Potent CTLs can be induced against tumor cells in an environment of lower levels of systemic MFG-E8.

The direction and magnitude of immune responses are critically affected when dead cells are disposed of. Milk fat globule-epidermal growth factor-factor 8 (MFG-E8) promotes the engulfment of apoptotic normal and cancerous cells without inducing inflammation. We have previously reported that a certain proportion of the cancer cells express abundant MFG-E8, and that such expression is associated with the shorter survival of patients with esophageal cancer who had received chemotherapy before surgery. However, the influence of tumor-derived and systemically existing MFG-E8 on antitumor immune responses has not yet been fully investigated. Herein, we showed that CTL-dependent antitumor immune responses were observed in mice with no or decreased levels of systemic MFG-E8, and that such responses were enhanced further with the administration of anti-PD-1 antibody. In mice with decreased levels of systemic MFG-E8, the dominance of regulatory T cells in tumor-infiltrating lymphocytes was inverted to CD8+ T cell dominance. MFG-E8 expression by tumor cells appears to affect antitumor immune responses only when the level of systemic MFG-E8 is lower than the physiological status. We have also demonstrated in the clinical setting that lower levels of plasma MFG-E8, but not MFG-E8 expression in tumor cells, before the treatment was associated with objective responses to anti-PD-1 therapy in patients with non-small cell lung cancer. These results suggest that systemic MFG-E8 plays a critical role during the immunological initiation process of antigen-presenting cells to increase tumor-specific CTLs. Regulation of the systemic level of MFG-E8 might induce efficient antitumor immune responses and enhance the potency of anti-PD-1 therapy.

Association Between Arterial Pulse Waveform Analysis and Mortality in Patients With Septic Shock: A Retrospective Cohort Study Using Japanese Diagnosis Procedure Combination Data.

Purpose: Specialized pressure transducers for arterial pulse waveform analysis (S-APWA) devices are dedicated kits connected to an arterial pressure catheter that monitors hemodynamic parameters, such as cardiac output, pulse pressure variation, and stroke volume variation, less invasively. While the association between the use of S-APWA devices and clinical outcomes in perioperative patients has been previously evaluated, its assessment in patients with septic shock remains inadequate. Materials and Methods: This retrospective cohort study utilized a nationwide Diagnosis Procedure Combination database in Japan. Adult patients with septic shock admitted to the intensive care unit (ICU) with arterial pressure catheter placement on the admission day from August 2012 to February 2021 were included. Hospitalizations meeting the eligibility criteria were categorized into groups based on S-APWA device usage. The primary outcome, evaluated using Cox regression analysis, was 30-day all-cause mortality in the propensity score overlap-weighted population. Secondary outcomes included in-hospital mortality, ICU duration, and overall hospital stay. Results: Among 5130 eligible hospitalizations, 643 were in the S-APWA group and 4487 were in the conventional pressure transducer group. Cox regression analysis within the propensity score overlap-weighted population showed no significant difference in 30-day mortality (adjusted hazard ratio: 0.94; 95% confidence interval: 0.9-1.38; P = .58). Logistic regression analysis indicated no significant differences in the in-hospital mortality. While the S-APWA group had prolonged ICU stays, no significant difference in the overall hospital stay was observed according to linear regression analyses. Conclusions: Our study found no significant association between S-APWA use and 30-day mortality in patients with septic shock. These findings offer insights into optimizing monitoring systems in ICUs.

Validity of Using Japanese Administrative Data to Identify Inpatients With Acute Pulmonary Embolism: Referencing the COMMAND VTE Registry.

