Evaluation of Hedera species as herbal medicine raw materials.

This study aimed to evaluate the potential of Hedera colchica as an alternative to Hedera helix species for the treatment of mild inflammatory conditions of the upper respiratory tract and chronic inflammatory bronchial diseases. The H. colchica extract with the highest saponin content (C3S; 468.19 ± 16.01 mg HE/g dry weight) and the extract with the highest total phenol content (C1F; 108.60 ± 5.61 mg GAE/g dry weight). Chemical analysis and standardisation of the extract with the highest selective COX-2 inhibitory effect was performed using the LC-MS/MS technique. It was determined that the substances found in the highest ratio in the C1F extract were quinic acid (45.909 µg/g extract) and hesperidin (37.077 µg/g extract). As a result, secondary metabolites, in addition to saponins, found in Hedera species may also contribute to the extract's effectiveness, more potent extracts can be obtained compared to the total extract-containing preparations available in the market.

Different type of pay later facility for green product with selling price dependent demand using grey wolf optimizer.

The use of trade credit finance is becoming more widely acknowledged as a crucial approach to improving inventory system profitability. We review an inventory model with depending on permitted payment delays for which, if the retailer place an orders higher than or equal to a predefined quantity S 1 , then the supplier will provide a fully pay in later facility of ξ periods (i.e., there will be no charge of interest until ξ ). On the other hand the retailer need to pay a partial amount of payment to the supplier if the order quantity is less than S 1 , and the remaining amount may be deferred for up to ξ periods. Main objective of this study is to investigate the inventory model with different situations under delayed payment facility. In addition, determining the product's demand also involves taking into account the item's greenness and selling price. We have also considered the fact that the cost of buying is influenced by the product's degree of greenness. We employ the meta heuristic algorithm Grey Wolf Optimizar (GWO) to assist us in solving the problem, and we compare the outcomes with the aid of a few other algorithms (Whale optimisation algorithm (WOA) and Artificial electric field algorithm (AEFA)). In the end, we resolve several numerical cases to support the model. The concavity of the desired function is graphically displayed using MATLAB software.

Honokiol as an α-glucosidase inhibitor.

Honokiol, a naturally occurring compound from Magnolia obovata Thunb., has many biological activities, but its anti-α-glucosidase activity is still unclear. Therefore, we determined its inhibitory effects against α-glucosidase. Activity assays showed that honokiol was a reversible mixed-type inhibitor of α-glucosidase, and its IC50 value was 317.11 ± 12.86 µM. Fluorescence results indicated that the binding of honokiol to α-glucosidase caused a reduction in α-glucosidase activity. 3D fluorescence and CD spectra results indicated that the binding of honokiol to α-glucosidase caused conformational change in α-glucosidase. Docking simulated the detailed interactions between honokiol and α-glucosidase, including hydrogen and hydrophobic bonds. All findings showed that honokiol could be used as a natural inhibitor to develop α-glucosidase agents.

Attentional Bias, Pupillometry, and Spontaneous Blink Rate: Eye Characteristic Assessment Within a Translatable Nicotine Cue Virtual Reality Paradigm.

Background: Incentive salience processes are important for the development and maintenance of addiction. Eye characteristics such as gaze fixation time, pupil diameter, and spontaneous eyeblink rate (EBR) are theorized to reflect incentive salience and may serve as useful biomarkers. However, conventional cue exposure paradigms have limitations that may impede accurate assessment of these markers. Objective: This study sought to evaluate the validity of these eye-tracking metrics as indicators of incentive salience within a virtual reality (VR) environment replicating real-world situations of nicotine and tobacco product (NTP) use. Methods: NTP users from the community were recruited and grouped by NTP use patterns: nondaily (n=33) and daily (n=75) use. Participants underwent the NTP cue VR paradigm and completed measures of nicotine craving, NTP use history, and VR-related assessments. Eye-gaze fixation time (attentional bias) and pupillometry in response to NTP versus control cues and EBR during the active and neutral VR scenes were recorded and analyzed using ANOVA and analysis of covariance models. Results: Greater subjective craving, as measured by the Tobacco Craving Questionnaire-Short Form, following active versus neutral scenes was observed (F1,106=47.95; P<.001). Greater mean eye-gaze fixation time (F1,106=48.34; P<.001) and pupil diameter (F1,102=5.99; P=.02) in response to NTP versus control cues were also detected. Evidence of NTP use group effects was observed in fixation time and pupillometry analyses, as well as correlations between these metrics, NTP use history, and nicotine craving. No significant associations were observed with EBR. Conclusions: This study provides additional evidence for attentional bias, as measured via eye-gaze fixation time, and pupillometry as useful biomarkers of incentive salience, and partially supports theories suggesting that incentive salience diminishes as nicotine dependence severity increases.

