Prevalence of medical factors related to aging among older car drivers: a multicenter, cross-sectional, descriptive study.

AIM: An increasing number of older adults in Japan are at an increased risk of road traffic crashes. This study aimed to investigate the prevalence of potential underlying medical factors that increase the risk of road traffic crashes among older people. METHODS: This cross-sectional observational study was conducted in 11 medical institutions in Japan using self-administered questionnaires and physical examination from January to May 2021. The background and social data, data on the use of nursing care insurance, and clinical data suggestive of polypharmacy, sarcopenia, cognitive impairment, and frailty/oral frailty were obtained. The prevalence of these factors was compared between everyday and occasional drivers. RESULTS: Data of 127 patients were collected; their median (interquartile range) age was 73 (70-78) years. Of the total participants, 82 were men (64.6%) and 45 were women (35.4%). There were 77 everyday drivers and 50 occasional drivers. Of these, 121 (95.3%) had not applied for nursing care insurance, but the numbers of those who required help 1 and 2 were 1 (0.8%) and 3 (2.4%), respectively. Prevalence of medical factors was as follows: polypharmacy, 27.6%; sarcopenia, 8.7%; dementia, 16.4%; frailty, 15.0%; and oral frailty, 54.3%; it was not significantly different between every day and occasional drivers. Intention to return the car license was significantly higher among the occasional drivers (2.6% vs. 14.0%; odds ratio: 6.7, 95% confidence interval: 1.2-70.6, p = 0.024). CONCLUSION: We uncovered the prevalence of medical factors that can be associated with road traffic crashes among Japanese older people aged ≥ 65 years in our community.

Discovery of clinical candidate Sivopixant (S-600918): Lead optimization of dioxotriazine derivatives as selective P2X3 receptor antagonists.

In previous work, we discovered a lead compound and conducted initial SAR studies on a novel series of dioxotriazines to identify the compound as one of the P2X3 receptor antagonists. This compound showed high P2X3 receptor selectivity and a strong analgesic effect. Although not selected for clinical development, the compound was evaluated from various aspects as a tool compound. In the course of the following study, the molecular structures of the dioxotriazines were modified based on pharmacokinetic/pharmacodynamic (PK/PD) analyses. As a result of these SAR studies, Sivopixant (S-600918) was identified as a clinical candidate with potent and selective antagonistic activity (P2X3 IC50, 4.2 nM; P2X2/3 IC50, 1100 nM) and a strong analgesic effect in the rat partial sciatic nerve ligation model (Seltzer model) of allodynia (ED50, 0.4 mg/kg).

Involvement of clock gene expression, bone morphogenetic protein and activin in adrenocortical steroidogenesis by human H295R cells.

Functional interactions between the levels of clock gene expression and adrenal steroidogenesis were studied in human adrenocortical H295R cells. Fluctuations of Bmal1, Clock, Per2 and Cry1 mRNA levels were found in H295R cells treated with forskolin (FSK) in a serum-free condition. The changes of clock gene expression levels were diverged, with Clock mRNA level being significantly higher than Cry1 and Per2 mRNA levels after 12-h stimulation with FSK. After FSK induction, mRNA levels of StAR and CYP11B2 were highest at 12 hours and CYP17 mRNA level reached a peak at 6 hours, but HSD3B1 mRNA level was transiently decreased at 3 hours. The expression levels of Clock mRNA showed a significant positive correlation with StAR among the interrelationships between mRNA levels of key steroidogenic factors and clock genes. Knockdown of Clock gene by siRNA led to a significant reduction of FSK-induced expression of StAR and CYP17 after 12-h treatment with FSK. BMP-6 and activin, which modulate adrenal steroidogenesis, had inhibitory effects on Clock mRNA expression, whereas treatment with follistatin, a binding protein of activin, increased Clock mRNA levels in the presence of FSK, suggesting an endogenous function of activin in regulation of Clock mRNA expression. Collectively, the results indicated that changes of Clock mRNA expression, being upregulated by FSK and suppressed by BMP-6 and activin, were tightly linked to StAR expression by human adrenocortical cells.

Predictors of resignation and sick leave after cancer diagnosis among Japanese breast cancer survivors: a cross-sectional study.

