Development of two fully automated quick, easy, cheap, effective, rugged, and safe pretreatment methods for the extraction of psychotropic drugs from whole blood samples.

Quick, easy, cheap, effective, rugged, and safe extraction strategies are becoming increasingly adopted in various analytical fields to determine drugs in biological specimens. In the present study, we developed two fully automated quick, easy, cheap, effective, rugged, and safe extraction methods based on acetonitrile salting-out assisted liquid-liquid extraction (method 1) and acetonitrile salting-out assisted liquid-liquid extraction followed by dispersive solid-phase extraction (method 2) using a commercially available automated liquid-liquid extraction system. We applied these methods to the extraction of 14 psychotropic drugs (11 benzodiazepines and carbamazepine, quetiapine, and zolpidem) from whole blood samples. Both methods prior to liquid chromatography-tandem mass spectrometry analysis exhibited high linearity of calibration curves (correlation coefficients, > 0.9997), ppt level detection sensitivities, and satisfactory precisions (< 8.6% relative standard deviation), accuracies (within ± 16% relative error), and matrix effects (81-111%). Method 1 provided higher recovery rates (80-91%) than method 2 (72-86%), whereas method 2 provided higher detection sensitivities (limits of detection, 0.003-0.094 ng/mL) than method 1 (0.025-0.47 ng/mL) owing to the effectiveness of its dispersive solid-phase extraction cleanup step. These fully automated extraction methods realize reliable, labor-saving, user-friendly, and hygienic extraction of target analytes from whole blood samples.

Easily Operable Quantification Method of 21 Plant-Derived Alkaloids in Human Serum by Automatic Sample Preparation and Liquid Chromatography-Tandem Mass Spectrometry.

In this study, we developed an easily operable quantification method for 21 plant-derived alkaloids in human serum by automatic sample preparation and liquid chromatography-tandem mass spectrometry. We designed to perform parallel sample preparation by a developed apparatus, which increased sample throughput. We conducted an automatic sample preparation through de-proteinization with 0.1% formic acid in methanol and achieved recovery rates of 89-107% (2.0-14% RSD) for all targeted analytes, demonstrating its high repeatability. The method validation results were satisfactory as follows: the linearity (r 2) of each calibration curve ranged from 0.978 to 1.000; the inter- and intra-day accuracies were 89.0-125% and 82.1-110%, respectively; the inter- and intra-day precisions were below 13% and 10%, respectively. Additionally, the lower limits of detection and quantification were 0.0044-0.047 and 0.013-0.14 ng/mL, respectively. Finally, the developed method was applied to pseudo-protoveratrine A poisoning serum and pseudo-colchicine poisoning serum, which were prepared by diluting acute-poisoning mice serum with human serum. Our method successfully quantitated protoveratrine A (0.15-0.25 ng/mL) and colchicine (4.8-6.0 ng/mL). Thus, our method is essential for prompt clinical treatment and critical care on patient in acute intoxication cases caused by plant-derived alkaloids. Supplementary Information: The online version contains supplementary material available at 10.1007/s10337-022-04212-5.

Increasing canopy photosynthesis in rice can be achieved without a large increase in water use-A model based on free-air CO2 enrichment.

Achieving higher canopy photosynthesis rates is one of the keys to increasing future crop production; however, this typically requires additional water inputs because of increased water loss through the stomata. Lowland rice canopies presently consume a large amount of water, and any further increase in water usage may significantly impact local water resources. This situation is further complicated by changing the environmental conditions such as rising atmospheric CO2 concentration ([CO2 ]). Here, we modeled and compared evapotranspiration of fully developed rice canopies of a high-yielding rice cultivar (Oryza sativa L. cv. Takanari) with a common cultivar (cv. Koshihikari) under ambient and elevated [CO2 ] (A-CO2 and E-CO2 , respectively) via leaf ecophysiological parameters derived from a free-air CO2 enrichment (FACE) experiment. Takanari had 4%-5% higher evapotranspiration than Koshihikari under both A-CO2 and E-CO2 , and E-CO2 decreased evapotranspiration of both varieties by 4%-6%. Therefore, if Takanari was cultivated under future [CO2 ] conditions, the cost for water could be maintained at the same level as for cultivating Koshihikari at current [CO2 ] with an increase in canopy photosynthesis by 36%. Sensitivity analyses determined that stomatal conductance was a significant physiological factor responsible for the greater canopy photosynthesis in Takanari over Koshihikari. Takanari had 30%-40% higher stomatal conductance than Koshihikari; however, the presence of high aerodynamic resistance in the natural field and lower canopy temperature of Takanari than Koshihikari resulted in the small difference in evapotranspiration. Despite the small difference in evapotranspiration between varieties, the model simulations showed that Takanari clearly decreased canopy and air temperatures within the planetary boundary layer compared to Koshihikari. Our results indicate that lowland rice varieties characterized by high-stomatal conductance can play a key role in enhancing productivity and moderating heat-induced damage to grain quality in the coming decades, without significantly increasing crop water use.

