Efficacy of Venetoclax and Azacitidine in Acute Myeloid Leukemia Compared to Azacitidine Monotherapy: Real-World Experience.

BACKGROUND/AIM: The combination of venetoclax (VEN) and azacitidine (AZA) (VEN+AZA) leads to higher complete remission rates and longer overall survival (OS) in patients with untreated acute myeloid leukemia (AML) who are ineligible for intensive combination chemotherapy. In practice, the doses of VEN and AZA are reduced at the attending physician's discretion to avoid adverse events; however, the impact of dose and duration reductions has not been fully clarified. We analyzed whether the efficacy was maintained with reduced VEN+AZA compared to AZA monotherapy in the real world. PATIENTS AND METHODS: A total of 33 patients were included; 17 (10 newly diagnosed, 7 primary refractory or relapsed) received VEN+AZA, and 16 (7 newly diagnosed, 9 primary refractory or relapsed) received AZA. We analyzed complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates, OS, and the incidence of adverse events. RESULTS: CR/CRi were achieved in 7/17 (41.2%) and 11/17 (64.7%) patients in the VEN+AZA group and 0/15 (0%) and 2/15 (6.7%) patients in the AZA group, respectively. The CR/CRi rate was higher in the VEN+AZA group than in the AZA group (p=0.001). OS was longer in the VEN+AZA group than in the AZA group (p=0.03), with a median of 506 days [95% confidence interval (CI)=234-585 days] and 208 days (95% CI=52-343 days), respectively. CONCLUSION: The doses of the VEN+AZA combination were reduced at the attending physician's discretion, resulting in a higher CR/CRi rate and longer OS than AZA monotherapy and is considered useful for AML in the real world.

Laryngopharyngeal Mucosal Injury Due to Nasogastric Tube Insertion during Cardiopulmonary Resuscitation: A Retrospective Cohort Study.

BACKGROUND: Patients under cardiopulmonary resuscitation (CPR) are at high risk of aspirating gastric contents. Nasogastric tube insertion (NGTI) after tracheal intubation is usually performed blindly. This sometimes causes laryngopharyngeal mucosal injury (LPMI), leading to severe bleeding. This study clarified the incidence of LPMI due to blind NGTI during CPR. METHODS: We retrospectively analyzed 84 patients presenting with cardiopulmonary arrest on arrival, categorized them into a Smooth group (Smooth; blind NGTI was possible within 2 min), and Difficult group (blind NGTI was not possible), and consequently performed video laryngoscope-assisted NGTI. The laryngopharyngeal mucosal condition was recorded using video laryngoscope. Success rates and insertion time for the Smooth group were calculated. Insertion number and LPMI scores were compared between the groups. Each regression line of outcome measurements was obtained using simple regression analysis. We also analyzed the causes of the Difficult group, using recorded video laryngoscope-assisted videos. RESULTS: The success rate was 78.6% (66/84). NGTI time was 48.8 ± 4.0 s in the Smooth group. Insertion number and injury scores in the Smooth group were significantly lower than those in the Difficult group. The severity of LPMI increased with NGT insertion time and insertion number. CONCLUSIONS: Whenever blind NGTI is difficult, switching to other methods is essential to prevent unnecessary persistence.

Fibrates and the risk of cardiovascular outcomes in chronic kidney disease patients.

BACKGROUND AND HYPOTHESIS: The high risk of major adverse cardiovascular events (MACE) in patients with chronic kidney disease (CKD) has been well described. However, the efficacy of fibrates on the risk of MACE in patients with CKD remains unclear. METHODS: We conducted a nested case-control study using data from a large administrative database that included more than 1.5 million Japanese patients. We defined cases as CKD patients with incidences of MACE and matched them with controls based on age, sex, calendar year of cohort entry, and CKD stage. Fibrate exposure timing was categorized as current, recent, or past. A conditional logistic regression analysis was used to investigate the association between fibrate use and the risk of MACE. RESULTS: Our study included 47 490 patients with CKD, with 15 830 MACE identified during a median follow-up of 9.4 months. The number of fibrates used during the study period were 556 (3.5%) in the case group and 1 109 (3.5%) in the control group. Fibrate use was significantly associated with a decreased risk of MACE (odds ratio [OR], 0.84; 95% confidence interval [CI], 0.75 to 0.94), particularly for current (OR, 0.81; 95% CI, 0.68-0.97) and recent use (OR, 0.65; 95% CI, 0.48-0.90). Regarding the class effect of fibrates, pemafibrate use, but not bezafibrate or fenofibrate use, was significantly associated with a decreased risk of MACE (OR, 0.73; 95% CI, 0.528-0.997). CONCLUSION: Recent and current fibrate use, especially pemafibrate use, was associated with a reduced risk of MACE in patients with CKD. This suggests the potential benefits of continuous fibrate therapy and the possible superiority of pemafibrate over other fibrates. However, further investigations in different populations are required to confirm the generalizability of these findings.

