A decision tree model for predicting high mono-N-desethylamiodarone concentrations and reducing tissue toxicity in patients with low-dose amiodarone therapy: A multicentral retrospective cohort study.

OBJECTIVE: High plasma levels of mono-N-desethylamiodarone (MDEA), an active amiodarone metabolite, may be associated with tissue toxicity in heart failure (patients with heart rhythm disturbances); therefore, a tool that can identify patients for whom therapeutic drug monitoring (TDM) of MDEA is required. This multicenter study aimed to develop a decision tree (DT) model that can identify patients with heart rhythm disturbances at high MDEA concentrations. MATERIALS AND METHODS: A multicenter retrospective cohort study was conducted, including 157 adult patients with heart failure who received oral amiodarone treatment. A χ2 automatic interaction-detection algorithm was used to construct a DT model. In the DT analysis, the dependent variable was set as an MDEA trough plasma concentration of ≥ 0.6 µg/mL during the steady-state period. Explanatory variables were selected as factors with p < 0.05 in multivariate logistic regression analysis. RESULTS: The adjusted odds ratios for the daily dose of amiodarone and body mass index were 1.01 (95% coefficient interval: 1.008 - 1.021, p < 0.001) and 0.91 (95% confidence interval: 0.834 - 0.988, p = 0.025), respectively. For DT analysis, the risk of reaching plasma MDEA concentrations ≥ 0.6 µg/mL was relatively high, combined with a daily dose of amiodarone > 100 mg and body mass index ≤ 22.3 kg/m2 at 69.0% (20/29), and its trend was also detected in the sensitivity analysis. CONCLUSION: Patients taking a daily amiodarone dose > 100 mg and with a body mass index ≤ 22.3 kg/m2 warrant TDM implementation for MDEA to minimize the risk of MDEA-induced tissue toxicity.

Investigation of geriatric syndromes associated with medication in Japan using insurance claims data.

AIM: Multiple risk factors are involved in geriatric syndrome (GS) occurring in older adults. Although drug therapy often contributes to GS, the specific causes among older adults in Japan remain unclear. In this study, we examined the possible prescribing cascade rate among older outpatients eligible for Late-stage Elderly Health Insurance and elucidated the differences between GS and GS associated with medication (GSAM) trends. METHODS: This retrospective study enrolled patients from health insurance claims data in Japan between October 2018 and March 2019; hospitalized patients were excluded. Two groups were identified among the participants with GS: GS (no use of GS-causing medications) and possible-GSAM (p-GSAM; use of GS-causing medications). The collected data were analyzed using the Bell Curve for Excel, and statistical significance was set at P < 0.05. RESULTS: In total, 137 781 outpatients were enrolled. Of the 32 259 outpatients who did not use GS-causing medications, 7342 were classified into the GS group. Among 105 522 outpatients who used GS-causing medications, 8347 were classified as having p-GSAM. The mean number of prescriptions was significantly higher in the p-GSAM group than in the GS group (P < 0.01). Furthermore, all GS symptoms showed significant differences, with impaired appetite being the most prevalent in the p-GSAM group than in the GS group (P < 0.01). A possible prescribing cascade was suspected in 2826 (33.9%) of 8347 outpatients in the p-GSAM group. CONCLUSION: Impaired appetite in patients taking GS-causing medications might lead to prescribing cascades. Further studies are needed to prevent such prescribing cascades. Geriatr Gerontol Int 2024; 24: 61-67.

Machine learning versus binomial logistic regression analysis for fall risk based on SPPB scores in older adult outpatients.

