Quantification of Chemical Uptake into the Skin by Vibrational Spectroscopies and Stratum Corneum Sampling.

Evaluation of the bioavailability of drugs intended to act within the skin following the application of complex topical products requires the application of multiple experimental tools, which must be quantitative, validated, and, ideally and ultimately, sufficiently minimally invasive to permit use in vivo. The objective here is to show that both infrared (IR) and Raman spectroscopies can assess the uptake of a chemical into the stratum corneum (SC) that correlates directly with its quantification by the adhesive tape-stripping method. Experiments were performed ex vivo using excised porcine skin and measured chemical disposition in the SC as functions of application time and formulation composition. The quantity of chemicals in the SC removed on each tape-strip was determined from the individually measured IR and Raman signal intensities of a specific molecular vibration at a frequency where the skin is spectroscopically silent and by a subsequent conventional extraction and chromatographic analysis. Correlations between the spectroscopic results and the chemical quantification on the tape-strips were good, and the effects of longer application times and the use of different vehicles were clearly delineated by the different measurement techniques. Based on this initial investigation, it is now possible to explore the extent to which the spectroscopic approach (and Raman in particular) may be used to interrogate chemical disposition deeper in the skin and beyond the SC.

A vaccination model for COVID-19 in Gauteng, South Africa.

The COVID-19 pandemic provides an opportunity to explore the impact of government mandates on movement restrictions and non-pharmaceutical interventions on a novel infection, and we investigate these strategies in early-stage outbreak dynamics. The rate of disease spread in South Africa varied over time as individuals changed behavior in response to the ongoing pandemic and to changing government policies. Using a system of ordinary differential equations, we model the outbreak in the province of Gauteng, assuming that several parameters vary over time. Analyzing data from the time period before vaccination gives the approximate dates of parameter changes, and those dates are linked to government policies. Unknown parameters are then estimated from available case data and used to assess the impact of each policy. Looking forward in time, possible scenarios give projections involving the implementation of two different vaccines at varying times. Our results quantify the impact of different government policies and demonstrate how vaccinations can alter infection spread.

Skin pharmacokinetics of diclofenac and co-delivered functional excipients.

An important question in the development of a dermatological drug product is whether a target concentration has been achieved in, for example, the viable epidermis following topical administration. When attempting to address this challenge, it is essential to consider the role of excipients in the formulation that may influence drug partitioning and diffusion in the different layers of the skin. The objective, therefore, was to correlate, in human subjects, the skin pharmacokinetics of diclofenac (specifically, its uptake into and clearance from the stratum corneum (SC)) from an approved drug product (Voltaren® medicated plaster) with the in vivo co-uptake of two key excipients, namely propylene glycol and butylene glycol. SC sampling was used to assess diclofenac input into the skin during patch application, and its subsequent clearance post-removal of the delivery system. In parallel the uptake of the two glycol excipients was also measured. Drug and excipient amounts in the SC increased with time of application up to 6 h and, for diclofenac, no further increase was observed when the administration was prolonged to 12 h. When the plaster was removed after 6 h of wear, diclofenac cleared relatively slowly from the SC suggesting that drug binding with a slow off-rate had occurred. The results indicate that the optimisation of drug delivery from a topical formulation must take into account the disposition of key excipients and their impact on dermato-pharmacokinetics in general.

Assessment of dermal bioavailability: predicting the input function for topical glucocorticoids using stratum corneum sampling.

Predicting the dermal bioavailability of topically delivered drugs is challenging. In this work, minimally invasive stratum corneum (SC) sampling was used to quantify the delivery of betamethasone valerate (BMV) into the viable skin. Betnovate® cream (0.1% w/w BMV) was applied at three doses (2, 5, and 10 mg cm-2) to the ventral forearms of 12 healthy volunteers. The mass of drug in the SC was measured using a validated tape-stripping method (a) after a 4-h "uptake" period, and (b) following a 6-h "clearance" period subsequent to cream removal. Concomitantly, the skin blanching responses to the same doses were assessed with a chromameter over 22 h post-application. BMV uptake into the SC was significantly higher for the 5 mg cm-2 dose compared to those of 2 and 10 mg cm-2. In all cases, ~30% of the drug in the SC at the end of the uptake period was cleared in the subsequent 6 h. From the SC sampling data, the average drug flux into the viable epidermis and its first-order elimination rate constant from the SC were estimated as 4 ng cm-2 h-1 and 0.07 h-1, respectively. In contrast, skin blanching results were highly variable and insensitive to the dose of cream applied. The SC sampling method was able to detect a 50% difference between two applied doses with 80% power; detection of a 20% difference would require a larger sample size. SC sampling enabled quantitative metrics describing corticosteroid delivery to the viable epidermis to be determined.

