Safety and effectiveness of empagliflozin according to body mass index in Japanese patients with type 2 diabetes: a subgroup analysis of a 3-year post-marketing surveillance study.

BACKGROUND: Empagliflozin, a glucose-lowering drug licensed for type 2 diabetes (T2D), demonstrated tolerability and effectiveness overall in a post-marketing surveillance (PMS) study in Japan. However, the impact of body mass index (BMI) is unclear. RESEARCH DESIGN AND METHODS: This was a prespecified sub-analysis of the prospective, 3-year, PMS study of empagliflozin in Japan where the primary endpoint was adverse drug reactions (ADRs). We evaluated results according to BMI. RESULTS: We enrolled 7931 T2D patients treated with empagliflozin. Baseline mean age was 58.7 years; 63.01% were male. Baseline BMI was <20 kg/m2 in 2.06% of patients, while 21.28%, 37.35%, and 24.97% had BMI 20-<25, 25-<30 and ≥30 kg/m2, respectively. ADRs occurred in 19 (11.66%), 203 (12.03%), 411 (13.88%), and 295 (14.90%) patients with BMI <20, 20-<25, 25-<30 and ≥30 kg/m2, respectively. Excessive/frequent urination was the most frequent ADR of special interest in all BMI subgroups except 20-<25 kg/m2 (urinary tract infection). Mean change in glycated hemoglobin from baseline was -0.75%, with similar magnitude across BMI subgroups. Body-weight reduction seemed dependent on BMI, with almost no change in the <20 kg/m2 subgroup. CONCLUSIONS: Empagliflozin appeared well tolerated and effective in Japanese T2D patients regardless of BMI, although the number of patients with BMI <20 kg/m2 was small in this study.

Nationwide multicenter questionnaire surveys on countermeasures against antimicrobial resistance and infections in hospitals.

BACKGROUND: The goals of the National Action Plan on Antimicrobial Resistance (AMR) of Japan include "implementing appropriate infection prevention and control" and "appropriate use of antimicrobials," which are relevant to healthcare facilities. Specifically, linking efforts between existing infection control teams and antimicrobial stewardship programs was suggested to be important. Previous studies reported that human resources, such as full-time equivalents of infection control practitioners, were related to improvements in antimicrobial stewardship. METHODS: We posted questionnaires to all teaching hospitals (n = 1017) regarding hospital countermeasures against AMR and infections. To evaluate changes over time, surveys were conducted twice (1st survey: Nov 2016, 2nd survey: Feb 2018). A latent transition analysis (LTA) was performed to identify latent statuses, which refer to underlying subgroups of hospitals, and effects of the number of members in infection control teams per bed on being in the better statuses. RESULTS: The number of valid responses was 678 (response rate, 66.7%) for the 1st survey and 559 (55.0%) for the 2nd survey. More than 99% of participating hospitals had infection control teams, with differences in activity among hospitals. Roughly 70% had their own intervention criteria for antibiotics therapies, whereas only about 60 and 50% had criteria established for the use of anti-methicillin-resistant Staphylococcus aureus antibiotics and broad-spectrum antibiotics, respectively. Only 50 and 40% of hospitals conducted surveillance of catheter-associated urinary tract infections and ventilator-associated pneumonia, respectively. Less than 50% of hospitals used maximal barrier precautions for central line catheter insertion. The LTA identified five latent statuses. The membership probability of the most favorable status in the 2nd study period was slightly increased from the 1st study period (23.6 to 25.3%). However, the increase in the least favorable status was higher (26.3 to 31.8%). Results of the LTA did not support a relationship between increasing the number of infection control practitioners per bed, which is reportedly related to improvements in antimicrobial stewardship, and being in more favorable latent statuses. CONCLUSIONS: Our results suggest the need for more comprehensive antimicrobial stewardship programs and increased surveillance activities for healthcare-associated infections to improve antimicrobial stewardship and infection control in hospitals.

Code-Sharing in Cost-of-Illness Calculations: An Application to Antibiotic-Resistant Bloodstream Infections.

