give learners the opportunity to begin developing the skills and strategies to take on self-directed opportunities in the future may lend themselves to these contexts. However, in health professions education contexts, few guidelines exist for designing effective assignments that foster independence in learning. These twelve tips provide recommendations for how to improve structured independent learning assignments for health professions learners and help them develop the skills and experience required for more self-directed opportunities and for lifelong learning.

Orphan drug development: the increasing role of clinical pharmacology.

Over the last few decades there has been a paradigm shift in orphan drug research and development. The development of the regulatory framework, establishment of rare disease global networks that support drug developments, and advances in technology, has resulted in tremendous growth in orphan drug development. Nevertheless, several challenges during orphan drug development such as economic constraints; insufficient clinical information; fewer patients and thus inadequate power; etc. still exist. While the standard regulatory requirements for drug approval stays the same, applications of scientific judgment and regulatory flexibility is significantly important to help meeting some of the immense unmet medical need in rare diseases. Clinical pharmacology presents a vital role in accelerating orphan drug development and overcoming some of these challenges. This review highlights the critical contributions of clinical pharmacology in orphan drug development; for example, dose finding, optimizing clinical trial design, indication expansion, and population extrapolation. Examples of such applications are reviewed in this article.

Amikacin Pharmacokinetic-Pharmacodynamic Analysis in Pediatric Cancer Patients.

We performed pharmacokinetic-pharmacodynamic (PK-PD) and simulation analyses to evaluate a standard amikacin dose of 15 mg/kg once daily in children with cancer and to determine an optimal dosing strategy. A population pharmacokinetic model was developed from clinical data collected in 34 pediatric patients and used in a simulation study to predict the population probability of various dosing regimens to achieve accepted safety (steady-state unbound trough plasma concentration [fCmin] of <10 mg/liter)- and efficacy (free, unbound plasma concentration-to-MIC ratio [fCmax/MIC] of ≥8)-linked targets. In addition, an adaptive resistance PD (ARPD) model of Pseudomonas aeruginosa was built based on literature time-kill curve data and linked to the PK model to perform PK-ARPD simulations and compare results with those of the probability approach. Using the probability approach, an amikacin dose of 60 mg/kg administered once daily is expected to achieve the target fCmax/MIC in 80% of pediatric patients weighing 8 to 70 kg with a 97.5% probability, and almost all patients were predicted to have fCmin of <10 mg/liter. However, PK-ARPD simulation predicted that 60 mg/kg/day is unlikely to suppress bacterial resistance with repeated dosing. Furthermore, PK-ARPD simulation suggested that amikacin at 90 mg/kg, given in two divided doses (45 mg/kg twice a day), is expected to hit safety and efficacy targets and is associated with a lower rate of bacterial resistance. The disagreement between the two methods is due to the inability of the probability approach to predict development of drug resistance with repeated dosing. This originates from the use of PK-PD indices based on the MIC that neglects measurement errors, ignores the time course dynamic nature of bacterial growth and killing, and incorrectly assumes the MIC to be constant during treatment.

A model-based approach to assess the exposure-response relationship of Lorenzo's oil in adrenoleukodystrophy.

AIMS: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder, most commonly affecting boys, associated with increased very long chain fatty acids (C26:0) in all tissues, causing cerebral demyelination and adrenocortical insufficiency. Certain monounsaturated long chain fatty acids including oleic and erucic acids, known as Lorenzo's oil (LO), lower plasma C26:0 levels. The aims of this study were to characterize the effect of LO administration on plasma C26:0 concentrations and to determine whether there is an association between plasma concentrations of erucic acid or C26:0 and the likelihood of developing brain MRI abnormalities in asymptomatic boys. METHODS: Non-linear mixed effects modelling was performed on 2384 samples collected during an open label single arm trial. The subjects (n = 104) were administered LO daily at ~2-3 mg kg(-1) with a mean follow-up of 4.88 ± 2.76 years. The effect of erucic acid exposure on plasma C26:0 concentrations was characterized by an inhibitory fractional Emax model. A Weibull model was used to characterize the time-to-developing MRI abnormality. RESULTS: The population estimate for the fractional maximum reduction of C26:0 plasma concentrations was 0.76 (bootstrap 95% CI 0.73, 0.793). Our time-to-event analyses showed that every mg l(-1) increase in time-weighted average of erucic acid and C26:0 plasma concentrations was, respectively, associated with a 3.7% reduction and a 753% increase in the hazard of developing MRI abnormality. However, the results were not significant (P = 0.5344, 0.1509, respectively). CONCLUSIONS: LO administration significantly reduces the abnormally high plasma C26:0 concentrations in X-ALD patients. Further studies to evaluate the effect of LO on the likelihood of developing brain MRI abnormality are warranted.

A hierarchical Bayesian approach for combining pharmacokinetic/pharmacodynamic modeling and Phase IIa trial design in orphan drugs: Treating adrenoleukodystrophy with Lorenzo's oil.