ToF-SIMS evaluation of PEG-related mass peaks and applications in PEG detection in cosmetic products.

Polyethylene glycols (PEGs) are used in industrial, medical, health care, and personal care applications. The cycling and disposal of synthetic polymers like PEGs pose significant environmental concerns. Detecting and monitoring PEGs in the real world calls for immediate attention. This study unveils the efficacy of time-of-flight secondary ion mass spectrometry (ToF-SIMS) as a reliable approach for precise analysis and identification of reference PEGs and PEGs used in cosmetic products. By comparing SIMS spectra, we show remarkable sensitivity in pinpointing distinctive ion peaks inherent to various PEG compounds. Moreover, the employment of principal component analysis effectively discriminates compositions among different samples. Notably, the application of SIMS two-dimensional image analysis visually portrays the spatial distribution of various PEGs as reference materials. The same is observed in authentic cosmetic products. The application of ToF-SIMS underscores its potential in distinguishing PEGs within intricate environmental context. ToF-SIMS provides an effective solution to studying emerging environmental challenges, offering straightforward sample preparation and superior detection of synthetic organics in mass spectral analysis. These features show that SIMS can serve as a promising alternative for evaluation and assessment of PEGs in terms of the source, emission, and transport of anthropogenic organics.

Rational approach to the prescription of anti-rheumatic drugs in rheumatoid arthritis: a product leaflet-based strategy in Italy.

The treatment of patients with rheumatoid arthritis (RA) has dramatically changed in the past 30 years. Currently, numerous conventional, biologic, and targeted synthetic DMARDs have been licensed and used following recommendations provided by international and national scientific societies. However, the availability of biosimilars and the increasing necessity of savings impacted on the local/national prescription of these drugs. The information provided by data sheet of every single drug is a decisive factor on the choice of a certain treatment merged with the patient's profile. Thus, our purpose was to construct a rational algorithm for the treatment strategy in RA according to costs and the product leaflet of the biologic and targeted-synthetic DMARDs currently licensed in Italy. We used the most recent available recommendations and then we performed a review of the literature considering all the factors that are known to influence drug safety/effectiveness. All these factors were considered in the context of the data sheets of currently available originators and biosimilars.

Tissue-free water tritium and non-exchangeable organically bound tritium concentrations in fish near coastline during and after operation of Japan's first nuclear fuel reprocessing facility.

The risks from radioactive wastewater release from nuclear facilities into the ocean are a global concern. Radioactive contaminants, such as tritium (3H), in both forms of tissue free water tritium (TFWT) and non-exchangeable organically bound tritium (NE-OBT), can be incorporated into marine biota and cause radiation doses to biota and future consumers. However, no studies have been conducted to measure both forms of 3H in marine fish as well as evaluate the residence time in the vicinity of a nuclear fuel reprocessing facility. Here, fish from a brackish lake and from the Pacific Ocean coastline of Japan, which are near such a facility, were collected between 2006 and 2021. The reprocessing facility was operational between 2006 and 2009, during which time about 300 times more tritiated water was discharged per year into the ocean compared to the period when the facility was not operational. During operation the annual release was 30 times higher than the treated water released annually from Fukushima Daiichi. As expected, TFWT and NE-OBT concentrations increased in marine fish during operations and had peak values of 3.59 ± 0.03 and 0.56 ± 0.03 Bq/L, respectively. Total dose rates to the fish were 36,000 times lower than the 10 µGy h-1 benchmark. Concentrations gradually decreased to pre-operational levels as the facility was turned off with NE-OBT taking twice as long. Fish sampled from the brackish lake tended to have more incorporated TFWT and NE-OBT concentrations than ocean fish. This indicates that ocean tides might have contributed to the accumulation of discharged tritiated water in the lake via a narrow water channel, which highlights the importance of examining all marine ecosystems in future operations. In both marine environments, the estimated committed effective dose using the highest observed data through ingestion was well below public limits (91,000 times lower).