Background: More data-driven evidence is needed on the cost of antibiotic resistance. Both Japan and England have large surveillance and administrative datasets. Code sharing of costing models enables reduced duplication of effort in research. Objective: To estimate the burden of antibiotic-resistant Staphylococcus aureus bloodstream infections (BSIs) in Japan, utilizing code that was written to estimate the hospital burden of antibiotic-resistant Escherichia coli BSIs in England. Additionally, the process in which the code-sharing and application was performed is detailed, to aid future such use of code-sharing in health economics. Methods: National administrative data sources were linked with voluntary surveillance data within the Japan case study. R software code, which created multistate models to estimate the excess length of stay associated with different exposures of interest, was adapted from previous use and run on this dataset. Unit costs were applied to estimate healthcare system burden in 2017 international dollars (I$). Results: Clear supporting documentation alongside open-access code, licensing, and formal communication channels, helped the re-application of costing code from the English setting within the Japanese setting. From the Japanese healthcare system perspective, it was estimated that there was an excess cost of I$6,392 per S. aureus BSI, whilst oxacillin resistance was associated with an additional I$8,155. Conclusions:S. aureus resistance profiles other than methicillin may substantially impact hospital costs. The sharing of costing models within the field of antibiotic resistance is a feasible way to increase burden evidence efficiently, allowing for decision makers (with appropriate data available) to gain rapid cost-of-illness estimates.

Correction: Effects of night-time and weekend admissions on in-hospital mortality in acute myocardial infarction patients in Japan.

[This corrects the article DOI: 10.1371/journal.pone.0191460.].

Effect of methicillin-resistant Staphylococcus aureus in Japan.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is the most common antimicrobial-resistant organism identified in Japanese health care facilities. This study analyzed the clinical and economic burdens attributable to methicillin resistance in S aureus in Japanese hospitals. METHODS: We retrospectively investigated data from 14,905 inpatients of 57 hospitals combined with data from nosocomial infection surveillance and administrative claim databases. The participants were inpatients with admission from April 1, 2014, to discharge on March 31, 2016. The outcomes were evaluated according to length of stay, hospital charges, and in-hospital mortality. We compared the disease burden of MRSA infections with methicillin-susceptible S aureus (MSSA) infections based on patients' characteristics and onset periods. RESULTS: We categorized 7,188 and 7,717 patients into MRSA and MSSA groups, respectively. The adjusted effects of the MRSA group were 1.03-fold (95% confidence interval [CI] 1.01-1.05) and 1.04-fold (95% CI, 1.01-1.06), respectively, with an odds ratio of 1.14 (95% CI, 1.02-1.27). CONCLUSIONS: The results of this study found that patient severity and onset delays were positively associated with both MRSA and burden and that the effect of methicillin resistance remained significant after adjustment.

Effects of night-time and weekend admissions on in-hospital mortality in acute myocardial infarction patients in Japan.

BACKGROUND: Patients admitted to hospital during off-hours may experience poorer quality of care and clinical outcomes. However, few studies have examined the variations in clinical processes and outcomes across admission times and days of the week in acute myocardial infarction (AMI) patients. This study aimed to comparatively analyze the effect of weekend and weekday admissions stratified by admission time on in-hospital mortality in AMI patients. METHODS AND RESULTS: Using a large nationwide administrative database, we analyzed 103,908 AMI patients admitted to 639 Japanese acute care hospitals between April 2011 and March 2015. We divided patients into the following 4 groups: weekday daytime admissions, weekday night-time admissions, weekend daytime admissions, and weekend night-time admissions. A hierarchical logistic regression model was used to comparatively examine in-hospital mortality among the groups after adjusting for age, sex, ambulance use, Killip class, comorbidities, and the number of cardiologists in the admitting hospital. In addition, we also calculated and compared the adjusted odds ratios of various AMI therapies among the groups. The in-hospital mortality rate of weekend daytime admissions was higher than those admitted during other times (weekday daytime: 6.8%; weekday night-time; 6.5%, weekend daytime; 7.6%; weekend night-time: 6.6%; P < 0.001), even after adjusting for the covariates (adjusted odds ratio for weekend daytime admissions: 1.10; 95% confidence interval: 1.03-1.19). The prescription rates of guideline-based medications provided on the first day of admission were higher in night-time admissions than in daytime admissions. CONCLUSIONS: In-hospital mortality rates were higher in AMI patients admitted during weekend daytime hours when compared with patients admitted during other times. Furthermore, patients admitted during daytime hours had lower prescription rates of guideline-based medications. Our findings indicate that weekend daytime admissions may be a potential target for improvement in the Japanese healthcare system.