BACKGROUND: Acute pulmonary embolism (PE) is a life-threatening in-hospital complication. Recently, several studies have reported the clinical characteristics of PE among Japanese patients using the diagnostic procedure combination (DPC)/per diem payment system database. However, the validity of PE identification algorithms for Japanese administrative data is not yet clear. The purpose of this study was to evaluate the validity of using DPC data to identify acute PE inpatients. METHODS: The reference standard was symptomatic/asymptomatic PE patients included in the COntemporary ManageMent AND outcomes in patients with Venous ThromboEmbolism (COMMAND VTE) registry, which is a cohort study of acute symptomatic venous thromboembolism (VTE) patients in Japan. The validation cohort included all patients discharged from the six hospitals included in both the registry and DPC database. The identification algorithms comprised diagnosis, anticoagulation therapy, thrombolysis therapy, and inferior vena cava filter placement. Each algorithm's sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were estimated. RESULTS: A total of 43.4% of the validation cohort was female, with a mean age of 67.3 years. The diagnosis-based algorithm showed a sensitivity of 90.2% (222/246; 95% confidence interval [CI], 85.8-93.6%), a specificity of 99.8% (228,485/229,027; 95% CI, 99.7-99.8%), a PPV of 29.1% (222/764; 95% CI, 25.9-32.4%) and an NPV of 99.9% (228,485/229,509; 95% CI, 99.9-99.9%) for identifying symptomatic/asymptomatic PE. Additionally, 94.6% (159/168; 95% CI, 90.1-97.5%) of symptomatic PE patients were identified using the diagnosis-based algorithm. CONCLUSION: The diagnosis-based algorithm may be a relatively sensitive method for identifying acute PE inpatients in the Japanese DPC database.

Effect of multidisciplinary care on diabetic kidney disease: a retrospective cohort study.

BACKGROUND: Diabetic kidney disease (DKD) is the most common disease among patients requiring dialysis for the first time in Japan. Multidisciplinary care (MDC) may prevent the progression of kidney failure. However, the effectiveness and timing of MDC to preserve kidney function in patients with DKD is unclear. Therefore, the aim of this study was to investigate whether MDC for patients with DKD affects the preservation of kidney function as well as the timing of MDC in clinical practice. METHODS: In this retrospective cohort study, we identified patients with type 2 diabetes mellitus and DKD from April 2012 to January 2020 using a nationwide Japanese healthcare record database. The fee code for medical guidance to prevent dialysis in patients with diabetes was used to distinguish between the MDC and non-MDC groups. The primary outcome was a 40% decline in the estimated glomerular filtration rate, and secondary outcomes were death, hospitalization, permanent dialysis, kidney failure with replacement therapy, and emergency temporary catheterization. Propensity score matching was performed, and Kaplan-Meier and multivariable Cox regression analyses were performed. RESULTS: Overall, 9,804 eligible patients met the inclusion criteria, of whom 5,614 were matched for the main analysis: 1,039 in the MDC group, and 4,575 in the non-MDC group. The primary outcome did not differ between the groups (hazard ratio: 1.18, [95% confidence interval: 0.99-1.41], P = 0.07). The groups also did not differ in terms of the secondary outcomes. Most patients with DKD received their first MDC guidance within 1 month of diagnosis, but most received guidance only once per year. CONCLUSIONS: Although we could not demonstrate the effectiveness of MDC on kidney function in patients with DKD, we clarified the characteristics of such patients assigned the fee code for medical guidance to prevent dialysis related to diabetes.

Knowledge and practical skills for cancer pain management among nurses on remote islands in Japan and related factors nationwide.

OBJECTIVE: To clarify the knowledge and practical skills needed for cancer pain management among nurses on remote islands in Japan and related factors nationwide. SETTING: Due to geographical factors, nurses working on remote islands in Japan have few opportunities to attend training programs, which makes it difficult to acquire the knowledge and practical skills needed to provide pain management for patients with cancer. METHODS: We conducted a self-administered questionnaire survey regarding knowledge and practical skills in pain management for patients with cancer. DESIGN: Cross-sectional study. PARTICIPANTS: Nurses working in cancer pain care in medical facilities and home care on remote islands throughout Japan. RESULTS: We analysed 128 responses. Regarding knowledge, the average accuracy level was 49.1%. Items with a low accuracy rate included selecting medicine according to the type of pain and the patient's condition. Regarding practice, the items with low scores included analgesics appropriate for the type of pain and relating physical pain to mental, social and spiritual aspects. The most common significant factor in both knowledge and practice was related to postgraduate training. CONCLUSIONS: These findings suggest that to improve the knowledge and practical skills for cancer pain management among nurses on remote islands in Japan, it is necessary to incorporate clinical reasoning into basic education and establish remote education systems and consultation systems with other facilities.

Comprehensive survey on the use of plastic additives in toy products used in Japan.

