Incidence of sodium-glucose cotransporter-2 inhibitor-associated perioperative ketoacidosis in surgical patients: a prospective cohort study.

PURPOSE: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are commonly prescribed anti-diabetic medications with various beneficial effects; however, they have also been associated with ketoacidosis. The aim of this study was to determine the incidence of SGLT2i-associated perioperative ketoacidosis (SAPKA) in surgical patients. METHODS: We conducted a multicenter, prospective cohort study across 16 centers in Japan, enrolling surgical patients with diabetes who were prescribed SGLT2is between January 2021 and August 2022. Patients were monitored until the third postoperative day to screen for SAPKA, defined as urine ketone positivity with a blood pH of < 7.30 and HCO3 level ≤ 18.0 mEq/L, excluding cases of respiratory acidosis. RESULTS: In total, 759 of the 762 evaluated patients were included in the final analysis. Among these, three patients (0.40%) had urine ketones with a blood pH of < 7.30; however, blood gas analysis revealed respiratory acidosis in all three, and none of them was considered to have SAPKA. The estimated incidence of SGLT2i-associated postoperative ketoacidosis was 0% (95% confidence interval, 0%-0.4%). CONCLUSIONS: The observed incidence of SAPKA in our general surgical population was lower than expected. However, given that the study was observational in nature, interpretation of study results warrants careful considerations for biases.

A rad50 germline mutation induces tumorigenesis and ataxia-telangiectasia phenotype in a transparent medaka model.

The MRE11A-RAD50-NBS1 complex activates the ataxia-telangiectasia mutated (ATM) pathway and plays a central role in genome homeostasis. The association of RAD50 mutations with disease remains unclear; hence, we adopted a medaka rad50 mutant to demonstrate the significance of RAD50 mutation in pathogenesis using the medaka as an experimental animal. A 2-base pair deletion in the rad50 gene was introduced into transparent STIII medaka using the CRISPR/Cas9 system. The mutant was analyzed histologically for tumorigenicity and hindbrain quality, as well as for swimming behavior, to compare with existing ATM-, MRE11A-, and NBS1-mutation-related pathology. Our results revealed that the medaka rad50 mutation concurrently reproduced tumorigenesis (8 out of 10 rad50Δ2/+ medaka), had a decrease in median survival time (65.7 ± 1.1 weeks in control vs. 54.2 ± 2.6 weeks in rad50Δ2/+ medaka, p = 0.001, Welch's t-test), exhibited semi-lethality in rad50Δ2/Δ2 medaka and most of the major ataxia-telangiectasia phenotypes, including ataxia (rheotaxis ability was lower in rad50Δ2/+ medaka than in the control, Mann-Whitney U test, p < 0.05), and telangiectasia (6 out of 10 rad50Δ2/+ medaka). The fish model may aid in further understanding the tumorigenesis and phenotype of ataxia-telangiectasia-related RAD50 germline mutations and in developing novel therapeutic strategies against RAD50 molecular disorders.

Excised human larynx in N-vinyl-2-pyrrolidone-embalmed cadavers can produce voiced sound by pliable vocal fold vibration.

Tissue-hardening effect and health-hazard issue of formaldehyde (FA) have long been a great disadvantage of this conventional fixative in anatomical research. We recently developed a FA-free embalming method for cadavers which utilizes N-vinyl-2-pyrrolidone (NVP) and enables assessment of motion kinetics by maintaining the softness of embalmed tissue. By assessing the feasibility of NVP-embalmed tissue to mimic vocalization, this study aimed to prove the potential of embalmed cadavers, which have previously been used only for the understanding of anatomical morphology, for the assessment of precise motion physiology in the human body. Ten cadavers embalmed in NVP (n = 6) and FA (n = 4) were incorporated in this study. Excised larynges underwent experimental phonation to mimic vocalization with fast and pliable vibration of vocal folds. High-speed digital imaging was utilized for the assessment of vocal fold vibration. Furthermore, acoustic analysis of the voiced sound, and reproducibility examination were also performed. Regular vocal fold vibrations successfully produced voiced sounds during experimental phonation using NVP-embalmed larynges. The vibratory frequency, vibration amplitude, and stretch rate of the vocal folds were comparable to those of living humans. Six months after the first experiment, the vocal parameters were reproduced, to suggest the long-term preservation potential of our NVP-embalming technique. On the other hand, neither voiced sound nor vocal fold vibration were observed in FA-embalmed larynges. This novel embalming technique could pioneer the next era to utilize embalmed cadavers for the examination of motion physiology in the human body.

