Cefmetazole (CMZ), a cephamycin, has a protein-binding rate of approximately 85%. The unbound concentration is microbiologically active and may vary greatly depending on variations in human serum albumin (HSA) concentration. However, the binding parameters and sites of HSA have not been clarified, and the predicted unbound concentrations using these parameters have not been evaluated. This study aimed to clarify these binding characteristics and evaluate unbound CMZ concentrations predicted using the calculated binding parameters. Total and unbound CMZ concentrations in the HSA solutions were measured at several HSA concentrations (10 g/L, 25 g/L, and 40 g/L) and total CMZ concentrations (10, 60, and 150 mg/L). A Scatchard plot was constructed. To identify specific binding sites, competitive binding assays were performed using the site markers warfarin, dansylsarcosine, bicalutamide, and bilirubin. Unbound CMZ concentrations were predicted using binding parameters from total CMZ and albumin concentrations in 37 patients. The association constant (K) for CMZ to HSA was determined to be 6.59 × 103 M-1, with number of binding sites (n) of 1.08. The binding rate decreased as the CMZ concentration increased or the HSA concentration decreased. Competitive binding assays revealed that CMZ binds to Subdomain IB on HSA. A strong correlation (r=0.907) was observed between predicted and measured unbound CMZ concentrations. This study successfully defined the binding parameters and specific binding sites of CMZ on HSA, and unbound CMZ concentrations were accurately predicted from the total CMZ concentrations in clinical patients using these binding parameters.
In Japan, general medicine (GM) has been recognized as a unique specialty addressing the needs of an aging society with complex comorbidities. GM physicians act as essential "gatekeepers," managing initial evaluations for diverse conditions and facilitating collaboration among various medical departments. This case study presents the critical nature of this role when clinical suspicion encounters diagnostic limitations. A young pathologist presented with recurrent fever. She expressed concern regarding possible occupational exposure during an autopsy and pathological specimen preparation performed months earlier on a deceased patient with an undetermined infection. Although the autopsy revealed widespread necrotizing granulomatous lesions associated with yeast-like fungi, the hospital's central laboratory was unable to identify the species. The GM physician used a professional network to consult an infectious disease specialist, who subsequently engaged a fungal expert. The pathogen was identified as Histoplasma capsulatum via PCR sequencing. However, the patient's subsequent test for histoplasma antibodies was negative, and a causal relationship between the recurrent fever and potential histoplasma exposure could not be established. Histoplasmosis is extremely rare in Japan and is typically associated with international travel. However, the deceased patient in this case had no recent history of overseas travel. Because laboratory assays for this high-risk fungus are not currently covered by the Japanese health insurance, such cases may remain undiagnosed. This report demonstrates that a general physician's ability to establish and coordinate specialist networks is crucial for resolving complex diagnostic challenges and ensuring the safety of healthcare workers.
Children with underlying medical conditions, such as neuromuscular diseases, craniofacial malformations, or chromosomal abnormalities, are at increased risk of obstructive sleep apnea (OSA). Although polysomnography remains the diagnostic gold standard for OSA, its feasibility in children is limited. Overnight pulse oximetry is a widely used screening tool, but its diagnostic accuracy may be compromised by first-night effects and night-to-night variability, particularly in children with neurodevelopmental or craniofacial disorders. Therefore, we evaluated night-to-night agreement of pulse oximetry indices in children with underlying medical conditions using correlation and Bland-Altman analysis. We retrospectively analyzed thirty-two children with underlying medical conditions under 15 years of age (median age 3 years) who underwent two consecutive nights of overnight pulse oximetry to evaluate night-to-night agreement of oximetry indices. Oxygen desaturation indices (ODI3, ODI4) and desaturation times <90% (DT90) and <95% (DT95) were evaluated. Correlations between nights were moderate to high (ODI3: r =0.71; DT90: r =0.72), but Bland-Altman analysis revealed wide 95% limits of agreement for ODI3 (-7.06 to +8.14 events/h), comparable to the diagnostic threshold of 7/h, leading to diagnostic reclassification in 25% of cases. Despite moderate to strong correlations, Bland-Altman analysis demonstrated clinically meaningful variability near diagnostic thresholds. In children with underlying conditions, a single-night oximetry study may under- or over-diagnose OSA. While two-night assessments should remain the standard, we propose a stepwise diagnostic algorithm in which a markedly elevated first-night ODI3 (≥15/h) may justify immediate intervention, whereas further evaluation is warranted in cases suspected to represent mild-to-moderate disease.