X-linked adrenoleukodystrophy (X-ALD) is a rare, progressive, and typically fatal neurodegenerative disease. Lorenzo's oil (LO) is one of the few X-ALD treatments available, but little has been done to establish its clinical efficacy or indications for its use. In this article, we analyze data on 116 male asymptomatic pediatric patients who were administered LO. We offer a hierarchical Bayesian statistical approach to understand LO pharmacokinetics (PK) and pharmacodynamics (PD) resulting from an accumulation of very long-chain fatty acids. We experiment with individual- and observational-level errors and various choices of prior distributions and deal with the limitation of having just one observation per administration of the drug, as opposed to the more usual multiple observations per administration. We link LO dose to the plasma erucic acid concentrations by PK modeling, and then link this concentration to a biomarker (C26, a very long-chain fatty acid) by PD modeling. Next, we design a Bayesian Phase IIa study to estimate precisely what improvements in the biomarker can arise from various LO doses while simultaneously modeling a binary toxicity endpoint. Our Bayesian adaptive algorithm emerges as reasonably robust and efficient while still retaining good classical (frequentist) operating characteristics. Future work looks toward using the results of this trial to design a Phase III study linking LO dose to actual improvements in health status, as measured by the appearance of brain lesions observed via magnetic resonance imaging.

NON-COMPLIANCE TO ANTI-HYPERTENSIVE MEDICATION AND ITS ASSOCIATED FACTORS AMONG HYPERTENSIVES.

BACKGROUND: Non-compliance to anti-hypertensive drugs can have negative impact on cardiovascular outcome. Various studies have been conducted on the issue but the factors are not yet explored properly, particularly in Pakistan. This study was conducted to determine the frequency and factors associated with non-compliance to anti-hypertensive medications in Karachi. METHODS: This descriptive cross sectional study was conducted on 113 indoor hypertensive patients included by purposive sampling, aged 30 years and above diagnosed at least 6 months back in public sector tertiary care institutes of Karachi from March to October 2011. Data was collected through a questionnaire in Urdu. Demographic data, hypertension diagnosis, medical co-morbidity, current number of anti-hypertensive medicines, frequency of missing prescribed antihypertensive therapy and other factors affecting compliance pertaining to medicines, patient, physician and health care centre were included in the questionnaire. RESULTS: This study revealed that 68.14% patients were non-compliant. Non-compliance was found to be associated with gender and socioeconomic status. Duration of hypertension, duration between follow up visits to physician, number of drugs, careless attitude, role of physician and limiting access to health care center are found to be important factors in non-compliance. CONCLUSIONS: Multiple factors including patients, medicine and health care system related, which can be prevented with simple measures, were found responsible for higher prevalence of non-compliance against anti-hvnertensive medicines.

Environmental impact of phytobiotic additives on greenhouse gas emission reduction, rumen fermentation manipulation, and performance in ruminants: an updated review.

Ruminal fermentation is a natural process involving beneficial microorganisms that contribute to the production of valuable products and efficient nutrient conversion. However, it also leads to the emission of greenhouse gases, which have detrimental effects on the environment and animal productivity. Phytobiotic additives have emerged as a potential solution to these challenges, offering benefits in terms of rumen fermentation modulation, pollution reduction, and improved animal health and performance. This updated review aims to provide a comprehensive understanding of the specific benefits of phytobiotic additives in ruminant nutrition by summarizing existing studies. Phytobiotic additives, rich in secondary metabolites such as tannins, saponins, alkaloids, and essential oils, have demonstrated biological properties that positively influence rumen fermentation and enhance animal health and productivity. These additives contribute to environmental protection by effectively reducing nitrogen excretion and methane emissions from ruminants. Furthermore, they inhibit microbial respiration and nitrification in soil, thereby minimizing nitrous oxide emissions. In addition to their environmental impact, phytobiotic additives improve rumen manipulation, leading to increased ruminant productivity and improved quality of animal products. Their multifaceted properties, including anthelmintic, antioxidant, antimicrobial, and immunomodulatory effects, further contribute to the health and well-being of both animals and humans. The potential synergistic effects of combining phytobiotic additives with probiotics are also explored, highlighting the need for further research in this area. In conclusion, phytobiotic additives show great promise as sustainable and effective solutions for improving ruminant nutrition and addressing environmental challenges.

Lanadelumab in Patients 2 to Less Than 12 Years Old With Hereditary Angioedema: Results From the Phase 3 SPRING Study.

