Adverse Event Profile of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel Combination Therapy Based on JADER.

BACKGROUND/AIM: There have been advances in the development of immune checkpoint inhibitors for monotherapy and combination therapy with other anticancer agents in recent years. The combination of bevacizumab, carboplatin, and paclitaxel with atezolizumab, an anti-programmed death ligand 1 antibody (ABCP therapy), has been reported to be effective for treating non-small cell lung cancer. However, reports on its adverse events are limited. In this study, a survey and disproportionality analysis based on the Japanese Adverse Drug Event Report (JADER) database was conducted to elucidate the adverse event profile of ABCP therapy. MATERIALS AND METHODS: The reporting odds ratio (ROR) and information component were used as indicators for the disproportionality analysis. The ROR was also used to assess the changes in the reporting intensity with combination therapy, and the mutual exclusivity of the 95% confidence interval between the compared groups was considered. RESULTS: The reported adverse events of ABCP therapy mirrored those of the individual drugs that constituted it. ABCP therapy enhanced the reporting intensity of adverse events related to leukocytes and the skin, while decreased those related to interstitial lung disease and hepatic function abnormality as immune-related adverse events caused by atezolizumab, and gastrointestinal perforation caused by bevacizumab. CONCLUSION: Our analysis of data from the JADER database has revealed the adverse event profile of ABCP therapy. Our findings emphasize the importance of effectively managing febrile neutropenia and skin-related adverse events in ABCP therapy.

The vision for public health dietitians' skill improvement over the next 10 years in Japan: A qualitative study.

Objectives: To obtain the basis for developing a new human resource development program. We examined the association between their position type and their vision for skill improvement in the profession in the next 10 years. Study design: This was a qualitative study. Methods: In 2021, we conducted an exhaustive survey of Japanese public health dietitians working in Japanese local governments. Using qualitative content analysis, we analyzed the participants' descriptions of how the profession could improve their skills over the next 10 years. Results: Regardless of the participants' organization of employment or their target position type, seven common categories were extracted; [goals], [health promotion activities], [organizational activities], [evaluation from others], [cooperation], [skills to be acquired], and [means for improving skills]. Depending on the organization type, 35-40 subcategories were extracted from those who wanted to be staff, 35-38 subcategories from those who wanted to be supervisors, and 20-37 subcategories from those who wanted to be managers. Different subcategories were extracted to describe the difference between specialists and generalists in [goals]. Participants described challenges with [evaluation from others] and [collaboration], regardless of the target position type or [goals]. Conclusion: The vision for Japanese public health dietitians' skill improvement to achieve in the next 10 years describes challenges with business evaluation and collaborative work. However, participants differed across what skills they wanted to improve based on the direction of their careers. To offer public health dietitians learning content that connects with their desired direction, a new human resource development program needs to be considered.

Individual Learning Needs of Japanese Public Health Dietitians by Years of Experience in Health Promotion.

Lifelong education for dietitians in Japan is based mainly on competencies according to years of experience. Because learning content differs depending on the desired position and specialty, training programs that reflect the individual learning needs of public health dietitians are needed. This study aimed to assess the individual learning needs of public health dietitians via years of experience in health promotion. In 2021, an online survey of public health dietitians involved in health promotion in prefectures, designated cities, and other municipalities throughout Japan was conducted. Years of experience in health promotion were categorized as early (<10 years), mid-career (10-19 years), and leadership (≥20 years) periods. To ascertain individual learning needs, the survey asked about respondents' desired final position, career path, and skills they felt they needed to improve in the future. Of the 1649 public health dietitians analyzed, all administrative categories preferred to work as public health generalists in mid-career or leadership periods rather than in the early period. In municipalities, more public health dietitians across all experience categories selected "professional competence", such as knowledge in specialized areas and nutritional guidance techniques. It was suggested that public health dietitians in the mid-career and leadership periods have individual learning needs, in both nutrition specialists and public health generalists.

Exposure to brefeldin A induces unusual expression of hybrid- and complex-type free N-glycans in HepG2 cells.