Sedating antihistamines (sAH) are widely used as premedication to prevent infusion-related reactions (IRRs). Subcutaneous daratumumab (DARA-SC) is administered in a shorter time than its intravenous form. Therefore, sedation caused by sAH after DARA-SC administration may also pose a concern. We investigated the efficacy and safety of sAH and non-sedating antihistamines (nsAH) premedication. This multicenter, retrospective, observational study was conducted from six hospitals in Japan. Data from the electronic medical records of consecutive patients with multiple myeloma who received DARA-SC injection between 19 May 2021 and 31 December 2022 was analyzed. The incidence of IRR and drowsiness was investigated as efficacy and safety endpoints, respectively. Differences in incidence between patients treated with nsAH and those treated with sAH were compared. Thirty-one patients in the nsAH group and 130 patients in the sAH group were evaluated. All patients in the nsAH group were treated with levocetirizine, while patients in the sAH group were treated with dexchlorpheniramine or diphenhydramine. The incidence of IRRs was 0% (0/31) in the nsAH group and 1.5% (2/130) in the sAH group. The incidence of drowsiness was 6.5% (2/31) in the nsAH group and 7.7% (10/130) in the sAH group. These differences were not statistically significant. This study showed that levocetirizine is not obviously inferior in efficacy and safety relative to sAH in preventing IRRs and drowsiness. Therefore, levocetirizine can be considered as a substitute for patients for whom the use of sAH is not acceptable.
Loneliness is associated with medication use and that health literacy influences medication adherence. However, limited knowledge exists regarding the self-medication of over-the-counter (OTC) drugs among patients with COVID-19 during the pandemic. Therefore, this study aimed to examine the relationship between loneliness, health literacy, and OTC self-medication in home care settings during the Omicron BA.5-Dominant Wave (the 7th COVID-19 wave, July-September 2022) in Japan. Individuals aged 20 to 49 years were randomly selected from the web panel of a research company (Macromill, Inc.). Participants who had contracted COVID-19 during the Omicron BA.5-Dominant Wave were asked to complete the Three-Item Loneliness Scale (TIL) and the 14-item Health Literacy Scale (HLS-14). Logistic regression analysis was conducted using disregard for OTC drug package inserts and OTC drug overuse as objective variables. Valid responses were obtained from 197 men and 180 women. Among OTC drug users (n =282), 18% disregarded the OTC drug package inserts, and 9% used more than the recommended amount of OTC drugs. Disregarding OTC drug package inserts was significantly associated with HLS-14 score ≤51, indicating low health literacy (odds ratio (OR): 2.43, 95% confidence interval (CI): 1.26-4.79, P = 0.008). OTC drug overuse was significantly associated with TIL score ≥6, indicating high loneliness (OR: 3.97, 95% CI: 1.64-10.63, P = 0.002). The findings of this study highlight the importance of communication in addressing the disregard of OTC drug package inserts and the overuse of OTC drugs in patients with COVID-19, taking into account both health literacy and loneliness.
