Light and Shadow of Na-Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Points for Improvement Based on Our Clinical Experience.

We analyzed the effect of Na-glucose cotransporter 2 inhibitors (SGLT2-I) in diabetic patients visiting our hospital. The study included 236 patients treated with SGLT2-I alone or with codiabetic drugs for at least two years. We analyzed overtime changes in glycosylated hemoglobin A1c (HbA1c) in the patients by repeated analyses of variance (ANOVA) and evaluated the therapeutic effect. HbA1c levels decreased significantly in the first six months after treatment. Afterward, they leveled off and increased slightly over the next two years. Six months after treatment, the mean (SD) of HbA1c was 8.19 (1.46) %; the mean difference dropped by 0.91%, and HbA1c in mild DM2 did not drop by below 8.0%. Overall, there was only a slight improvement. We performed multivariate logistic regression analysis using a model with or without improvement as the objective variable and several explanatory variables. Na and Hct were significant factors. They increased considerably over six months and then leveled off. eGFR significantly reduced in the hyperfiltration group six months after treatment. The annual decline rate in eGFR was also faster, even in the nonhyperfiltration group than in the healthy subjects, which may be a characteristic of renal clearance in SGLT2-I treatment. In conclusion, SGLT2-I is an excellent antidiabetic, nephroprotective agent to eliminate hyperfiltration, but unfortunately, SGLT2-I alone does not have enough power to reduce blood glucose levels. SGLT2-I, with insulin or insulin secretagogues, enhances insulin resistance, induces hyperinsulinemia, and exacerbates type 2 DM. In contrast, SGLT2-I, with noninsulin antidiabetic agents and a low-carbohydrate diet, may bring better results.

Effectiveness of weight-loss prevention with continual nutrition counseling in postoperative outpatients with stage IA and IB gastric cancer.

Outpatient nutritional counseling by a registered dietitian is often performed to prevent weight loss, but evidence supporting this practice is insufficient. In this study, we aimed to clarify the effectiveness of four-time outpatient nutritional counseling in weight-loss prevention compared with conventional intervention limited to one-time nutritional counseling. This study was designed as a retrospective cohort study. The target population was postoperative patients with stage IA and IB gastric cancer. Groups that received one-time and four-time nutritional counseling included patients who underwent gastrectomy from May 2014 to April 2017 and May 2017 to December 2019, respectively. The one-time group received counseling at discharge; the four-time group received counseling at discharge, at the first outpatient visit, and at 3 and 6 months postoperatively. There were 58 patients in the one-time group and 27 patients in the four-time group, with a significant difference in length of hospital stay (p = 0.042). Thirty-six patients (62.1%) in the one-time nutritional counseling group and 12 (44.4%) in the four-time group had a weight loss of 5% or more from hospital discharge to 6 months postoperatively. The adjusted risk ratio for the effectiveness of four counseling sessions compared with one session was 0.69 (95% confidence interval 0.35-1.34). In subgroup analysis, the effect of nutritional guidance was greater for patients with body mass index ≥23 kg/m2, but this depended on the outcome and number of cases, and there was no essential difference between the groups. In postoperative patients with stage IA and stage IB gastric cancer, four sessions of outpatient nutrition counseling may be not superior to one counseling session in preventing weight loss.

A case of Robinsoniella peoriensis bacteremia during using piperacillin-tazobactam.

Infections caused by Robinsoniella peoriensis, particularly bacteremia, are rare, of which only six cases were reported R. peoriensis bloodstream infections. This case report describes an instance of R. peoriensis bacteremia arising while we treated the patient with piperacillin-tazobactam. We treated an 84-year-old female patient with peritoneal carcinoma and febrile neutropenia using piperacillin-tazobactam. The patient's fever subsided. However, she developed a fever again on the fourth day of treatment with piperacillin-tazobactam. Blood cultures taken at this time were positive for R. peoriensis. We substituted meropenem and vancomycin for piperacillin-tazobactam, after which the patient improved. We administered meropenem and vancomycin for 17 days. There is currently no appropriate established treatment for R. peoriensis. In this case, we isolated R. peoriensis from blood cultures using piperacillin-tazobactam, although it was susceptible to piperacillin-tazobactam in vitro. Therefore, monotherapy with penicillins, especially piperacillin-tazobactam, may not be sufficient for R. peoriensis infections, although it was susceptible in vitro. Carbapenem may be effective in the treatment of R. peoriensis bloodstream infections.

