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Aims/Introduction To investigate the national trend in the prescription of first‐line non‐insulin antidiabetic agents and total medical costs (TMCs) after prescribing the drug in Japanese patients with type 2 diabetes. Materials and Methods Using the National Database of Health Insurance Claims and Specific Health Check‐ups of Japan covering almost the entire Japanese population, we calculated the proportion of each antidiabetic drug from 2014 to 2017, and determined the factors associated with drug selection. The TMCs in the first year after starting the drugs were calculated, and factors associated with the costs were also determined. Results Among 1,136,723 new users of antidiabetic agents, dipeptidyl peptidase‐4 inhibitors were the most prescribed (65.1%), followed by biguanides (15.9%) and sodium–glucose cotransporter 2 inhibitors (7.6%). Sodium–glucose cotransporter 2 inhibitor and biguanide use increased during 2014–2017 (2.2%–11.4% and 13.7%–17.2%, respectively), whereas the others decreased. Biguanides were not prescribed at all in 38.2% of non‐Japan Diabetes Society‐certified facilities. The TMCs were the lowest among those who started with biguanides. Fiscal year, age, sex, facility, number of beds and comorbidities were associated with drug choice and TMCs. There were wide regional variations in the drug choice, but not in the TMCs. Conclusions Unlike in the USA and Europe, dipeptidyl peptidase‐4 inhibitor is the most prescribed first‐line medication for type 2 diabetes patients in Japan, while there is a wide variation in the drug choice by facility‐type and prefecture. In this large‐scale, nationwide study of Japanese patients with type 2 diabetes, dipeptidyl peptidase‐4 inhibitors were the most prescribed followed by biguanides, with a wide variation in the drug choice by facility and prefecture. The total medical costs were the lowest among patients who started with biguanides.

Large bowel preparation may cause a substantial change in the gut microbiota and metabolites. Here, we included a bowel prep group and a no-procedure control group and evaluated the effects of bowel prep on the stability of the gut microbiome and metabolome as well as on recovery. Gut microbiota and metabolome compositions were analyzed by 16S rRNA sequencing and capillary electrophoresis time-of-flight mass spectrometry, respectively. Analysis of coefficients at the genus and species level and weighted UniFrac distance showed that, compared with controls, microbiota composition was significantly reduced immediately after the prep but not at 14 days after it. For the gut metabolome profiles, correlation coefficients between before and immediately after the prep were significantly lower than those between before and 14 days after prep and were not significantly different compared with those for between-subject differences. Thirty-two metabolites were significantly changed before and immediately after the prep, but these metabolites recovered within 14 days. In conclusion, bowel preparation has a profound effect on the gut microbiome and metabolome, but the overall composition recovers to baseline within 14 days. To properly conduct studies of the human gut microbiome and metabolome, fecal sampling should be avoided immediately after bowel prep.

Indigenous bacteriophage communities (virome) in the human gut have a huge impact on the structure and function of gut bacterial communities (bacteriome), but virome variation at a population scale is not fully investigated yet. Here, we analyse the gut dsDNA virome in the Japanese 4D cohort of 4198 deeply phenotyped individuals. By assembling metagenomic reads, we discover thousands of high-quality phage genomes including previously uncharacterised phage clades with different bacterial hosts than known major ones. The distribution of host bacteria is a strong determinant for the distribution of phages in the gut, and virome diversity is highly correlated with anti-viral defence mechanisms of the bacteriome, such as CRISPR-Cas and restriction-modification systems. We identify 97 various intrinsic/extrinsic factors that significantly affect the virome structure, including age, sex, lifestyle, and diet, most of which showed consistent associations with both phages and their predicted bacterial hosts. Among the metadata categories, disease and medication have the strongest effects on the virome structure. Overall, these results present a basis to understand the symbiotic communities of bacteria and their viruses in the human gut, which will facilitate the medical and industrial applications of indigenous viruses. Here, Nishijima et al . perform a large-scale analysis of the human gut virome in the Japanese 4D cohort of 4198 deeply phenotyped individuals, revealing thousands of bacteriophage genomes, virus-bacteria interactions, and describing associations with various host and environmental factors.

Dynamic metabolic changes occur in the liver during the transition between fasting and feeding. Here we show that transient ER stress responses in the liver following feeding terminated by Sdf2l1 are essential for normal glucose and lipid homeostasis. Sdf2l1 regulates ERAD through interaction with a trafficking protein, TMED10. Suppression of Sdf2l1 expression in the liver results in insulin resistance and increases triglyceride content with sustained ER stress. In obese and diabetic mice, Sdf2l1 is downregulated due to decreased levels of nuclear XBP-1s, whereas restoration of Sdf2l1 expression ameliorates glucose intolerance and fatty liver with decreased ER stress. In diabetic patients, insufficient induction of Sdf2l1 correlates with progression of insulin resistance and steatohepatitis. Therefore, failure to build an ER stress response in the liver may be a causal factor in obesity-related diabetes and nonalcoholic steatohepatitis, for which Sdf2l1 could serve as a therapeutic target and sensitive biomarker. Endoplasmic reticulum (ER) stress has been proposed to play a role in metabolic diseases. Here, Sasako and colleagues identify stromal cell-derived factor 2 like 1 (Sdf2l1) as a regulator of the ER stress response to feeding in the liver, and suggest that its downregulation may promote diabetes and hepatic steatosis in humans.

