Sarcoidosis and sarcoidal foreign body reaction after permanent eye makeup application: Analysis by immunohistochemistry with commercially available antibodies specific to Cutibacterium acnes and Mycobacteria.

We report two cases of eyebrow granulomas in patients who underwent a permanent eye makeup procedure. A rash was observed 16 months after the procedure in Case 1, and 10 years after the procedure in Case 2. Histopathologically, both patients exhibited noncaseating epithelioid cell granulomas. In Case 1, most of the black-brown granules of the permanent makeup were not present in the granulomas but were localized in the upper dermis. In contrast, in Case 2, some of the black-brown granules were phagocytized in the granulomas, preferentially within the giant cells. Based on systemic examinations, the patients from Cases 1 and 2 were diagnosed with sarcoidosis and sarcoidal foreign body reaction, respectively. To clarify the pathogenesis of our cases, we performed immunohistochemistry using commercially available monoclonal antibodies specific to Cutibacterium acnes, previously Propionibacterium acnes (PAB), and Mycobacteria (LAM antibody). PAB antibody results were positive in granulomas only in Case 1, and the LAM antibody results were negative in both cases. Immunohistochemical detection of C. acnes in granulomas could provide useful information for differentiating between cutaneous sarcoidosis and sarcoidal foreign body reactions.

Effectiveness of a Simulation-Based Education Program to Improve Novice Nurses' Clinical Judgment Skills.

INTRODUCTION: We assessed the effectiveness of a simulation-based education program to improve novice nurses' clinical judgment skills. METHODS: A simulation education program was implemented for 21 novice nurses. Surveys were conducted on program satisfaction, learning, and clinical judgment skills before, immediately after, and two months after the program. RESULTS: Novice nurses were highly satisfied with the simulation education program. The following nine categories were identified as learnings: provide psychological care for patients, conduct sufficient observation, conduct assessment and make judgment based on observational findings, consult and report appropriately to senior nurses, take response action calmly, collect necessary information, acquire knowledge, predict patients' conditions, and make environmental arrangements. The subscale score for theoretical and practical reasoning was significantly higher immediately after and two months after the program than before it. In addition, the subscale for grasping the condition by observation was significantly higher two months after the program than before and immediately after it. CONCLUSION: The novice nurses learned to sufficiently observe, obtain necessary information, and prospectively assess patients' conditions by taking part in the simulation education program. The subscale score for grasping the condition by observation was significantly higher two months after the program than before and immediately after it. After the simulation program, novice nurses were likely actively practicing nursing; therefore, this program may not be directly responsible for the improvement of these new nurses' clinical judgment. Nevertheless, we found that the completion of the simulation program was correlated with enhanced clinical judgment.

Development of a Clinical Judgment Scale for Japanese Nurses.

BACKGROUND: The purpose of this study was to develop a scale to assess the clinical judgment of nurses based on the clinical judgment process. METHOD: Based on a qualitative analysis of interviews with specialized and certified nurses and extant literature, a scale comprising 44 question items was created. A questionnaire survey was conducted with 1,444 nurses working in 28 general hospitals, psychiatric wards, cardiac care units, and intensive care units in Japan. RESULTS: Valid responses were obtained from 610 nurses. Exploratory factor analysis was performed on the 23 items extracted by item analysis, and two factors, "theoretical and practical reasoning" and "grasping the condition by observation," were extracted. Confirmatory factor analysis revealed the fit of the model. Cronbach's alpha confidence factor was 0.943 for the first factor and 0.924 for the second factor. CONCLUSION: These results support the factor validity and reliability of the clinical judgment scale. [J Contin Educ Nurs. 2021;52(8):383-391.].

In silico classification of major clearance pathways of drugs with their physiochemical parameters.

Predicting major clearance pathways of drugs is important in understanding their pharmacokinetic properties in clinical use, such as drug-drug interactions and genetic polymorphisms, and their subsequent pharmacological/toxicological effects. In this study, we established an in silico classification method to predict the major clearance pathways of drugs by identifying the boundaries of physicochemical parameters in empirical decisions for each clearance pathway. It requires only four physicochemical parameters [charge, molecular weight (MW), lipophilicity (log D), and protein unbound fraction in plasma (f(up))] that were predicted from their molecular structures without performing any benchwork experiments. The training dataset consisted of 141 approved drugs whose major clearance pathways were determined to be metabolism by CYP3A4, CYP2C9, and CYP2D6, hepatic uptake by OATPs, or renal excretion in an unchanged form. After grouping by charge, each drug was plotted in a three-dimensional space according to three axes of MW, log D, and f(up). Then, rectangular boxes for each clearance pathway were drawn mathematically under the criterion of "maximizing F value (harmonic mean of precision and recall) with minimum volume," yielding to a precision of 88%, which was confirmed through two types of validation: leave-one-out method and validation using a new dataset. With further modification toward multiple pathways and/or other pathways, not only would this in silico classification system be useful for industrial scientists at the early stage of drug development, which can lead to the selection of candidate compounds with optimal pharmacokinetic properties, but also for regulators in evaluating new drugs and giving regulatory requirements that are pharmacokinetically reasonable.