Skin Pharmacokinetics of Transdermal Scopolamine: Measurements and Modeling.

Prediction of skin absorption and local bioavailability from topical formulations remains a difficult task. An important challenge in forecasting topical bioavailability is the limited information available about local and systemic drug concentrations post application of topical drug products. Commercially available transdermal patches, such as Scopoderm (Novartis Consumer Health UK), offer an opportunity to test these experimental approaches as systemic pharmacokinetic data are available with which to validate a predictive model. The long-term research aim, therefore, is to develop a physiologically based pharmacokinetic model (PBPK) to predict the dermal absorption and disposition of actives included in complex dermatological products. This work explored whether in vitro release and skin permeation tests (IVRT and IVPT, respectively), and in vitro and in vivo stratum corneum (SC) and viable tissue (VT) sampling data, can provide a satisfactory description of drug "input rate" into the skin and subsequently into the systemic circulation. In vitro release and skin permeation results for scopolamine were consistent with the previously reported performance of the commercial patch investigated. New skin sampling data on the dermatopharmacokinetics (DPK) of scopolamine also accurately reflected the rapid delivery of a "priming" dose from the patch adhesive, superimposed on a slower, rate-controlled input from the drug reservoir. The scopolamine concentration versus time profiles in SC and VT skin compartments, in vitro and in vivo, taken together with IVRT release and IVPT penetration kinetics, reflect the input rate and drug delivery specifications of the Scopoderm transdermal patch and reveal the importance of skin binding with respect to local drug disposition. Further data analysis and skin PK modeling are indicated to further refine and develop the approach outlined.

The Effect of Covert and Overt Infections on Disease Dynamics in Honey-Bee Colonies.

Viral diseases of honey bees are important economically and ecologically and have been widely modelled. The models reflect the fact that, in contrast to the typical case for vertebrates, invertebrates cannot acquire immunity to a viral disease, so they are of SIS or (more often) SI type. Very often, these diseases may be transmitted vertically as well as horizontally, by vectors as well as directly, and through the environment, although models do not generally reflect all these transmission mechanisms. Here, we shall consider an important additional complication the consequences of which have yet to be fully explored in a model, namely that both infected honey bees and their vectors may best be described using more than one infection class. For honey bees, we consider three infection classes. Covert infections occur when bees have the virus under control, such that they do not display symptoms of the disease, and are minimally or not at all affected by it. Acutely overtly infected bees often exhibit severe symptoms and have a greatly curtailed lifespan. Chronically overtly infected bees typically have milder symptoms and a moderately shortened lifespan. For the vector, we consider just two infection classes which are covert infected and overt infected as has been observed in deformed-wing virus (DWV) vectored by varroa mites. Using this structure, we explore the impact of spontaneous transition of both mites and bees from a covertly to an overtly infected state, which is also a novel element in modelling viral diseases of honey bees made possible by including the different infected classes. The dynamics of these diseases are unsurprisingly rather different from the dynamics of a standard SI or SIS disease. In this paper, we highlight how our compartmental structure for infection in honey bees and their vectors impact the disease dynamics observed, concentrating in particular on DWV vectored by varroa mites. If there is no spontaneous transition, then a basic reproduction number [Formula: see text] exists. We derive a condition for [Formula: see text] that reflects the complexities of the system, with components for vertical and for direct and vector-mediated horizontal transmission, using the directed graph of the next-generation matrix of the system. Such a condition has never previously been derived for a honey-bee-mite-virus system. When spontaneous transitions do occur, then [Formula: see text] no longer exists, but we introduce a modification of the analysis that allows us to determine whether (i) the disease remains largely covert or (ii) a substantial outbreak of overt disease occurs.

Modeling the Effect of HIV/AIDS Stigma on HIV Infection Dynamics in Kenya.