BACKGROUND: In Japan, 55.5% of breast cancer survivors (BCSs) are of working age, so various perspectives regarding return to work (RTW) after cancer diagnosis need to be considered. Therefore, this study aimed to clarify the risk factors for resignation and taking sick leave (SL) among BCSs in continued employment at the time of diagnosis. METHODS: A web-based retrospective cross-sectional survey was conducted on BCSs using data from a 2018 Japanese national research project (Endo-Han) commissioned by the Ministry of Health, Labour and Welfare of Japan. The subjects were women aged 18-69 years who had been diagnosed with breast cancer for the first time at least 1 year previously. The risk factors for resignation and taking SL after breast cancer diagnosis, including age at diagnosis, education level, cancer stage, surgery, chemotherapy, radiotherapy, employment status, and occupational type, were then analyzed using a logistic regression model. RESULTS: In total, 40 (14.9%) of 269 BCSs quit their jobs at least 1 year after being diagnosed with breast cancer. The results of the multivariable analysis indicated that lower education level (odds ratio [OR]: 3.802; 95% confidence interval [CI]: 1.233-11.729), taking SL (OR: 2.514; 95%CI: 1.202-5.261), and younger age at diagnosis (OR: 0.470; 95%CI: 0.221-0.998) were predictors of resignation. Of 229 patients who continued working, SL was taken by 72 (31.4%). In addition, undergoing surgery was found to be a predictor of taking SL (OR: 8.311; 95%CI: 1.007-68.621). CONCLUSIONS: In total, 40 (14.9%) of 269 BCSs quit their jobs at least 1 year after being diagnosed with breast cancer. The results of this study indicated that younger age, lower education level, and taking SL were predictors of resignation after breast cancer diagnosis.

Clinical Manifestations of Patients with Influenza Differ by Age : A Prospective, Multi-centered Study in the Setouchi Marine Area.

Influenza potentially has a high mortality rate when it affects the elderly. We aimed to examine the differences in clinical manifestations in patients with influenza according to their age. This multicenter prospective study was performed in six medical institutions in Okayama and Kagawa prefectures (Japan). Between December 1, 2019 and March 31, 2020, we collected data on adult patients diagnosed with influenza type A, who were strat-ified into younger (20-49 years), middle-aged (50-64 years), and older groups (≥ 65 years). We compared the presence or absence of fever, respiratory symptoms, and extrapulmonary symptoms according to age group. In total, 203 patients (113, younger; 51, middle-aged; and 39, older) were eligible for the analysis. The maxi-mum body temperature and temperature at first physician visit in the older group were significantly lower than those in the younger group. The incidence of respiratory symptoms was not different among the three groups. Chills, muscle pain, and arthralgia as systemic symptoms were noted significantly more frequently in the younger (80.9%) and middle-aged (75.5%) groups than in the older group (51.3%) (p = 0.002). Fever and sys-temic symptoms were less likely to appear in older patients, possibly resulting in the delaying of hospital visits among older adults.

Interrelationships Between Serum Levels of Procalcitonin and Inflammatory Markers in Patients Who Visited a General Medicine Department.

Various laboratory markers of inflammation are utilized in general practice, but their clinical diagnostic significance is often ambiguous. In the present study, we determined the clinical significance of the examination of serum levels of procalcitonin (PCT) by comparing the PCT levels with the levels of other inflammatory markers, based on a retrospective review of 332 PCT-positive patients, including cases of bacterial infection (20.5%), non-specific inflammation (20.8%), neoplasm (9.9%), connective tissue diseases (8.4%), and non-bacterial infection (7.2%), were analyzed. The serum PCT level was highest in the bacterial infection group (1.94 ng/ml) followed by the non-specific inflammatory group (0.58 ng/ml) and neoplastic diseases group (0.34 ng/ml). The serum PCT level was positively correlated with serum levels of C-reactive protein (rho=0.62), soluble interleukin-2 receptor (sIL-2R; rho=0.69), and ferritin, the plasma level of D-dimer, and white blood cell count, and negatively correlated with the serum albumin level (rho=-0.52), hemoglobin concentration, and platelet count. The serum PCT level showed a stronger positive correlation with the serum sIL-2R level than the other biomarkers. The results suggest that an increased PCT level may indicate not only an infectious state but also a non-bacterial inflammatory condition in the diagnostic process in general practice.