Effects of sulfur dioxide fumigation on mortality of confused flour beetle (Coleoptera: Tenebrionidae) and rice weevil (Coleoptera: Curculionidae).

Sulfur dioxide (SO2) fumigation was studied in laboratory to determine its potential as an alternative treatment for postharvest control of stored product insects, confused flour beetle, Tribolium confusum Jacquelin du Val (Coleoptera: Tenebrionidae), and rice weevil, Sitophilus oryzae (L.) (Coleoptera: Curculionidae). Three-hour fumigations with 0.1%-2.0% SO2 were conducted against eggs, immature stages, and adults of the 2 insects at 20 °C. Effective control of both insects was achieved. However, there were considerable variations between the 2 insects and among different life stages. Confused flour beetle was more susceptible to SO2 fumigation than rice weevil. Complete control of adults and all life stages of confused flour beetle was achieved in 3-h fumigations with 0.5% and 2.0% SO2, respectively. For rice weevil, 3-h fumigation with 1.5% SO2 resulted in 96.5% adult mortality and the fumigation with 2.0% SO2 resulted in 99.27% mortality of adults and 87.5% mortality of immature stages. Three-hour fumigations with 1% SO2 resulted in <5% egg survival to adults. The study demonstrated high efficacy of SO2 fumigation against the insects and suggested that SO2 fumigation has good potential for postharvest pest control on stored products.

Patient-specific Effective Dose Estimation from Dose-Length Product in Lung Computed Tomography Using Monte Carlo Simulation.

Background: Computed tomography (CT) imaging has a large portion in the dose of patients from radiological procedures; therefore, accurate calculation of radiation risk estimation in this modality is inevitable. In this study, a method for determining the patient-specific effective dose using the dose-length product (DLP) index in lung CT scan using Monte Carlo (MC) simulation is introduced. Methods: EGSnrc/BEAMnrc MC code was used to simulate a CT scanner. The DOSxyznrc simulation code was used to simulate a specific voxelized phantom from the patient's lungs and irradiate it according to X-ray parameter of routing lung CT scan, and dose delivered to thorax organs was calculated. Three types of phantoms were simulated according to three different body habits (slim, standard, and fat patients) in two groups of men and women. A factor was used to convert the relative dose per particle in MC code to the absolute dose. The dose was calculated in all lung organs, and the effective dose was calculated for all three groups of patient body habits. DLP index and volume CT dose index (CTDIvol) were extracted from the patient's dose report in the CT scanner. The DLP to effective dose conversion factor (k-factor) for patients with different body habitus was calculated. Results: Lung radiation dose in slim, standard, and fat patients in men was 0.164, 0.103, and 0.078 mGy/mAs and in women was 0.164, 0.105, and 0.079 mGy/mAs, respectively. The k-factor in the group of slim patients, especially in women, was higher than in other groups. Conclusions: CT scan dose indexes for slim patients are reported to be underestimated in studies. The dose report in CT scan systems should be modified in proportion to the patient's body habitus, to accurately estimate the radiation risk.

AI as a Medical Device Adverse Event Reporting in Regulatory Databases: Protocol for a Systematic Review.

