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Background & aims: Severe Acute Malnutrition (SAM) in children is determined using anthropometry. However, bio-electrical impedance (BI) analysis could improve the estimation of altered body composition linked to edema and/or loss of lean body mass in children with SAM. We aimed to assess: 1) the changes in BI parameters during clinical stabilization and 2) whether BI parameters add prognostic value for clinical outcome beyond the use of anthropometry. Methods: This prospective observational study enrolled children, aged 6–60 months, that were admitted at Queen Elizabeth Central Hospital in Blantyre, Malawi, for complicated SAM (i.e., having either severe wasting or edematous SAM with a complicating illness). Height, weight, mid-upper arm circumference (MUAC), and BI were measured on admission and after clinical stabilization. BI measures were derived from height-adjusted indices of resistance (R/H), reactance (Xc/H), and phase angle (PA) and considered to reflect body fluids and soft tissue in BI vector analysis (BIVA). Results: We studied 183 children with SAM (55% edematous; age 23.0 ± 12.0 months; 54% male) and 42 community participants (age 20.1 ± 12.3 months; male 62%). Compared to community participants, the BIVA of children with edematous SAM were short with low PA and positioned low on the hydration axis which reflects severe fluid retention. In contrast, children with severe wasting had elongated vectors with a PA that was higher than children with edematous SAM but lower than community participants. Their BIVA position fell within the top right quadrant linked to leanness and dehydration. BIVA from severely wasted and edematous SAM patients differed between groups and from community children both at admission and after stabilization (p < 0.001). Vector position shifted during treatment only in children with edematous SAM (p < 0.001) and showed a upward translation suggestive of fluid loss. While PA was lower in children with SAM, PA did not contribute more than anthropometry alone towards explaining mortality, length of stay, or time-to-discharge or time-to-mortality. The variability and heterogeneity in BI measures was high and their overall added predictive value for prognosis of individual children was low. Conclusions: BIVA did not add prognostic value over using anthropometry alone to predict clinical outcome. Several implementation challenges need to be optimized. Thus, in low-resource settings, the routine use of BI in the management of pediatric malnutrition is questionable without improved implementation.

Blood cultures are essential diagnostic tools to identify pathogens in systemic infections. However, logistics of blood culture performance is often suboptimal. This study analyses the pre-analytic phase of blood culture processing through different types of risk assessments.We performed direct observations to gain in-depth knowledge of the root causes of suboptimal blood culture performance. These findings were summarised in a Bow-Tie chart. We then utilised a healthcare failure mode and effect analysis to prioritise failures per step in the process and to organise improvement activities. Finally, improvement actions were planned.Not obtaining a second set of blood cultures in the logistics of blood culture performance had the highest priority for action. Several failure modes, including human and system factors, were identified. Improvement actions included training and clinical lessons for nurses in the emergency department, updating hospital search engines to ease identification of relevant protocols, and an evaluation of the workload at the emergency department. Failure modes caused by human factors appear easy to address, however changing human behaviour is challenging.The analysis provided useful insight into the different steps in the logistics of blood culture performance and facilitated the organisation of actions focused on addressing the most urgent root causes.

Objective The relation between malnutrition and exocrine pancreatic insufficiency (EPI) has been described previously, but it is unclear if malnutrition leads to EPI or vice versa. We systematically synthesized current evidence evaluating the association between malnutrition and EPI in children. Methods Pubmed, Embase, and Cochrane databases were searched from inception until February 2017. We included cohort or case-controlled studies in children reporting on prevalence or incidence of EPI and malnutrition. Data generation was performed independently by 2 authors. Quality was assessed by using quality assessment tools from the National Heart, Lung, and Blood Institute. Results Nineteen studies were divided into 2 groups: 10 studies showing EPI leading to malnutrition, and 9 studies showing malnutrition leading to EPI. Because of heterogeneity in design, definitions, and outcome measures, pooling of results was impossible. Quality was good in 4 of 19 studies. Pancreatic insufficiency was linked to decreased nutritional status in 8 of 10 articles, although this link was not specified properly in most articles. In malnourished children, improvement was seen in pancreatic function in 7 of 9 articles after nutritional rehabilitation. The link between the 2 was not further specified. Heterogeneity exists with respect to definitions, outcome measures, and study design. Conclusions There is sufficient evidence for an association between EPI and malnutrition. We could not confirm whether there is a correlation or causality between EPI or malnutrition. It was therefore not possible to draw firm conclusions from this systematic review on underlying pathophysiological mechanisms between EPI and malnutrition. More observational clinical trials are crucially needed.