The effect of Humanitude care methodology on improving empathy: a six-year longitudinal study of medical students in Japan.

BACKGROUND: Empathy, which involves understanding another person's experiences and concerns, is an important component for developing physicians' overall competence. This longitudinal study was designed to test the hypothesis that medical students' empathy can be enhanced and sustained by Humanitude Care Methodology, which focuses on perception, emotion and speech. METHODS: This six-year longitudinal observational study examined 115 students who entered Okayama University Medical School in 2013. The study participants were exposed to two empathy-enhancing programs: (1) a communication skills training program (involving medical interviews) and (2) a Humanitude training program aimed at enhancing their empathy. They completed the Jefferson Scale of Empathy (JSE) seven times: when they entered medical school, before participation in the first program (medical interview), immediately after the first program, before the second program (Humanitude exercise), immediately after the second program, and in the 5th and 6th year (last year) of medical school. A total of 79 students (69% of the cohort) completed all seven test administrations of the JSE. RESULTS: The mean JSE scores improved significantly after participation in the medical interview program (p < 0.01) and the Humanitude training program (p = 0.001). However, neither program showed a sustained effect. CONCLUSIONS: The Humanitude training program as well as medical interview training program, had significant short-term positive effects for improving empathy among medical students. Additional reinforcements may be necessary for a long-term sustained effect.

Antibiotic literacy among Japanese medical students.

Antimicrobial resistance (AMR) is an urgent global issue. After the AMR action plan was introduced in 2016, a study on antibiotic literacy (i.e., awareness, knowledge, and attitude relating to antimicrobial use) among clinicians and lay people was conducted in Japan. However, no studies have hitherto targeted medical students who are expected to have a high level of antibiotic literacy. The present study was conducted between September 2019 and February 2020, enrolling undergraduate students at Okayama University Medical School. We collected data using a paper-based questionnaire form with 11 questions about antibiotic literacy. The response rate was 93.8% (661/705 students). Overall, 92.6% of the students knew that antibiotics inhibit the growth of bacteria. Student reporting that antibiotics could treat the common cold accounted for 77.0% (Year 1), 50.9% (Year 2), 48.2% (Year 3), 49.1% (Year 4), 23.8% (Year 5), and 26.2% (Year 6). Only 43 (6.5%) had heard about the AMR action plan. The study data suggested that medical students' level of literacy on antimicrobial use should be further enhanced to address AMR and promote antimicrobial stewardship.

Clinical Application of the Ratio of Serum Bone Isoform to Total Alkaline Phosphatase in General Practice.

Alkaline phosphatase (ALP) is an enzyme that is expressed in a variety of tissues. Among the isoforms of ALP, bone-specific alkaline phosphatase (BAP) is used as a marker for evaluating bone metabolism. We investigated the clinical usefulness of the ratio of serum BAP to total ALP for the diagnosis of various disorders in general practice. We retrospectively analyzed the cases of 107 Japanese patients whose serum BAP levels were exam-ined, focusing on clinical characteristics. We observed that the BAP/ALP ratios of the patients with fever and those with inflammatory diseases were significantly lower than the ratios of other patient groups. The BAP/ALP ratios of the patients with osteoporosis and those with metabolic bone diseases were higher than those of the patients with other conditions. The BAP/ALP ratio was found to be negatively correlated with age, a cor-relation that has not been found in other ethnicities. The serum BAP/ALP ratio was inversely correlated with serum CRP levels but was positively correlated with serum albumin levels and hemoglobin concentrations. Collectively, our results suggest that the BAP/ALP ratio could be a useful predictor for important geriatric con-ditions seen in general practice.

Clinical Relevance of Serum Prolactin Levels to Inflammatory Reaction in Male Patients.