BACKGROUND: The reporting of adverse events (AEs) relating to medical devices is a long-standing area of concern, with suboptimal reporting due to a range of factors including a failure to recognize the association of AEs with medical devices, lack of knowledge of how to report AEs, and a general culture of nonreporting. The introduction of artificial intelligence as a medical device (AIaMD) requires a robust safety monitoring environment that recognizes both generic risks of a medical device and some of the increasingly recognized risks of AIaMD (such as algorithmic bias). There is an urgent need to understand the limitations of current AE reporting systems and explore potential mechanisms for how AEs could be detected, attributed, and reported with a view to improving the early detection of safety signals. OBJECTIVE: The systematic review outlined in this protocol aims to yield insights into the frequency and severity of AEs while characterizing the events using existing regulatory guidance. METHODS: Publicly accessible AE databases will be searched to identify AE reports for AIaMD. Scoping searches have identified 3 regulatory territories for which public access to AE reports is provided: the United States, the United Kingdom, and Australia. AEs will be included for analysis if an artificial intelligence (AI) medical device is involved. Software as a medical device without AI is not within the scope of this review. Data extraction will be conducted using a data extraction tool designed for this review and will be done independently by AUK and a second reviewer. Descriptive analysis will be conducted to identify the types of AEs being reported, and their frequency, for different types of AIaMD. AEs will be analyzed and characterized according to existing regulatory guidance. RESULTS: Scoping searches are being conducted with screening to begin in April 2024. Data extraction and synthesis will commence in May 2024, with planned completion by August 2024. The review will highlight the types of AEs being reported for different types of AI medical devices and where the gaps are. It is anticipated that there will be particularly low rates of reporting for indirect harms associated with AIaMD. CONCLUSIONS: To our knowledge, this will be the first systematic review of 3 different regulatory sources reporting AEs associated with AIaMD. The review will focus on real-world evidence, which brings certain limitations, compounded by the opacity of regulatory databases generally. The review will outline the characteristics and frequency of AEs reported for AIaMD and help regulators and policy makers to continue developing robust safety monitoring processes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/48156.

The anti-tubercular callyaerins target the Mycobacterium tuberculosis-specific non-essential membrane protein Rv2113.

Spread of antimicrobial resistances urges a need for new drugs against Mycobacterium tuberculosis (Mtb) with mechanisms differing from current antibiotics. Previously, callyaerins were identified as promising anti-tubercular agents, representing a class of hydrophobic cyclopeptides with an unusual (Z)-2,3-di-aminoacrylamide unit. Here, we investigated the molecular mechanisms underlying their antimycobacterial properties. Structure-activity relationship studies enabled the identification of structural determinants relevant for antibacterial activity. Callyaerins are bacteriostatics selectively active against Mtb, including extensively drug-resistant strains, with minimal cytotoxicity against human cells and promising intracellular activity. By combining mutant screens and various chemical proteomics approaches, we showed that callyaerins target the non-essential, Mtb-specific membrane protein Rv2113, triggering a complex dysregulation of the proteome, characterized by global downregulation of lipid biosynthesis, cell division, DNA repair, and replication. Our study thus identifies Rv2113 as a previously undescribed Mtb-specific drug target and demonstrates that also non-essential proteins may represent efficacious targets for antimycobacterial drugs.

Distribution Clearance: Significance and Underlying Mechanisms.

PURPOSE: Evaluation of distribution kinetics is a neglected aspect of pharmacokinetics. This study examines the utility of the model-independent parameter whole body distribution clearance (CLD) in this respect. METHODS: Since mammillary compartmental models are widely used, CLD was calculated in terms of parameters of this model for 15 drugs. The underlying distribution processes were explored by assessment of relationships to pharmacokinetic parameters and covariates. RESULTS: The model-independence of the definition of the parameter CLD allowed a comparison of distributional properties of different drugs and provided physiological insight. Significant changes in CLD were observed as a result of drug-drug interactions, transporter polymorphisms and a diseased state. CONCLUSION: Total distribution clearance CLD is a useful parameter to evaluate distribution kinetics of drugs. Its estimation as an adjunct to the model-independent parameters clearance and steady-state volume of distribution is advocated.

Discovery of Fluorescent Naturally-occurring Inhibitor of SARS-CoV-2 Main Protease By AIE Fluorescent Probe.

Target-based high-throughput screening (HTS) is an efficient way to identify potent drugs. However, the accuracy of HTS could be affected by Pan-Assay Interference Compounds (PAINS). One reason for the generation of PAINS is that the inherent photophysical property of screened compounds could interfere with typically used assay signals including absorption and fluorescence. Our previous studies indicate that the fluorescent probe based on the fluorophore with characteristics of aggregation-induced emission (AIE) could provide high accuracy of HTS, especially for the fluorescent natural products. Herein, we report an AIE-based fluorescent probe for the main protease (Mpro) of SARS-CoV-2. We designed and synthesized an AIE fluorescent probe ZLHG5, which has a site that can be specifically cleaved by Mpro to produce a light-up fluorescence. Thanks to the large Stokes shift of AIE fluorophore (~300 nm), the probe could be effectively used for HTS of Mpro inhibitors. After screening a library of fluorescent natural products with ZLHG5, we obtained two coumarin-originated natural compounds with potent inhibitory activity towards Mpro protease. This study provides both useful fluorescent HTS probe and potent inhibitors for Mpro protease.