BACKGROUND: Plastic additives have adverse effects on human health. Children frequently use toys that contain various substances found in paints, plasticizers, and other materials, which heighten the risk of specific chemical exposure. Infants are particularly prone to chemical exposure through the "mouthing" behavior because of the possibility of placing toys in their mouths. Thus, this vulnerability should be considered during risk assessments of chemical exposure. METHODS: This study performed a comprehensive analysis of the chemical components in various 84 plastic toys including "designated toys" (toys that may be harmful to infant health if in contact with their mouths: Article 78 of the Enforcement Regulations of the Food Sanitation Law by the Minister of Health, Labor and Welfare) such as dolls, balls, blocks, bathing toys, toy vehicles, pacifiers, and household items, purchased in the Japanese market by nontargeted and targeted analysis. RESULTS: Plasticizers, flame retardants, and fragrances were the main compounds in almost all the toy products. The results showed that plastic products made in China tended to contain high levels of phthalate esters. In particular, hazardous plasticizers, such as diisodecyl, di-n-octyl, and diisononyl phthalates were detected above the regulatory limit (0.1%) in used products manufactured before regulations were passed in Japan. Furthermore, we detected alternative plasticizers, such as acetyl tributyl citrate (ATBC; 52%), diisononyl adipate (DINA; 50%), and di(2-ethylhexyl) terephthalate (DEHT; 40%). ATBC was detected at high concentrations in numerous toy products. Thus, infants with free access to indoor plastic toys might be exposed to these chemicals. CONCLUSIONS: This study observed that the chemical profiles of toy products were dependent on the year of manufacture. Furthermore, the detection of currently regulated plasticizers in secondhand products manufactured before regulations were enforced, along with the increasing trend of using alternative substances to regulated phthalate esters in products, suggests the potential exposure of infants to these plasticizers through the use of toys. Therefore, regular fact-finding surveys should continue to be conducted for the risk assessment and safety management of domestic toy products.

Frequency and determinants of serum calcium monitoring during eldecalcitol therapy in patients with osteoporosis.

INTRODUCTION: Eldecalcitol (ELD) is an active vitamin D3 analog (AVD) commonly used to treat osteoporosis in Japan. Although routine monitoring of serum calcium levels during ELD therapy is recommended, little is known about the actual frequency and determinants of monitoring. MATERIALS AND METHODS: This was a descriptive cohort study using a Japanese electronic medical records database. We identified osteoporosis patients who initiated treatment with ELD or other AVDs (alfacalcidol and calcitriol) between April 1, 2011 and September 10, 2021. The index date for cohort entry was the first prescription date of ELD or other AVDs. The frequency of serum calcium monitoring was evaluated every 6 months. Determinants of serum calcium monitoring were identified using multivariable logistic regression models. We also calculated the incidence of hypercalcemia and the frequency of serum calcium monitoring within 6 months before hypercalcemia. RESULTS: We identified 12,671 ELD users and 7867 other AVD users. Within 6 months after cohort entry, 45.9% of ELD users and 58.7% of other AVD users underwent serum calcium monitoring. Female sex, no use of systemic corticosteroids, moderate-to-good renal function, treatment in smaller hospitals, and treatment in orthopedic surgery departments were associated with a lower likelihood of receiving serum calcium monitoring during ELD therapy. The incidence of hypercalcemia among ELD users was 6.36 per 100 person-years, with 20.6% of cases not receiving serum calcium monitoring before hypercalcemia. CONCLUSION: Our findings suggest that serum calcium monitoring is not given adequate attention during ELD therapy in routine clinical practice.

Association between combined spinal-epidural analgesia and neurodevelopment at 3 years old: The Japan Environment and Children's Study.

AIM: To investigate the association between maternal combined spinal-epidural analgesia during vaginal delivery and neurodevelopment in 3-year-old children. METHODS: Using data from the Japan Environment and Children's Study, a birth cohort study on pregnant women and their offspring, we described the background, perinatal outcomes, and neurodevelopmental outcomes of participants with a singleton pregnancy who received combined spinal-epidural analgesia during vaginal delivery and those who did not. The association between maternal combined spinal-epidural analgesia and abnormalities in five domains of the Ages and Stages Questionnaire, Third Edition, was analyzed using univariable and multivariable logistic regression analyses. Crude and adjusted odds ratios with 95% confidence intervals (95% CI) were calculated. RESULTS: Among 59 379 participants, 82 (0.1%) children (exposed group) were born to mothers who received combined spinal-epidural analgesia during vaginal delivery. In the exposed versus control groups, 1.2% versus 3.7% had communication abnormalities (adjusted odds ratio [95% CI]: 0.30 [0.04-2.19]), 6.1% versus 4.1% exhibited gross-motor abnormalities (1.36 [95% CI: 0.55-3.36]), 10.9% vs. 7.1% had fine-motor abnormalities (1.46 [95% CI: 0.72-2.96]), 6.1% vs. 6.9% showed difficulties with problem-solving (0.81 [95% CI: 0.33-2.01]), and 2.4% vs. 3.0% had personal-social problems (0.70 [95% CI: 0.17-2.85]). CONCLUSIONS: Exposure to combined spinal-epidural analgesia during vaginal delivery was not associated with the risk of neurodevelopmental abnormalities; however, the sample size of our study might not be appropriate for the study design.

