Development and external validation of the DOAT and DOATS scores: simple decision support tools to identify disease progression among nonelderly patients with mild/moderate COVID-19.

BACKGROUND: During the fifth wave of the coronavirus disease 2019 (COVID-19) pandemic in Japan, which took place between June and September 2021, a significant number of COVID-19 cases with deterioration occurred in unvaccinated individuals < 65 years old. However, the risk factors for COVID-19 deterioration in this specific population have not yet been determined. This study developed a prediction method to identify COVID-19 patients < 65 years old who are at a high risk of deterioration. METHODS: This retrospective study analyzed data from 1,675 patients < 65 years old who were admitted to acute care institutions in Fukushima with mild-to-moderate-1 COVID-19 based on the Japanese disease severity criteria prior to the fifth wave. For validation, 324 similar patients were enrolled from 3 hospitals in Yamagata. Logistic regression analyses using cluster-robust variance estimation were used to determine predictors of disease deterioration, followed by creation of risk prediction scores. Disease deterioration was defined as the initiation of medication for COVID-19, oxygen inhalation, or mechanical ventilation starting one day or later after admission. RESULTS: The patients whose condition deteriorated (8.6%) tended to be older, male, have histories of smoking, and have high body temperatures, low oxygen saturation values, and comorbidities, such as diabetes/obesity and hypertension. Stepwise variable selection using logistic regression to predict COVID-19 deterioration retained comorbidities of diabetes/obesity (DO), age (A), body temperature (T), and oxygen saturation (S). Two predictive scores were created based on the optimism-corrected regression coefficients: the DOATS score, including all of the above risk factors, and the DOAT score, which was the DOATS score without oxygen saturation. In the original cohort, the areas under the receiver operating characteristic curve (AUROCs) of the DOATS and DOAT scores were 0.81 (95% confidence interval [CI] 0.77-0.85) and 0.80 (95% CI 0.76-0.84), respectively. In the validation cohort, the AUROCs for each score were both 0.76 (95% CI 0.69-0.83), and the calibration slopes were both 0.80. A decision curve analysis confirmed the clinical practicability of both scores in the validation cohort. CONCLUSIONS: We established two prediction scores that can quickly evaluate the risk of COVID-19 deterioration in mild/moderate patients < 65 years old.

Real-world clinical outcomes of treatment with casirivimab-imdevimab among patients with mild-to-moderate coronavirus disease 2019 during the Delta variant pandemic.

Background: Mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may reduce the efficacy of neutralizing monoclonal antibody therapy against coronavirus disease 2019 (COVID-19). We here evaluated the efficacy of casirivimab-imdevimab in patients with mild-to-moderate COVID-19 during the Delta variant surge in Fukushima Prefecture, Japan. Methods: We enrolled 949 patients with mild-to-moderate COVID-19 who were admitted to hospital between July 24, 2021 and September 30, 2021. Clinical deterioration after admission was compared between casirivimab-imdevimab users (n = 314) and non-users (n = 635). Results: The casirivimab-imdevimab users were older (P < 0.0001), had higher body temperature (≥ 38°C) (P < 0.0001) and greater rates of history of cigarette smoking (P = 0.0068), hypertension (P = 0.0004), obesity (P < 0.0001), and dyslipidemia (P < 0.0001) than the non-users. Multivariate logistic regression analysis demonstrated that receiving casirivimab-imdevimab was an independent factor for preventing deterioration (odds ratio 0.448; 95% confidence interval 0.263-0.763; P = 0.0023). Furthermore, in 222 patients who were selected from each group after matching on the propensity score, deterioration was significantly lower among those receiving casirivimab-imdevimab compared to those not receiving casirivimab-imdevimab (7.66% vs 14.0%; p = 0.021). Conclusion: This real-world study demonstrates that casirivimab-imdevimab contributes to the prevention of deterioration in COVID-19 patients after hospitalization during a Delta variant surge.