To clarify the relevance of prolactin (PRL) to clinical parameters in patients who visited our general medicine department, medical records of 353 patients in whom serum PRL levels were measured during the period from 2016 to 2018 were retrospectively reviewed. Data for 140 patients (M/F: 42/98) were analyzed after excluding patients lacking detailed records and patients taking dopaminergic agents. Median serum PRL levels were significantly lower in males than females: 6.5 ng/ml (IQR: 4.2-10.3) versus 8.1 ng/ml (5.9-12.9), respectively. Pain and general fatigue were the major symptoms at the first visit, and past histories of hypertension and dyslipidemia were frequent. Male patients with relatively high PRL levels (≥ 10 ng/ml) had significantly lower levels of serum albumin and significantly higher levels of serum LDH than those with low PRL (< 10 ng/ml). There were significant correlations of male PRL level with the erythrocyte sedimentation rate (R=0.62), serum LDH level (R=0.39) and serum albumin level (R=-0.52), while the level of serum CRP (R=0.33) showed an insignificant but weak positive correlation with PRL level. Collectively, these results show that PRL levels had gender-specific relevance to various clinical factors, with PRL levels in males being significantly related to inflammatory status.

Clinical Relevance of Blood Glucose and Gastroesophageal Reflux Symptoms to Depressive Status in Patients with Type 2 Diabetes Mellitus.

A relationship between diabetes and depression is apparent. To clarify the clinical relevance of diabetic patients' gastroesophageal symptoms to their psychological status, we retrospectively analyzed the data from a Selfrating Depression Scale (SDS) and a Frequency Scale for Symptoms of Gastroesophageal reflux disease (FSSG) among 143 type 2 diabetic patients who visited a general medicine department. Among the 45 Japanese patients enrolled, the group with relatively high SDS scores (≥ 36) showed higher (FSSG) dysmotility symptom scores versus the low-SDS (< 36) group, although the 2 groups' characteristics and laboratory data were not significantly different. Positive correlations of postprandial plasma glucose (PPG) levels with FSSG scores (R=0.321, p<0.05), particularly with reflux scores (R=0.455, p<0.01) were revealed. PPG and HbA1c levels were not correlated with SDS scores. The patients' SDS scores were significantly correlated with their FSSG scores (R=0.41, p<0.01), suggesting that depressive status is linked to GERD-related manifestations. Considering that the patients' PPG levels were correlated with GERD-related symptoms, diabetic patients' blood glucose levels are associated with depressive status. Collectively, key symptoms related to GERD and glucose level values would be helpful.

Clinical and biochemical characteristics of patients having general symptoms with increased serum IgG4.

Objective: To differentiate patients with IgG4-related diseases (RD) from patients with other hyper IgG4 conditions who visit general medicine department.Methods: Fifty-six patients with high serum IgG4 levels (>135 mg/dL) were classified into three groups based on the final diagnosis: definite and possible IgG4-RD and others. Clinical and laboratory characteristics of the three groups of patients were retrospectively analyzed.Results: Major manifestations were renal dysfunction and general malaise, while thirst was the most frequent symptom in the definite group, in which submandibular glands and lymph nodes were likely to be affected. Biopsy of minor salivary glands was the least diagnostic for IgG4-RD despite the high frequency of biopsy. In the definite group, serum levels of IgG4 and IgG, IgG4/IgG ratio and basophil number were increased, while serum levels of CRP, IgA and complements were decreased. A negative correlation between serum levels of IgG4 and IgM was found in the definite group.Conclusion: The results indicated that in patients with renal dysfunction, malaise, thirst or weight loss, measurements of the levels of basophils, immunoglobulins and complements are helpful for diagnosing IgG4-RD. Considering distribution of affected tissues and localization of diagnostic biopsies, physical examination and laboratory workup are required for early diagnosis.

Can communication skills training improve empathy? A six-year longitudinal study of medical students in Japan.

BACKGROUND: Empathy is an important component of overall clinical competence; thus, enhancing empathy in medical education is essential for quality patient care. AIM: This longitudinal study was designed to address the following questions: 1. Can a targeted educational program in communication skills training enhance empathy in medical students? and 2. Can such a program have a sustained effect? METHODS: Study participants included 116 students who entered Okayama University Medical School in 2011. Students participated in a communication skills training program aimed to enhance their empathy, and completed the Jefferson Scale of Empathy (JSE) five times: at the beginning of medical school, prior to participation in the program, immediately after the program, and in last years of medical school. A total of 69 students, representing 59% of the cohort, completed the JSE in all five test administrations. RESULTS: Students' total scores on the JSE and its two factors (Perspective Taking and Compassionate Care) increased significantly (p < 0.001) after participation in the communication skills training program. However, the program did not have a sustained effect. CONCLUSIONS: Targeted educational programs to enhance empathy in medical students can have a significant effect; however, additional reinforcements may be needed for a sustained effect.