It is possible to define multiresolution by reversing the process of subdivision. One approach to reverse a subdivision scheme appropriates pure numerical algebraic relations for subdivision using the interaction of diagrams (Bartels and Samavati, 2011; Samavati and Bartels, 2006). However, certain assumptions carried through the available work, two of which we wish to challenge: (1) the construction of multiresolutions for irregular meshes are reconsidered in the presence of any extraordinary vertex rather than being prepared beforehand as simple available relations and (2) the connectivity graph of the coarse mesh would have to be a subgraph of the connectivity graph of the fine mesh. 3 subdivision (Kobbelt, 2000) lets us engage both of these concerns. With respect to (2), the 3 post-subdivision connectivity graph shares no interior edge with the pre-subdivision connectivity graph. With respect to (1), we observe that no subdivision produces an arbitrary connectivity graph. Rather, there are local regularities imposed by the subdivision on the fine mesh, which may be exploited to establish, in advance, the decomposition and reconstruction filters of a multiresolution for an initially given irregular coarse mesh. We provide indications that our proposed approach for 3 subdivision is potentially useful for other primal subdivision schemes by mentioning results for the Loop (1987) and CatmullClark subdivisions (Catmull and Clark, 1978). Finally, after showing some results, we analyze the quality of the reversal matrix and present a technique using numerical optimization. We extend diagrammatic approaches to construct multiresolution for semiregular meshes with extraordinary vertices.We examine our technique for 3 subdivision in detail.We also show that our approach is useful for other primal subdivision schemes such as Loop and CatmullClark.We analyze the quality of the reversal matrix and present a technique using numerical optimization.

Objectives To compare morbidity and mortality in patients with advanced ovarian cancer undergoing cytoreductive surgery (CRS) for primary and recurrent disease. Methods A literature search was performed for publications reporting morbidity and mortality in patients undergoing CRS in primary and recurrent ovarian malignancy. Two independent reviewers applied inclusion and exclusion criteria to select included papers. A total of 215 citations were reviewed; 6 studies comprising 641 patients were selected for the analysis. Literature search was performed using PRISMA guidelines. Results were reported as mean differences or pooled odds ratios (OR) with 95% confidence intervals (95% CI). Results The overall morbidity rate was 38.4%, and this did not differ between the two groups (p=0.97). This did not change when only Clavien-Dindo grade 3 and 4 morbidities were accounted for (14% primary CRS, 15% recurrent, p=0.83). Compared to primary CRS, secondary CRS was associated with a similar operative time (mean 400 minutes, I2=79%, p=0.45), rate of bowel resection (I2=75%, p=0.37) and transfusion requirements (MD -0.7L, I2=76%, p=0.45). The rate of complete (R0) resection was 69.4%, with no significant difference between primary and recurrent disease (p=0.46). Although all studies commented on postoperative mortality, there were too few deaths in either group to allow meaningful meta-analysis, with 4 deaths in the group undergoing primary CRS (1.0%) and 2 deaths in the group with recurrent disease (0.9%). Conclusions Secondary CRS for recurrent ovarian cancer is a safe and feasible option in carefully pre-selected patients with comparable morbidity and survival outcomes to primary CRS.

Prevention of nonmelanoma skin cancers remains a health priority due to high costs associated with this disease. Diclofenac and difluoromethylornithine (DFMO) have demonstrated chemopreventive efficacy for cutaneous squamous cell carcinomas. We designed a randomized study of the combination of DFMO and diclofenac in the treatment of sun-damaged skin. Individuals with visible cutaneous sun damage were eligible. Subjects were randomized to one of the three groups: topical DFMO applied twice daily, topical diclofenac applied daily, or DFMO plus diclofenac. The treatment was limited to an area on the left forearm, and the duration of use was 90 days. We hypothesized that combination therapy would have increased efficacy compared with single-agent therapy. The primary outcome was change in karyometric average nuclear abnormality (ANA) in the treated skin. Individuals assessing the biomarkers were blinded regarding the treatment for each subject. A total of 156 subjects were randomized; 144 had baseline and end-of-study biopsies, and 136 subjects completed the study. The ANA unexpectedly increased for all groups, with higher values correlating with clinical cutaneous inflammation. Nearly all of the adverse events were local cutaneous effects. One subject had cutaneous toxicity that required treatment discontinuation. Significantly more adverse events were seen in the groups taking diclofenac. Overall, the study indicated that the addition of topical DFMO to topical diclofenac did not enhance its activity. Both agents caused inflammation on a cellular and clinical level, which may have confounded the measurement of chemopreventive effects. More significant effects may be observed in subjects with greater baseline cutaneous damage. Cancer Prev Res; 9(2); 128–34. ©2015 AACR. See related article by Tsai and Hawk, p. 125