Effectiveness of intraoperative nicorandil in patients with a history of ischemic heart disease undergoing high-risk noncardiac surgery: a retrospective cohort study.

PURPOSE: Nicorandil is occasionally administered to prevent myocardial ischemia during the perioperative period in patients with ischemic heart disease (IHD); however, its effectiveness has not been clarified. In this study, we examined the effectiveness of intraoperative nicorandil administration in noncardiac surgery. METHODS: We identified patients with a history of IHD who had undergone high-risk noncardiac surgery between April 2015 and March 2020 from a nationwide in-patient database in Japan. The patients were divided into those who received nicorandil (nicorandil group) and those who did not (control group). The primary outcome was the 30-day in-hospital mortality. The secondary outcome was major adverse cardiovascular events (MACE), defined as the composite outcome of the 30-day in-hospital mortality, acute myocardial infarction, percutaneous coronary intervention, and coronary artery bypass grafting. One-to-one propensity score matching was performed. The outcomes were analyzed using a Cox proportional hazards model. RESULTS: Of 8037 patients, 2886 received nicorandil during surgery. After propensity score matching, 2554 pairs were analyzed. There was no significant difference in the 30-day in-hospital mortality (26 [1.02%] vs. 36 [1.41%]; hazard ratio [HR] 1.36; 95% confidence interval [CI] 0.82-2.26; P = 0.229) or incidence of MACE (42 [1.64%] vs. 55 [2.15%]; HR 1.24; 95% CI 0.86-1.93; P = 0.216) between the control and nicorandil groups. CONCLUSION: The findings of this study suggest that intraoperative nicorandil administration is not associated with the 30-day in-hospital mortality in high-risk noncardiac surgery.

A prospective cohort study of the association between the Apgar score and developmental status at 3 years of age: the Japan Environment and Children's Study (JECS).

Apgar score (AS) is a well-established tool for assessing viability of newborns, and its association with subsequent child development has been suggested. We aimed to assess whether Apgar scores (ASs) ≥ 7 (generally considered normal) are associated with the developmental status at 3 years of age while adjusting for perinatal and socioeconomic confounders. We extracted the data of ASs at 1 and 5 min among participants of the Japan Environment and Children's Study datasets, which were used in this nationwide cohort study. The outcomes comprised developmental status that was less than each cutoff value for the following five domains of the Ages & Stages Questionnaire (Japanese version, 3rd edition): communication, gross and fine motor, problem-solving, and personal-social domains. For this objective, we conducted multivariable logistic regression analyses on the data of 54,716 children. Compared with ASs ≥ 9 at 5 min, the adjusted odds ratios (aOR) for delayed development in children with ASs ≤ 8 were 1.31 (95% confidence interval, 1.11-1.56), 1.20 (1.04-1.38), and 1.16 (1.01-1.34), respectively, for gross and fine motor, and problem-solving domains. Among neonates with ASs ≤ 8 at 1 min, when those with ASs ≤ 8 at 5 min were compared with those with ASs ≥ 9 at 5 min, the aOR for gross motor domain was 1.34 (1.11-1.61).Conclusion: ASs ≤ 8 compared with those ≥ 9 at 5 min, even considering the change of AS from 1 to 5 min, were associated with increased ORs for developmental delay in 3-year-olds. Even ASs that are considered normal might affect the subsequent development. What is Known: • Apgar score is a general tool for evaluating the vitality of newborns. It is also basically measured at 1 minute and 5 minutes after birth and the scores of ≥7 are considered normal. • The Apgar scores at each minute affect clinical findings of neonates after birth and the subsequent long-term development. What is New: • Neonates with Apgar scores of ≤8 at 5 minutes compared with those of ≥9, including the change in Apgar score from 1 minute to 5 minutes, are associated with increased odds ratios for developmental status at 3 years of age adjusting for perinatal and socioeconomic confounders.