Prescription Patterns in Jails Before and Since the COVID-19 Pandemic: A Multisite Serial Cross-Sectional Investigation.

In response to the COVID-19 pandemic, jails were advised to reduce facility census, particularly the growing population of those with medical/behavioral health vulnerabilities that increased susceptibility to adverse outcomes. Although jail census decreased across the nation in the initial days to months following pandemic declaration, there are minimal data regarding the health status of those who remained in jail. The current investigation aspired to describe jail census trends before/since the onset of COVID-19 and offer snapshots of temporal changes and context for prevalence estimates of medical/behavioral health conditions in jail detainees from 2019 to 2023. Using a serial cross-sectional design, prescription information for individuals residing in 18 jails across the United States on June 30 of each respective year was extracted and categorized using MediSpan's ontological system to determine prevalence estimates of prescribed agents/products. Although data evidenced an initial 31% census reduction (followed by gradual return to prepandemic rates), prescribing patterns for all major therapeutic drug classes steadily increased, with 10% more individuals prescribed at least one agent in 2023 than 2019. The largest increases were observed for behavioral health agents (e.g., 32.4% of the sample was prescribed psychotropic agents in 2023 compared with 25.7% in 2019). We provide considerations for future investigations.

Design and validation of a GMP stem cell manufacturing protocol for MPSII hematopoietic stem cell gene therapy.

Hematopoietic stem cell gene therapy (HSCGT) is a promising therapeutic strategy for the treatment of neurodegenerative, metabolic disorders. The approach involves the ex vivo introduction of a missing gene into patients' own stem cells via lentiviral-mediated transduction (TD). Once transplanted back into a fully conditioned patient, these genetically modified HSCs can repopulate the blood system and produce the functional protein, previously absent or non-functional in the patient, which can then cross-correct other affected cells in somatic organs and the central nervous system. We previously developed an HSCGT approach for the treatment of Mucopolysaccharidosis type II (MPSII) (Hunter syndrome), a debilitating pediatric lysosomal disorder caused by mutations in the iduronate-2-sulphatase (IDS) gene, leading to the accumulation of heparan and dermatan sulfate, which causes severe neurodegeneration, skeletal abnormalities, and cardiorespiratory disease. In HSCGT proof-of-concept studies using lentiviral IDS fused to a brain-targeting peptide ApoEII (IDS.ApoEII), we were able to normalize brain pathology and behavior of MPSII mice. Here we present an optimized and validated good manufacturing practice hematopoietic stem cell TD protocol for MPSII in preparation for first-in-man studies. Inclusion of TEs LentiBOOST and protamine sulfate significantly improved TD efficiency by at least 3-fold without causing adverse toxicity, thereby reducing vector quantity required.

Persistent and Bioaccumulative Halogenated Natural Products in Various Tropical Reef Fish Species from the Seychelles, Western Indian Ocean.

Gas chromatography with electron capture negative ion mass spectrometry (GC/ECNI-MS) was used to quantify and compare halogenated natural products (HNPs) and selected anthropogenic persistent organic pollutants (POPs) in individual samples of 17 fish species from the Seychelles (Western Indian Ocean). The sum-HNP amounts (9.5-1100 ng/g lipid mass (lm)) were between 1 and 2 orders of magnitude higher than those of the sum of seven abundant polychlorinated biphenyl (PCB) congeners (0.2-15 ng/g lm) and dichlorodiphenyltrichloroethane-related compounds (DDTs) (<1.1-43 ng/g lm). Within the group of HNPs, the two tetrabrominated phenoxyanisoles (aka methoxylated diphenyl ethers, MeO-BDEs), 2'-MeO-BDE 68 ≫ 6-MeO-BDE 47, were predominant in most cases. Pearson correlation analysis showed that MeO-BDE levels were positively correlated with less abundant HNPs (2,2'-diMeO-BB 80, 2',6-diMeO-BDE 68, and Br6-DBP) (p < 0.01). Accordingly, HNPs, rather than PCBs and DDTs, were the predominant polyhalogenated contaminants in the current species.

Trends in amorphous solid dispersion drug products approved by the U.S. Food and Drug Administration between 2012 and 2023.