Stigma toward people living with HIV/AIDS (PLWHA) has impeded the response to the disease across the world. Widespread stigma leads to poor adherence of preventative measures while also causing PLWHA to avoid testing and care, delaying important treatment. Stigma is clearly a hugely complex construct. However, it can be broken down into components which include internalized stigma (how people with the trait feel about themselves) and enacted stigma (how a community reacts to an individual with the trait). Levels of HIV/AIDS-related stigma are particularly high in sub-Saharan Africa, which contributed to a surge in cases in Kenya during the late twentieth century. Since the early twenty-first century, the United Nations and governments around the world have worked to eliminate stigma from society and resulting public health education campaigns have improved the perception of PLWHA over time, but HIV/AIDS remains a significant problem, particularly in Kenya. We take a data-driven approach to create a time-dependent stigma function that captures both the level of internalized and enacted stigma in the population. We embed this within a compartmental model for HIV dynamics. Since 2000, the population in Kenya has been growing almost exponentially and so we rescale our model system to create a coupled system for HIV prevalence and fraction of individuals that are infected that seek treatment. This allows us to estimate model parameters from published data. We use the model to explore a range of scenarios in which either internalized or enacted stigma levels vary from those predicted by the data. This analysis allows us to understand the potential impact of different public health interventions on key HIV metrics such as prevalence and disease-related death and to see how close Kenya will get to achieving UN goals for these HIV and stigma metrics by 2030.

[Reliability and Validity of Korean Version of Nursing Students' Anxiety and Self-Confidence with Clinical Decision Making Scale].

PURPOSE: The purpose of this study was to adapt, modify, and validate the Nursing Anxiety and Self-Confidence with Clinical Decision-Making Scale (NASC-CDM©) for Korean nursing students. METHODS: Participants were 183 nursing students with clinical practice experience in two nursing colleges. The construct validity and reliability of the final Korean version of the NASC-CDM© were examined using exploratory and confirmatory factor analyses and testing of internal consistency reliability. For adaptation and modification, the instrument was translated from English to Korean. Expert review and a cross-sectional survey were used to test the instrument's validity. RESULTS: The Korean version of the NASC-CDM© (KNASC-CDM) was composed of 23 items divided into four dimensions: (i) Listening fully and using resources to gather information; (ii) Using information to see the big picture; (iii) Knowing and acting; and (iv) Seeking information from clinical instructors. The instrument explained 60.1% of the total variance for self-confidence and 63.1% of the variance for anxiety; Cronbach's α was .93 for self-confidence and .95 for anxiety. CONCLUSION: The KNASC-CDM can be used to identify anxiety and self-confidence in nursing students' clinical decision-making in Korea. However, further research should be done to test this instrument, as it is classified differently from the original NASC-CDM© version.

A mechanistic approach to modelling the formation of a drug reservoir in the skin.

It has been shown that prolonged systemic presence of a drug can cause a build-up of that drug in the skin. This drug 'reservoir', if properly understood, could provide useful information about recent drug-taking history of the patient. We create a pair of coupled mathematical models which combine to explore the potential for a drug reservoir to establish based on the kinetic properties of the drug. The first compartmental model is used to characterise time-dependent drug concentrations in plasma and tissue following a customisable drug regimen. Outputs from this model provide boundary conditions for the second, spatio-temporal model of drug build-up in the skin. We focus on drugs that are highly bound as this will restrict their potential to move freely into the skin but which are lipophilic so that, in the unbound form, they would demonstrate an affinity to the outer layers of the skin. Buprenorphine, a drug used to treat opiate addiction, is one example of a drug satisfying these properties. In the discussion we highlight how our study might be used to inform future experimental design and data collection to provide relevant parameter estimates for reservoir formation and its potential to contribute to enhanced drug monitoring techniques.

Prediabetes: The Variation between HbA1c and Fasting Plasma Glucose.