Changes in Serum Biochemical Markers in Relation to Chief Complaints and Aging in General Medicine.

To clarify potential relationships between chief complaints of patients and laboratory data with a focus on aging-related changes, we retrospectively analyzed the data of 843 patients who visited a general medicine department for the first time. Their chief complaints were classified into 8 major symptoms: visceral pain, somatic pain, fever, cough, dizziness, fatigue, appetite loss, and edema. We compared the laboratory data obtained from the patients with complaints with the data of symptom-free (control) patients. The serum sodium and potassium levels in the fever group were decreased compared to those in the control group. In the fever group, the serum sodium level was inversely correlated with age. The ratio of serum urea nitrogen to creatinine (UN/Cr) was increased in the appetite-loss group. There were significant age-dependent increases in the UN/Cr ratio in the appetite-loss and edema groups. Of note, serum levels of free thyroxin were lower in the dizziness group compared to the control group. In addition, the free thyroxin level was inversely correlated with age in the dizziness group but not in the asymptomatic control group. Collectively, the results indicated that osmolality-related laboratory data are strongly associated with individual primary symptoms at the first visit regardless of the final diagnosis. The consideration of age-dependent changes of these markers is helpful for diagnosing latent disorders based on various primary symptoms.

ADAMTS1 inhibits lymphangiogenesis by attenuating phosphorylation of the lymphatic endothelial cell-specific VEGF receptor.

Angiogenesis and lymphangiogenesis play roles in malignant tumor progression, dissemination, and metastasis. ADAMTS1, a member of the matrix metalloproteinase family, is known to inhibit angiogenesis. Recombinant ADAMTS1 was shown to strongly inhibit angiogenesis. We investigated whether ADAMTS1 inhibited lymphangiogenesis in the present study. We examined cell proliferation and cell migration in normal human dermal lymphatic microvascular endothelial cells (HMVEC-dLy) transduced with or without adenoviral human ADAMTS1 gene therapy. We then examined the VEGFC/VEGFR3 signal transduction pathway in ADAMTS1-transduced HMVEC-dLy. Cell proliferation and tube formation in Matrigel were significantly lower with transduced ADAMTS1 than with control (non-transduced HMVEC-dLy). The phosphorylation of VEGFR3 was also attenuated by ADAMTS1 gene therapy in HMVEC-dLy. Immunoprecipitation assays revealed that ADAMTS1 formed a complex with VEGFC. Our results demonstrated that ADAMTS1 inhibited lymphangiogenesis in vitro. The data highlight the new function of ADAMTS1 in the regulation of lymphangiogenesis and the therapeutic potential of ADAMTS1 in cancer therapy.

Aortic vascular graft infection caused by Cardiobacterium valvarum: a case report.

A 53-year-old man with a past medical history of total arch replacement surgery and severe aortic regurgitation presented with a 1-month history of persistent general malaise, anorexia, body weight loss and night sweats. His recent history included gingival hyperplasia for 6 years, gingivitis after tooth extraction 3 years before, prolonged inflammatory status for 4 months, fundal hemorrhage and leg tenderness for 2 months. A pathogen was detected from blood culture, but conventional microbiological examination failed to identify the pathogen. The organism was eventually identified as Cardiobacterium valvarum by 16S rRNA analysis, and the patient was diagnosed with infective endocarditis and prosthetic vascular graft infection. The patient received intravenous antibiotic therapy using a combination of ceftriaxone and levofloxacin for 5 weeks and was discharged with a good clinical course. C. valvarum is a rare human pathogen in clinical settings. Only 10 cases have been reported to date worldwide, and therefore, the clinical characteristics of C. valvarum infection are not fully known. This is a first well-described case of C. valvarum infection in Japan, and further, a first report of aortic prosthetic vascular graft infection worldwide. Identification of C. valvarum is usually difficult due to its phenotypic characteristics, and molecular approaches would be required for both clinicians and microbiologists to facilitate more reliable diagnosis and uncover its clinical picture more clearly.