Alzheimer's disease (AD) affects approximately 50 million individuals worldwide and is projected to triple by 2050. Ligustilide is a naturally occurring compound with varied pharmacological actions. Ligustilide has been reported to ameliorate AD by inhibiting PKA/AKAP1 or inducing α-secretase, but no prior research has examined its ability to activate the inflammasome in AD. We aimed to investigate the potential therapeutic effects of ligustilide in rats with AD by assessing the inflammatory and fibrotic pathways. AD was induced in rats by aluminum chloride. Subsequently, some rats were orally administered 20 mg/kg of ligustilide. For structural assessment, hippocampal brain tissue sections were stained with hematoxylin/eosin and subjected to anti-mTOR and anti-phospho-tau antibody staining. The collected samples were then analyzed for gene expression and protein levels of mTOR, STAT3, TGF-β, β-catenin, NFκB, TNF-α, TLR4, and NLRP3. We found that rats treated with ligustilide displayed marked improvements in their behavior. Furthermore, microscopic analysis of hematoxylin/eosin-stained images revealed that ligustilide reduced inflamed tissues and partially dilated blood vessels, without gliosis or vacuolated neuropil. Additionally, ligustilide decreased the expression of mTOR, STAT3, TGF-β, β-catenin, NFκB, TNF-α, TLR4, and NLRP3. In conclusion, ligustilide improved AD in rats and reduced inflammation and fibrosis. This effect is attributed to ligustilide's ability to reduce mTOR and STAT3 activity, thereby suppressing NFκB, TNF-α, TLR4, and NLRP3, and inhibiting the inflammasome pathway. Consequently, this cascade results in decreased STAT3 and TGF-β levels, thereby reducing fibrosis.
Japan has the lowest vaccine confidence worldwide. Although community pharmacists are expected to support public health, it remains unclear whether Japanese community pharmacists-who cannot administer vaccines-engage in vaccine consultation and promotion. This cross-sectional study used a paper-based, self-administered, anonymous questionnaire distributed to randomly selected community pharmacists in Japan to investigate their attitudes and experiences regarding vaccination, exploring issues related to the prevalence of the vaccine-related roles of community pharmacists. One thousand pharmacies were chosen, and the valid response rate was 44.6%. While 86.5% of respondents had experience with vaccine consultation, only 59.2% had experience with vaccine promotion. The rate of vaccine promotion was significantly higher among community pharmacists who recognized Japan's low vaccine confidence and held positive attitudes toward vaccine promotion (P < 0.001). Most respondents (76.9%) desired training to expand pharmacists' roles in vaccination. Additionally, 62.1% supported pharmacist-administered vaccines, though many were concerned about technical skills (83.3%) and potential anaphylaxis (63.6%). These findings suggest that promoting awareness of vaccine hesitancy and strengthening attitudes toward vaccine promotion could increase the number of community pharmacists involved in such activities. Japanese pharmacists may also need appropriate vaccine administration knowledge and skills to prepare for potential future responsibilities in vaccine administration.
Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants and young children worldwide. Although most RSV hospitalizations occur at secondary hospitals, information on RSV-related healthcare costs in these settings is limited. A retrospective analysis of RSV-related hospitalizations was conducted at Saitama City Hospital, a secondary hospital, between April 2018 and May 2024. Patients with laboratory-confirmed RSV infection were included. The study period was divided into three phases based on revisions of the national medical reimbursement schedule. Hospitalization costs were calculated, and high-cost outliers were identified using the interquartile range (IQR) method. A total of 345 patients were hospitalized for RSV, with a marked reduction in Phase II admissions corresponding to the early COVID-19 pandemic. Median hospitalization costs per episode increased in all three phases, from JPY 318,930 to JPY 393,930. Eighteen admissions were identified as cost outliers and classified into three subgroups: (1) children with airway or neurologic disorders, often older than 24 months; (2) otherwise healthy infants under 12 months; and (3) children eligible for palivizumab who contracted RSV before or after the recommended prophylaxis period. Our findings emphasize the existence of high-cost RSV cases outside the currently recognized high-risk groups, including older children with chronic airway disease and healthy young infants. Clinical burden and healthcare costs may be reduced by refining prophylaxis strategies and early intervention in Japan.