Intravascular ultrasound imaging of isolated and non aorto-ostial coronary Takayasu arteritis: a case report.

BACKGROUND: Isolated coronary Takayasu arteritis is a rare form of ischemic heart disease that typically appears as an aorto-ostial lesion. Although several vascular imaging modalities including ultrasonography, computed tomographic angiography, magnetic resonance angiography or catheter angiography, play crucial roles for diagnosing Takayasu arteritis, the intravascular ultrasound imaging of Takayasu arteritis is not well studied. CASE PRESENTATION: A 55-year-old woman who was diagnosed with heterozygous familial hypercholesterolemia underwent coronary angiography due to effort angina, which showed ostial left anterior descending coronary artery (LAD) stenosis. Although directional coronary atherectomy followed by drug-coated balloon was successfully performed, 6 months later restenosis occurred at the ostial LAD, and the ostial left circumflex coronary artery (LCx) progressed significantly. The intravascular ultrasound imaging in these lesions was noteworthy, in which the media was partly unrecognizable and an echo intensity similar to fibrotic intimal thickening traversed from the intima to the adventitia, thereby causing the whole image of the coronary artery to become unclear. Directional coronary atherectomy followed by drug-coated balloon procedures for both LAD and LCx lesions were performed again. Systemic examination of computed tomographic angiography found no other stenotic lesions except for those in the coronary arteries. Five months later, the LAD and LCx lesions progressed diffusely, therefore the coronary artery bypass graft was done. The histopathological findings of specimens of the coronary artery that were obtained during the bypass graft showed excessive fibrous thickening of the intima and adventitia, with granulomatous inflammation in the media, which led to the diagnosis of isolated coronary Takayasu arteritis. Systemic corticosteroid therapy was then started. CONCLUSIONS: We described an extremely rare case of isolated and non aorto-ostial Takayasu arteritis. The characteristic intravascular ultrasound images of diseased coronary arteries may help in the diagnosis of coronary Takayasu arteritis.

Significance of monitoring trough plasma concentration levels for invasive fungal infection prophylaxis with itraconazole oral solution in patients with hematological malignancies: a prospective study.

In this prospective study, we examined the prophylactic effect of itraconazole oral solution (ITCZ-OS) against invasive fungal disease in hematologic malignancy patients. The participants were 36 patients, at least 16 years of age, with hematologic malignancies treated at our hospital. ITCZ-OS 200 mg/day was administered orally twice a day with a target trough plasma concentration of 350 ng/ml. If the patient did not achieve the target trough plasma concentration, the dose was increased. The success rate of achieving the target trough plasma concentration of ITCZ with a dose of 200 mg/day was 63.9%. During the observation period, 2 patients (5.6%) were diagnosed with possible invasive fungal disease according to the EORTC/MSG 2008 criteria. Adverse events were observed in 2 patients (5.6%). The results showed administration of ITCZ-OS while monitoring ITCZ trough plasma concentrations to be effective for preventing invasive fungal disease, and no serious adverse events occurred. Since predicting trough levels in response to ITCZ administrations is difficult, its measurement is necessary to maintain the prophylactic effect of ITCZ.

The Impact of Phenological Gaps on Leaf Characteristics and Foliage Dynamics of an Understory Dwarf Bamboo, Sasa kurilensis.

Phenological gaps exert a significant influence on the growth of dwarf bamboos. However, how dwarf bamboos respond to and exploit these phenological gaps remain enigmatic. The light environment, soil nutrients, leaf morphology, maximum photosynthetic rate, foliage dynamics, and branching characteristics of Sasa kurilensis were examined under the canopies of Fagus crenata and Magnolia obovata. The goal was to elucidate the adaptive responses of S. kurilensis to phenological gaps in the forest understory. The findings suggest that phenological gaps under an M. obovata canopy augment the available biomass of S. kurilensis, enhancing leaf area, leaf thickness, and carbon content per unit area. However, these gaps do not appreciably influence the maximum photosynthetic rate, total leaf number, leaf lifespan, branch number, and average branch length. These findings underscore the significant impact of annually recurring phenological gaps on various aspects of S. kurilensis growth, such as its aboveground biomass, leaf morphology, and leaf biochemical characteristics. It appears that leaf morphology is a pivotal trait in the response of S. kurilensis to phenological gaps. Given the potential ubiquity of the influence of phenological gaps on dwarf bamboos across most deciduous broadleaf forests, this canopy phenomenon should not be overlooked.