Tumor growth inhibitory effect of ADAMTS1 is accompanied by the inhibition of tumor angiogenesis.

Angiogenesis plays an important role in tumor progression. Several reports have demonstrated that a disintegrin and metalloproteinase with thrombospondin motifs1 (ADAMTS1) inhibited angiogenesis via multiple mechanisms. The aim of this study was to investigate the effect of ADAMTS1 on endothelial cells in vitro and on tumor growth with regard to angiogenesis in vivo. We examined the effects of the transfection of ADAMTS1 using two constructs, full-length ADAMTS1 (full ADAMTS1) and catalytic domain-deleted ADAMTS1 (delta ADAMTS1). Transfection of both the full ADAMTS1 and delta ADAMTS1 gene constructs demonstrated the secretion of tagged-ADAMTS1 protein into the conditioned medium, so we examined the effects of ADAMTS1-containing conditioned medium on endothelial cells. Both types of conditioned media inhibited endothelial tube formation, and this effect was completely abolished after immunoprecipitation of the secreted protein from the medium. Both types of conditioned media also inhibited endothelial cell migration and proliferation. We then examined the impact of ADAMTS1 on endothelial cell apoptosis. Both conditioned media increased the number of Annexin V-positive endothelial cells and caspase-3 activity and this effect was attenuated when z-vad was added. These results indicated that ADAMTS1 induced endothelial cell apoptosis. We next examined the effects of ADAMTS1 gene transfer into tumor-bearing mice. Both full ADAMTS1 and delta ADAMTS1 significantly inhibited the subcutaneous tumor growth. Collectively, our results demonstrated that ADAMTS1 gene transfer inhibited angiogenesis in vitro and in vivo, likely as a result of the induction of endothelial cell apoptosis by ADAMTS1 that occurs independent of the protease activity.

Key signs indicating mesenteric panniculitis.

Since patients with mesenteric panniculitis (MP) present non-specific symptoms, diagnosing MP is challenging. We describe a 45-year-old man who developed MP with radiologic findings of a "fat ring sign" and a "tumoral pseudocapsule sign." These signs shown in the present case are crucial for a precise diagnosis of MP.

Relationship between patients' characteristics and efficacy of calcimimetics for primary hyperparathyroidism in the elderly.

Calcimimetic treatment has been reported to be effective for primary hyperparathyroidism (PHPT). Nine elderly PHPT patients who had been treated with calcimimetics were retrospectively analyzed. It was found that calcimimetics can reduce elevated serum calcium levels in elderly PHPT patients with low femoral DEXA %YAM and low urinary cAMP levels.

Antimicrobial prescription practices for outpatients with uncomplicated cystitis in Japan.

To promote antimicrobial stewardship, we studied antimicrobial prescription rates for uncomplicated cystitis, a common outpatient disease requiring antibiotic treatment. This multicenter retrospective study was performed from January 1, 2018, to December 31, 2020, in Japan, targeting outpatients aged ≥ 20 years whose medical records revealed International Classification of Diseases (ICD-10) codes suggesting uncomplicated cystitis (N300). The data of 1445 patients were collected and that of 902 patients were analyzed. The overall median patient age was 71 years and a proportion of those aged less than 50 years was 18.8% with a female dominance (82.6%). Antimicrobials were prescribed for 884 patients (98.0%) and a total of 623 patients (69.1%) were treated with broad-spectrum drugs, including fluoroquinolones (36.0%), third-generation cephalosporins (29.9%) and faropenem (3.1%). A logistic regression model revealed that the broad-spectrum agents were significantly prescribed for the older patients, male patients, and those who visited internists. Recurrence was observed in 37 (4.1%) cases, and the multivariate analysis suggested any of age, sex, or antimicrobial types were not associated with the recurrence. Collectively, approximately two-thirds of antimicrobials prescribed for uncomplicated cystitis were broad-spectrum agents. The present data would be an indicator for antimicrobial prescriptions in uncomplicated cystitis in Japan.