Evidence-based practice (EBP) plays a crucial role in improving healthcare quality; however, there is still a lack of insight into EBP education for nursing in Japan. We aimed to evaluate the acceptability and preliminary effects of an online EBP education program on undergraduate nursing students in Japan. A pilot, single-armed, pre- and post-intervention design study using mixed methods was conducted with 11 nursing students. Participants completed an 8-h EBP education program over a 2-day period, which provided introductory knowledge and skills based on the five steps of EBP. The total score of the Student-Evidence-Based Practice Questionnaire showed a trend toward improvement with a medium effect size (P = 0.06, d =0.51). The following subscales displayed improvement with small to medium effect sizes: "frequency of practice" (P = 0.14, d =0.34), "retrieving/reviewing evidence" (P = 0.04, d = 0.59), and "sharing and applying EBP" (P = 0.13, d = 0.36). The focus group interviews revealed an enhanced understanding of EBP, improved skills for reading articles, and highlighted the importance of interactive teaching and access to on-demand learning materials. Our results suggested that the online EBP education program was acceptable and demonstrated preliminary effects in enhancing the skills of undergraduate nursing students in retrieving and reviewing evidence and results in thematic analysis. Further research such as a controlled trial including a more diverse sample with longer follow-up should be conducted to validate our findings and examine the program's long-term effects on clinical practice.
Digital therapeutics (DTx) have demonstrated promising potential as a novel therapeutic approach, with their clinical development gaining momentum. Comparison of DTx development between Japan, a relative newcomer, and Germany and the U.S., known for favorable circumstances, is a topic of interest. DTx developed in Japan as of November 2023 were identified on the Pharmaceuticals and Medical Devices Agency (PMDA) website and in the literature. Similar DTx available in the U.S. and Germany were identified in the databases maintained by the U.S. Food and Drug Administration (USFDA) and Federal Institute for Drugs and Medical Devices (BfArM). Data on their clinical trials and regulatory status were obtained from these databases and their respective national clinical trial registries. The data obtained were compared and analyzed. By November 2023, Japan had developed DTx, encompassing 11 therapeutic areas. Seven DTx had reached or completed the confirmatory study stage, whereas five DTx were in the exploratory phase. Twenty DTx in the therapeutic areas were selected from the U.S. and Germany. A total of 27 DTx were reviewed regarding the designs of confirmatory studies and regulatory actions taken. Trial designs demonstrated more similarities than differences across the countries and therapeutic areas. Placebo trial design-associated difficulties were conspicuous. Although regulatory actions to place DTx in the market differed across countries, they effectively ensured the efficacy and safety of DTx that were suitable for marketing considering the most current science. The regulatory measures in the three countries seem to have positively impacted DTx development.
Colorectal large villous adenomas are sometimes associated with McKittrick-Wheelock syndrome, a condition characterized by severe diarrhea leading to dehydration, electrolyte depletion, and acute renal failure, which can be life-threatening in some cases. The efficacy of radiotherapy for colorectal villous adenoma has rarely been reported. We present a rare case of McKittrick-Wheelock syndrome in an older man caused by a large colorectal villous adenoma. This case is notable because palliative external beam radiotherapy of 30 Gy in 10 fractions not only reduced the tumor size but also resulted in significant symptom relief. This report demonstrates the efficacy of palliative radiotherapy for severe colorectal villous adenomas as a valid treatment option, particularly in older patients with complications.
The incidence of breast cancer in patients with pre-existing interstitial lung disease has been rarely reported. Consequently, evidence supporting the safety of chemotherapy in this population remains limited. This report describes the case of a 55-year-old woman with a history of cryptogenic organizing pneumonia who received adjuvant chemotherapy for the management of breast cancer. The chemotherapy regimen comprised the administration of epirubicin/cyclophosphamide followed by the weekly administration of paclitaxel. This regimen was selected based on the findings of previous studies that assessed the utility of chemotherapy regimens for the treatment of lung cancer in patients with interstitial lung disease. Chemotherapy was completed without worsening of the cryptogenic organizing pneumonia or the appearance of new abnormal lung fields. Therefore, the administration of epirubicin/cyclophosphamide followed by the weekly administration of paclitaxel may be safe in patients with pre-existing interstitial lung disease. This regimen may be a suitable choice for the perioperative management of this population.