A large body of epidemiologic evidence has shown that use of progestin-containing preparations lowers ovarian cancer risk. The purpose of the current study was to gather further preclinical evidence supporting progestins as cancer chemopreventives by demonstrating progestin-activation of surrogate endpoint biomarkers pertinent to cancer prevention in the genital tract of women at increased risk of ovarian cancer. There were 64 women enrolled in a multi-institutional randomized trial who chose to undergo risk-reducing bilateral salpingo-oophorectomy (BSO) and to receive the progestin levonorgestrel or placebo for 4 to 6 weeks prior to undergoing BSO. The ovarian and fallopian tube epithelia (FTE) were compared immunohistochemically for effects of levonorgestrel on apoptosis (primary endpoint). Secondary endpoints included TGFβ isoform expression, proliferation, and karyometric features of nuclear abnormality. In both the ovary and fallopian tube, levonorgestrel did not confer significant changes in apoptosis or expression of the TGFβ1, 2, or 3 isoforms. In the ovarian epithelium, treatment with levonorgestrel significantly decreased the proliferation index. The mean ovarian Ki-67 value in the placebo arm was 2.027 per 100 cells versus 0.775 per 100 cells in the levonorgestrel arm (two-sided P value via Mann–Whitney U test = 0.0114). The karyometric signature of nuclei in both the ovarian and FTE deviated significantly from normal controls (women at average risk of ovarian cancer), but was significantly less abnormal in women treated with levonorgestrel. These karyometric data further support the idea that progestins may clear genetically abnormal cells and act as chemopreventive agents against ovarian and fallopian tube cancer.

Objective: To assess the benefits of pancreatic enzyme replacement therapy (PERT) in children with complicated severe acute malnutrition.Study design: We conducted a randomized, controlled trial in 90 children aged 6-60 months with complicated severe acute malnutrition at the Queen Elizabeth Central Hospital in Malawi. All children received standard care; the intervention group also received PERT for 28 days.Results: Children treated with PERT for 28 days did not gain more weight than controls (13.7 +/- 9.0% in controls vs 15.3 +/- 11.3% in PERT; P = .56). Exocrine pancreatic insufficiency was present in 83.1% of patients on admission and fecal elastase-1 levels increased during hospitalization mostly seen in children with nonedematous severe acute malnutrition (P Conclusions: PERT does not improve weight gain in severely malnourished children but does increase the rate of hospital discharge. Mortality was lower in patients on PERT, a finding that needs to be investigated in a larger cohort with stratification for edematous and nonedematous malnutrition. Mortality in severe acute malnutrition is associated with markers of poor digestive function.

UDP-glucuronosyltransferases (UGT) catalyze the biotransformation of many endobiotics and xenobiotics, and are coded by polymorphic genes. However, knowledge about the effects of these polymorphisms is rarely used for the individualization of drug therapy. Here, we present a quantitative systematic review of clinical studies on the impact of UGT variants on drug metabolism to clarify the potential for genotype-adjusted therapy recommendations. Data on UGT polymorphisms and dose-related pharmacokinetic parameters in man were retrieved by a systematic search in public databases. Mean estimates of pharmacokinetic parameters were extracted for each group of carriers of UGT variants to assess their effect size. Pooled estimates and relative confidence bounds were computed with a random-effects meta-analytic approach whenever multiple studies on the same variant, ethnic group, and substrate were available. Information was retrieved on 30 polymorphic metabolic pathways involving 10 UGT enzymes. For irinotecan and mycophenolic acid a wealth of data was available for assessing the impact of genetic polymorphisms on pharmacokinetics under different dosages, between ethnicities, under comedication, and under toxicity. Evidence for effects of potential clinical relevance exists for 19 drugs, but the data are not sufficient to assess effect size with the precision required to issue dose recommendations. In conclusion, compared to other drug metabolizing enzymes much less systematic research has been conducted on the polymorphisms of UGT enzymes. However, there is evidence of the existence of large monogenetic functional polymorphisms affecting pharmacokinetics and suggesting a potential use of UGT polymorphisms for the individualization of drug therapy.