A case of bloodstream co-infection of Saccharomyces cerevisiae and Candida glabrata while using micafungin.

BACKGROUND: Saccharomyces cerevisiae is ubiquitous in the gastrointestinal tract and known as brewer's or baker's yeast. We experienced a case of S. cerevisiae and Candida glabrata co-infectious bloodstream infection. It is rare to detect both S. cerevisiae and Candida species in blood cultures together. CASE: We treated a 73-year-old man who developed a pancreaticoduodenal fistula infection after pancreaticoduodenectomy. The patient had a fever on postoperative day 59. We took blood cultures and detected C. glabrata. Thus, we started micafungin. On postoperative day 62, we retested blood cultures, and detected S cerevisiae and C. glabrata. We changed micafungin to liposomal amphotericin B. Blood cultures became negative on postoperative day 68. We changed liposomal amphotericin B to fosfluconazole and micafungin because of hypokalemia. He got well, and we terminated antifungal drugs 18 days after the blood cultures became negative. CONCLUSION: Co-infection with S. cerevisiae and Candida species is rare. In addition, in this case, S. cerevisiae developed from blood cultures during micafungin administration. Thus, micafungin may not be effective enough to treat S. cerevisiae fungemia, although echinocandin is considered one of the alternative therapy for Saccharomyces infections.

The first case of deep neck abscess due to Filifactor alocis co-infected with Eggerthia catenaformis, Parvimonas micra, and Streptococcusconstellatus.

Filifactor alocis, an anaerobic Gram-positive rod, has garnered interest from its association with periodontal disease. Extraoral infections by F. alocis are rare; only seven cases have been reported. We report the first case in which we identified F. alocis as one of the causative organisms of a deep neck abscess. A 71-year-old male on hemodialysis came to our hospital with a fever and left buccal pain. The patient's left neck was swollen, and contrast-enhanced computed tomography showed an abscess with gas extending from the left cheek to the deep neck. We diagnosed the patient with a deep neck abscess and performed an urgent neck drainage. We isolated F. alocis, Eggerthia catenaformis, Parvimonas micra, and Streptococcus constellatus in the abscess and identified them using matrix-assisted laser desorption ionization-time of flight mass spectrometry. Blood cultures were negative. We initiated treatment with piperacillin-tazobactam and vancomycin. The patient improved but developed a hemorrhagic duodenal ulcer on the third day of admission. We attempted endoscopic hemostasis, but the patient's bleeding continued. Ultimately, he died of the duodenal ulcer hemorrhage on the sixth day of admission. This is the first case of F. alocis detected in a deep neck abscess.

The Ventricular Hypokinesis at the Apical Pacing Site due to the Early Shortening and Rebound Stretch in a Case with Fontan Procedure.

The left ventricular (LV) apex is recommended as the first choice for positioning the epicardial pacing. We encountered a patient with congenital heart disease (CHD) showing hypokinesis of the LV apical pacing site after implantation of a pacemaker with epicardial leads. This phenomenon was revealed by the early shortening and systolic rebound stretch of the same lesion on two-dimensional speckle tracking echocardiography, which developed in the intraventricular dyssynchrony between the LV apex and base. Cardiac resynchronization therapy provided an excellent result around the hypokinetic lesion. It is wise to arrange detailed evaluations in each patient with complicated CHD, aiming at a successful treatment to enable ventricular synchronicity.

Focal cutaneous telangiectasia in a young dog of probable congenital origin.

BACKGROUND: Idiopathic cutaneous telangiectasia has been rarely described in the dog. OBJECTIVES: We present the first case of idiopathic focal cutaneous telangiectasia in a young dog of probable congenital origin. METHODS: An 18-month-old spayed female Maltese dog presented with demarcated erythema of the skin on the right thorax. The lesion consisted of scattered, florid, ramified macules with mild dermatrophia and desquamation. The lesion was examined with histopathology and immunohistochemistry using antibodies for alfa-SMA. RESULTS: Diascopy revealed a blanchable lesion. Tortuous capillary expansion was observed by dermoscopy. The histopathological examination revealed dilated but otherwise unremarkable capillaries in the superficial dermis compatible with cutaneous telangiectasia. The lesion was followed up over a 3-year period and had essentially remained stable. Other vascular anomalies displaying similarities with telangiectasia are discussed. CONCLUSIONS: In human vascular anomalies, this case would be presumably classified as 'telangiectasia' by the International Society for the Study of Vascular Anomalies. We propose that primary cutaneous telangiectasia should be included in the list of differential diagnoses for this type of lesions in dogs. We also suggest that dermoscopy would be a valuable tool for the identification of vascular anomalies in dogs.