Objective: To compare the performance of the diagnostic model for fall risk based on the short physical performance battery (SPPB) developed using commercial machine learning software (MLS) and binomial logistic regression analysis (BLRA). Methods: We enrolled 797 out of 850 outpatients who visited the clinic between March 2016 and November 2021. Patients were categorized into the development (n = 642) and validation (n = 155) datasets. Age, sex, number of comorbidities, number of medications, body mass index (BMI), calf circumference (left-right average), handgrip strength (left-right average), total SPPB score, and history of falls were determined. We defined fall risk by an SPPB score of ≤6 in men and ≤9 in women. The main metrics used for evaluating the machine learning model and BLRA were the area under the curve (AUC), accuracy, precision, recall (sensitivity), specificity, and F-measure. The commercial MLS automatically calculates the parameter range of the highest contribution. Results: The participants included 797 outpatients (mean age, 76.3 years; interquartile range, 73.0-81.0; 288 men). The metrics of the current diagnostic model in the commercial MLS were as follows: AUC = 0.78, accuracy = 0.74, precision = 0.46, recall (sensitivity) = 0.81, specificity = 0.71, F-measure = 0.59. The metrics of the current diagnostic model in the BLRA were as follows: AUC = 0.77, accuracy = 0.75, precision = 0.47, recall (sensitivity) = 0.67, specificity = 0.77, F-measure = 0.55. The risk factors for falls in older adult outpatients were handgrip strength, female sex, experience of falls, BMI, and calf circumference in the commercial MLS. Conclusions: The diagnostic model for fall risk based on SPPB scores constructed using commercial MLS is noninferior to BLRA.

Machine Learning-Based Prediction of Digoxin Toxicity in Heart Failure: A Multicenter Retrospective Study.

Digoxin toxicity (plasma digoxin concentration ≥0.9 ng/mL) is associated with worsening heart failure (HF). Decision tree (DT) analysis, a machine learning method, has a flowchart-like model where users can easily predict the risk of adverse drug reactions. The present study aimed to construct a flowchart using DT analysis that can be used by medical staff to predict digoxin toxicity. We conducted a multicenter retrospective study involving 333 adult patients with HF who received oral digoxin treatment. In this study, we employed a chi-squared automatic interaction detection algorithm to construct DT models. The dependent variable was set as the plasma digoxin concentration (≥ 0.9 ng/mL) in the trough during the steady state, and factors with p < 0.2 in the univariate analysis were set as the explanatory variables. Multivariate logistic regression analysis was conducted to validate the DT model. The accuracy and misclassification rates of the model were evaluated. In the DT analysis, patients with creatinine clearance <32 mL/min, daily digoxin dose ≥1.6 µg/kg, and left ventricular ejection fraction ≥50% showed a high incidence of digoxin toxicity (91.8%; 45/49). Multivariate logistic regression analysis revealed that creatinine clearance <32 mL/min and daily digoxin dose ≥1.6 µg/kg were independent risk factors. The accuracy and misclassification rates of the DT model were 88.2 and 46.2 ± 2.7%, respectively. Although the flowchart created in this study needs further validation, it is straightforward and potentially useful for medical staff in determining the initial dose of digoxin in patients with HF.

Effects of discontinuation of antihypertensive drugs on frailty syndrome in outpatients: a 1-year prospectively designed retrospective chart-review pilot study.

OBJECTIVE: To investigate the effects of discontinuing antihypertensive drugs on the characteristics of patients with frailty syndrome. METHODS: This prospective pilot study was conducted between March 2016 and July 2019. Among patients who visited the frailty clinic within this period, outpatients who received antihypertensive drugs at their first visit and were followed-up for about 1 year were enrolled. Participants who discontinued or continued antihypertensive drugs during 1 year of follow-up were classified into a discontinuation group or continuation group, respectively. Each domain in the Kihon checklist (KCL), fall risk score, short physical performance battery (SPPB) score, and skeletal muscle index (SMI) were assessed at the first visit and 1-year follow-up assessment, and were compared between the two groups. RESULTS: Among 498 patients who attended the frailty clinic, 78 were enrolled (discontinuation group, n = 19; continuation group, n = 59). At the first visit, SMI scores were significantly higher in the discontinuation versus continuation group. At the 1-year assessment, physical strength in the KCL for the discontinuation group and various SPPB scores for both groups were significantly improved, and the fall risk score was improved in the continuation group. CONCLUSION: Discontinuation of antihypertensive drugs may positively affect physical performance.

[A case of unresectable gastric cancer treated with triplet combination chemotherapy with itraconazole and conversion surgery].