Impact of state of emergency for coronavirus disease 2019 on hospital visits and disease exacerbation: the Japan COVID-19 and Society Internet Survey.

BACKGROUND: Studies on the impact of coronavirus disease 2019 (COVID-19) on people's routine medical care are limited, and understanding the factors associated with medical care avoidance can inform us about the ongoing pandemic. OBJECTIVES: We aimed to assess the impact of Japan's state of emergency and stay-at-home policy for COVID-19 on hospital visits and disease exacerbation; we also identified related factors. METHODS: This cross-sectional study used data from the Japan COVID-19 and Society Internet Survey (JACSIS), which included randomly sampled research agency panellists in Japan. Among the 28,000 participants, we included 7,747 respondents who reported having any disease. We described baseline characteristics and avoidance-related hospital visit outcomes. We used multivariable logistic regression analyses to assess the association between chronic diseases and outcomes of hospital visit avoidance. RESULTS: Among 7,747 participants, 17.7% of patients with chronic diseases avoided hospital visits, 2.1% of patients postponed hospitalization or surgery, 4.9% of patients ran out of drug, and 5.3% of patients experienced disease exacerbation during the COVID-19 pandemic in April and May 2020. Exacerbations occurred mostly in participants with mental diseases, chronic pain and headache, and diabetes (OR 3.33 [95% confidence interval (CI): 2.51-4.41], 2.83 [95% CI: 2.19-3.66], and 1.53 [95% CI: 1.10-2.13], respectively). Patients with cardiovascular disease or cancer did not experience exacerbation [OR 0.55 (95% CI: 0.31-0.97), 0.79 (95% CI: 0.43-1.45)]. CONCLUSIONS: The rates of hospital visit avoidance and exacerbation varied among patients with different diseases under the COVID-19 stay-at-home policy in April and May 2020, and disease-specific preparedness may be necessary for the pandemic.

There are few studies available on the effect of coronavirus disease 2019 (COVID-19) on people's routine medical care or hospital visits. It is important to understand the factors associated with hospital avoidance in order to be informed about this pandemic. Therefore, we assessed how the declaration of a state of emergency and a stay-at-home order in Japan affected hospital visits and the worsening of diseases; we also identified some risk factors involved. We included 7,747 participants of the Japan COVID-19 and Society Internet Survey, who reported having conditions, such as mental diseases, chronic pain and headache, diabetes, cardiovascular diseases, and cancer. We evaluated the association between chronic diseases and outcomes of hospital visits avoidance, and our findings showed that exacerbations occurred mostly in participants with mental diseases, chronic pain and headache, and diabetes. Though our study only focussed on hospital/clinic visits and did not consider acute health care, including mortality, the rates of hospital visits avoidance and exacerbation varied among patients with different diseases under the COVID-19 stay-at-home policy. It is particularly important to follow up patients with mental diseases during the pandemic, and disease-specific planning is necessary.

Association between topical ß-blocker use and asthma attacks in glaucoma patients with asthma: a cohort study using a claims database.

PURPOSE: To investigate the association between the use of topical ß-blockers and subsequent asthma attacks in glaucoma patients with asthma. METHODS: This was a retrospective longitudinal cohort study using an administrative claims database. All patients aged 20 years or older who were registered in the health insurance claims database updated and managed by JMDC Inc. (Tokyo, Japan). Patients who were newly prescribed eye drops for glaucoma treatment were identified between 2011 and 2017. The patients with glaucoma were divided into two groups: ß-blocker users and non-ß-blocker users, based on the presence of a ß-blocker in the prescribed eye drops. We investigated whether the incidence of asthma attacks in patients with previously treated asthma differed between the two groups. RESULTS: We categorized 17,666 patients in the ß-blocker-user group and 12,609 patients in the non-ß-blocker-user group. A total of 580 patients in the ß-blocker group (3.28%) and 847 in the non-ß-blocker group (6.72%) underwent asthma treatment before the prescription of anti-glaucoma eye drops (P < 0.001). Furthermore, 94 patients in the ß-blocker-user group (0.53%) and 278 in the non-ß-blocker user group (2.20%) were undergoing current treatment for asthma (P < 0.001). The adjusted hazard ratios of asthma attacks were 0.73 (95% confidence interval, 0.46-1.16, P = 0.18) in patients with a history of asthma treatment and 1.22 (95% confidence interval, 0.56-2.70, P = 0.62) in patients with current asthma treatment, compared to the non-ß-blocker-user group. CONCLUSION: Our results clarified that several patients with asthma were prescribed topical ß-blockers for glaucoma treatment. However, asthma attacks may not be significantly attributed to topical ß-blockers, even in glaucoma patients under current asthma treatment. The administration of topical ß-blockers to asthma patients could be a treatment option in the absence of other treatment options, if adequate informed consent is obtained. Further studies are needed to draw a firm conclusion on this clinical question.