Real-world clinical outcomes of treatment with molnupiravir for patients with mild-to-moderate coronavirus disease 2019 during the Omicron variant pandemic.

It is unclear whether molnupiravir has a beneficial effect on vaccinated patients infected with the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We here evaluated the efficacy of molnupiravir in patients with mild-to-moderate coronavirus disease 2019 (COVID-19) during the Omicron variant surge in Fukushima Prefecture, Japan. We enrolled patients with mild-to-moderate COVID-19 who were admitted to hospitals between January and April, 2022. Clinical deterioration after admission was compared between molnupiravir users (n = 230) and non-users (n = 690) after 1:3 propensity score matching. Additionally, we performed forward stepwise multivariate logistic regression analysis to evaluate the association between clinical deterioration after admission and molnupiravir treatment in the 1:3 propensity score-matched subjects. The characteristics of participants in both groups were balanced as indicated by covariates with a standardized mean difference of < 0.1. Regarding comorbidities, there was no imbalance between the two groups, except for the presence of hypertension, dyslipidemia, diabetes mellitus, and cardiac disease. The clinical deterioration rate was significantly lower in the molnupiravir users compared to the non-users (3.90% vs 8.40%; P = 0.034). Multivariate logistic regression analysis demonstrated that receiving molnupiravir was a factor for preventing deterioration (odds ratio 0.448; 95% confidence interval 0.206-0.973; P = 0.042), independent of other covariates. This real-world study demonstrates that molnupiravir contributes to the prevention of deterioration in COVID-19 patients after hospitalization during the Omicron variant phase.

Genetic analysis around aminoalcohol dehydrogenase gene of Rhodococcus erythropolis MAK154: a putative GntR transcription factor in transcriptional regulation.

NADP(+)-dependent aminoalcohol dehydrogenase (AADH) of Rhodococcus erythropolis MAK154 catalyzes the reduction of (S)-1-phenyl-1-keto-2-methylaminopropane ((S)-MAK) to d-pseudoephedrine, which is used as a pharmaceutical. AADH is suggested to participate in aminoalcohol or aminoketone metabolism in this organism because it is induced by the addition of several aminoalcohols, such as 1-amino-2-propanol. Genetic analysis of around the aadh gene showed that some open reading frames (ORFs) are involved in this metabolic pathway. Four of these ORFs might form a carboxysome-like polyhedral organelle, and others are predicted to encode aminotransferase, aldehyde dehydrogenase, phosphotransferase, and regulator protein. OrfE, a homologous ORF of the FadR subfamily of GntR transcriptional regulators, lies downstream from aadh. To investigate whether or not orfE plays a role in the regulation of aadh expression, the gene disruption mutant of R. erythropolis MAK154 was constructed. The ΔorfE strain showed higher AADH activity than wild-type strain. In addition, a transformed strain, which harbored multi-orfE, showed no AADH activity even in the induced condition with 1-amino-2-propanol. These results suggest that OrfE is a negative regulator that represses aadh expression in the absence of 1-amino-2-propanol.

A Novel Hematopoietic Progenitor Cell Mobilization Regimen Comprising Bortezomib, G-CSF, and Preemptive Plerixafor for Multiple Myeloma.