A 73-year-old woman visited our hospital due to carcinoembryonic antigen (CEA) level elevation (110ng/ml). She underwent an upper gastrointestinal endoscopy (EGD), enhanced computed tomography (CT), and positron emission tomography (PET) -CT. She was diagnosed with type 3 esophagogastric junction cancer with paraaortic lymph node (LN) metastases at stage IVA (cT3N4M0). She underwent triplet combination chemotherapy with itraconazole (ITCZ):nab-paclitaxel, oxaliplatin, and S-1 with ITCZ. After six cycles of this regimen, the CEA level was within normal range, and EGD and PET-CT showed no evidence of malignancy. She underwent laparoscopic proximal gastrectomy and lower esophagectomy. The surgical specimen revealed no residual tumor (pathological complete response). Three months later, her CEA level increased to 60.5ng/ml, and she had longitudinal LN recurrence. However, she took S-1 orally for 11 cycles, and the recurrent metastatic LNs improved. She received chemotherapy, including nivolumab followed by ramucirumab and nab-paclitaxel with ITCZ. The CEA level returned to the normal range, and PET-CT showed no evidence of malignancy. Her progression has been stable for 45 months after diagnosis. In summary, we encountered a case of unresectable gastric cancer with conversion surgery after triplet combination chemotherapy with ITCZ.

Sex differences in associations among metabolic syndrome, obesity, related biomarkers, and colorectal adenomatous polyp risk in a Japanese population.

To investigate sex differences in the associations among metabolic syndrome, obesity, adipose tissue-related biomarkers, and colorectal adenomatous polyps, a cross-sectional, multicenter study was conducted on 489 consecutive individuals who underwent their first colonoscopy at 3 hospitals. Plasma concentrations of adiponectin and leptin, as well as homeostatic model assessment of insulin resistance were also evaluated. The presence and number of adenomatous polyps, including advanced adenoma, were higher in men than in women. Metabolic syndrome was a risk factor for adenomatous polyps in both sexes. Large waist circumference was an independent risk factor for adenomatous polyps in men, and high BMI and large waist circumference were risk factors for adenomatous polyps in women. Interestingly, low BMI was associated with large adenomatous polyps (≥10 mm) and advanced adenoma, and waist-hip ratio was involved in proximal adenomatous polyp development only in women. In contrast, the highest quartile of leptin concentration had a 3.67-fold increased adenomatous polyp risk compared with the lowest quartile only in men. These results indicate that regarding colorectal pathogenesis, sex differences were identified in obesity but not in metabolic syndrome. Visceral obesity and a high serum leptin level may be risk factors for colorectal adenomatous polyp development in Japanese men.

Simple and rapid method for routine screening of bovine leukemia virus by loop-mediated isothermal amplification assay.

Various techniques for screening and detection of bovine leukemia virus (BLV) were compared to ascertain a rapid and simple technique for routine examination. The performance of real-time PCR, nested PCR and loop-mediated isothermal amplification (LAMP) assays was compared using DNA extracted from whole blood instead of white blood cells (WBCs) of 23 cattle. Real-time PCR, LAMP and nested PCR detected 18, 16 and 11 BLV-positive cattle, respectively. These results suggest that LAMP using DNA from whole blood could enable rapid examination, as isolation of WBCs and electrophoresis is time-consuming and could be useful as a simple and rapid method for routine screening of BLV.

Cutaneous Pseudallescheria boydii/Scedosporium apiospermum Complex (Molecular type: Scedosporium apiospermum [Clade 4]) Infection: A Case Report and Literature Review of Cases from Japan.

We report a case of subcutaneous Pseudallescheria boydii/Scedosporium apiospermum complex infection occurring in a 77-year-old Japanese female farmer suffering from interstitial pneumonia. Seven months prior to the current presentation, she noticed nodes on her right forearm after pulling up weeds, and the nodes grew larger. Two soft dome-shaped, protruded nodes ( 15 mm and 30 mm in size ) had fused together on the extensor surface of the right forearm. Yellowish-white, rice-grain-sized pustules clustered on the surface. Histopathological examination of the skin specimen showed large and small abscesses surrounded by epithelioid granuloma; separate branching hyphae within the granulation tissue were stained with PAS. No grains were observed. Fungal culture yielded fast-growing, grayish-white, fluffy colonies which were identified as Scedosporium apiospermum (Clade 4) using sequence analysis of the ß-tubulin gene. We also reviewed 28 previously reported Japanese cases of P. boydii or S. apiospermum infection presenting with skin manifestations.