Multicentre prospective observational study of sodium-glucose cotransporter-2 inhibitor-associated postoperative ketoacidosis: the SAPKA study protocol.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antihyperglycaemic agents that promote urinary glucose excretion in the renal proximal tubule and have cardio-protective and renal-protective properties. However, there are several safety concerns related to increased risks of hypoglycaemic, urinary tract infections and ketoacidosis. Ketoacidosis is a potentially fatal complication that often presents as euglycaemic ketoacidosis during SGLT2 inhibitor treatment. Furthermore, invasive treatment and related surgical stress may increase the risk of ketogenesis. Therefore, this study aims to clarify the incidence of SGLT2 inhibitor-associated postoperative ketoacidosis (SAPKA) among patients who are receiving SGLT2 inhibitors and undergoing surgery under general anaesthesia. METHODS AND ANALYSIS: This multicentre, prospective, observational study will recruit 750 adult Japanese patients with diabetes who are receiving SGLT2 inhibitors and undergoing surgery under general anaesthesia. Urine samples will be collected on postoperative days 0, 1, 2 and 3. Blood gas analysis will be performed when urine ketone positivity is detected. The incidence of postoperative ketoacidosis will be identified based on urine ketone positivity and a blood pH of ≤7.3. The study will also collect data to identify risk factors for SAPKA. ETHICS AND DISSEMINATION: The study protocol has been approved by the ethics committee of Kyorin University (approval number: 785, 26 October 2020) and local ethical approval will be required at each participating centre. Study findings will be submitted to peer-reviewed journals and abstracts will be submitted to relevant national and international meetings. TRIAL REGISTRATION NUMBER: UMIN000042795.

Polyethylene microbeads are more critically toxic to the eyes and reproduction than the kidneys or growth in medaka, Oryzias latipes.

Many studies using experimental and wild animals have reported negative effects of microplastic beads (MPs) ingestion. However, data regarding the lowest observed adverse effect levels (LOAELs) of MPs remain limited. Our aim was to evaluate the adverse effect levels of polyethylene MPs (10-63 µm diameter) with respect to growth, reproduction, and the eyes and kidneys of medaka (Oryzias latipes) under breeding conditions to contribute to future research involving LOAEL determinations. Fish were exposed to 0.009 mg-MPs (approximately 1000 particles)/L to 0.32 mg-MPs (approximately 40,000 particles)/L for 12 weeks. The eyes and kidneys were evaluated by histopathologic analysis. Although histologic analyses indicated an absence of MPs in the tissues, the eyes and kidneys as well as reproduction were adversely affected by increasing MP concentrations. The number of spawned eggs decreased, and changes were noted in the eyes of fish exposed to ≥0.032 mg-MPs/L under breeding conditions. The eyes exhibited thinning of the optic nerve fiber layer and dilatation of retinal capillaries compared with medaka not treated with MPs. Changes in the kidneys were observed in fish exposed to ≥0.065 mg-MPs/L. The mesangial matrix in the glomerulus of the kidneys was expanded compared with non-treated medaka, suggesting a deterioration in renal function. Analyses of an oxidative stress marker in the tissues indicated that lesion progression was associated with increased oxidative stress. Furthermore, a comparison of adverse effect levels suggested that MPs were more toxic to the eyes and reproduction than the kidneys or growth. Our data should prove useful for determining the LOAELs of polyethylene beads on vertebrates and enhance understanding of the mechanism underlying the biological toxicity of polyethylene MPs.

Ingestion of polyethylene microbeads affects the growth and reproduction of medaka, Oryzias latipes.

Research using various species of wild and cultured fish has identified negative effects of short-term exposure to microbeads. Although wild animals might be contaminated with microbeads and/or other pharmaceuticals, data regarding the long-term effects remain limited. To clearly elucidate the effects of microbeads, studies of long-term exposure using animal models are necessary. Our aim was to elucidate the effects of microbeads alone on the growth and fecundity of medaka following long-term exposure (12 weeks). In experiment 1, fish groups (except controls) were temporarily exposed to polyethylene microbeads (10-63 µm diameter) a low dose of 0.065 microbeads-mg/L and high dose of 0.65 microbeads-mg/L. In experiment 2, see-through medaka and fluorescent polyethylene microbeads (10-45 µm diameter) were used to estimate the retention time of ingested microbeads in the digestive tract, which was 4-9 days. The low dose of microbeads did not affect growth but did decrease the number of eggs and the hatching rate. The high dose decreased growth, the number of eggs, and hatching rate. Growth differences were recognized for the first time at 7 weeks, and differences in the number of eggs at 12 weeks. Thus, long-term tests using medaka indicated that microbeads per se exhibit growth inhibition and reproductive toxicity. These effects could be associated with nutritional factors resulting from the long retention time of microbeads in the digestive tract. We also determined the dose that affects only fecundity. This suggests that normal growth of medaka in the wild does not mean the environment is free from microbead contamination. We are thus attempting to identify new biological indexes for monitoring the status of microbead contamination using our system.