PURPOSE: The prevalence of Diabetes Type 2 is on the rise internationally. Currently, Fasting Plasma Glucose (FPG) and HbA1c are both used to determine if an individual is diabetic or prediabetic. We aimed to describe the prevalence of diabetes, prediabetes, and glycemic control in a population-based sample of elderly Hispanic and non-Hispanic White participants in New Mexico. METHODS: To do this, we compared HbA1c with FPG using Chi-Square analysis across gender and ethnicity to provide information for future health care policy. We also performed non-parametric regression using a locally weighted smoothing technique to investigate the relationship between FPG and HbA1c levels. RESULTS: Our analysis identifies a large variation between the sensitivity of HbA1c and FPG in the identification of both prediabetes and diabetes. Interestingly, 95% of diabetics defined by FPG are also defined by HbA1c, representing overlap between the two measures. When comparing the prevalence of prediabetes between the two measures, the overlap of FPG with HbA1c was only 30% and HbA1c identifies more individuals as prediabetic than FPG. Prevalence of diabetes was also higher when defined by HbA1c compared to FPG and the overall agreement between HbA1c and FPG appears to be poor particularly by sex and ethnicity (K=0.22-0.34). Glycemic control was poor overall with Hispanics displaying a larger amount of uncontrolled diabetes. CONCLUSION: We compared HbA1c and FPG by gender and ethnicity and showed both measures of diabetes differ in their sensitivity across ethnic groups. Our results suggest that using HbA1c, rather than FPG, results in higher rates of prediabetes and diabetes, a finding with numerous implications for health care practice.

Genetic factors associated with naevus count and dermoscopic patterns: preliminary results from the Study of Nevi in Children (SONIC).

BACKGROUND: Melanocytic naevi are an important risk factor for melanoma. Naevi with distinct dermoscopic patterns can differ in size, distribution and host pigmentation characteristics. OBJECTIVES: We examined MC1R and 85 other candidate loci in a cohort of children to test the hypothesis that the development and dermoscopic type of naevi are modulated by genetic variants. METHODS: Buccal DNAs were obtained from a cohort of 353 fifth graders (mean age 10·4 years). Polymorphisms were chosen based on a known or anticipated role in naevi and melanoma. Associations between single-nucleotide polymorphisms (SNPs) and baseline naevus count were determined by multivariate regression adjusting for sex, race/ethnicity and sun sensitivity. Dermoscopic images were available for 853 naevi from 290 children. Associations between SNPs and dermoscopic patterns were determined by polytomous regression. RESULTS: Four SNPs were significantly associated with increasing (IRF4) or decreasing (PARP1, CDK6 and PLA2G6) naevus count in multivariate shrinkage analyses with all SNPs included in the model; IRF4 rs12203952 showed the strongest association with log naevus count (relative risk 1·56, P < 0·001). Using homogeneous naevi as the reference, IRF4 rs12203952 and four other SNPs in TERT, CDKN1B, MTAP and PARP1 were associated with either globular or reticular dermoscopic patterns (P < 0·05). CONCLUSIONS: Our results provide evidence that subsets of naevi defined by dermoscopic patterns differ in their associations with germline genotypes and support the hypothesis that dermoscopically defined subsets of naevi are biologically distinct. These results require confirmation in larger cohorts. If confirmed, these findings will improve the current knowledge of naevogenesis and assist in the identification of individuals with high-risk phenotypes.

Approximating optimal controls for networks when there are combinations of population-level and targeted measures available: chlamydia infection as a case-study.

Using a modified one-dimensional model for the spread of an SIS disease on a network, we show that the behaviour of complex network simulations can be replicated with a simpler model. This model is then used to design optimal controls for use on the network, which would otherwise be unfeasible to obtain, resulting in information about how best to combine a population-level random intervention with one that is more targeted. This technique is used to minimise intervention costs over a short time interval with a target prevalence, and also to minimise prevalence with a specified budget. When applied to chlamydia, we find results consistent with previous work; that is maximising targeted control (contact tracing) is important to using resources effectively, while high-intensity bursts of population control (screening) are more effective than maintaining a high level of coverage.

Airway CD8(+) T cells induced by pulmonary DNA immunization mediate protective anti-viral immunity.

Vaccination strategies for protection against a number of respiratory pathogens must induce T-cell populations in both the pulmonary airways and peripheral lymphoid organs. In this study, we show that pulmonary immunization using plasmid DNA formulated with the polymer polyethyleneimine (PEI-DNA) induced antigen-specific CD8(+) T cells in the airways that persisted long after antigen local clearance. The persistence of the cells was not mediated by local lymphocyte proliferation or persistent antigen presentation within the lung or airways. These vaccine-induced CD8(+) T cells effectively mediated protective immunity against respiratory challenges with vaccinia virus and influenza virus. Moreover, this protection was not dependent upon the recruitment of T cells from peripheral sites. These findings demonstrate that pulmonary immunization with PEI-DNA is an efficient approach for inducing robust pulmonary CD8(+) T-cell populations that are effective at protecting against respiratory pathogens.