Thyrotoxic periodic paralysis (TPP) is characterized by muscle paralysis and significant intracellular potassium movement resulting in hypokalemia. Since TPP is a rare condition, only a few studies have explicated the clinical characteristics of patients with this disease. This study aimed to elucidate the clinical characteristics of patients with TPP by comparing them with those with thyrotoxicosis without paralysis (non-TPP) and sporadic periodic paralysis (SPP). This was a single-center retrospective cohort study. Clinical data of patients with hyperthyroidism (n = 62) or periodic paralysis (n = 92) who were emergently admitted to our hospital was extracted from the electronic medical records and analyzed. All patients in the TPP group (15 males and 2 females) had Graves' disease, with 14 being newly diagnosed. The average serum potassium level on admission was 2.3±0.75 mEq/L. No significant correlation was observed among serum potassium level, amount of potassium required for normalization, and thyroid hormone levels. The TPP group showed significantly younger age, higher male ratio and body mass index (BMI), and lower serum potassium and phosphorus levels than the non-TPP group, which comprised 36 patients with Graves' disease. No significant differences were observed between the TPP and SPP (n = 11) groups in terms of age, sex, BMI, serum electrolyte levels, potassium requirement for normalization, and recovery time. Considering that most patients with TPP have undiagnosed Graves' disease, distinguishing TPP from SPP based on clinical information and course alone is difficult in emergency settings. Therefore, for early detection and launch of specific treatment of Graves' disease, screening for thyroid hormone and anti-thyroid stimulating hormone receptor antibody levels is necessary when treating patients with periodic paralysis.

The integrative multi-kingdom interaction of the gut microbiome in ulcerative colitis (UC) and Crohn’s disease (CD) remains underinvestigated. Here, we perform shotgun metagenomic sequencing of feces from patients with UC and CD, and healthy controls in the Japanese 4D cohort, profiling bacterial taxa, gene functions, and antibacterial genes, bacteriophages, and fungi. External metagenomic datasets from the US, Spain, the Netherlands, and China were analyzed to validate our multi-biome findings. We found that Enterococcus faecium and Bifidobacterium spp. were enriched in both diseases. Enriched Escherichia coli was characteristic of CD and was linked to numerous antibiotic resistance genes involved in efflux pumps and adherent-invasive Escherichia coli virulence factors. Virome changes correlated with shifts in the bacteriome, including increased abundances of phages encoding pathogenic genes. Saccharomyces paradoxus and Saccharomyces cerevisiae were enriched in UC and CD, respectively. Saccharomyces cerevisiae and Escherichia coli had negative associations with short-chain fatty acid (SCFA)-producing bacteria in CD. Multi-biome signatures and their interactions in UC and CD showed high similarities between Japan and other countries. Since bacteria, phages, and fungi formed multiple hubs of intra- or trans-kingdom networks with SCFA producers and pathobionts in UC and CD, an approach targeting the interaction network may hold therapeutic promise. Here, the authors perform a multi-biome analysis in ulcerative colitis and Crohn’s disease patients from the Japanese 4D cohort, identifying intra- and trans-kingdom interactions including bacteria, phages, and fungi, providing potential candidate therapeutic targets.

Background: Regular visits with healthcare professionals are important for preventing serious complications in patients with diabetes. The purpose of this retrospective cohort study was to clarify whether there was any suppression of physician visits among patients with diabetes during the spread of the novel coronavirus 2019 (COVID-19) in Japan and to assess whether telemedicine contributed to continued visits.Methods: We used the JMDC Claims database, which contains the monthly claims reported from July 2018 to May 2020 and included 4,595 (type 1) and 123,686 (type 2) patients with diabetes. Using a difference-in-differences analysis, we estimated the changes in the monthly numbers of physician visits or telemedicine per 100 patients in April and May 2020 compared with the same months in 2019.Results: For patients with type 1 diabetes, the estimates for total overall physician visits were −2.53 (95% confidence interval [CI], −4.63 to 0.44) in April and −8.80 (95% CI, −10.85 to −6.74) in May; those for telemedicine visits were 0.71 (95% CI, 0.47–0.96) in April and 0.54 (95% CI, 0.32–0.76) in May. For patients with type 2 diabetes, the estimates for overall physician visits were −2.50 (95% CI, −2.95 to −2.04) in April and −3.74 (95% CI, −4.16 to −3.32) in May; those for telemedicine visits were 1.13 (95% CI, 1.07–1.20) in April and 0.73 (95% CI, 0.68–0.78) in May.Conclusion: The COVID-19 pandemic was associated with suppression of physician visits and a slight increase in the utilization of telemedicine among patients with diabetes during April and May 2020.