Longevity-associated mitochondrial DNA 5178 C/A polymorphism modifies effect of aging on renal function in male Japanese health checkup examinees: an exploratory cross-sectional study.

BACKGROUND: Mitochondrial DNA 5178 (Mt5178) C/A polymorphism is reportedly associated with longevity in the Japanese population. The objective of this study was to investigate whether Mt5178 C/A polymorphism influences the effect of physiological aging on renal function in male Japanese health checkup examinees. METHODS: A total of 404 male subjects (mean age ± SD, 53.9 ± 7.8 years; range, 29-76 years) were selected from among individuals visiting the hospital for regular medical checkups. After Mt5178 C/A genotyping, a cross-sectional study assessing the joint effects of Mt5178 C/A polymorphism and aging on renal function was then conducted. Renal function was evaluated by estimated glomerular filtration rate (eGFR). Subjects were divided into three age groups (< 50, 50-59, ≥ 60 years). RESULTS: In simple linear regression analysis, a significant negative association between aging and eGFR was observed in both Mt5178C and Mt5178A genotypic men (P < 0.001 and P = 0.003, respectively). However, in multiple linear regression analysis, a significant effect of aging on reduced eGFR was observed only in Mt5178C genotypic men (P < 0.001). Logistic regression analysis showed that, in the case of reduced eGFR defined as < 75 mL/min/1.73 m2, reduced eGFR was dependent on aging in both Mt5178C and Mt5178A genotypic men (P for trend < 0.001 and P for trend = 0.002, respectively). After adjusting for smoking status and alcohol consumption, reduced eGFR was also dependent on aging in both Mt5178C and Mt5178A genotypic men (P for trend < 0.001 and P for trend = 0.014, respectively). However, in reduced eGFR defined as < 90 mL/min/1.73 m2, reduced eGFR was dependent on aging only in Mt5178C genotypic men (P for trend < 0.001). CONCLUSIONS: This cross-sectional study suggests that Mt5178 C/A polymorphism modulates the effects of physiological aging on kidney function in Japanese men.

For making a declaration of countermeasures against the falling birth rate from the Japanese Society for Hygiene: summary of discussion in the working group on academic research strategy against an aging society with low birth rate.

In 1952, the Japanese Society for Hygiene had once passed a resolution at its 22nd symposium on population control, recommending the suppression of population growth based on the idea of cultivating a healthier population in the area of eugenics. Over half a century has now passed since this recommendation; Japan is witnessing an aging of the population (it is estimated that over 65-year-olds made up 27.7% of the population in 2017) and a decline in the birth rate (total fertility rate 1.43 births per woman in 2017) at a rate that is unparalleled in the world; Japan is faced with a "super-aging" society with low birth rate. In 2017, the Society passed a resolution to encourage all scientists to engage in academic researches to address the issue of the declining birth rate that Japan is currently facing. In this commentary, the Society hereby declares that the entire text of the 1952 proposal is revoked and the ideas relating to eugenics is rejected. Since the Society has set up a working group on the issue in 2016, there have been three symposiums, and working group committee members began publishing a series of articles in the Society's Japanese language journal. This commentary primarily provides an overview of the findings from the published articles, which will form the scientific basis for the Society's declaration. The areas we covered here included the following: (1) improving the social and work environment to balance between the personal and professional life; (2) proactive education on reproductive health; (3) children's health begins with nutritional management in women of reproductive age; (4) workplace environment and occupational health; (5) workplace measures to counter the declining birth rate; (6) research into the effect of environmental chemicals on sexual maturity, reproductive function, and the children of next generation; and (7) comprehensive research into the relationship among contemporary society, parental stress, and healthy child-rearing. Based on the seven topics, we will set out a declaration to address Japan's aging society with low birth rate.