Adequate hematopoietic progenitor cell collection is critical for autologous peripheral blood stem cell transplantation. Conventionally, patients with multiple myeloma are treated with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) or G-CSF alone to mobilize their peripheral blood stem cells. However, some patients exhibit insufficient stem cell recruitment in response to these regimens. Recently, plerixafor has been approved for coverage by insurance in Japan. Combination treatment with plerixafor and G-CSF is now a standard procedure. In addition, treatment with bortezomib and G-CSF results in efficient stem cell recruitment. On the basis of the results from mouse studies, we hypothesized that combination treatment with bortezomib ensures efficient mobilization and mediates in vivo purging of malignant cells. Therefore, we administered a regimen of bortezomib, G-CSF, and preemptive plerixafor to 10 patients with multiple myeloma, and analyzed its efficacy and safety. The median patient age was 68 years. We collected CD34-positive cells (median: 4.9×106/kg) in a single session of apheresis from all patients. We observed no obvious myeloma cell contamination in the collected product or serious toxicity during treatment and collection. After collection, we performed autologous peripheral blood stem cell transplantation and confirmed engraftment in all patients (median: day 10). We found that the regimen is safe and reliably facilitated the collection of sufficient autologous peripheral blood stem cells by apheresis from all patients in a single day. Despite the small patient group size, we conclude that the regimen is promising for safe and efficient collection of peripheral blood stem cells for autologous transplantation in patients with multiple myeloma.

Short-term outcome of percutaneous coronary intervention with directional coronary atherectomy followed by drug-coated balloon: a preliminary report.

Directional coronary atherectomy (DCA) is a unique technique used in percutaneous coronary intervention (PCI) which involves the removal of plaque from the coronary artery. Treatment with a drug-coated balloon (DCB) appears to be effective, especially when a predilatation of the lesion is performed appropriately. We hypothesize that the combination therapy of DCA with DCB is an effective strategy in PCI. PCI with DCA followed by DCB was performed for 23 patients from December 2014 to April 2017. All DCA procedures were performed under the guidance of intravascular ultrasound (IVUS) findings and all procedures were successfully performed without incurring major complications such as a coronary perforation. Plaque area (PA) was reduced from 77.3 ± 10.4% at baseline to 50.9 ± 9.2% after DCA and luminal cross-sectional area (CSA) after PCI was enlarged from 3.6 ± 1.8 to 9.3 ± 3.3 mm2. Follow-up coronary angiography (CAG) performed at 6-10 months showed no cases having incurred restenosis. Plaque area at follow-up CAG was 52.0 ± 8.5% and luminal CSA was 9.5 ± 2.1 mm2. There were no cases undergoing target vessel revascularization (TVR) and target lesion revascularization (TLR) during the follow-up periods. PCI with DCA followed by DCB might be an effective strategy for de novo lesions.

Quadricuspid pulmonary valve stenosis treated by transcatheter pulmonary valvuloplasty with inoue balloon catheter.

The quadricuspid pulmonary valve is a relatively common congenital anomaly which is rarely complicated clinically and also tends to be under-diagnosed. The following case report shows a 62-year-old man with exertional dyspnea due to quadricuspid pulmonary valve stenosis that was diagnosed by using electrocardiography-gated multiple detector computed tomography. He was then treated effectively by transcatheter balloon pulmonary valvuloplasty using an Inoue balloon catheter. .

Cord Blood Transplantation Following Reduced-intensity Conditioning for Adult-onset Inherited Hemophagocytic Lymphohistiocytosis.

Inherited hemophagocytic lymphohistiocytosis (HLH) is a genetic anomaly disorder in which abnormally activated cytotoxic T lymphocytes cannot induce the apoptosis of target cells and antigen-presenting cells, leading to hemophagocytosis, pancytopenia, and a variety of symptoms such as a high fever. The present patient with adult-onset HLH developed refractory disease despite receiving immunosuppressive treatments. He underwent a reduced-intensity conditioning (RIC) regimen that comprised antithymocyte globulin (ATG) followed by cord blood transplantation (RIC-CBT). He achieved and maintained a complete donor type. The incorporation of ATG into RIC-CBT may prevent graft failure and control hemophagocytosis, however, further efforts are necessary to reduce infectious complications.