This study determined the effect of brefeldin A (BFA) on the free N-glycomic profile of HepG2 cells to better understand the effect of blocking intracellular vesicle formation and transport of proteins from the endoplasmic reticulum to the Golgi apparatus. A series of exoglycosidase- and endoglycosidase-assisted analyses clarified the complex nature of altered glycomic profiles. A key feature of BFA-mediated alterations in Gn2-type glycans was the expression of unusual hybrid-, monoantennary- and complex-type free N-glycans (FNGs). BFA-mediated alterations in Gn1-type glycans were characterized by the expression of unusual hybrid- and monoantennary-FNGs, without significant expression of complex-type FNGs. A time course analysis revealed that sialylated hybrid- and complex-type Gn2-type FNGs were generated later than asialo-Gn2-type FNGs, and the expression profiles of Gn2-type FNGs and N-glycans were found to be similar, suggesting that the metabolic flux of FNGs is the same as that of protein-bound N-glycans. Subcellular glycomic analysis revealed that almost all FNGs were detected in the cytoplasmic extracts. Our data suggest that hybrid-, monoantennary- and complex-type Gn2-type FNGs were cleaved from glycoproteins in the cytosol by cytosolic PNGase, and subsequently digested by cytosolic endo-ß-N-acetylglucosaminidase (ENGase) to generate Gn1-type FNGs. The substrate specificity of ENGase explains the limited expression of complex Gn1 type FNGs.

The association of low serum salivary and pancreatic amylases with the increased use of lipids as an energy source in non-obese healthy women.

OBJECTIVE: It is unknown whether low serum levels of salivary and pancreatic amylases are associated with the high combustion of carbohydrates or lipids for energy. Elevated blood ketones and a low respiratory quotient (RQ) can reflect the preferential combustion of lipids relative to carbohydrates. Therefore, using the data from our previous study, we investigated if low levels of serum amylases were associated with a high serum ketone level and low RQ in 60 healthy non-obese young women aged 20-39 years old. RESULTS: Serum ketones [3-hydroxybutyric acid (3-HBA) and acetoacetic acid (AA)] were inversely correlated with RQs, but not body mass index (BMI) or glycated haemoglobin (HbA1c) levels. Logistic regression analysis showed that high levels of serum ketones (3-HBA ≥ 24 µmol/L and AA ≥ 17 µmol/L) and a low RQ (< 0.766) were significantly associated with low serum salivary (< 60 U/L) and pancreatic (< 29 U/L) amylase levels, respectively. These associations were not altered by further adjustments for age, BMI, HbA1c, and estimated glomerular filtration rate. These results confirm the high combustion of lipids for energy in individuals with low serum amylase levels, suggesting a close relationship between circulating amylases and internal energy production.

Copy Number Variation of the Salivary Amylase Gene and Glucose Metabolism in Healthy Young Japanese Women.

BACKGROUND: Many studies have shown that low copy number variation (CNV) of the salivary amylase gene (AMY1) and low serum amylase concentration are associated with impaired glucose metabolism and obesity. We aimed to clarify the conflicting results of previous studies by examining AMY1 expression and metabolic indices in a homogenous group of healthy participants. METHODS: Sixty healthy non-obese young Japanese women aged 20 - 39 years were examined for AMY1 CNV, salivary amylase, body mass index (BMI) and serum parameters including glycated hemoglobin (HbA1c), ketones, and total, salivary and pancreatic amylase. Respiratory quotient at rest and changes in blood glucose after starch loading were also examined. RESULTS: AMY1 CNV (range, 4 - 14) and the level of serum salivary amylase were correlated inversely with HbA1c (r = -0.36, P = 0.003 and r = -0.30, P = 0.02, respectively), whereas the percentage of serum salivary amylase in total serum amylase was positively correlated with blood glucose at 30 and 45 min after starch loading (r = 0.38, P = 0.004 and r = 0.27, P = 0.04, respectively). The level of serum total amylase, but not AMY1 CNV, was correlated inversely with BMI (r = -0.29, P = 0.02). Logistic regression analysis showed that low AMY1 CNV (4 - 7) was significantly associated with an HbA1c of ≥ 5.4% (34 mmol/mol) even after adjustment for age, BMI and energy consumption, compared with high AMY1 CNV (8 - 14). CONCLUSIONS: Although a higher percentage of serum salivary amylase was associated with higher levels of blood glucose at the early stage after starch loading, low AMY1 CNV was associated with chronic unfavorable glucose metabolism in healthy non-obese young women in Japan.

Analysis of amino acid profiles of blood over time and biomarkers associated with non-alcoholic steatohepatitis in STAM mice.