In-hospital mortality and treatment patterns in acute myocardial infarction patients admitted during national cardiology meeting dates.

BACKGROUND: Many hospitals experience a reduction in the number of available physicians on days when national scientific meetings are conducted. This study investigates the relationship between in-hospital mortality in acute myocardial infarction (AMI) patients and admission during national cardiology meeting dates. METHODS: Using an administrative database, we analyzed patients with AMI admitted to acute care hospitals in Japan from 2011 to 2013. There were 3 major national cardiology meetings held each year. A hierarchical logistic regression model was used to compare in-hospital mortality and treatment patterns between patients admitted on meeting dates and those admitted on identical days during the week before and after the meeting dates. RESULTS: We identified 6,332 eligible patients, with 1,985 patients admitted during 26 meeting days and 4,347 patients admitted during 52 non-meeting days. No significant differences between meeting and non-meeting dates were observed for in-hospital mortality (7.4% vs. 8.5%, respectively; p=0.151, unadjusted odds ratio: 0.861, 95% confidence interval: 0.704-1.054) and the proportion of percutaneous coronary intervention (PCI) performed on the day of admission (75.9% vs. 76.2%, respectively; p=0.824). We also found that some low-staffed hospitals did not treat AMI patients during meeting dates. CONCLUSION: Little or no "national meeting effect" was observed on in-hospital mortality in AMI patients, and PCI rates were similar for both meeting and non-meeting dates. Our findings also indicated that during meeting dates, AMI patients may have been consolidated to high-performance and sufficiently staffed hospitals.

Structure and host recognition of serotype 13 glycopeptidolipid from Mycobacterium intracellulare.

The Mycobacterium avium-M. intracellulare complex (MAIC) is divided into 28 serotypes by a species-specific glycopeptidolipid (GPL). Previously, we clarified the structures of serotype 7 GPL and two methyltransferase genes (orfA and orfB) in serotype 12 GPL. This study elucidated the chemical structure, biosynthesis gene, and host innate immune response of serotype 13 GPL. The oligosaccharide (OSE) structure of serotype 13 GPL was determined to be 4-2'-hydroxypropanoyl-amido-4,6-dideoxy-ß-hexose-(1 → 3)-4-O-methyl-α-L-rhamnose-(1 → 3)-α-L-rhamnose-(1 → 3)-α-L-rhamnose-(1 → 2)-α-L-6-deoxy-talose by using chromatography, mass spectrometry, and nuclear magnetic resonance (NMR) analyses. The structure of the serotype 13 GPL was different from those of serotype 7 and 12 GPLs only in O-methylations. We found a relationship between the structure and biosynthesis gene cluster. M. intracellulare serotypes 12 and 13 have a 1.95-kb orfA-orfB gene responsible for 3-O-methylation at the terminal hexose, orfB, and 4-O-methylation at the rhamnose next to the terminal hexose, orfA. The serotype 13 orfB had a nonfunctional one-base missense mutation that modifies serotype 12 GPL to serotype 13 GPL. Moreover, the native serotype 13 GPL was multiacetylated and recognized via Toll-like receptor 2. The findings presented here imply that serotypes 7, 12, and 13 are phylogenetically related and confirm that acetylation of the GPL is necessary for host recognition. This study will promote better understanding of the structure-function relationships of GPLs and may open a new avenue for the prevention of MAIC infections.

Novel rhamnosyltransferase involved in biosynthesis of serovar 4-specific glycopeptidolipid from Mycobacterium avium complex.