Analysis of pharmaceutical safety-related regulatory actions in Japan: do tradeoffs exist between safer drugs and launch delay?

BACKGROUND: Prediction and management of drug safety is a global regulatory issue. Safety-related regulatory actions (SRRAs) are taken mostly when unexpected adverse drug reactions occur. Currently, Japan is reconciled to delayed access to new drugs (ie, launch delay compared to Western countries), but may have been benefiting by free-riding on safety data accumulated in other countries prior to Japanese launch. OBJECTIVE: To identify factors that are significantly associated with SRRAs, and to discuss the challenges that Japan might have to face with increasing access to new drugs. METHODS: The SRRAs of 135 new drugs approved from January 2000 to December 2005 were analyzed to investigate association with launch lag, company and drug characteristics, market size, submission data, and regulatory status. SRRAs were measured in terms of the number of emergency safety information notifications and official safety instructions issued by the Japanese regulatory agency within 3 years after approval. A negative binomial distribution model was used for regression analysis. RESULTS: Longer launch lags and presence of drugs with similar modes of action were associated with fewer SRRAs. Bridging strategy showed increased SRRAs. No significant association was observed between SRRAs and the subject number in clinical data packages. Occurrence of SRRAs was varied among development strategy, preceding products, and regional regulations. CONCLUSIONS: The occurrence of SRRAs was associated with the accumulation of both foreign and domestic postmarketing evidence rather than with clinical trial data upon launch. Considering the paradigm shift to simultaneous global drug development and filing for regulatory approval, this study indicates the importance of intensive data collection in the early postmarketing phase and use of safety information in early markets. However, even if we would be sufficiently cautious about safety risks of new drugs, a population that enjoys first-in-class drugs probably has to bear the risks.

Emotional Intelligence and Work Perceptions Among Nurse Managers.

BACKGROUND: Emotional intelligence (EI) refers to a person's ability to acknowledge the feelings of oneself and others, and to control those feelings so as to behave in a socially acceptable manner. We investigated the relationships between the characteristics of EI among nurse managers, and their perceptions of how much their position's roles and responsibilities can be delegated to other staff members. METHODS: We surveyed 150 nurse managers working at 30 hospitals by using an anonymous questionnaire. The questionnaire consists of basic attributes, EI and work perception. The emotional intelligence scale (EQS) domain scores were analyzed by means of one-way repeated-measures analysis of variance. EQS scores were compared with corresponding averages for working adults in the instructions. The perceived importance of duties of nurse managers was compared between the resulting EQS scores 'High' and 'Low' groups. RESULTS: The analysis population consisted of 105 nurse managers. Their EQS scored higher in all three domains, and with the exception of Altruism for all factor scores than the average for working adults. The perceived importance of the typical duties of nurse managers were compared between the High and Low groups for each EQS domain. Significant differences were observed between nurse managers with High and Low Intrapersonal emotional quotient (EQ) on four tasks. No significant differences were found for any of the responsibilities when nurse managers with High and Low Interpersonal EQ or Situational EQ were compared. CONCLUSION: The nurse managers' average EQS scores were higher in all areas. The high scores that were exhibited by could be considered desirable qualities for nurse managers. It seemed nurse managers with high scores in intrapersonal EQ struck a good balance between placing importance on EI considerations like managing relationships and creating a comfortable workplace, and management and leadership behaviors like department management and operations and data management.

Development of a drug-coated microneedle array and its application for transdermal delivery of interferon alpha.

Interferon alpha (IFNα) is one of the most famous drugs for the treatment of chronic hepatitis C and various types of human malignancy. Protein drugs, including IFNα, are generally administered by subcutaneous or intramuscular injection due to their poor permeability and low stability in the bloodstream or gastrointestinal tract. Therefore, in the present study, novel IFNα-coated polyvinyl alcohol-based microneedle arrays (IFNα-MNs) were fabricated for the transdermal delivery of IFNα without the painful injection. IFNα was rapidly released from MNs in phosphate buffered solution and these MNs presented piercing ability in the rat skin. Slight erythema and irritation were observed when MNs were applied to the rat skin, but these skin damages completely disappeared within 24 h after removing the IFNα-MNs. Furthermore, the pharmacokinetic parameters of IFNα-MNs were similar to those of IFNα subcutaneous administration. Finally, IFNα-MNs showed a significant antitumor effect in tumor bearing mice similar to that of IFNα subcutaneous administration. These results indicate that IFNα-MNs are a useful biomaterial tool for protein drug therapy and can improve the quality of life in patients by avoidance of painful injections.