A case of recurrent acute cholecystitis caused by Actinomyces odontolyticus, rare actinomycosis.

BACKGROUNDS: Actinomyces species are gram-positive, obligate anaerobic rods and are rare causes of cholecystitis. Because Actinomyces species are anaerobic bacteria, it is difficult for Actinomyces to survive in bile apart from A. naeslundii. We experienced a case of recurrent acute cholecystitis caused by A. odontolyticus. CASE PRESENTATION: A patient had been diagnosed with acute cholecystitis and treated one month before and after that, admitted to our hospital because of recurrent cholecystitis. Gram stain of the bile revealed gram-positive rods and gram-positive cocci. We found A. odontolyticus and MRSA in bile culture and MRSA in blood culture. We administered piperacillin-tazobactam and then changed it to ampicillin-sulbactam and vancomycin. The patient underwent laparoscopic cholecystectomy and was discharged safely. CONCLUSIONS: To our knowledge, this is the first case of cholecystitis caused by A. odontolyticus. Cholecystitis caused by Actinomyces species is rare. In addition, we may overlook it with the low positivity of bile cultures of Actinomyces. Whenever the cholecystitis recurs without any obstruction of the biliary tract, we should search for the gram-positive rods hidden in the bile, such as A. odontolyticus, as the causative organism, even if the bile culture is negative.

Usefulness of subclassification of adult diabetes mellitus among inpatients in Japan.

AIMS/INTRODUCTION: We aimed to replicate a new diabetes subclassification based on objective clinical information at admission in a diabetes educational inpatient program. We also assessed the educational outcomes for each cluster. METHODS: We included diabetes patients who participated in the educational inpatient program during 2009-2020 and had sufficient clinical information for the cluster analysis. We applied a data-driven clustering method proposed in a previous study and further evaluated the clinical characteristics of each cluster. We investigated the association between the clusters and changes in hemoglobin A1c level from the start of the education program. We also assessed the risk of re-admission for the educational program. RESULTS: We divided a total of 651 patients into five clusters. Their clinical characteristics followed the same pattern as in previous studies. The intercluster ranking of the cluster center coordinates showed strong correlation coefficients with those of the previous studies (mean ρ = 0.88). Patients classified as severe insulin-resistant diabetes (cluster 3) showed a more pronounced progression of renal dysfunction than patients classified as the other clusters. The patients classified as severe insulin-deficient diabetes (cluster 2) had the highest rate of reduction in hemoglobin A1c level from the start of the program (P < 0.01) and a tendency toward a lower risk of re-admission for the education program (hazard ratio 0.47, P = 0.09). CONCLUSION: We successfully replicated the diabetes subclassification using objective clinical information at admission for the education program. In addition, we showed that severe insulin-deficient diabetes patients tended to have better educational outcomes than patients classified as the other clusters.

A case of retinitis pigmentosa homozygous for a rare CNGA1 causal variant.

Retinitis pigmentosa (RP) is a heterogenous hereditary disorder leading to blindness. Despite using next-generation sequencing technologies, causal variants in about 60% of RP cases remain unknown. The heterogeneous genetic inheritance pattern makes it difficult to pinpoint causal variants. Besides, rare penetrating variants are hardly observed in general case-control studies. Thus, a family-based analysis, specifically in a consanguineous family, is a clinically and genetically valuable approach for RP. We analyzed a Japanese consanguineous family with a member suffering from RP with a typical autosomal recessive pattern. We sequenced five direct descendants and spouse using Whole-exome sequencing (WES) and Whole-genome sequencing (WGS). We identified a homozygous pathogenic missense variant in CNGA1 (NM_000087.3, c.839G > A, p.Arg280His) in the proband, while we found no homozygous genotypes in the other family members. CNGA1 was previously reported to be associated with RP. We confirmed the genotypes by the Sanger sequencing. Additionally, we assessed the homozygous genotype in the proband for the possibility of a founder mutation using homozygosity analysis. Our results suggested the two copies of the variant derived from a founder mutation. In conclusion, we found the homozygotes for c.839G > A in CNGA1 as causal for RP.