[Political Measures against Declining Birthrate-Implication of Good Family Policies and Practice in Sweden or France].

Although the birthrate greatly declined from the 1960s to the mid-1970s amongst many developed countries, the downturn has steadily been reversed by promoting women's rights and reviewing family policies in some European countries such as Sweden and France. The current total fertility rate in Sweden or France is approximately around 1.9 children per woman. The favorable state can be partly explained by the active family policies of these countries. The government of Sweden has implemented a wide range of measures including tax allowances, childcare services, and other subsidies, as well as an18 month parental leave to be shared between mothers and fathers. The government of France has expanded childcare and provided incentives by increasing childcare/family benefits with each subsequent child.In Japan, the fertility rate has changed from a downward trend to an upward trend, but only very slightly over the last decade. The legislative systems and enforcement remain totally inadequate to maintain stable a fertility rate. The Japanese government should try to change the social security/labor policies into more active and generous ones, with enhancement of economic support and promotion of work-life balance. Other attempts including removing barriers to encourage the youth to start a family are needed to overcome declining birth rates in Japan.

NADH Dehydrogenase Subunit-2 237 Leu/Met Polymorphism Influences the Association of Coffee Consumption with Serum Chloride Levels in Male Japanese Health Checkup Examinees: An Exploratory Cross-Sectional Analysis.

BACKGROUND: Nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit-2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism has been shown to modify the association of coffee consumption with the risk of hypertension, dyslipidemia, and abnormal glucose tolerance, and low serum chloride levels have been shown to be associated with all-cause and cardiovascular disease mortality. Therefore, the purpose of the present study was to investigate whether ND2-237 Leu/Met polymorphism influences the association of coffee consumption with serum chloride levels in male Japanese health checkup examinees. METHODS: From among individuals visiting the hospital for a regular medical checkup, 402 men (mean age ± standard deviation, 53.9 ± 7.8 years) were selected for inclusion in the study. After ND2-237 Leu/Met genotyping, we conducted an exploratory cross-sectional study to examine the combined association of ND2-237 Leu/Met polymorphism and coffee consumption with serum electrolyte levels. RESULTS: After adjusting for age, body mass index, habitual smoking, alcohol consumption, green tea consumption, and antihypertensive medication, coffee consumption significantly increased serum chloride levels (p for trend = 0.001) in men with the ND2-237Leu genotype. After these adjustments, the odds ratios (ORs) for low levels of serum chloride, defined as <100 mEq/L, were found to be dependent on coffee consumption (p for trend = 0.001). In addition, the OR for low levels of serum chloride was significantly lower in men with the ND2-237Leu genotype who consumed ≥4 compared with <1 cup of coffee per day (OR = 0.096, 95% confidence interval = 0.010⁻0.934; p = 0.044). However, neither serum chloride levels nor risk of low levels of serum chloride appeared to be dependent on coffee consumption. CONCLUSIONS: The results suggest that ND2-237 Leu/Met polymorphism modifies the association of coffee consumption with serum chloride levels in middle-aged Japanese men.

Assessment of Cardiac Autonomic Function in Relation to Methylmercury Neurotoxicity.

After the European Food Safety Authority reviewed reports of methylmercury and heart rate variability (HRV) in 2012, the panel concluded that, although some studies of cardiac autonomy suggested an autonomic effect of methylmercury, the results were inconsistent among studies and the implications for health were unclear. In this study, we reconsider this association by adding a perspective on the physiological context. Cardiovascular rhythmicity is usually studied within different frequency domains of HRV. Three spectral components are usually detected; in humans these are centered at <0.04 Hz, 0.15 Hz (LF), and 0.3 Hz (HF). LF and HF (sympathetic and parasympathetic activities, respectively) are evaluated in terms of frequency and power. By searching PubMed, we identified 13 studies examining the effect of methylmercury exposure on HRV in human populations in the Faroe Islands, the Seychelles and other countries. Considering both reduced HRV and sympathodominant state (i.e., lower HF, higher LF, or higher LF/HF ratio) as autonomic abnormality, eight of them showed the significant association with methylmercury exposure. Five studies failed to demonstrate any significant association. In conclusion, these data suggest that increased methylmercury exposure was consistently associated with autonomic abnormality, though the influence of methylmercury on HRV (e.g., LF) might differ for prenatal and postnatal exposures. The results with HRV should be included in the risk characterization of methylmercury. The HRV parameters calculated by frequency domain analysis appear to be more sensitive to methylmercury exposure than those by time domain analysis.