Longitudinal study of body mass index and percentage of overweight in Japanese children grouped by maturity.

Childhood obesity is a known risk factor for adult diseases, making its evaluation highly important. However, the evaluation is complex because there is no gold standard method. Body mass index (BMI) and percentage of overweight (POW) are widely used in Japan. However, they have the following limitations: it is difficult to set cutoffs for BMI because it dynamically varies in childhood, and POW has not been studied extensively, especially regarding its difference during maturity. Therefore, our study analyzed BMI/POW in Japanese children grouped by maturity. We used longitudinal school check-up data collected from elementary and junior high schools in 20 municipalities. We made percentile curves of BMI/POW and calculated the percentage of participants considered overweight/obese by sex, age, and maturity. Maximum increment age (MIA) was calculated using the graphical fitting method. We included 35,461 subjects aged 15 in 2018. Early-maturing children had higher BMI. The difference among maturity groups decreased by shifting the percentile curves by differences in MIA. Therefore, the use of BMI might lead to the overestimation of overweight/obesity in early-maturing children and underestimation in late-maturing children. The POW percentile curves were "N"-shaped around the MIA, indicating the inappropriate evaluation during this period. The percentile curves of children categorized as overweight/obese were also "N"-shaped, confirming that MIA affects the evaluation of childhood obesity. The possibility of overestimation/underestimation needs verification with the data of accurate age, pubertal changes, and adult diseases. In conclusion, it is difficult to evaluate childhood obesity only with height and weight.

Large-scale health insurance study showed that antibiotic use in infancy was associated with an increase in atopic dermatitis.

AIM: This retrospective large-scale study examined the association between prescribing antibiotics for infants and subsequent atopic dermatitis (AD). METHODS: The data covered the period from 1 January 2005 to 31 December 2014 and were extracted from a Japanese health insurance claims database. The exposure was being prescribed antibiotics at less than 12 months of age and the outcome was a subsequent diagnosis of AD. The primary analysis method was multivariable Cox proportional hazard regression analysis. A sibling-matched analysis was also performed to adjust for shared familial and environmental confounders. RESULTS: This study comprised 85 954 infants: 8654 (10.1%) who had received antibiotics and 77 300 who had not. AD was diagnosed in 1183 (13.7%) and 10 325 (13.4%) infants respectively. The exposed group was more likely to develop AD than the non-exposed group, but this association disappeared when we carried out the secondary, sibling-matched analysis of the two groups. Other risk factors for AD were macrolides, aminoglycosides, food allergies and histamine H1 receptor antagonists. CONCLUSION: Antibiotic use in infancy was associated with a subsequent increase in the incidence of AD. This association should be considered when prescribing antibiotics, but antibiotic use may not be a critical factor for the development of AD.

Clinical epidemiology and pharmacoepidemiology studies with real-world databases.

Hospital-based registry data, including patients' information collected by academic societies or government based research groups, were previously used for clinical research in Japan. Now, real-world data routinely obtained in healthcare settings are being used in clinical epidemiology and pharmacoepidemiology. Real-world data include a database of claims originating from health insurance associations for reimbursement of medical fees, diagnosis procedure combinations databases for acute inpatient care in hospitals, a drug prescription database, and electronic medical records, including patients' medical information obtained by doctors, derived from electronic records of hospitals. In the past ten years, much evidence of clinical epidemiology and pharmacoepidemiology studies using real-world data has been accumulated. The purpose of this review was to introduce clinical epidemiology and pharmacoepidemiology approaches and studies using real-world data in Japan.

The α1-adrenergic receptors in the amygdala regulate the induction of learned despair through protein kinase C-beta signaling.