TogoTable: cross-database annotation system using the Resource Description Framework (RDF) data model.

TogoTable (http://togotable.dbcls.jp/) is a web tool that adds user-specified annotations to a table that a user uploads. Annotations are drawn from several biological databases that use the Resource Description Framework (RDF) data model. TogoTable uses database identifiers (IDs) in the table as a query key for searching. RDF data, which form a network called Linked Open Data (LOD), can be searched from SPARQL endpoints using a SPARQL query language. Because TogoTable uses RDF, it can integrate annotations from not only the reference database to which the IDs originally belong, but also externally linked databases via the LOD network. For example, annotations in the Protein Data Bank can be retrieved using GeneID through links provided by the UniProt RDF. Because RDF has been standardized by the World Wide Web Consortium, any database with annotations based on the RDF data model can be easily incorporated into this tool. We believe that TogoTable is a valuable Web tool, particularly for experimental biologists who need to process huge amounts of data such as high-throughput experimental output.

Recurrent Staphylococcus aureus abscess and fatal pneumococcal septicemia due to IRAK-4 deficiency.

We describe the case of an infant with recurrent episodes of staphylococcal skin abscess and subsequent lethal pneumococcal meningitis/septicemia due to interleukin-1 receptor-associated kinase 4 (IRAK-4) deficiency. In this case, systemic signs of inflammatory response were poor and delayed. Among all other reported cases of IRAK-4 deficiency, none involved severe viral or fungal disease, and the range of infecting bacteria was narrow.

Late-maturing cooking rice Sensyuraku has excellent properties, equivalent to sake rice, for high-quality sake brewing.

Low protein content and sufficient grain rigidity are desired properties for the rice used in high-quality sake brewing such as Daiginjo-shu (polishing ratio of the rice, less than 50%). Two kinds of rice, sake rice (SR) and cooking rice (CR), have been used for sake brewing. Compared with those of SR, analyses of CR for high-quality sake brewing using highly polished rice have been limited. Here we described the original screening of late-maturing CR Sensyuraku (SEN) as rice with low protein content and characterization of its properties for high-quality sake brewing. The protein content of SEN was lower than those of SR Gohyakumangoku (GOM) and CR Yukinosei (YUK), and its grain rigidity was higher than that of GOM. The excellent properties of SEN with respect to both water-adsorption and enzyme digestibility were confirmed using a Rapid Visco Analyzer (RVA). Further, we confirmed a clear taste of sake produced from SEN by sensory evaluation. Thus, SEN has excellent properties, equivalent to those of SR, for high-quality sake brewing.

Exogenous and endogenous factors affecting stock market transactions: A Hawkes process analysis of the Tokyo Stock Exchange during the COVID-19 pandemic.

Transactions in financial markets are not evenly spaced but can be concentrated within a short period of time. In this study, we investigated the factors that determine the transaction frequency in financial markets. Specifically, we employed the Hawkes process model to identify exogenous and endogenous forces governing transactions of individual stocks in the Tokyo Stock Exchange during the COVID-19 pandemic. To enhance the accuracy of our analysis, we introduced a novel EM algorithm for the estimation of exogenous and endogenous factors that specifically addresses the interdependence of the values of these factors over time. We detected a substantial change in the transaction frequency in response to policy change announcements. Moreover, there is significant heterogeneity in the transaction frequency among individual stocks. We also found a tendency where stocks with high market capitalization tend to significantly respond to external news, while their excitation relationship between transactions is weak. This suggests the capability of quantifying the market state from the viewpoint of the exogenous and endogenous factors generating transactions for various stocks.

Polishing properties of sake rice Koshitanrei for high-quality sake brewing.

The Japanese high-quality sake Daiginjo-shu is made from highly polished rice (polishing ratio, less than 50%). Here we showed that the sake rice Koshitanrei (KOS) has an excellent polishing property. Rice grains of KOS had the same lined white-core region as the sake rice Yamadanishiki (YAM). The grain rigidity/hardness of KOS was higher than that of the sake rice Gohyakumangoku (GOM). The loss ratio of KOS after high polishing by an industrial polishing machine was lower than that of GOM. Further, a clear taste of sake produced from KOS was confirmed by sensory evaluation.