Effect of co-culture with intact embryos on development of bovine separated blastomeres.

To improve embryo development in bovine separated blastomeres, we evaluated applicability of co-culture with intact embryos. The morphological quality of blastocysts derived from separated blastomeres and rate of blastocyst formation were only slightly increased when the cells were co-cultured with intact embryos, which did not provide significant differences when statistically analyzed. However, the cell count of inner cell mass (ICM), trophectoderm (TE) and total number of cells in Day 8 blastocysts were significantly higher when the cells were co-cultured with the intact embryos than those with the cells cultured individually (P<0.05). Transfer of four monozygotic pairs of blastocysts derived from the cells co-cultured with intact embryos led to three pregnancies even when the blastomeres were produced by in vitro maturation and in vitro fertilization of oocytes collected by ovum pick-up from elite cows. These results suggest that co-culturing with intact embryos may enhance development of bovine separated blastomere.

[Antiemetic effect of palonosetron in advanced colorectal cancer patients receiving mFOLFOX6 and FOLFIRI: a retrospective survey].

Controlling chemotherapy-induced nausea and vomiting(CINV)is very important for the continuation of chemotherapy. CINV can significantly affect a patient's quality of life, leading to poor compliance with further chemotherapy treatment. In this retrospective study, we assessed the efficacy of palonosetron versus granisetron for the incidence of CINV induced by mFOLFOX6 and FOLFIRI in patients with advanced colorectal cancer. Eighty-eight patients were included in the efficacy analyses: 39 patients in the palonosetron group and 49 patients in the granisetron group. The incidence of nausea in the granisetron group(Grade 1: 40. 8%, Grade 2: 10. 2% and Grade 3: 4. 1%)was significantly higher than in the palonosetron group (Grade 1: 25. 6% and Grade 2: 7. 7%, p=0. 0422). The incidence of vomiting and appetite loss in the granisetron group was not significantly higher than in the palonosetron group(p=0. 2419, p=0. 2648, respectively). This suggests that palonosetron exerts better efficacy against chemotherapy-induced nausea than granisetron in patients receiving mFOLFOX6 and FOLFIRI. Information on such analyses is useful to promote the effectiveness of cancer chemotherapy.

Genetic Analyses of an H3N8 Influenza Virus Isolate, Causative Strain of the Outbreak of Equine Influenza at the Kanazawa Racecourse in Japan in 2007.

In August 2007, an outbreak of equine influenza occurred among vaccinated racehorses with Japanese commercial equine influenza vaccine at Kanazawa Racecourse in Ishikawa prefecture in Japan. Apparent symptoms were pyrexia (38.2-41.0 degrees C) and nasal discharge with or without coughing, although approximately half of the infected horses were subclinical. All horses had been shot with a vaccine that contained two inactivated H3N8 influenza virus strains [A/equine/La Plata/93 (La Plata/93) of American lineage and A/equine/Avesta/93 (Avesta/93) of European lineage] and an H7N7 strain (A/equine/Newmarket/1/77). Influenza virus, A/equine/Kanazawa/1/2007 (H3N8) (Kanazawa/07), was isolated from one of the nasal swab samples of diseased horses. Phylogenetic analysis indicated that Kanazawa/07 was classified into the American sublineage Florida. In addition, four amino acid substitutions were found in the antigenic sites B and E in the HA1 subunit protein of Kanazawa/07 in comparison with that of La Plata/93. Hemagglutination-inhibition (HI) test using 16 serum samples from recovering horses revealed that 1.4- to 8-fold difference in titers between Kanazawa/07 and either of the vaccine strains. The present findings suggest that Japanese commercial inactivated vaccine contributed to reducing the morbidity rate and manifestation of the clinical signs of horses infected with Kanazawa/07 that may be antigenically different from the vaccine strains.

Vaccination with recombinant whole heavy chain fragments of Clostridium botulinum Type C and D neurotoxins.