Hyperactivity of amygdala is observed in patients with major depressive disorder. Although the role of α1-adrenoceptor in amygdala on fear memory has been well studied, the role of α1-adrenoceptor in amygdala on depression-like behaviors remains unclear. Therefore, we investigated the effect of α1A-adrenoreceptor in amygdala on despair behavior, evaluated by the immobility time during tail suspension test (TST), pharmacological intervention, and immunohistological methods. C57BL6/J mice given a bilateral intra-amygdala injection of artificial cerebrospinal fluid exhibited an increased duration of immobility in the latter half of both trials of TST with a 24-h interval, a phenomenon known as learned despair. Intra-amygdala injection of WB4101 (1.7 nmol/0.1 µl), an α1 adrenoreceptor antagonist, but not propranolol (250 pmol/0.1 µl), a ß-adrenoreceptor antagonist, blocked the induction of learned despair during TST. Immunostaining experiments revealed that ~61-75% of α1A-adrenoreceptor-positive neurons were colocalized with GAD65/67 in amygdala, implying that the α1-adrenoceptors in amygdala may enormously regulate the GABA release. Protein kinase C-beta (PKCß) was predominantly expressed in the α1A-adrenoreceptor-positive neurons in the BLA, whereas protein kinase C-epsilon (PKCε) was highly expressed with the α1A-adrenoreceptor in the Central nucleus of amygdala. Intra-amygdala injection of ruboxistaurin (10 pmol/0.1 µl), a PKCß inhibitor, blocked the induction of learned despair during TST, whereas neither TAT-εV1-2 (500 ng/0.1 µl), a cell-permeant PKCε inhibitory peptide, nor HBDDE (50 pmol/0.1 µl), an inhibitor of PKCα and -γ, affected the duration of immobility during TST. These data suggest that the α1-adrenoreceptor in amygdala regulates the induction of learned despair via PKCß.

Assessment of asthma severity according to treatment steps in Japanese pediatric patients: a descriptive cross-sectional study using an administrative claims database.

OBJECTIVES: Japan has one of the highest asthma prevalence rates in Asia; however, there is a lack of epidemiological studies on asthma among children in Japan. This study aimed to describe the severity of asthma and the prescription patterns for its treatment among pediatric patients, by using a large-scale claims database. METHODS: The analysis datasets were extracted from the JMDC database for the period of April 1, 2009 to March 30, 2015; included records were restricted to patients between 2 and 15 years of age. The Japanese Pediatric Guidelines for the treatment and management of asthma (JPGL) steps were used as a proxy for asthma treatment and severity. We also described the characteristics of asthma in children by stratifying the prevalence and incidence cohorts by index years. RESULTS: In the prevalence cohort (56% male), from 2010 to 2014, approximately 80-90% of the children received step 1 or 2 treatment, with the remainder receiving step 3 or 4 treatment, as defined by the JPGL. The majority (approximately 90%) of patients visited clinics for asthma treatment, while a minority visited hospitals. CONCLUSIONS: Our study showed the severity of asthma among Japanese pediatric patients, as well as their demographic characteristics, using a large-scale claims database. The majority of pediatric asthma patients received treatment for mild-to-moderate asthma, while less than 10% received treatment for severe asthma.

Trends and patterns in antibiotic prescribing for adult outpatients with acute upper respiratory tract infection in Japan, 2008-2018.

INTRODUCTION: This study aimed to characterize the patterns and trends in the use of major oral antibiotics prescribed for adult outpatients diagnosed with acute upper respiratory tract infections (AURTIs) in Japan between 2008 and 2018. METHODS: We analyzed administrative claims data for adults in Japan, between April 2008 and September 2018. The trends in oral antibiotic prescription were illustrated using the prescribing rate, and tested using interrupted time series analysis. We also assessed the factors associated with antibiotic prescription for AURTIs. RESULTS: Data on 7.54 million antibiotic prescriptions in 1,937,379 adults with AURTIs were analyzed; people ≥65-years old were scarcely included. The antibiotic prescribing rate declined from 49.9% in 2008 to 39.0% in 2018, and the rate of decrease accelerated after the national action plan on antimicrobial resistance was launched in April 2016. Acute nasopharyngitis was the most common indication. Cephalosporins (35.2%), macrolides (32.2%), fluoroquinolones (24.6%), and penicillins (5.88%) were the most commonly prescribed antibiotic classes. Sex, age, type and specialty of the facility, and season affected the likelihood of being prescribed antibiotics. The majority of antibiotics prescribed were broad-spectrum, but use of penicillins showed a higher rate of increase after 2016. CONCLUSIONS: The percentage of antibiotic prescriptions for AURTIs decreased significantly after implementing the action plan, indicating that it was effective to some extent. However, since the use of broad-spectrum antibiotics was high, there is scope for improving the prescribing pattern, including the types of antimicrobial agents; this is considered to be a future issue.