[Dilemma of Environmental Health Research].

This article presents not only a brief overview of birth cohort studies focusing on environmental health in which the associations between health and environment were examined, but also a tentative plan to apply epidemiological data to benchmark dose calculation. According to the preceding studies, the checkpoints to be scrutinized when a result is not consistent with those of other researchers are as follows: (1) whether the study included all crucial confounders, (2) whether it included any exposure marker or confounder with a U-shaped dose-response curve, (3) whether the outcome measure was conducted by two or more examiners that might lead to measurement bias, (4) whether such examiners picked up information about exposure levels of the subjects before measuring the endpoints, and (5) whether subjects with different genetic factors were included in the analysis. In addition, (6) researchers conducting a children's study on developmental effects due to toxic substances must keep in mind that the impact of prenatal methylmercury exposure, independent of postnatal exposure, may continue for at least seven years. (7) When an environmental health research emphasizes to be population-based study, the levels of exposure to environmental chemical substances in developed countries with strict environmental regulations may be too low to examine a dose-response relationship for critical dose estimation. Such risk assessment should be carried out among the subjects with a wide range of exposure levels.

Recent Epidemiological Studies on Methylmercury, Mercury and Selenium.

More than sixty years has passed since the outbreak of Minamata disease, and high-level methylmercury contaminations now seem nonexistent in Japan. However, mercury has been continuously discharged from natural sources and industrial activities, and the health effects on children susceptible to methylmercury exposure at low levels, in addition to mercury contamination from mercury or gold mining areas in developing countries, become a worldwide concern. In this article, we provide a recent overview of epidemiological studies regarding methylmercury and mercury. The following findings were obtained. (1) Many papers on exposure assessment of methylmercury/mercury have been published since the Minamata Convention on Mercury was adopted in 2013. (2) The most crucial problem is child developmental neurotoxicity resulting from prenatal exposure to methylmercury, but its precise assessment seems to be difficult because most of such effects are neither severe nor specific. (3) Several problems raised in birth cohort studies (e.g., whether IQ deficits due to prenatal methylmercury exposure remain when the children become adults, or whether the postnatal exposure at low levels also causes such adverse effects in children) remain unsolved. (4) Concurrent exposure models of methylmercury, lead, polychlorinated biphenyls, aresenic, and organochlorine pesticides, as well as possible antagonists such as polyunsaturated fatty acids and selenium, should be considered in the study design because the exposure levels of methylmercury are extremely low in developed countries. (5) Further animal experiments and molecular biological studies, in addition to human studies, are required to clarify the mechanism of methylmercury toxicity.

Mitochondrial DNA 5178 C/A polymorphism modulates the effects of coffee consumption on elevated levels of serum liver enzymes in male Japanese health check-up examinees: an exploratory cross-sectional study.

BACKGROUND: Longevity-associated mitochondrial DNA 5178 cytosine/adenine (Mt5178 C/A) polymorphism modulates the effects of coffee consumption on the risk of hypertension, dyslipidemia, and abnormal glucose tolerance. The objective of this study was to investigate whether Mt5178 C/A polymorphism modifies the effects of coffee consumption on abnormally elevated levels of serum liver enzymes in male Japanese health check-up examinees. METHODS: A total of 421 male subjects (mean age ± SD, 54.1 ± 7.7 years) were selected from among individuals visiting the hospital for regular medical check-ups. After Mt5178 C/A genotyping, a cross-sectional study assessing the joint effects of Mt5178 C/A polymorphism and coffee consumption on elevated levels of serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), and serum gamma-glutamyl transpeptidase (GGT) was then conducted. RESULTS: For men with Mt5178C, after adjustment for age, body mass index, alcohol consumption, habitual smoking, green tea consumption, antihypertensive treatment, and antidiabetic treatment, elevated levels of serum AST, as defined as ≥30 U/L; those of serum ALT, as defined as ≥25 U/L; or those of serum GGT, as defined as ≥60 or >51 U/L, may depend on coffee consumption (P for trend = 0.013, P for trend <0.001, P for trend = 0.002, and P for trend <0.001, respectively). On the other hand, no significant joint effects of Mt5178A genotype and coffee consumption on elevated levels of serum liver enzymes were observed. CONCLUSIONS: The present results suggest that Mt5178 C/A polymorphism modifies the effects of coffee consumption on abnormally elevated levels of serum liver enzymes in male Japanese health check-up examinees.