Glycopeptidolipids (GPLs) are one of the major glycolipid components present on the surface of Mycobacterium avium complex (MAC) that belong to opportunistic pathogens distributed in the natural environment. The serovars of MAC, up to around 30 types, are defined by the variable oligosaccharide portions of the GPLs. Epidemiological studies show that serovar 4 is the most prevalent type, and the prognosis of pulmonary disease caused by serovar 4 is significantly worse than that caused by other serovars. However, little is known about the biosynthesis of serovar 4-specific GPL, particularly the formation of the oligosaccharide portion that determines the properties of serovar 4. To investigate the biosynthesis of serovar 4-specific GPL, we focused on one segment that included functionally unknown genes in the GPL biosynthetic gene cluster of a serovar 4 strain. In this segment, a putative hemolytic protein gene, hlpA, and its downstream gene were found to be responsible for the formation of the 4-O-methyl-rhamnose residue, which is unique to serovar 4-specific GPL. Moreover, functional characterization of the hlpA gene revealed that it encodes a rhamnosyltransferase that transfers a rhamnose residue via 1→4 linkage to a fucose residue of serovar 2-specific GPL, which is a key pathway leading to the synthesis of oligosaccharide of serovar 4-specific GPL. These findings may provide clues to understanding the biological role of serovar 4-specific GPL in MAC pathogenicity and may also provide new insights into glycosyltransferase, which generates structural and functional diversity of GPLs.

'Lysobacter enzymogenes ssp. cookii ' Christensen 1978 should be recognized as an independent species, Lysobacter cookii sp. nov.

'Lysobacter enzymogenes ssp. cookii' was proposed by Christensen and Cook in 1978; however, this subspecies name has not been cited in the Approved Lists of Bacterial Names and therefore the nomenclature has not been validated. In our genetic approach to clarify the relationships of the designated type strain of 'L. enzymogenes ssp. cookii' PAGU 1119 (GenBank accession number ATCC29488) within the genus Lysobacter revealed that the strain was closely related to Lysobacter capsiciYC5194(T) (99.4%) rather than L. enzymogenesDSM2043(T) (97.2%). The value for whole genome DNA-DNA relatedness between strain PAGU 1119 and L. enzymogenes DSM 2043(T) or L. capsiciYC5194(T) was 20.7-26.1% or 60.9-62.0%, respectively. Although PAGU 1119 and L. capsiciYC5194(T) showed relatively high DNA relationships, the fatty acid profiles and some phenotypic characteristics were different, and we concluded that PAGU 1119 should be placed in a new species. We therefore propose a new species with the name Lysobacter cookii sp. nov. The type strain is PAGU 1119(T) (ATCC29488).

Serum nutritional status of tocopherol and retinol normalized to lipids of persons living in the southern rural Terai region in Nepal.

OBJECTIVE: The present study examined the levels of serum α-Tocopherol (Toc), retinol (Ret), cholesterol (Chol) and triglycerides (TG), and their correlations in the sera of people in Nepal. METHODS: The survey was conducted on the general populace in the agricultural Terai region in southern Nepal. The study population consisted of 93 males and 83 females aged 10-68 years. Serum Toc and Ret were measured by high-performance liquid chromatography. RESULTS: No significant differences were observed between the genders for the average of total Chol (T-Chol) (140 and 145 mg/100 ml, respectively), HDL-C (45 and 47 mg/100 ml), LDL-C (94 and 97 mg/100 ml), and TG (106 and 110 mg/100 ml), and the ratio of LDL/HDL (2.16). The levels of mean Toc (4.32 and 4.27 µg/ml) were about the same for both genders, while the mean Ret levels were significantly higher for males (624 ng/ml) than for females (535 ng/ml) (p<0.001). A direct relationship was found between the levels of Toc and Ret (r=0.46, p<0.001 and r=0.28, p<0.05 for males and females, respectively). Serum levels of Toc and Ret were positively related to the levels of Chol (r=0.48 and r=0.58, p<0.001 for males and r=0.49, p<0.01 and r-0.28, p<0.05 for females, respectively). The ratio of Toc/TG normalized to serum TG was directly correlated to the ratio of Ret/TG (r=0.79 for males, and r=0.72 for females, p<0.001, respectively) and the ratios of Toc/TG and Ret/TG were negatively related to the LDL/HDL levels (r=-0.49 and r=-0.43, for males, and r=-0.46 and r=-0.57 for females, p<0.001, respectively). CONCLUSION: The levels of Toc and Ret were low in the sera of people living in the southern rural Terai region in Nepal, and it was found that lower levels of Toc and Ret normalized to TG increased the ratio of LDL/HDL. These results suggest that greater intake of foods rich in Toc and Ret should be encouraged to reduce the erisk of coronary heart disease.