A surge in respiratory syncytial virus infection-related hospitalizations associated with the COVID-19 pandemic: An observational study at pediatric emergency referral hospitals in Tokushima Prefecture.

The outbreak of coronavirus disease (COVID-19) resulted in implementation of social distancing and other public health measures to control the spread of infection and improve prevention, resulting in a decrease in respiratory syncytial virus (RSV) and pediatric respiratory tract infection rates. However, there was a rapid and large re-emergence of RSV infection in Japan. Notably, we were faced with a difficult situation wherein there was a shortage of hospital beds. This study aimed to examine the epidemiological patterns of RSV-related hospitalizations among children before and after the COVID-19 pandemic onset at two pediatric emergency referral hospitals covering the entire Tokushima Prefecture. Data were extracted from electronic medical records of children hospitalized with RSV infection between January 1, 2018, and December 31, 2021. All patients meeting the eligibility criteria were included in this study. The rates of study outcomes were documented annually during 2018-2021 and compared between the 2018-2020 and 2021 periods. In 2020, there was no RSV infection outbreak. Hospitalizations at the peak week in 2021 were 2.2- and 2.8-fold higher than those in 2018 and 2019, respectively. Hospitalizations in 2021 were concentrated within a short period. In addition, there was a significant increase in hospitalizations among children aged 3-5 months and those older than 24 months. The high-flow nasal cannula (HFNC) use rate nearly doubled in 2021. A new pandemic in the future may cause an outbreak of RSV infection that can result in an intensive increase in the number of hospitalizations of pediatric patients requiring respiratory support, especially in infants aged <6 months. There is an urgent need to improve the preparedness of medical systems, particularly in terms of the number of inpatient beds and the immediate availability of HFNC.

Japan's voluntary lockdown: further evidence based on age-specific mobile location data.

Changes in people's behavior during the COVID-19 pandemic can be regarded as the result of two types of effects: the "intervention effect" (changes resulting from government orders for people to change their behavior) and the "information effect" (voluntary changes in people's behavior based on information about the pandemic). Using age-specific mobile location data, we examine how the intervention and information effects differ across age groups. Our main findings are as follows. First, the age profile of the intervention effect shows that the degree to which people refrained from going out was smaller for older age groups, who are at a higher risk of serious illness and death, than for younger age groups. Second, the age profile of the information effect shows that the degree to which people stayed at home tended to increase with age for weekends and holidays. Thus, while Acemoglu et al. (2020) proposed targeted lockdowns requiring stricter lockdown policies for the oldest group in order to protect those at a high risk of serious illness and death, our findings suggest that Japan's government intervention had a very different effect in that it primarily reduced outings by the young, and what led to the quarantining of older groups at higher risk instead was people's voluntary response to information about the pandemic. Third, the information effect has been on a downward trend since the summer of 2020. It is relatively more pronounced among the young, so that the age profile of the information effect remains upward sloping.

Japan's voluntary lockdown.

Japan's government has taken a number of measures, including declaring a state of emergency, to combat the spread COVID-19. We examine the mechanisms through which the government's policies have led to changes in people's behavior. Using smartphone location data, we construct a daily prefecture-level stay-at-home measure to identify the following two effects: (1) the effect that citizens refrained from going out in line with the government's request, and (2) the effect that government announcements reinforced awareness with regard to the seriousness of the pandemic and people voluntarily refrained from going out. Our main findings are as follows. First, the declaration of the state of emergency reduced the number of people leaving their homes by 8.5% through the first channel, which is of the same order of magnitude as the estimates obtained for lockdowns in the United States. Second, a 1% increase in new infections in a prefecture reduces people's outings in that prefecture by 0.027%. Third, the government's requests are responsible for about one quarter of the decrease in outings in Tokyo, while the remaining three quarters are the result of citizens obtaining new information through government announcements and the daily release of the number of infections. The findings suggest that what mattered for containing the spread of COVID-19 was not strong, legally binding measures but the provision of appropriate information that encouraged people to change their behavior.

Visualizing Social and Behavior Change due to the Outbreak of COVID-19 Using Mobile Phone Location Data.

We visualize the rates of stay-home for residents by region using the difference between day-time and night-time populations to detect residential areas, and then observing the numbers of people leaving residential areas. There are issues with measuring stay-home rates by observing numbers of people visiting downtown areas, such as central urban shopping centers and major train stations. The first is that we cannot eliminate the possibility that people will avoid areas being observed and go to other areas. The second is that for people visiting downtown areas, we cannot know where they reside. These issues can be resolved if we quantify the degree of stay-home using the number of people leaving residential areas. There are significant differences in stay-home levels by region throughout Japan. By this visualization, residents of each region can see whether their level of stay-home is adequate or not, and this can provide incentive toward compliance suited to the residents of the region.