Assessment of Diagnosis Timing of Attention-Deficit/Hyperactivity Disorder in Working-Age Workers with Psychiatric Diseases Using Large Claims Data.

Attention deficit/hyperactivity disorder (ADHD) is a common developmental disorder. This study aims to clarify the timing of diagnosis of ADHD in working-age workers with psychiatric comorbidities using large claims data in Japan. Based on a literature survey, we identified 10 typical comorbidities of ADHD. Among 3064162 participants with social insurance, 215060 working-age workers who were diagnosed with the 10 typical comorbidities of ADHD were included. Cohort 1 consisted of 96994 patients with the index date set as the earliest date of diagnosis of a comorbidity within the 12-month screening and 12-month observation periods. In cohort 2, 107436 patients were included, and the first date of diagnosis of each comorbidity was used as the index month. In cohort 1, 0.19% of the patients were diagnosed with ADHD after being diagnosed with a typical comorbidity. In cohort 2, 4 out of 4 patients with ADHD and obsessive-compulsive disorders were diagnosis ADHD after obsessive-compulsive disorders. Pervasive developmental disorders were the highest comorbidity of ADHD for 62 out of 566 (11.0%) patients. This is the first study to determine the proportion of ADHD with typical comorbidities in working-age workers in Japan. Our findings highlight the need for timely diagnosis of ADHD to improve patients' QOL.

Descriptive Study on a Nationwide Exploratory Questionnaire Survey of Emergency Contraceptive Pills and Their Sexual History and Knowledge in Japan.

A shift towards obtaining emergency contraceptives without a prescription have been discussed in Japan. In response to this social background, we aimed at investigating the background of sexual intercourse, emergency contraceptive use, and knowledge of sexual and reproductive health education among women of reproductive age in Japan. In this study, we conducted a national wide cross-sectional questionnaire survey using a total of 4 web-based domains (background, sexual history, emergency contraceptives, and sexual and reproduction-related knowledge) composed of 50 questions. We obtained responses from a total of 4,631 participants of varying age groups (18-25, 26-35, and 36-45 years old) and 47 prefectures (84 to 118 from each prefecture). Among participant responses, 69.7% are sexually active, of which 49.0% had experiences of sexual intercourse with an unknown person. The responses from a total of 737 participants who have sexual intercourse, know of emergency contraceptives, and have experienced a situation that necessitated the use of emergency contraceptives, were analyzed. Of these participants, 46.4% (342/737) took emergency contraceptives, while 43.6% (321/737) participants did not take emergency contraceptives. Participants who have the knowledge for obtaining emergency contraceptives through the correct means were 52.6% (2438/4631). This study showed that approximately half of participants may not have correct knowledge of emergency contraceptives. In addition, approximately half of sexually active participants are facing unintended pregnancies due to a lack of sexual and reproductive awareness. Hence, comprehensive sex education is necessary to achieve social and regulatory changes centered on emergency contraceptives.

A Study on Pharmacokinetics of Acetylsalicylic Acid Mini-Tablets in Healthy Adult Males-Comparison with the Powder Formulation.

Children with Kawasaki disease are prescribed acetylsalicylic acid powder as an antipyretic analgesic and antiplatelet agent; however, some of it remains in the mouth, leading to a bitter or sour taste. To address this issue, an in-hospital mini-tablet formulation of acetylsalicylic acid was developed. In order to use the mini-tablets safely and effectively, dissolution tests alone are not sufficient. Therefore, an open-label crossover study on six healthy participants was conducted to evaluate comparative pharmacokinetic parameters. The pharmacokinetic parameters of salicylic acid were Cmax: 4.80 ± 0.79 mg/L (powder; P), 5.03 ± 0.97 mg/L (mini-tablet; MT), AUC0-12: 18.0 ± 3.03 mg-h/L (P), 18.9 ± 4.59 mg-h/L (MT), those of acetylsalicylic acid Cmax: 0.50 ± 0.20 mg/L (P), 0.41 ± 0.24 mg/L (MT), AUC0-12: 0.71 ± 0.27 mg-h/L (P), 0.61 ± 0.36 mg-h/L (MT), with no significant differences between the mini-tablet and powder formulations. Although pharmacokinetic results obtained from adults cannot be directly applied to children, the results of this study are important for predicting pharmacokinetics. Furthermore, a formulation that can improve medication adherence in children who have difficulty taking acetylsalicylic acid powder, thus contributing to pediatric drug therapy.