Photoactivatable Cre knock-in mice for spatiotemporal control of genetic engineering in vivo.

Although the Cre-loxP recombination system has been extensively used to analyze gene function in vivo, spatiotemporal control of Cre activity is a critical limitation for easy and precise recombination. Here, we established photoactivatable-Cre (PA-Cre) knock-in (KI) mice at a safe harbor locus for the spatial and temporal regulation of Cre recombinase activity. The mice showed whole-body Cre recombination activity following light exposure for only 1 h. Almost no leaks of Cre recombination activity were detected in the KI mice under natural light conditions. Spot irradiation could induce locus-specific recombination noninvasively, enabling us to compare phenotypes on the left and right sides in the same mouse. Furthermore, long-term irradiation using an implanted wireless LED substantially improved Cre recombination activity, especially in the brain. These results demonstrate that PA-Cre KI mice can facilitate the spatiotemporal control of genetic engineering and provide a useful resource to elucidate gene function in vivo with Cre-loxP.

Immunoglobulin free light chains as an inflammatory biomarker of heart failure with myocarditis.

BACKGROUND: In this study, we measured immunoglobulin free light chains (FLC), a biomarker of inflammation in the sera of patients with heart failure due to myocarditis. METHODS: FLC kappa and FLC lambda were assayed in stored serum samples from patients with heart failure with myocarditis from the US myocarditis treatment trial by a competitive-inhibition multiplex Luminex® assay. RESULTS: The median concentration of circulating FLC kappa/lambda ratio was significantly lower in the sera from patients with heart failure with myocarditis than in healthy controls, and FLC kappa/lambda ratio had good diagnostic ability for identification of heart failure with myocarditis. Further, FLC kappa/lambda ratio was an independent prognostic factor for overall survival, and allowed creation of three prognostic groups by combining with N-terminal pro-B-type natriuretic peptide. CONCLUSIONS: This study suggests that FLC kappa/lambda ratio is a promising biomarker of heart failure with myocarditis.

Correction to: Immunoglobulin free light chains: an inflammatory biomarker of diabetes.

In the original publication of this paper contains some typographical errors in Table 1.

Immunoglobulin free light chains: an inflammatory biomarker of diabetes.

OBJECTIVE: Inflammation is increasingly understood as playing an important role in type 2 diabetes mellitus (T2D) development. A critical mechanism of the inflammatory cascade in developing T2D is nuclear factor-kappa B (NF-kB) activation. As immunoglobulin free light chains (FLC) could be a biomarker of activation of NF-kB, we measured FLC in patients with T2D. SUBJECTS: The age range of the 77 patients with T2D and the 75 healthy control participants were 45-87 years (median 60) and 25-72 years (median 51), respectively. METHODS: Serum FLC kappa and lambda were assayed by a competitive-inhibition multiplex Luminex assay. RESULTS: The concentration of circulating FLC the kappa/lambda ratio was lower in patients with T2D than in healthy volunteers. The area under the receiver operating curve (ROC-AUC) of the FLC kappa/lambda ratio showed the largest ROC-AUC compared with other FLC variables and hemoglobin A1c (HbA1c). The diagnostic performance for distinguishing between T2D and healthy control was a sensitivity of 0.96 and a specificity of 1. The odds ratio was 0.000018. CONCLUSIONS: These results suggest that FLC kappa/lambda may be more specific and sensitive for the diagnosis of T2D than HbA1c, and thus represents a potentially promising biomarker of inflammation.

The cause of anorexia and proportion of its recovery in older adults without underlying disease: Results of a retrospective study.