Internal RNA Replication Elements are Prevalent in Tombusviridae.

Internal replication elements (IREs) are RNA structures that are present at internal positions in the genomes of different types of plus-strand RNA viruses. Members of the genus Tombusvirus (family Tombusviridae) contain an IRE within the polymerase coding region of their genomes and this RNA element participates in both genome targeting to sites of replication and replicase complex assembly. Here we propose that other members of the virus family Tombusviridae also possess comparable IREs. Through sequence and structural analyses, candidate IREs in several genera of this family were identified, including aureusviruses, necroviruses, carmoviruses, and pelarspoviruses. The results from subsequent mutational analysis of selected proposed IREs were consistent with a critical role for these structures in viral genome accumulation during infections. Our study supports the existence of IREs in several genera in Tombusviridae and points to previously unappreciated similarities in genome replication strategies between members of this virus family.

Exploring short-term responses to changes in the control strategy for Chlamydia trachomatis.

Chlamydia has a significant impact on public health provision in the developed world. Using pair approximation equations we investigate the efficacy of control programmes for chlamydia on short time scales that are relevant to policy makers. We use output from the model to estimate critical measures, namely, prevalence, incidence, and positivity in those screened and their partners. We combine these measures with a costing tool to estimate the economic impact of different public health strategies. Increasing screening coverage significantly increases the annual programme costs whereas an increase in tracing efficiency initially increases annual costs but over time reduces costs below baseline, with tracing accounting for around 10% of intervention costs. We found that partner positivity is insensitive to changes in prevalence due to screening, remaining at around 33%. Whether increases occur in screening or tracing levels, the cost per treated infection increases from the baseline because of reduced prevalence.

The role of optimal control in assessing the most cost-effective implementation of a vaccination programme: HPV as a case study.

Vaccination against the human papillomavirus (HPV) is a recent development in the UK. This paper uses an optimal control model to explore how best to target vaccination. We find that the vaccination of sexually active individuals has a greater impact on disease control than the vaccination of sexually non-active individuals. Extending the model to include male vaccination, we find that including males in a vaccination strategy is cost-effective. We compare the optimal control solution to that from a constant control model and show that the optimal control model is more efficient at forcing the system to a disease-controlled steady state.

Modelling formation of a drug reservoir in the stratum corneum and its impact on drug monitoring using reverse iontophoresis.

Reverse iontophoresis is a relatively new technique for non-invasive drug monitoring in the body. It involves a small electrical current being passed through the skin to facilitate the movement of small charged ions and polar molecules on the skin's surface where the amount of drug can then be measured and hence an accurate estimate of the blood concentration can be made. In vivo studies for several molecules show that initially large amounts of drug are extracted from the body, which are unrelated to the magnitude of the blood concentration; over time the fluxes of extraction decrease to a level proportional to the steady state blood concentration. This suggests that, at first, the drug is being extracted from some source other than the blood; one such candidate for this source is the dead cells which form the stratum corneum. In this paper, we construct two related mathematical models; the first describes the formation of the drug reservoir in the stratum corneum as a consequence of repeated drug intake and natural death of skin cells in the body. The output from this model provides initial conditions for the model of reverse iontophoresis in which charged ions from both the blood and the stratum corneum reservoir compete for the electric current. Model parameters are estimated from data collected for lithium monitoring. Our models will improve interpretation of reverse iontophoretic data by discriminating the subdermal from the skin contribution to the fluxes of extraction. They also suggest that analysis of the skin reservoir might be a valuable tool to investigate patients' exposure to chemicals including therapeutic drugs.

The HPV vaccination strategy: could male vaccination have a significant impact?

We investigate the potential success of the human papilloma virus (HPV) vaccine, taking into consideration possible waning immunity and the influence of behavioural parameters. We use a compartmental, population-level ordinary differential equation (ODE) model. We find the effective reproductive value for HPV, Re0, which measures the threshold for infection outbreak in a population that is not entirely susceptible, together with infection prevalence. We study the effects of different parameters on both of these quantities. Results show that waning immunity plays a large part in allowing infection to persist. The proportion of the population not sexually active when vaccination occurs affects Re0, as does the rate at which individuals become sexually active. In several cases, infection persists as a result of an infection reservoir in the male cohort. To explore this further, we introduce male vaccination and find the conditions for which vaccination of males could be considered appropriate.