Practical resolution system for DL-pantoyl lactone using the lactonase from Fusarium oxysporum.

We developed an enzymatic resolution system for DL-pantoyl lactone that uses immobilized mycelia of Fusarium oxysporum, which produce a lactone-hydrolyzing enzyme (lactonase). The lactonase catalyzes the stereospecific hydrolysis of D-pantoyl lactone. One hundred eighty repeated batch reactions (total reaction time, 3780 h) were made with mycelia entrapped in calcium alginate gels as the catalyst, in the presence of 90 mM CaCl2. With a 300 gl(-1)DL-pantoyl lactone solution as the substrate, the hydrolysis rate for DL-pantoyl lactone was > 40% and the optical purity of D-pantoic acid was 90% enantiomer excess. Immobilized mycelia retained 70% of their initial lactonase activity, even after 180 batch reactions. The estimated half-life of the lactonase activity of the immobilized mycelia was 6000 h, which is 35 times higher than that of the free mycelia. The process has been exploited commercially since 1999.

Purification and characterization of a novel esterase promising for the production of useful compounds from Microbacterium sp. 7-1W.

A novel esterase catalyzing regioselective hydrolysis was purified from the membrane fraction of Microbacterium sp. 7-1W, and characterized. The enzyme was solubilized with Brij 58 and purified 13.8-fold to apparent homogeneity with 2.58% overall recovery. The relative molecular mass of the native enzyme as estimated by gel filtration was more than 600,000 Da, and the subunit molecular mass was 62,000 Da. The enzyme catalyzed cleavage of the terminal ester bonds of cetraxate esters and pantothenate esters. The K(m) and V(max) values for methyl cetraxate were 0.380 mM and 7.76 micromole min(-1) mg(-1) protein, respectively. The enzyme was inhibited by serine hydrolase inhibitors.

A case of massive pericardial effusion associated with hypocalcemic cardiomyopathy.

A 60-year-old woman with a 6-year history of numbness in her hands was admitted to hospital with dyspnea. Laboratory findings showed the elevation of creatine kinase (creatine kinase MB isoenzyme was less than 4 IU/l). Chest X-ray revealed cardiomegaly and pulmonary edema. Electrocardiogram showed a T wave inversion in V2-5 and a prolonged QT interval. Echocardiography demonstrated reduced left ventricular ejection fraction (LVEF) and massive pericardial effusion. The patient was diagnosed with heart failure. Further testing found hypocalcemia and idiopathic hypoparathyroidism. In addition to diuretics, calcium replacement therapy for hypocalcemia improved the LVEF and reduced pericardial effusion. Hypocalcemia rarely leads to heart failure and pericardial effusion. In our case, heart failure and the massive pericardial effusion were secondary to hypocalcemia due to idiopathic hypoparathyroidism. .

Successful treatment of invasive zygomycosis based on a prompt diagnosis using molecular methods in a patient with acute myelogenous leukemia.

Zygomycosis is a lethal and invasive mold infection that is often associated with hematological malignancies. The keys for successful treatment include making a rapid diagnosis and appropriately administering antifungal agents. We herein report the early diagnosis of a case of zygomycosis in a patient with acute myeloid leukemia using a deoxyribonucleic acid sequence analysis. We successfully performed allogeneic hematopoietic stem cell transplantation with the use of high-dose liposomal amphotericin B and granulocyte transfusion.

Directed evolution of an aminoalcohol dehydrogenase for efficient production of double chiral aminoalcohols.