Aim To determine the epidemiological characteristics and risk factors for heart failure (HF) among Japanese patients with type 2 diabetes. Methods A retrospective cohort analysis, using J‐DREAMS database, was conducted from December 2015 to January 2020 with type 2 diabetes. The primary objectives were to describe patient characteristics stratified by HF history at baseline and new HF events during follow‐up. The secondary objectives were to clarify the association between HF history or new HF events and clinical characteristics. The association between renal disease stage and HF was also studied. Results Among 18,250 adult patients with type 2 diabetes, 3,613 (19.8%) patients had HF history and the mean age was 68.46 years, predominantly male (66.4%) with 13.32 years of mean duration of type 2 diabetes. Patients with HF history had a higher proportion of patients with nephropathy (51.2%) and coronary heart disease (55.6%) than those without HF history. Coronary heart disease (CHD) and deteriorating renal function were strongly associated with both HF history (CHD adjusted odds ratio [OR]: 7.41, 95% confidence interval [CI]: 6.05–9.08; eGFR G5 stage adjusted OR: 6.56, 95% CI: 2.97–14.49) and new HF events (CHD adjusted OR: 1.63, 95% CI: 1.17–2.29; eGFR G4 stage adjusted OR: 3.42, 95% CI: 1.81–6.47). Conclusions Comorbidities, especially CHD and deteriorating renal function, were strongly associated with HF history and new HF events among Japanese patients with type 2 diabetes. The study results suggested the importance of early intervention to treat comorbidities and maintain renal function. The study aimed to identify the epidemiological characteristics and risk factors for heart failure (HF) in Japanese patients with type 2 diabetes. It found that comorbidities, particularly coronary heart disease (CHD) and deteriorating renal function, were strongly associated with both HF history and new HF events. The results highlight the importance of early intervention to manage comorbidities and maintain renal function.

Aims/Introduction This study aimed to investigate the risk factors for diabetic retinopathy (DR) and diabetic kidney disease (DKD) in Japanese patients with diabetes mellitus (DM). Identifying these factors could provide insights into the shared and distinct mechanisms contributing to these complications in the diabetic population. Materials and Methods We conducted a retrospective analysis using the J‐DREAMS (Japan Diabetes compREhensive database project based on an Advanced electronic Medical record System) database, which is directly linked to electronic medical records. The study included Japanese people aged 18 years and older with diabetes, who were registered at a referral center between December 1, 2015, and March 31, 2021, and had simultaneous measurements of serum creatinine and hemoglobin A1c (HbA1c). The presence or absence of DR and DKD was determined for 8,794 and 8,770 patients, respectively. Multivariable logistic regression analyses were used to identify risk factors, considering patient characteristics, comorbid conditions, and laboratory data as explanatory variables. Results Common risk factors for both DR and DKD included hypertension, anemia, diabetic neuropathy, cerebrovascular disease, chronic heart failure, low serum albumin levels, and elevated HbA1c. The contributions of age, duration of DM, and body mass index (BMI) differed between the DR and DKD groups. Conclusions In addition to poor glycemic control and hypertension, anemia, low serum albumin, cerebrovascular disease, and heart failure were identified as independent common risk factors for DR and DKD, suggesting the existence of cardio‐renal anemia syndrome in patients with DM. Using a large‐scale database directly linked to electronic medical records known as J‐DREAMS, we retrospectively investigated risk factors for diabetic retinopathy (DR) and diabetic kidney disease (DKD) in Japanese patients with diabetes mellitus. In addition to known risk factors such as poor glycemic control and hypertension, we identified that anemia, low serum albumin, cerebrovascular disease, and heart failure are independent common risk factors for DR and DKD, suggesting the existence of cardio‐renal anemia syndrome in patients with diabetes mellitus. There are risk factors with different contributions (age, BMI, diabetes duration, and HDL‐C), underscoring the fact that the pathogenesis and patient background factors for those two complications are different from DR and DKD.

Background: Several epidemiological studies have determined the relationship between diabetes and the incidence and/or prevalence of recently identified comorbid conditions (cancer, periodontal disease, fracture, cognitive impairment, and depression). These relationships may vary by country or race/ethnicity. We aimed to systematically review studies in this field conducted with the Japanese population because such a review in the Japanese population has never been undertaken. Methods: We conducted systematic literature searches in PubMed and Ichushi-Web databases for studies published until December 2016. Studies comparing the incidence and/or prevalence of the comorbidities among the Japanese population were included. The studies were classified as integrated analyses, cohort studies, case-control studies, or cross-sectional studies. Results: We identified 33 studies (cancer: 17, periodontal disease: 5, fracture: 5, cognitive impairment: 4, and depression: 2). Although several cohort studies and meta-analyses had assessed the development of cancer in diabetes, there was scant epidemiological evidence for the other conditions. Indeed, only one cohort study each had been conducted for periodontal disease, fracture, and cognitive impairment, whereas other evidence was cross-sectional, some of which was induced from baseline characteristic tables of studies designed for other purposes. Conclusion: In Japan, there is insufficient evidence about the relationship between diabetes and the incidence/prevalence of periodontal disease, fracture, cognitive impairment, and depression. By contrast, several cohort studies and integrated analyses have been conducted for the relationship with cancer. Further studies should be undertaken to estimate the contribution of diabetes on the incidence/prevalence of comorbidities that may be specific to the Japanese population.