Forty-eight (48) drug products (DPs) containing amorphous solid dispersions (ASDs) have been approved by the U.S. Food and Drug Administration in the 12-year period between 2012 and 2023. These DPs comprise 36 unique amorphous drugs. Ten (10) therapeutic categories are represented, with most DPs containing antiviral and antineoplastic agents. The most common ASD polymers are copovidone (49%) and hypromellose acetate succinate (30%), while spray drying (54%) and hot melt extrusion (35%) are the most utilized manufacturing processes to prepare the ASD drug product intermediate (DPI). Tablet dosage forms are the most common, with several capsule products available. Line extensions of several DPs based on flexible oral solids and powders for oral suspension have been approved which provide patient-centric dosing to pediatric and other patient populations. The trends in the use of common excipients and film coating types are discussed. Eighteen (18) DPs are fixed-dose combinations, and some contain a mixture of amorphous and crystalline drugs. The DPs have dose/unit of amorphous drug ranging from <5 mg up to 300 mg, with the majority being ≤100 mg/unit. This review details several aspects of DPI and DP formulation and manufacturing of ASDs, as well as trends related to therapeutic category, dose, and patient-centricity.

The influence of the language style of the anchor on consumers' purchase intention.

Remarkably, e-commerce anchors have become one of the hot careers in the new media era. As a link between goods and consumers, anchors affect the willingness of consumers to purchase, which eventually impacts the sales volume of commodities in the live broadcast. Therefore, the language style of anchors is of vital significance. However, local and foreign research rarely investigates the interaction between the language style of anchors and different product types and the influential mechanism on consumers' purchase willingness. In light of the SOR theory's logic and from the viewpoint of consumer perceived value, this research study scrutinizes the interaction between the language styles of different authors (appealing to emotion and appealing to logic) and different types of products (hedonic products and practical products), as well as the effect mechanism on the consumers' willingness to purchase. Using questionnaire surveys and empirical analysis, this paper intends to analyze the inherent correlation between study variables, in order to extend valuable suggestions for enterprise practice.

Optimization of Enzyme-Assisted Extraction from Ginger (Zingiber officinale) Leaf and Its Immune-Stimulating Effects on Macrophages.

The ginger leaves contain terpenoids and phenolic compounds, such as gingerol and shogaol, which exert various physiological effects. This study focused on determining the optimal conditions for an enzyme (Ultimase MFC) extraction to enhance the bioactive components of underutilized ginger leaves using the response surface method. The extracted material was evaluated in terms of its yield and antioxidant capacity (total phenolic content, total flavonoid content, and activities of 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid). As a result, the optimal conditions included an enzyme concentration of 0.1% (v/v), a liquid-solid ratio of 33.939 mL/g, and an extraction time of 4 h. The optimized conditions resulted in an improvement in yield and antioxidant capacity, except for the total phenolic content of ginger leaves, when compared to the reference control extract. Additionally, the possibility of improving immunity was confirmed as nitric oxide and cytokines increased in macrophage cells compared with non-treatment control. Therefore, these extraction conditions enhance the potential industrial value of ginger leaves and underscore their promise as a natural ingredient for functional foods.

Visible particles in parenteral drug products: A review of current safety assessment practice.

Parenteral drug products (PDPs) are administered extensively to treat various diseases. Product quality plays a critical role in ensuring patient safety and product efficacy. One important quality challenge is the contamination of particles in PDPs. Particle presence in PDPs represents potential safety risk to patients. Differential guidance and practice have been in place for visible (VPs) and subvisible particles (SVPs) in PDPs. For SVPs, the amount limits have been harmonized in multiple Pharmacopeias. The pharmaceutical industry follows the guided limits for regulatory and quality compliance. However, for VPs, no such acceptable limit has been set. This results in not only quality but also safety challenges for manufacturers and drug developers in managing and evaluating VPs. It is important to understand the potential safety risk of VPs so these can be weighed against the benefit of the PDPs. To evaluate their potential risk(s), it is necessary to understand their nature, origin, frequency of their occurrence, safety risk, the risk mitigation measures, and the method to evaluate their safety. The current paper reviews the critical literature on these aspects and provides insight into considerations when performing safety assessment and managing the risk(s) for VPs in PDPs.