Thyroid dysfunction with atezolizumab plus bevacizumab after lenvatinib in hepatocellular carcinoma: A case series.

Atezolizumab plus bevacizumab is the recommended first-line treatment for unresectable hepatocellular carcinoma, based on guidelines from the Barcelona Clinic Liver Cancer prognosis and treatment strategy. However, atezolizumab plus bevacizumab may be used after administration of lenvatinib. Here, we present four patients who developed thyroid dysfunction after second-line treatment with atezolizumab plus bevacizumab, but not after lenvatinib alone. The patients were treated with lenvatinib and/or atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma at Showa University Northern Yokohama Hospital. Of patients treated with only lenvatinib or atezolizumab plus bevacizumab, 2/18 (11%) and 4/15 (27%) developed thyroid dysfunction, respectively. All four patients treated with atezolizumab plus bevacizumab after lenvatinib developed hypothyroidism after 2-14 doses of atezolizumab plus bevacizumab. Three patients developed Grade 2 symptoms and were treated with levothyroxine sodium. In patients with hepatocellular carcinoma, the incidence of thyroid dysfunction may be higher among patients treated with atezolizumab plus bevacizumab after lenvatinib than those treated with lenvatinib or atezolizumab plus bevacizumab alone.

Implementation of a Transdiagnostic Universal Prevention Program on Anxiety in Junior High School Students After School Closure During the COVID-19 Pandemic.

School closures due to the coronavirus disease 2019 (COVID-19) pandemic have worsened mental health problems for children and adolescents worldwide. We aimed to examine the follow-up effectiveness of a transdiagnostic universal prevention program for anxiety of junior high school students after a nationwide school closure during the COVID-19 outbreak in Japan. A total of 117 junior high school students were included in the analysis. We used the Unified Universal Prevention Program for Diverse Disorders (Up2-D2) program; the Up2-D2 comprises cognitive-behavioral and positive psychological interventions provided over twelve 45-minute sessions. The program was originally implemented between June and July 2020, immediately after pandemic-related school closures had ended in Japan. The program assessments were based on students' responses to a questionnaire incorporating five scales to measure indicators such as internalizing and externalizing problems. Assessments were carried out before, immediately after, two-month, and six-month after implementing the program. Mixed models for the whole sample showed small anxiety improvement effects immediately post-intervention and two-month, and six-month assessments (g = -0.25, g = -0.44, and g = -0.30, respectively). The anxiety reducing effects were even greater for the higher-anxiety group at the post-, 2-month, and 6-month assessments (g = -1.48; g = -1.59; g = -1.06, respectively). Although there was no control group, these results indicate that the transdiagnostic universal prevention intervention reduce only anxiety, but not other outcomes (depression, anger, and self-efficacy) in junior high students returning to school following school closures related to the COVID-19 pandemic in Japan.

Comparison of Bitterness Intensity between Prednisolone and Quinine in a Human Sensory Test Indicated Individual Differences in Bitter-Taste Perception.

Prednisolone is a frequently prescribed steroid with a bitter, unpalatable taste that can result in treatment refusal. Oral suspensions or powder dosage forms are often prescribed, particularly to pediatric patients, as they improve swallowability and ease of dose adjustment. Consequently, the bitterness of prednisolone is more apparent in these dosage forms. Few studies have investigated prednisolone's bitterness. Thus, in this study, 50 adults evaluated the bitterness of prednisolone using the generalized Labeled Magnitude Scale (gLMS), in comparison with quinine, a standard bitter substance. Overall, prednisolone-saturated solution demonstrated the same extent (mean gLMS score: 46.8) of bitterness as 1 mM quinine solution (mean gLMS score: 40.1). Additionally, large individual differences were observed in the perception of the bitterness of prednisolone and quinine. Perceived flavors of some drugs are reportedly associated with bitter-taste receptor (TAS2Rs) polymorphisms. Therefore, we investigated the relationship between subjects' genetic polymorphisms of TAS2R19, 38, and 46, and their sensitivity to bitterness. Although a relationship between TAS2R19 polymorphisms and the perception of quinine bitterness was observed, no significant relationship was found between the perceived bitterness of prednisolone and the investigated genes. Ultimately, the results show that despite individual differences among subjects, the cause of prednisolone's strong bitterness is yet to be elucidated.