Aim This study aimed to explore the molecular mechanisms for the parietal cell loss and fundic hyperplasia observed in gastric mucosa of mice lacking the carbonic anhydrase 9 (CAIX). Methods We assessed the ability of CAIX-knockout and WT gastric surface epithelial cells to withstand a luminal acid load by measuring the pHi of exteriorized gastric mucosa in vivo using two-photon confocal laser scanning microscopy. Cytokines and claudin-18A2 expression was analysed by RT-PCR. Results CAIX-knockout gastric surface epithelial cells showed significantly faster pHi decline after luminal acid load compared to WT. Increased gastric mucosal IL-1β and iNOS, but decreased claudin-18A2 expression (which confer acid resistance) was observed shortly after weaning, prior to the loss of parietal and chief cells. At birth, neither inflammatory cytokines nor claudin-18 expression were altered between CAIX and WT gastric mucosa. The gradual loss of acid secretory capacity was paralleled by an increase in serum gastrin, IL-11 and foveolar hyperplasia. Mild chronic proton pump inhibition from the time of weaning did not prevent the claudin-18 decrease nor the increase in inflammatory markers at 1 month of age, except for IL-1β. However, the treatment reduced the parietal cell loss in CAIX-KO mice in the subsequent months. Conclusions We propose that CAIX converts protons that either backflux or are extruded from the cells rapidly to CO2 and H2O, contributing to tight junction protection and gastric epithelial pHi regulation. Lack of CAIX results in persistent acid backflux via claudin-18 downregulation, causing loss of parietal cells, hypergastrinaemia and foveolar hyperplasia.

To develop a quantitative histopathology algorithm to predict which patients with cutaneous squamous cell carcinoma (cSCC) were likely to experience recurrence or metastases.This retrospective study of cSCC lesions compared patients with aggressive disease (n = 40) and those with nonaggressive disease (n = 35). Based on a previous study using nuclear karyometry, we determined that aggressive lesions had a high proportion of a specific nuclear phenotype. The proportion of those nuclei was used to derive an aggressiveness score for each lesion. The mean age of patients was similar in both groups, as were the locations of index lesions.The mean aggressiveness scorefor cases with aggressive lesions was 0.60 ± 0.21 and was 0.28 ± 0.35 for those with nonaggressive lesions. The overall accuracy in properly characterizing lesions was 72%. The area under the receiver operating characteristic curve was 0.80 ± 0.05. In general, the aggressive nuclear phenotype is represented by elevated levels of chromatin clumps and short linear segments of dark chromatin/intense pixels.These data suggest that discriminant functions may be utilized to distinguish between aggressive and nonaggressive lesions at the time of diagnosis.

Objectives To assess whether pancreatic function is impaired in children with severe acute malnutrition, is different between edematous vs nonedematous malnutrition, and improves by nutritional rehabilitation.Study design We followed 89 children with severe acute malnutrition admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi. Stool and blood samples were taken on admission and 3 days after initial stabilization to determine exocrine pancreatic function via fecal elastase-1 (FE-1) and serum trypsinogen and amylase levels.Results A total of 33 children (37.1%) had nonedematous severe acute malnutrition, whereas 56 (62.9%) had edematous severe acute malnutrition. On admission, 92% of patients showed evidence of pancreatic insufficiency as measured by FE-1 57 ng/mL) in 28% and amylase in 21% (> 110 U/L) of children, suggesting pancreatic inflammation.Conclusion Exocrine pancreatic insufficiency is prevalent in children with severe acute malnutrition and especially in children with edematous severe acute malnutrition. In addition, biochemical signs suggestive of pancreatitis are common in children with severe acute malnutrition. These results have implications for standard rehabilitation treatment of children with severe acute malnutrition who may benefit from pancreatic enzyme replacement therapy.