In Japan, many schools include kendo as part of the school physical education program. Farther afield, kendo also serves as a life-long method to improve and retain physical fitness and mental skills for adults of all ages around the world. Therefore, kendo has the potential to be an inexpensive public health modality if proven safe. This study aimed to investigate the 1-year prevalence of kendo-related injuries in Japanese collegiate athletes. The factors associated with kendo injuries were explored in a retrospective observational study using an online survey between June 2022 and August 2023. Athlete characteristics and injury occurrence, location, type, and circumstances were recorded. The survey was completed by 143 athletes (average age 19.9 years) with an average of 12.9 years of experience in kendo. We found that the 1-year prevalence of injuries in Japanese kendo collegiate athletes was 43%. The only factors associated with injury were sex and body mass index (BMI) status. Female athletes were 4.9 time more likely to report an injury than male athletes, whereas athletes with overweight or obese status (BMI ≥ 25) were 3.7 times more likely to report an injury than athletes with underweight or normal BMI status (BMI < 25). Special attention should be given to injury prevention and long-term development in female kendo athletes, especially in strength training.
Hereditary breast and ovarian cancer syndrome (HBOC) is traditionally associated with mutations in the BRCA1 and BRCA2 genes, predominantly impacting breast, ovarian, pancreatic, and prostate cancers. However, recent research suggests that these mutations may also predispose carriers to a broader spectrum of malignancies, including biliary tract, cervical, colorectal, endometrial, esophageal, and gastric cancers. This review presents findings from extensive datasets, including a significant study from a nationwide Japanese biobank that examined cancer risks in 63,828 patients and 37,086 controls. Our review highlights notable associations, such as an increased risk of uterine and cervical cancers in BRCA1 mutation carriers and increased risk of esophageal and gastric cancers in BRCA2 mutation carriers. These emerging associations underscore the necessity of revisiting and potentially expanding current clinical guidelines to incorporate these additional risks. These findings advocate a comprehensive approach to genetic counseling and underscore the importance of tailored cancer surveillance strategies in populations carrying BRCA mutations. This expanded understanding could significantly influence preventive, diagnostic, and therapeutic strategies, promoting personalized approaches to manage and potentially prevent these malignancies in genetically susceptible populations.
A 0.04% mitomycin C (MMC) ophthalmic solution is not commercially available and is prepared in hospitals as required. The physical properties and stability of the MMC ophthalmic solution have not been clarified because of a lack of data. This study aimed to assess the stability of the MMC ophthalmic solution under various storage conditions. The MMC ophthalmic solution was prepared by dissolving 2 mg of MMC in 5 mL of saline solution. Each batch of ophthalmic solution was stored under three conditions [cold/shaded light, room temperature/shaded light, and room temperature/scattered light (approximately 4000 lx)], and MMC concentration was determined using high-performance liquid chromatography on days 0, 1, 3, 5, 7, 14, and 21. The expiry date was calculated based on the results of the degradation analysis. pH measurements and bacterial culture tests were conducted for each storage condition. The MMC concentrations on day 21 under cold/shaded light, room temperature/shaded light, and room temperature/scattered light were 340, 287, and 227 µg/mL, respectively. MMC concentrations decreased over time, and the decrease was highest when the samples were stored at room temperature and exposed to light, and lowest under cold conditions and protected from light. The pH of MMC solutions was 5.8 after preparation, which increased to 6.9 with time under all storage conditions. Culture tests did not detect any bacteria under any storage conditions. The MMC ophthalmic solution was most stable under cold/shaded conditions, and our study clarifies its expiry date for clinical use.
Undernutrition is a common risk after surgery or during periods when oral dietary intake is challenging. Enteral nutrients, frequently utilized in nutritional management, are drugs associated with multiple contraindications involving pathology and allergy, and they require careful attention in dispensing. However, the occurrence of nutrition-related incidents in community pharmacies remains unknown. This study aimed to identify issues regarding the safety of pharmacotherapy in patients requiring enteral nutrition using the database of Project to Collect and Analyze Pharmaceutical Near-Miss Event Information. We highlighted the critical information that pharmacists should focus on to prevent accidents and elucidated the details and prescription drugs of cases that matched the search for "Nutrition (all included)" in Japanese. There were 475 cases reported between January 2009 and September 2023. Of these, 347 cases (73%) were classified as "inquiry about prescription and provision of information to prescribing physician" (Category II) and 115 cases (24%) were classified as "drug dispensing" (Category I). In both cases, the top five drugs were enteral nutrients. Among the life-threatening Category II cases, 9 cases were for pathological contraindications including severe liver or renal dysfunction, 6 cases were for adverse reactions including diarrhea, and 5 cases were for allergies or patient constitutions. Notably, the incidence of adverse reactions was higher than in data for the latest annual reports. Therefore, pharmacists should be mindful while dealing with prescriptions involving possible contraindications in patients requiring enteral nutrition. Pharmacists should contribute to the provision of safe pharmacotherapy by remaining vigilant against dispensing errors.