[Association of prenatal maternal, prenatal secondhand, and postnatal secondhand smoking exposures with the incidence of asthma/atopic dermatitis in children: An epidemiological study using checkup data of mothers and children in Kobe city].

Objectives　Despite suggested associations among smoking exposures and the prevalence of allergic diseases in children, studies examining the effect of prenatal maternal smoking and secondhand smoking on the occurrence of these diseases in children are limited. Our study aimed to investigate the association between prenatal maternal smoking as well as secondhand smoking and the incidence of asthma or atopic dermatitis in children.Methods　We included checkup data of a total of 53,505 children living in Kobe, Japan, without missing values for exposure or outcome, between April 1, 2004, and March 31, 2013. The exposure variables were prenatal maternal smoking, prenatal secondhand smoking, and postnatal secondhand smoking till 4 months, which were assessed by maternal notification form and exclusively classified into eight categories. The outcome variables were the incidence of asthma or atopic dermatitis in the respective children up to 3 years of age assessed by a checkup questionnaire. The association between the smoking exposures and the development of asthma or atopic dermatitis up to 3 years was examined using a generalized linear mixed model with odds ratios and 95% confidence intervals (CI). Additionally, multiple imputation methods were used for the missing covariates.Results　Of the 53,505 children, 27,210 (50.9%) were males and 26,218 (49.0%) were females. In total, 5,810 (10.9%) children were diagnosed with asthma and 4,964 (9.3%) with atopic dermatitis up to 3 years of their age. Compared to the children born to nonsmoking mothers during pregnancy and those without exposure to postnatal secondhand smoking, the adjusted odds ratio for the incidence of asthma up to 3 years of their age was found to be 2.04 (95% CI: 1.38-3.01) in children exposed to prenatal maternal smoking. Similarly, the adjusted odds ratio for the incidence of asthma in children exposed to maternal secondhand smoking during pregnancy was 1.12 (95% CI: 1.01-1.25) when compared with children who were never exposed to any smoking. Additionally, the adjusted odds ratio increased to 1.86 (95% CI: 1.42-2.44) in children exposed to both prenatal maternal smoking and secondhand smoking. In contrast, no statistical significance was observed among the smoking exposures and the incidence of atopic dermatitis in the children.Conclusions　Our study confirmed that prenatal maternal and secondhand smoking were associated with the incidence of asthma in children. These findings suggest a need to focus on smoking cessation by pregnant women as well as by family members living together to prevent the development of asthma in children.

Risk factors of venous thromboembolism in patients with nephrotic syndrome: a retrospective cohort study.

BACKGROUND: Nephrotic syndrome is associated with an increased risk of venous thromboembolism (VTE). However, the risk factors of VTE in nephrotic syndrome, other than hypoalbuminemia and severe proteinuria, are not well established. Therefore we aimed to investigate the risk factors of VTE in patients with nephrotic syndrome. METHODS: This retrospective cohort study used data from a Japanese nationwide claims database. We identified patients ≥18 years of age hospitalized with nephrotic syndrome. Through multivariable logistic regression, we determined the risk factors of VTE in patients with nephrotic syndrome during hospitalization. RESULTS: Of the 7473 hospitalized patients with nephrotic syndrome without VTE, 221 (3.0%) developed VTE. In the VTE group, 14 (6.3%), 11 (5.0%) and 198 (89.6%) patients developed pulmonary embolism, renal vein thrombosis and deep vein thrombosis, respectively. We found that female sex {odds ratio [OR] 1.39 [95% confidence interval (CI) 1.05-1.85]}, body mass index (BMI) ≥30 [OR 2.01 (95% CI 1.35-2.99)], acute kidney injury [AKI; OR 1.67 (95% CI 1.07-2.62)], sepsis [OR 2.85 (95% CI 1.37-5.93)], lupus nephritis [OR 3.64 (95% CI 1.58-8.37)] and intravenous corticosteroids use [OR 2.40 (95% CI 1.52-3.80)] were associated with a significantly higher risk of developing VTE. CONCLUSIONS: In patients with nephrotic syndrome, female sex, BMI ≥30, AKI, sepsis, lupus nephritis and intravenous corticosteroid use may help evaluate the risk of VTE.