This small exploratory study was designed to test the hypothesis that thin melanoma lesions contain nuclei of two similar phenotypes, in different proportions. In lesions likely to progress to metastatic disease, one of these phenotypes predominates. Histopathological sections from 18 cases of thin melanomas which did not progress to metastasis, and from 10 cases which did progress were imaged and digitized at high resolution, with a total of 2084 and 1148 nuclei, respectively, recorded. Five karyometric features were used to discriminate between nuclei from indolent and from potentially metastatic lesions. For each case, the percentage of nuclei classified by the discriminant function as having come from a potentially metastatic lesion was determined and termed as case classification criterion. Standard histopathological criteria, such as ulceration and high mitotic index, indicated in this material the need for intensive therapy for only one of the 10 participants, as compared with 7/10 identified correctly by the karyometric measure. Using a case classification criterion threshold of 40%, the overall accuracy was 86% in the test set. The proportion of nuclei of an aggressive phenotype may lend itself as an effective prognostic clue for thin melanoma lesions. The algorithm developed in this training set appears to identify those patients at high risk for metastatic disease, and demonstrates a basis for a further study to assess the utility of prognostic clues for thin melanomas.

In previous work we introduced a construction to produce multiresolutions from given subdivisions. A portion of that construction required solving bilinear equations using a symbolic algebra system. Here we replace the bilinear equations with a pair of linear equation systems, resulting in a completely numerical construction. Diagrammatic tools provide assistance in carrying this out. The construction is shown for an example of univariate subdivision. The results for a bivariate subdivision are given to illustrate the construction's ability to handle multivariate meshes, as well as special points, without requiring any modification of approach. The construction usually results in analysis and reconstruction filters that are finite, since it seeks each filter locally for the neighborhood of the mesh to which it applies. The use of a set of filters constructed in this way is compared with filters based on spline wavelets for image compression to show that the construction can yield satisfactory results.

Difluoromethylornithine (DFMO) and nonsteroidal anti-inflammatory drugs have been shown to have a synergistic protective effect against colon cancer. As single agents, both DFMO and diclofenac have demonstrated efficacy in the treatment of actinic keratoses, the cutaneous precursors to cutaneous squamous cell carcinomas. We designed a study investigating the effects of these two medications, alone and in combination, on sun-damaged skin of the forearm. The primary objective is to determine whether a three-month course of combination therapy increases the efficacy over either agent used alone in the treatment of moderately sun-damaged skin. The primary endpoint is the change in karyometric values from skin biopsies before and after treatment. A total of 156 subjects were enrolled in the study and randomized to A: topical DFMO applied BID × 90 days; B: topical diclofenac applied QD × 90 days; or C: topical DFMO applied BID and topical diclofenac applied QD × 90 days. Planned sample size was 138 evaluable subjects to provide 80% power to detect the difference in response rate as measured by karyometric average nuclear abnormality (ANA) between the single-agent DFMO arm and the combination treatment arm at the 2.5% significance level. The results for efficacy and safety will be presented at the AACR Frontiers in Cancer Prevention meeting. Secondary biomarker and clinical endpoints will also be summarized. These findings will provide insight into the potential use of the combination of these medications as skin cancer chemopreventive agents. Citation Information: Cancer Prev Res 2010;3(12 Suppl):CN02-06.

Im Verlauf der letzten beiden Jahre fiel im Raum Magdeburg und Umgebung eine augenscheinliche Haufung von todlichen Kohlenstoffmonoxid- (CO-)Intoxikationen durch das Betreiben von Holzkohlegrills in geschlossenen Raumen auf. In einem experimentellen Ansatz wurde die Entwicklung der CO-Konzentrationen wahrend der Verbrennung unterschiedlicher Materialien (Holzkohle, Grillbriketts, Bambus Cook Chips) im Rahmen eines Grillvorgangs in einem geschlossenen Container gemessen. Die resultierenden Gaskonzentrationen sowie die Temperaturen im Raum und in der Glut wurden aufgezeichnet. Dabei wurden im Container CO-Konzentrationen erreicht, die den Tod in Abhangigkeit von den Randbedingungen (Art der Grillkohle, Menge und Zustand der Restglut) nach etwa 30–60 min eintreten lassen konnen. Insbesondere bei Verwendung eines Indoor-Grills ist nach einer Betriebszeit von 60 min mit dem Auftreten von gesundheitlich kritischen Situationen zu rechnen. Die Ergebnisse wurden dem Bundesministerium fur Ernahrung, Landwirtschaft und Verbraucherschutz mitgeteilt, um langfristig eine Risikominimierung hinsichtlich der Todesursache „CO-Intoxikation durch Betreiben eines Grills im geschlossenen Raum“, z. B. mithilfe eines entsprechenden auffalligen Warnhinweises auf den Grillkohleverpackungen, zu erreichen.