The aminoalcohol dehydrogenase (AADH) of Rhodococcus erythropolis MAK154, which can be used as a catalyst for the stereoselective reduction of (S)-1-phenyl-1-keto-2-methylaminopropane to d-pseudoephedrine (dPE), is inhibited by the accumulation of dPE in the reaction mixture, limiting the yield of dPE. To improve this weak point of the enzyme, random mutations were introduced into aadh, and a mutant enzyme library was constructed. The mutant library was screened with a color detectable high-throughput screening method to obtain the evolved enzymes showing the activity in the presence of a high concentration of dPE. Two mutant enzymes showed higher tolerability to dPE than the wild type enzyme. Each of these enzymes had a single amino acid substitution in a different position (G73S and S214R), and a third mutant enzyme carrying both of these amino acid substitutions was constructed. Escherichia coli transformant cells, which express mutant AADHs, showed activity in the presence of 100mg/ml dPE. A kinetic parameter analysis of the wild type and mutant enzymes was carried out. As compared with the wild type enzyme, the mutant enzymes carrying the S214R amino acid substitution or both the S214R and G73S substitutions showed higher k(cat) values, and the mutant enzymes carrying the G73S amino acid substitution or both the G73S and S214R substitutions showed higher K(m) values. These results suggest that the Ser214 residue plays an important role in enzyme activity, and that the Gly73 residue participates in enzyme-substrate binding.

Prediction of remote left ventricular volumes and functions after acute myocardial infarction with successful coronary intervention.

BACKGROUND: The scintigraphic perfusion defect size (DS) at 1 week after acute myocardial infarction (AMI) predicts remote left ventricular (LV) volumes and LV ejection fraction (LVEF). The present study examined whether LV volumes and LVEF 6 months after AMI may be better predicted by the combination of LV volumes and LVEF just after reperfusion, and DS at 1 week, after AMI in patients with Thrombolysis In Myocardial Infarction (TIMI) grade III reperfusion by percutaneous coronary intervention. METHODS AND RESULTS: In 48 patients with AMI and TIMI grade III reperfusion, quantitative gated SPECT (QGS) was performed just after reperfusion, and at 1 week and 6 months after AMI. LV end-diastolic volume index decreased (108+/-8 to 93+/-6 ml/m(2), p<0.05) and LVEF increased (44+/-3 to 50+/-2%, p<0.05) 6 months after AMI. In addition, they were better predicted by a combination of LV volumes and LVEF just after reperfusion and DS at 1 week after AMI. CONCLUSIONS: In AMI with TIMI grade III reperfusion, LV volumes and LVEF at 6 months after MI correlate with the values obtained just after reperfusion. Myocardial perfusion imaging combined with QGS at reperfusion may predict these late-phase parameters.

Microbial enzymes involved in lactone compound metabolism and their biotechnological applications.

Lactone compounds are widely distributed in nature and play important roles in organisms. These compounds are synthesized and metabolized enzymatically in vivo; however, detailed investigation of these enzymes lags behind that of other common enzymes. In this paper, recent work on the enzymes involved in the metabolism of lactone compounds will be reviewed. In particular, fundamental and application studies on lactonases and Baeyer-Villiger monooxgenases of microbial origin are described.

Expression of the Fusarium oxysporum lactonase gene in Aspergillus oryzae: molecular properties of the recombinant enzyme and its application.

The lactonase gene of Fusarium oxysporum was expressed in Aspergillus oryzae for optical resolution of DL-pantoyl lactone. When the chromosomal gene encoding the full-length form of the lactonase, which has its own NH2-terminal signal peptide, was introduced in the host cells, the resulting transformant produced an enzyme of 46,600 Da, which corresponded to the wild-type enzyme. In contrast, A. oryzae transformed with the cDNA coding the mature enzyme produced a protein of 41,300 Da. Deglycosylation analysis with an endoglycosidase revealed that the difference in molecular mass arose from the different sugar contents of the recombinant enzymes. The mycelia of the transformant were used as a catalyst for asymmetric hydrolysis of DL-pantoyl lactone. The initial velocity of the asymmetric hydrolysis reaction catalyzed by the transformant was estimated to be 30 times higher than that by F. oxysporum. When the mycelia of the transformant were incubated with a 20% DL-pantoyl lactone solution for 4 h, 49.9% of the racemic mixture was converted to D-pantoic acid (>95% ee).