Minimal residual disease-based augmented therapy in childhood acute lymphoblastic leukemia: a report from the Japanese Childhood Cancer and Leukemia Study Group.

BACKGROUND: The majority of minimal residual disease (MRD)-positive patients with acute lymphoblastic leukemia (ALL) have poor outcomes. The ALL2000 study was performed to evaluate the efficacy of augmented chemotherapy based on MRD-restratification in childhood ALL. PROCEDURE: Between 2000 and 2004, 305 eligible patients with precursor B or T-cell ALL were enrolled in the ALL2000 study. The ALL941-based therapy protocol utilized PCR MRD assays using Immunoglobulin and T-cell receptor gene rearrangements. They were initially stratified into three risk-groups according to leukocyte count and age, and MRD levels were measured at weeks 5 (TP1) and 12 (TP2) for a second stratification. From week 14, patients with MRD levels ≥ 10(-3) received an increase in therapy (one risk group higher), while the remainder continued to receive the initial risk-adapted therapy. RESULTS: The overall 5-year event-free survival (EFS) rate for ALL2000 was 79.7 ± 2.4%. MRD stratification was feasible for 234 of 301 patients (77%) who achieved complete remission. The EFS rate of the MRD stratifiable (MRD) group was 82.5 ± 2.6%, considerably superior to the 74.7 ± 5.7% of MRD non-stratifiable (Non-MRD) group (P = 0.084) and the 74.4 ± 2.1% for ALL 941 (P = 0.012). MRD-positive patients at TP2 showed inferior outcomes as compared with MRD-negative cases, but the difference did not reach a statistically significant level in any risk groups or immunophenotypes. CONCLUSIONS: These results suggest that augmented therapy for MRD-positive patients at TP2 contributed to better outcomes of the ALL2000 study.

Double apheresis of peripheral blood stem cells in a single day in children mobilized by granulocyte colony-stimulating factor for transplantation.

Due to the movement of hematopoietic stem cells through the bone marrow environment, it may be possible to effectively harvest peripheral blood stem cells in a second apheresis within a few hours after a first apheresis. In a retrospective analysis, 107 aphereses were performed in consecutive 33 pediatric and six healthy pediatric donors who received granulocyte-colony stimulating factor at 10 microg/kg/day or 400 microg/m(2)/day for five days. The median age and weight of cases were seven yr (range 1-19) and 20 kg (range 8-87). The toxicities related to apheresis procedure were minimal in both aphereses. In 22 double aphereses, the average number of CD34-positive cells per body weight (kg) collected was 5.3 +/- 4.2 (range 0.6-16.6) and 4.7 +/- 3.1 (range 0.2-10.9) x 10(6) in the first and second aphereses, respectively (p = 0.569). Multivariate analysis showed that number of CD34-positive cells collected in the first apheresis (p = 0.008) was an independent factor of increased CD34-positive cells in the second apheresis. Double apheresis in a single day was feasible and this procedure may be able to lessen the burden of apheresis compared to two consecutive-day apheresis.

Successful allogeneic unrelated bone marrow transplantation using reduced-intensity conditioning for the treatment of X-linked adrenoleukodystrophy in a one-yr-old boy.

The childhood cerebral form of X-linked ALD is a demyelinating disorder of the central nervous system, which rapidly leads to total disability and death. Allogeneic stem cell transplantation benefits patients who show early evidence of the demyelination. We report here a one-yr-old boy with ALD who received HLA-matched unrelated BMT in an early stage of the disease after careful planning and observation since his birth. BMT was performed when MRI began to show slight signal intensity changes in the white matter of the brain. Pretransplant conditioning consisted of fludarabine, l-PAM and TBI (2 Gy). GVHD prophylaxis consisted of cyclosporine A and short-course methotrexate. The patient showed an uneventful BMT course with fast and stable engraftment. Following BMT, the plasma levels of VLCFA decreased gradually and MRI changes improved. The patient did not have any evidence of further neurological deterioration 22 months following the transplant. Although this is still a short follow-up, it has been shown that BMT should be considered when a child has a biochemical diagnosis and MRI findings of ALD without any neurological signs. RIST should be considered as a pretransplant conditioning for ALD.

Interannual variability of leaf area index of an evergreen conifer stand was affected by carry-over effects from recent climate conditions.