AIM: It is difficult to determine whether or not end-of-life care is necessary for frail older adults complaining of anorexia without underlying disease, such as cancer or organ failure. The main reason for this is the lack of the specification of the anorexia cause and no understanding of the cause-providing factor and the prognostic factor. This study aimed to clarify the cause of anorexia, and the determinant of the cause and recovery from anorexia. METHODS: Retrospective chart reviews were conducted on patients with anorexia without an underlying disease who were aged ≥65 years and visited the emergency department of a single tertiary care center between 2016 and 2017. Patient characteristics at hospital visit, the cause of anorexia, and diagnostic modalities were summarized. The diagnosis-providing rate, recovery rate, and the association between them were analyzed. RESULTS: Eighty-three patients (mean age 82.3 years; 50.6% male) were investigated. In 67 patients (81%), the causes of anorexia were identified, including 18 patients (22%) with infection, 13 (16%) with benign gastrointestinal diseases, and 7 (8%) with cardiovascular diseases. In 16 patients (19%), the causes of anorexia were not identified despite examinations. The modality that most contributed to diagnosis was plain computed tomography followed by blood tests. The value regarding information in history-taking and physical examinations was limited. Sixty-five patients (78%) recovered. Only 73% of patients with a definite cause recovered; all patients with an unknown cause recovered. CONCLUSIONS: Older adults with anorexia are not always at the end of life, and efforts to identify the cause are crucial. Moreover, it is vital to realize the limitations associated with the treatment of infections and cardiovascular diseases.

A rare case of spontaneously dissolved calcification of the mitral annulus: Caseous calcification of the mitral annulus.

Caseous calcification of the mitral annulus is a rare variant of mitral annular calcification (MAC). MAC is detected using conventional echocardiography and is prevalent in the elderly. However, limited information is currently available on the transformation of MAC. We herein report a case of a sudden liquified change in MAC, which was diagnosed using echocardiography and computed tomography. .

Hepatitis B surface antigen incorporated in dissolvable microneedle array patch is antigenic and thermostable.

Alternatives to syringe-based administration are considered for vaccines. Intradermal vaccination with dissolvable microneedle arrays (MNA) appears promising in this respect, as an easy-to-use and painless method. In this work, we have developed an MNA patch (MNAP) made of hydroxyethyl starch (HES) and chondroitin sulphate (CS). In swines, hepatitis B surface antigen (HBsAg) formulated with the saponin QS-21 as adjuvant, both incorporated in HES-based MNAP, demonstrated the same level of immunogenicity as a commercially available aluminum-adjuvanted HBsAg vaccine, after two immunizations 28 days apart. MNAP application was associated with transient skin reactions (erythema, lump, scab), particularly evident when the antigen was delivered with the adjuvant. The thermostability of the adjuvanted antigen when incorporated in the HES-based matrix was also assessed by storing MNAP at 37, 45 or 50 °C for up to 6 months. We could demonstrate that antigenicity was retained at 37 and 45 °C and only a 10% loss was observed after 6 months at 50 °C. Our results are supportive of MNAP as an attractive alternative to classical syringe-based vaccination.

[How to Apply Bayesian Theorem to the Evaluation of Myocardial Injury by Measuring High Sensitive Cardiac Troponins in the Patients with Suspected Acute Myocardial Infarction].

118 consecutive patients of suspected acute myocardial infarction with acute chest pain and shortness of breath visiting our emergency room were subjected for this clinical study. Based on final diagnosis of acute myocardial infarction (AMI) comprehensively determined by medical record, physical examination, ECG, echocardiography, cardiac catheterization, etc., except for cardiac biomarkers, the patients were classified into two groups, with AMI group (1) and without AMI group (0) and then ROC curve analysis was performed between without AMI group (1) and with AMI group (0). As a result of ROC curve analysis, AUC, cutoff value, sensitivity, specificity and likelihood ratio (LR) were calculated as shown in Fig. 4 (1-7) and Table 2 (1-7). Based on calculating equation led from Bayesian rules, post-test odds were calculated as product of pre-test odds and LR at the cutoff value in each biomarker such as hsCTnT, hsCTnI, h-FABP CK, CKMB activity and CKMB mass. As a result, post-test probability was improved from predictive pre-test probability 30% to post-test probability 89% and 86% in hsCTnT and hsTnI, respectively but less improved from 30% to 68% in h-FABP and unexpectedly improved from 30% to 82% in CKMB mass compared with hsCTnT and hsTnI. Based on Bayesian rule, it is very valuable to predict post-test probability from predictive pre-test probability 30% by calculation in particular, when post-test probability is over 85-90%. In conclusion, we believe that prediction of post-test probability by Bayesian rule can be surely used to evaluate clinical quality of biomarkers which are not depend on at least, specialty and experience of physicians.