The management of hereditary breast and ovarian cancer (HBOC) in Japan has changed drastically with the expansion of indications for poly ADP-ribose polymerase inhibitors, the increase in diagnostic opportunities with the spread of companion diagnoses, and partial insurance coverage of HBOC management. These circumstances require a response that is coordinated across the entire hospital rather than from individual departments. In April 2021, we established the HBOC Center, which is operated by nine departments: Obstetrics and Gynecology, Reproduction, Surgery (breast group, hepato-pancreato-biliary group), Urology, Dermatology, Neuropsychiatry, the Center for Medical Genetics, and the Cancer Center. In addition to discussions of individual cases, our monthly conferences have enabled us to establish indication criteria and appropriate items for surveillance, visualize the examination flow in the hospital, construct a patient database, and provide open lectures to educate the public. The future HBOC management system should not only fulfill the existing requirements for risk-reducing surgery and facility standards but also offer comprehensive and diversified attention based on the needs of patients and their family members.
It is desirable for community pharmacists to be involved in promoting and maintaining the oral health of local residents. In this study, we conducted a questionnaire survey of Japanese community pharmacists to understand the actual conditions and the attitudes of these pharmacists regarding oral healthcare advice. A web-based anonymous self-administered questionnaire survey was completed by community pharmacists from March 26 to 29, 2021. We received responses from 324 pharmacists. A majority of respondents (66.0%) regarded dealing with "daily oral health issues and oral care" as a role of community pharmacists. Respondents also reported being consulted by patients or customers about mouth ulcers (70.1%) and xerostomia (54.6%). However, the frequency of consumer inquiries about these oral conditions was less than once per week. Just over half of the respondents (52.2%) said they were confident about dealing with mouth ulcers, whereas less than 40% were confident about handling other oral problems. The most common anxiety was a "lack of knowledge about appropriate responses to oral symptoms" (60.2%). The respondents desired education and training (75.6%) to better promote oral health-related activities. Japanese community pharmacists believe that they have a role to play in oral health issues and oral care, but their level of confidence in their ability to respond to oral health issues is low. Pharmacists are concerned about their lack of knowledge about oral healthcare and they desire more opportunities for education and training so that they can perform pharmacy-based maintenance and promotion of oral healthcare for local residents.
Finding cures is the ultimate goal of research on autoimmune diseases. Pemphigus is an autoantibody-mediated autoimmune skin disease in which specific autoantibodies target desmogleins 1 and 3 as autoantigens. The condition leads to painful blisters and erosions in the skin and oral mucosa, impacting patients' ability to eat and other daily activities, significantly affecting quality of life. The molecular mechanisms by which these pathogenic autoantibodies induce blisters have been extensively studied and understanding has advanced considerably. However, many critical questions remain, such as the exact cause of the disease, the mechanisms that normally prevent autoimmunity, and the pathogenic cells involved, other than autoantibodies. This article focuses on the role of autoreactive T cells in pemphigus and uses the pemphigus model to answer some of these questions. Research into pemphigus has enhanced our understanding of both the pathogenic and regulatory mechanisms involved, not only in pemphigus but also in other skin diseases caused by cellular autoimmunity. The growing body of scientific evidence on pemphigus has made it a model disease, paving the way for the development of novel therapeutic approaches, including antigen-specific immunotherapy for autoimmune diseases and chronic inflammatory disorders.