BACKGROUND: Symptoms of hereditary angioedema (HAE) often first occur during childhood, and HAE attacks in children can be severe and substantially affect health-related quality of life (HRQoL). However, there are no approved long-term prophylaxis treatments for children aged less than 6 years. OBJECTIVE: The SPRING Study (NCT04070326) evaluated the safety, pharmacokinetics, and efficacy of lanadelumab and HRQoL in patients aged 2 to less than 12 years. METHODS: Over 52 weeks of treatment, patients aged 2 to less than 6 years received lanadelumab 150 mg every 4 weeks (Q4W) and patients aged 6 to less than 12 years received 150 mg every 2 weeks (Q2W) but could switch to Q4W if they were attack-free for 26 weeks. RESULTS: We enrolled 21 patients (aged 2 to less than 6 years: n = 4; aged 6 to less than 12 years: n = 17), 20 of whom completed the study. There were no reported serious treatment-emergent adverse events or discontinuations resulting from such events. Treatment-emergent adverse events were reported for 17 patients (81.0%). The most common TEAE was injection site pain. Overall systemic exposure was comparable for both age groups. The mean (SD) attack rate during treatment decreased by 94.8% from baseline (1.84 [1.53] to 0.08 [0.17] attacks/mo), and 16 (76.2%) patients were attack-free. The attack rate reduction in both age groups was similar during the first 26-week fixed-dosing treatment. Seven patients switched from Q2W to Q4W and remained attack-free. A large, clinically meaningful increase in the Pediatric Quality of Life Inventory Generic Core Scale Total Score and a large increase in the Pediatric Quality of Life Inventory Generic Core Scale-Family Impact Module Total Score from baseline to end of study (better HRQoL) were observed. CONCLUSIONS: Findings support safety, efficacy, and improved HRQoL with lanadelumab 150 mg Q2W and Q4W regimens for the prevention of HAE attacks in patients aged 2 to less than 12 years.

Advancing the utilization of real-world data and real-world evidence in clinical pharmacology and translational research-Proceedings from the ASCPT 2023 preconference workshop.

Real-world data (RWD) and real-world evidence (RWE) are now being routinely used in epidemiology, clinical practice, and post-approval regulatory decisions. Despite the increasing utility of the methodology and new regulatory guidelines in recent years, there remains a lack of awareness of how this approach can be applied in clinical pharmacology and translational research settings. Therefore, the American Society of Clinical Pharmacology & Therapeutics (ASCPT) held a workshop on March 21st, 2023 entitled "Advancing the Utilization of Real-World Data (RWD) and Real-World Evidence (RWE) in Clinical Pharmacology and Translational Research." The work described herein is a summary of the workshop proceedings.

Covariate modeling in pharmacometrics: General points for consideration.

Modeling the relationships between covariates and pharmacometric model parameters is a central feature of pharmacometric analyses. The information obtained from covariate modeling may be used for dose selection, dose individualization, or the planning of clinical studies in different population subgroups. The pharmacometric literature has amassed a diverse, complex, and evolving collection of methodologies and interpretive guidance related to covariate modeling. With the number and complexity of technologies increasing, a need for an overview of the state of the art has emerged. In this article the International Society of Pharmacometrics (ISoP) Standards and Best Practices Committee presents perspectives on best practices for planning, executing, reporting, and interpreting covariate analyses to guide pharmacometrics decision making in academic, industry, and regulatory settings.

Ensiling Characteristics, In Vitro Rumen Fermentation Patterns, Feed Degradability, and Methane and Ammonia Production of Berseem (Trifolium alexandrinum L.) Co-Ensiled with Artichoke Bracts (Cynara cardunculus L.).

This study investigated the effect of co-ensiling increasing levels of artichoke bracts (Cynara cardunculus L.) with berseem (Trifolium alexandrinum L.) (100:0, 75:25, 50:50, 25:75, and 0:100, respectively) on silage quality after 0, 30, 60, and 120 days. Moreover, the in vitro rumen fermentation characteristics and methane (CH4) and ammonia (NH3-N) production were evaluated using a buffalo inoculum source. The results showed that pH of the silage and the concentration of acetic, propionic, butyric acid, and NH3-N significantly decreased (L; p < 0.01) with the increasing amounts of artichoke bracts in the mixture. At 30 and 60 days of ensiling, the highest lactic acid concentration was observed at intermediate proportions of artichoke bracts (p < 0.01). Cumulative gas production was higher in artichoke bracts than in the berseem silage. After 24 h of incubation, the highest value (p < 0.05) of truly dry matter, organic matter, natural detergent fiber degradability, and NH3-N concentration was recorded with 500 g/kg of forage mixtures. As the artichoke bract concentration increased, the partitioning factor and ruminal pH declined linearly (p ≤ 0.05). No significant differences were observed for total volatile fatty acids and volatile fatty acids molar proportions. In summary, co-ensiling artichoke bracts with berseem at a ratio of 1:1 might be a promising and easy method for the production of high-quality silage from legume forage with positively manipulating rumen fermentation.

Heavy migration of flood affectees in Pakistan and increased risk of autism spectrum disorder in children: a call to action.

Autism spectrum disorder (ASD) refers to various neurodevelopmental disabilities generally seen in kids. Pakistan, being vulnerable to natural disasters, faced one of the most devastating floods in July 2022 due to which many individuals were displaced. This not only affected the mental health of growing children but also the developing fetus of migrant mothers. This report establishes the link between the aftereffects of migration due to floods on children particularly associated with ASD in Pakistan. Flood affected families are devoid of basic necessities and are under a lot of psychological stress. On the other hand, Extensive treatment for autism is complicated, expensive, and provided in proper settings only which is not easily accessible to migrants. Considering all these factors, there are chances that ASD will be more prevalent in future generations of these migrants. Our study calls on respective authorities to take timely action for this growing concern.