Despite the relevance of leaf area index (LAI) to forest productivity, few studies have focused on the interannual variability of LAI of an evergreen stand and its relationship with stand growth and meteorological factors. We estimated the change in LAI of an evergreen conifer (Chamaecyparis obtusa) stand over 19 years from a dataset using allometric methods. The LAI varied between 7.1 and 8.8 m2 m-2, with a 95% confidence interval of <1.1 m2 m-2 over the 19 years. This LAI range was maintained such that the gradual increase in leaf area (LA) of the largest trees counterbalanced the gradual loss in LA of the smallest trees. Meanwhile, more trees showed a temporary decrease in LA in years with low summer precipitation. The LAI and current-year mean temperature for July and August (TJA) were weakly correlated, whereas the correlation coefficient increased (r = 0.93) when LAI was correlated with the moving average TJA over the previous 6 years, which agreed with the estimated turnover time of canopy foliage. The annual stem biomass growth rate was significantly positively correlated with summer precipitation, but not with LAI. These results will be useful for refining models in studies on forest growth and global climate change.

The gradual evolution of buyer-seller networks and their role in aggregate fluctuations.

Buyer-seller relationships among firms can be regarded as a longitudinal network in which the connectivity pattern evolves as each firm receives productivity shocks. Based on a data set describing the evolution of buyer-seller links among 55,608 firms over a decade and structural equation modeling, we find some evidence that interfirm networks evolve reflecting a firm's local decisions to mitigate adverse effects from neighbor firms through interfirm linkage, while enjoying positive effects from them. As a result, link renewal tends to have a positive impact on the growth rates of firms. We also investigate the role of networks in aggregate fluctuations.

Successful unrelated cord blood transplantation in an infant with Wiskott-Aldrich syndrome following recurrent cytomegalovirus disease.

We describe successful unrelated cord blood transplantation in a 14-month-old boy with Wiskott-Aldrich syndrome. He had been suffering from recurrent cytomegalovirus (CMV) pneumonia. Ganciclovir was given pretransplantation and posttransplantation, and CMV antigenemia was monitored as a marker of reactivation. The conditioning regimen was cyclophosphamide, busulfan, and antithymocyte globulin. The patient received an HLA 1-locus-mismatched cord blood unit, and the total number of infused nucleated cells was 9.0 x 10(7)/kg. Neutrophil engraftment was achieved on day +20, and a platelet count greater than 50 x 10(9)/L was achieved on day +51. A normal lymphoproliferative response to phytohemagglutinin mitogen was detectable 7 months posttransplantation. Long-term use of ganciclovir prevented CMV reactivation and did not compromise engraftment.

Effect of granulocyte colony-stimulating factor on bone metabolism during peripheral blood stem cell mobilization.

Granulocyte colony-stimulating factor (G-CSF) has been shown to affect the biochemical markers of bone metabolism, including serum bone alkaline phosphatase (BALP), serum osteocalcin, and urine deoxypyridinoline. To determine the association between bone resorption and formation and the G-CSF-induced mobilization of peripheral blood stem cells (PBSC), we examined these markers during mobilization in 19 healthy donors. The average (+/- SEM) serum BALP level before treatment was 81.6 +/- 17.0 IU/dL, and the level increased significantly to 117.7 +/- 15.8 IU/dL on day 5 of G-CSF administration (P < .0001). The urine deoxypyridinoline level before treatment was 12.3 +/- 2.4 nmol/mmol creatinine, and this level also increased significantly to 19.4 +/- 3.0 nmol/mmol creatinine on day 5 of G-CSF administration (P < .0001). In contrast, the average level of serum osteocalcin significantly decreased from 8.07 +/- 2.88 ng/mL to 1.53 +/- 0.18 ng/mL on day 5 (P = .0353). During G-CSF administration, we also studied the serum levels of various cytokines (IL-1beta, osteoclastogenesis inhibitory factor [OCIF], IL-6, tumor necrosis factor alpha, transforming growth factor beta, interferon-gamma, macrophage colony-stimulating factor) related to bone metabolism. Only the kinetics of OCIF were significantly affected. The serum level of OCIF increased immediately after the start of G-CSF administration and remained high during G-CSF administration. These results demonstrate that high-dose G-CSF affects bone metabolism and that OCIF may play a role in bone metabolism. Consistent with the notion that G-CSF affects bone metabolism, a significant correlation was observed between CD34+ cell yield and the increase in urine deoxypyridinoline but not for the changes in serum BALP and osteocalcin levels. This result suggests that bone resorption is either directly or indirectly related to the mobilization of PBSC by G-CSF.