Mice and ducks were subcutaneously immunized with recombinant whole heavy (H) chains of Clostridium botulinum type C and D neurotoxins, which were expressed as glutathione S-transferase fusion proteins. In the case of mice, it was confirmed that two immunizations with type C- and D-H chains, 10 microg each time, significantly increased the specific antibodies against 100-kDa H chains of type C and D neurotoxins in an immunoblot analysis and an enzyme-linked immunosorbent assay, respectively. The mice immunized with type C- and D-H chains showed no symptoms of botulism when they were challenged with C- and D-16 S toxins at doses, given intraperitoneally, of up to 10(5) and 10(6) minmum lethal doses (MLD), respectively, per mouse. Ducks were immunized with a total of 100 microg of type C-H chain. The ducks also developed specific antibodies to the type C-H chain and showed significant protection against a challenge with 10(3) duck MLD of C-16 S toxin given intravenously. These results indicate that recombinant whole H chains can be used as an effective and safe vaccine for type C and D botulism in domestic animals.

Serotyping of 800 strains of Erysipelothrix isolated from pigs affected with erysipelas and discrimination of attenuated live vaccine strain by genotyping.

Eight hundred Erysipelothrix strains isolated between 1992 and 2002 from swine with erysipelas in Japan were serotyped. Thirty-seven, 47, 73, and 643 strains were isolated from animals with acute septicemia, urticaria, chronic endocarditis, and chronic arthritis, respectively, of which 381, 146, 254, and 19 isolates belonged to serotypes 1a, 1b, and 2b and other serotypes, respectively. All serotype 1a isolates were further examined for acriflavine resistance and their genotypes to discriminate them from the attenuated live vaccine strain, defined as serotype 1a, which is resistant to 0.02% acriflavine and which shows low levels of pathogenicity in mice. Of the serotype 1a isolates, 64.6% were acriflavine resistant, with 98.4% of these acriflavine-resistant strains having been isolated from animals with chronic arthritis. By randomly amplified polymorphic DNA (RAPD) analysis, almost all the acriflavine-resistant serotype 1a strains showed the 253-bp band characteristic of vaccine strains and were easily discriminated from all 113 strains of acriflavine-sensitive serotype 1a strains from animals with acute and subacute swine erysipelas. The incidence of acriflavine-resistant strains of the distinctive RAPD type 1-2 was markedly higher than that of the other RAPD types and serotypes. RAPD type 1-2 strains also included a specific group identifiable by restriction fragment length polymorphism DNA analysis. Furthermore, the pathogenicities of 29 isolates of RAPD type 1-2 for mice were lower than those of the 21 isolates of other RAPD types. Our results indicate that RAPD type 1-2 strains are live vaccine strains and that 37% of the cases of chronic swine erysipelas detected in the past 11 years in Japan have occurred as a side effect of live vaccine use.

Phage conversion of exfoliative toxin A in Staphylococcus aureus isolated from cows with mastitis.

An exfoliative toxin produced by Staphylococcus aureus is the causative agent of staphylococcal scalded-skin syndrome (SSSS) in young children. Recently, we reported that only few isolates of S. aureus from bovine mastitis contained the eta gene encoding exfoliative toxin A (ETA) and produced ETA in vitro. In this study, we isolated temperate phages from two ETA-positive bovine isolates of S. aureus by treatment with mitomycin C. Polymerase chain reaction (PCR) assay of the phage genomes suggested that the temperate phages carried the structural gene for ETA. Moreover, the nucleotide sequence analysis of the PCR products revealed that the eta gene was located very close to an amidase gene on the phage genomes. The nucleotide sequence for the amidase gene of the bovine phage (bovine phi ETA) differed at nine positions from that of the amidase gene of phi ETA from a human isolate reported by Yamaguchi et al. [Mol. Microbiol. 38 (2000) 694], suggesting that eta-converting phages are heterogeneous. Bovine phi ETA had a head with a hexagonal outline and a non-contractile and flexible tail. Bovine phi ETA was able to lysogenize ETA-negative bovine isolates of S. aureus, and the lysogenized S. aureus isolates had the ability to produce ETA. These results suggest the possibility of horizontal transmission of the eta gene by temperate bacteriophages among bovine isolates of S. aureus.