Analysis of the success rates of new drug development in Japan and the lag behind the US.

OBJECTIVES: The launch delay of new drugs has been a major public concern in Japan. Although it is recognized that the delay results from industrial R&D behaviors and regulatory conditions in the global market, the specific mechanisms underlying the significant delay have been unexplained. This study analyzed the association between the success rates of clinical development programs of new molecular entities in Japan and the development lag behind the US and provides clues for policy planning. METHODS: The association between the success rates of clinical development and the development time lag between Japan and the US was estimated using the Cox proportional hazard model. RESULTS: The phase II transition success rates in Japan were positively associated with the lags behind US development. Cox regression analysis results of phase III success rates were similar to phase II success rate results but were not statistically significant. CONCLUSIONS: The advantageous effect of lags on development success in the latter country (i.e., Japan) appears to explain the persistent delays in development and launch. The government's countermeasures to reduce the access gap of new drugs must consider this mechanism and the influence on both the industry and the target population.

Development of a novel self-dissolving microneedle array of alendronate, a nitrogen-containing bisphosphonate: evaluation of transdermal absorption, safety, and pharmacological effects after application in rats.

Alendronate is a nitrogen-containing bisphosphonate that is widely used for the treatment of osteoporosis. In this study, we developed a novel self-dissolving micron-size needle array (microneedle array) containing alendronate, which was fabricated by micromodeling technologies using hyaluronic acid as a basic material. Micron-scale pores in the skin were seen after the application of the alendronate-loaded microneedle array, verifying establishment of transdermal pathways for alendronate. The absorption of alendronate after the application of alendronate-loaded microneedle array was almost equivalent to that after subcutaneous administration, and the bioavailability of alendronate was approximately 90% in rats. Furthermore, delivery of alendronate via this strategy effectively suppressed the decrease in the width of the growth plate in a rat model of osteoporosis. Although mild cutaneous irritation was observed after the application of the alendronate-loaded microneedle array, it resolved by day 15. These findings indicate that this alendronate-loaded microneedle array is a promising transdermal formulation for the treatment of osteoporosis.

Development of a novel transdermal patch of alendronate, a nitrogen-containing bisphosphonate, for the treatment of osteoporosis.

Bisphosphonates are widely used for the treatment and prevention of bone diseases, including Paget disease, hypercalcemia of malignancy, and postmenopausal osteoporosis. In this study, we developed a novel transdermal patch of alendronate, a nitrogen-containing bisphosphonate, for the treatment of bone diseases. The maximum permeation fluxes of alendronate through rat and human skin after application of this patch were 1.9 and 0.3 µg/cm(2) per hour, respectively. The bioavailability (BA) of alendronate in rats was approximately 8.3% after the application of alendronate patch and approximately 1.7% after oral administration. These results indicated that the transdermal permeation of alendronate using this patch system was sufficient for the treatment of bone diseases. The plasma calcium level was effectively reduced after application of the alendronate patch in 1α-hydroxyvitamin D(3) -induced hypercalcemia model rats. The alendronate patch also effectively suppressed the decrease in bone mass in model rats with osteoporosis. Modest alendronate-induced erythema of rat skin was observed after application of the alendronate patch. Incorporation of butylhydroxytoluene in the alendronate patch almost completely suppressed this alendronate-induced skin damage while maintaining the transdermal permeation and pharmacologic effects of alendronate. These findings indicate that our novel transdermal delivery system for alendronate is a promising approach to improve compliance and quality of life of patients in the treatment of bone diseases.

Effect of 2-methoxyestradiol, buthionine sulfoximine and hydrogen peroxide on the viability of renal carcinoma cell lines (ACHN and ACVB).

2-Methoxyestradiol (2-ME), an endogenous metabolite of 17beta-estradiol, induces the intracellular accumulation of superoxide anion (O2*-) and buthionine sulfoximine (BSO) is an inhibitor of glutathione (GSH) synthesis. We have examined the combination anticancer effect of 2-ME and BSO accompanied with hydrogen peroxide (H2O2). 2-ME inhibited cell growth in renal carcinoma cell lines (ACHN and ACVB) accompanied by an increase in the intracellular contents of GSH. The combination of 2-ME, BSO and H2O2 showed a significant antiproliferation effect in both ACHN and ACVB. The intracellular levels of reactive oxygen species (ROS) with a combination with 2-ME and H2O2 in ACHN and ACVB pretreated with BSO were markedly increased, which may have contributed to the potential antiproliferative action.