The changes in free amino acid (AA) levels in blood during the progression from non-alcoholic steatohepatitis (NASH) to hepatocellular carcinoma (HCC) are unclear. We investigated serum AA levels, along with biochemical and histological events, in a mouse model of NASH. We induced NASH in male C57BL/6J mice with a streptozotocin injection and high-fat diet after 4 weeks of age (STAM group). We chronologically (6, 8, 10, 12, and 16 weeks, n=4-12 mice/group) evaluated the progression from steatohepatitis to HCC by biochemical and histological analyses. The serum AA levels were determined using an AA analyzer. Serum aspartate aminotransferase and alanine aminotransferase levels were higher in the STAM group than in the normal group (non-NASH-induced mice). Histological analysis revealed that STAM mice had fatty liver, NASH, and fibrosis at 6, 8, and 10 weeks, respectively. Moreover, the mice exhibited fibrosis and HCC at 16 weeks. The serum branched-chain AA levels were higher in the STAM group than in the normal group, especially at 8 and 10 weeks. The Fischer ratio decreased at 16 weeks in the STAM group, with increasing aromatic AA levels. These results suggested that this model sequentially depicts the development of fatty liver, NASH, cirrhosis, HCC, and AA metabolism disorders within a short experimental period. Additionally, serum amyloid A was suggested to be a useful inflammation biomarker associated with NASH. We believe that the STAM model will be useful for studying AA metabolism and/or pharmacological effects in NASH.

Association between paraben exposure and menstrual cycle in female university students in Japan.

Parabens have been known to have estrogenic activity in many in vivo and in vitro studies and biomonitoring data indicated ubiquitous exposure in general populations. However, there are few human studies on reproductive effects of parabens. In this study, menstrual cycle length and its intra-individual variation were investigated by bleeding record over the period of 5 months and urinary concentrations of parabens were measured for 128 female Japanese university students. We found significantly negative relationships between menstrual cycle length and urinary estrogen-equivalent total paraben (odds=0.73, 95% CI 0.56-0.96) and butyl paraben concentrations (odds=0.83, 0.70-0.99), which indicated shortened cycle length in women with high urinary paraben concentrations. This study indicated that paraben exposure at not excessive levels is associated with menstrual cycle length or its variability among general female subjects. These results suggest a possibility that parabens exposure is one of the environmental causes of human reproductive problem.

[Menstrual cycle length and source of its variation in female university students majoring in nursing sciences].

OBJECTIVES: To acquire fundamental knowledge on menstrual cycle and its intraindividual variation in healthy Japanese female students and their association with biological attributes, lifestyle and food habit. METHODS: We asked female students of a nursing school to keep a diary of their menstruation over 5 consecutive months and to fill a questionnaire on their biological attributes, lifestyle and consumption frequency of some food items during the period from November 2012 to January 2014. RESULTS: The mean±standard deviation (SD) of cycle lengths of 180 women (20.4±0.9 yrs) was 34.2±10.5 days. Of these 180 women, 141 had a cycle length within the normal range (25-38 days) while 10 had a shorter cycle and 20 had a longer cycle. The intraindividual variations of the cycle, defined as "range" (difference between the longest and shortest cycles of an individual) and "SD" (SD of mean of multiple lengths within an individual), were 11.4±10.3 and 7.9±11.8 days, respectively. Of 177 women, 73 and 109 had normal range and SD (≤6 days), respectively. The mean age of women with long cycles was older than that of women with short cycle (Kruscal-Wallis test, p<0.05), and women with greater intraindividual variations were older than those with small variations (U-test, p<0.05). Subjects with menstrual pain had greater "SD" than did those without pain (Chi-square test, p<0.05). Neither lifestyle nor food habit was associated with the length and intraindividual variations of the menstrual cycle. CONCLUSIONS: The present results provided fundamental knowledge on the length and intraindividual variations of the menstrual cycle and the sources of these variations in female Japanese university students.

Association of antimüllerian hormone levels with menstrual-cycle type and dysmenorrhea in young asymptomatic women.

OBJECTIVE: To examine the association between antimüllerian hormone (AMH) levels and menstrual-cycle and lifestyle characteristics among young Japanese women. DESIGN: Cross-sectional study. SETTING: University. PATIENT(S): Female students aged 20-22 years (n=65) who had never used oral contraceptives. INTERVENTION(S): Participants completed a questionnaire on reproductive and lifestyle characteristics, and kept a menstrual-cycle diary for 5 consecutive months. Serum AMH was measured once during the study period. MAIN OUTCOME MEASURE(S): Serum AMH concentration. RESULT(S): Compared with women with very mild menstrual pain, serum AMH concentration was 49.6% (95% CI 6.5%-72.8%) lower among women with severe menstrual pain. Higher AMH concentration was associated with irregular menstrual cycles. Even after adjusting for menstrual-cycle regularity and its interaction, more-severe menstrual pain was associated with significantly lower AMH concentration. CONCLUSION(S): Circulating AMH concentration was significantly lower among young Japanese women who had more-severe menstrual pain. Underlying physiological mechanisms need to be addressed in future studies.