Zusammenfassung Das erste deutsche reichseinheitliche Fleischbeschaugesetz wurde 1900 verkundet. Es beschrankte sich in Aufgabenstellung und Wirkungsbereich im Grundsatz auf die klassische Aufgabe der „Fleischbeschau”. Bis 1960 wurde — trotz mehrfacher Anderungen — diese klassische Linie im wesentlichen beibehalten. Erst die Anderung von 1960 last die Einleitung einer echten Gesetzesreform erkennen. Rasch fortschreitende wissenschaftliche Erkenntnisse, insbesondere auf dem Gebiete der Zoonosen, der Einflus der Technisierung auf das Geschehen auch im biologischen Bereich sowie die internationale Entwicklung wandeln und erweitern die Aufgabe des tierarztlichen Fleischhygienikers, dessen Masnahmen sich zukunftig auf eine breite und einheitliche Ermachtigung in einem Fleisch-hygiene-Dachgesetz stutzen mussen, fur dessen grundsatzliche Gestaltung Vorschlage gemacht werden. Das Studium der Veterinarmedizin sowie Aufgabenstellung und praktische Erfullung des tierarztlichen Berufes mussen die Tatsache mehr berucksichtigen, das die tierarztliche Lebensmittelhygiene bei der Geburt des landwirtschaftlichen Nutztieres beginnt, das zu Lebzeiten Lebensmittel produziert und nach der Schlachtung im wesentlichen selbst zum Lebensmittel wird. Seine Gesunderhaltung ist mehr als „Erhaltung wirtschaftlicher Werte”. Sie ist auch praktische Gesundheitsprophylaxe fur den Menschen. Ein Fleischhygiene-Dachgesetz dient der Sicherung der einwandfreien Beschaffenheit des Fleisches vor seiner Inverkehrgabe und vor der Herstellung von Fleischerzeugnissen. Es grenzt sich klar vom Lebensmittelgesetz ab, das der Uberwachung der Lebensmittel bei der Herstellung sowie bei und nach der Inverkehrgabe dient. Die Entwicklung des klassischen Fleischbeschaugesetzes zum Fleischhygiene-Dachgesetz ist ein vordringliches Anliegen im Rahmen der offentlichen Gesundheitspflege.

The chemopreventive and antitumor properties of perillyl alcohol (POH) that were studied preclinically indicate that topical POH inhibits both UVB-induced murine skin carcinogenesis (squamous cell tumor models) and 7,12-dimethylbenz(a)anthracene–induced murine melanoma (transgenic models involving tyrosinase-driven Ras). A previous phase 1 clinical trial in participants with normal-appearing skin showed that topical POH cream was well tolerated at a dose of 0.76% (w/w). Here, we performed a 3-month, double-blind, randomized, placebo-controlled phase 2a trial of two different doses of topical POH in individuals with sun-damaged skin. Participants applied POH cream twice daily to each dorsal forearm. Baseline and end-of-study biopsies were taken from each participant to evaluate whether the topical application of POH was effective in reversing actinic damage as evidenced by normalization of quantitative skin histopathologic scores and change in nuclear chromatin pattern as measured by karyometric analysis. There was a borderline reduction in the histopathologic score of the lower-dose POH group compared with the placebo (P = 0.1), but this was not observed in the high-dose group. However, in the high-dose group, a statistically significant reduction in the proportion of nuclei deviating from normal was observed by the use of karyometric analysis (P < 0.01). There was no statistical significance shown in the lower-dose group. No changes were observed in p53 expression, cellular proliferation (by proliferating cell nuclear antigen expression), or apoptosis in either treatment group compared with the placebo group. These results suggest that whereas our karyometric analyses can detect a modest effect of POH in sun-damaged skin, improved delivery into the epidermis may be necessary. Cancer Prev Res; 3(2); 160–9