Evaluating the effectiveness of a transdiagnostic universal prevention program for both internalizing and externalizing problems in children: two feasibility studies.

BACKGROUND: The present study examined the effectiveness of the Universal Unified Prevention Program for Diverse Disorders (Up2-D2) for internalizing and externalizing problems for children aged 9-11 years. METHODS: We used two feasibility studies. The Up2-D2 entailed 12 sessions delivered by teachers; each session was developed based on cognitive-behavioral and positive psychological interventions. In Studies 1 and 2, 58 elementary school children aged 9-11 and 73 elementary school children aged 10-11 attended the Up2-D2. The teachers in Study 1 received 1.5 h of on-site teacher training for learning rationales for interventions, how to run the program, and received ongoing supervision by professionals with mental health expertise. In contrast, the teachers in Study 2 were given self-learning DVD materials in place of on-site training and ongoing supervision. RESULTS: Mixed models revealed that general difficulties, which is total score of both internalizing and externalizing problems, decreased in Study 1 but not in Study 2. Additional analyses for children with subclinical general difficulties revealed that general difficulties, internalizing problems, and externalizing problems decreased in Study 1, whereas in Study 2, general difficulties and internalizing problems decreased, except for externalizing problems. CONCLUSIONS: These results suggest that on-site teacher training and ongoing supervision are imperative for improving general difficulties in children at a universal level. In addition, universal preventive interventions by classroom teachers without on-site training and continuous supervision might be efficacious for reducing general difficulties and internalizing problems for children with subclinical difficulties.

Swallowability of Minitablets among Children Aged 6-23 Months: An Exploratory, Randomized Crossover Study.

Minitablets have garnered interest as a new paediatric formulation that is easier to swallow than liquid formulations. In Japan, besides the latter, fine granules are frequently used for children. We examined the swallowability of multiple drug-free minitablets and compared it with that of fine granules and liquid formulations in 40 children of two age groups (n = 20 each, aged 6-11 and 12-23 months). We compared the percentage of children who could swallow minitablets without chewing with that of children who could swallow fine granules or liquid formulations without leftover. The children who visited the paediatric department of Showa University Hospital were enrolled. Their caregivers were allowed to choose the administration method. In total, 37 out of 40 caregivers dispersed the fine granules in water. Significantly more children (80%, 95% CI: 56-94%) aged 6-11 months could swallow the minitablets than those who could swallow all the dispersed fine granules and liquid formulations (22%, 95% CI: 6-47% and 35%, 95% CI: 15-59%, respectively). No significant differences were observed in children aged 12-23 months. Hence, minitablets may be easier to swallow than dispersed fine granules and liquid formulations in children aged 6-11 months.

[The Safety and efficacy of airway-hyperresponsiveness test for asthma using by SK-1211 (Methacholine Chloride)].

BACKGROUND: In abroad, Methacholine Chloride (Provocholine®) is used to meet the indications of the diagnosis of bronchial airway hyperreactivity in subjects who do not have clinically apparent asthma. We examined efficacy, safety and pharmacokinetics of Methacholine Chloride (name of study drug: SK-1211) in order to get approved for the airway hyperresponsiveness test in Japan. METHODS: Fifteen adult healthy volunteers, fifteen adult patients with asthma and ten pediatric patients with asthma were enrolled in this study. The airway hyperresponsiveness test with SK-1211 was conducted in accordance with Japanese Society of Allergology Standard Method. RESULTS: When the threshold value of PC20 was 8 mg/mL, the sensitivity of adult patients with asthma was 66.7% (10/15 subjects) and the specificity of adult healthy volunteers was 86.7% (13/15 subjects). The sensitivity of pediatric patients with asthma was 70.0% (7/10 subjects). Not all subjects experienced some adverse reactions during inhalation of SK-1211, all of which were mild in severity and resolved soon with inhalation of a bronchodilator. There were no serious adverse reactions reported. CONCLUSION: The airway hyperresponsiveness test with SK-1211 was no specific concern with safety and useful in the diagnosis of bronchial airway hyperresponsiveness.