Adjunctive brexpiprazole 1 mg and 2 mg daily for Japanese patients with major depressive disorder following inadequate response to antidepressants: a phase 2/3, randomized, double-blind (BLESS) study.

AIMS: Inadequate antidepressant response interrupts effective treatment of major depressive disorder (MDD). The BLESS study evaluates the dosage, efficacy, and safety of brexpiprazole adjunctive therapy in Japanese patients with inadequate antidepressant therapy (ADT) response. METHODS: This placebo-controlled, randomized, multicenter, parallel-group phase 2/3 study randomized Japanese MDD patients (Hamilton Rating Scale for Depression 17-item total score ≥ 14; historical inadequate response to 1-3 ADTs) with inadequate response to 8-week single-blind, prospective SSRI/SNRI treatment to 6-week adjunctive treatment with brexpiprazole 1 mg, 2 mg, or placebo. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline. Secondary endpoints included MADRS response, remission rate, and Clinical Global Impression-Improvement score. Safety was comprehensively evaluated, especially regarding antipsychotic adverse events (AEs). RESULTS: Of 1194 screened patients, 740 were randomized and 736 (1 mg, n = 248; 2 mg, n = 245; placebo, n = 243) had ≥1 baseline/post-baseline MADRS total score. The LSM (SE) change from baseline in MADRS total score at Week 6 by MMRM analysis was -8.5 (0.47) with brexpiprazole 1 mg, -8.2 (0.47) with brexpiprazole 2 mg, and -6.7 (0.47) with placebo (placebo-adjusted LSM difference [95% CI]: 1 mg, -1.7 [-3.0, -0.4]; P = 0.0089; 2 mg, -1.4 [-2.7, -0.1]; P = 0.0312). Secondary efficacy results supported the primary endpoint. Brexpiprazole was generally well tolerated. CONCLUSION: Brexpiprazole 1 mg daily was an appropriate starting dose and both 1 mg and 2 mg daily were effective and well tolerated as adjunctive therapy for Japanese MDD patients not adequately responsive to ADT.

Boundary conditions for the Boltzmann equation from gas-surface interaction kinetic models.

Boundary conditions for the Boltzmann equation are investigated on the basis of a kinetic model for gas-surface interactions. The model takes into account gas and physisorbed molecules interacting with a surface potential and colliding with phonons. The potential field is generated by fixed crystal molecules, and the interaction with phonons represents the fluctuating part of the surface. The interaction layer is assumed to be thinner than the mean free path of the gas and physisorbed molecules, and the phonons are assumed to be at equilibrium. The asymptotic kinetic equation for the inner physisorbate layer is derived and used to investigate gas distribution boundary conditions. To be more specific, a model of the boundary condition for the Boltzmann equation is derived on the basis of an approximate iterative solution of the kinetic equation for the physisorbate layer, and the quality of the model is assessed by detailed numerical simulations, which also clarify the behavior of the molecules in the layer.

Aripiprazole in the real-world treatment for irritability associated with autism spectrum disorder in children and adolescents in Japan: 52-week post-marketing surveillance.

BACKGROUND: The purpose of this study was to evaluate the post-marketing safety and effectiveness of aripiprazole in treating irritability in pediatric patients (6-17 years) with autism spectrum disorder (ASD) in actual clinical sites of Japan. METHODS: In this post-marketing surveillance, patients were enrolled into the multicenter, prospective, non-interventional, observational study for 52 weeks, and were dosed with aripiprazole (1-15 mg/day) under daily clinical settings in Japan. RESULTS: In 510 patients, the continuation rate of aripiprazole treatment was 84.6% at day 168 (week 24) and 78.1% at day 364 (week 52). Adverse drug reactions (ADRs) occurred in 22.7% of patients (n = 116), and the most common ADRs were somnolence (9.4%), followed by weight increased (3.3%). At week 4, the mean change from baseline in the irritability subscale score for the Aberrant Behavior Checklist Japanese version (ABC-J) was - 5.7 ± 6.8 (n = 288). Based on multiple regression analysis, comorbid attention deficit and hyperactivity did not affect the ABC-J irritability subscale score at endpoint. At week 24, the mean change from baseline for the Strengths and Difficulties Questionnaire was - 3.3 ± 4.9 (n = 215) for the total difficulties score and 0.6 ± 1.7 (n = 217) for the prosocial behavior subscale score. CONCLUSIONS: Aripiprazole was well tolerated and effective in the long-term treatment of irritability associated with ASD in Japanese pediatric patients in the real-world clinical practice. TRIAL REGISTRATION: This surveillance was registered with Clinical Trial.gov (no. NCT03179787 ) on June 7, 2017 (retrospectively registered).

Safety of switching to brexpiprazole in Japanese patients with schizophrenia: A post-hoc analysis of a long-term open-label study.

OBJECTIVES: To determine the long-term safety of switching to brexpiprazole from aripiprazole or non-aripiprazole dopamine antagonists. METHODS: Post-hoc analysis of 56-week study of Japanese outpatients with schizophrenia switched to brexpiprazole 2 mg/day over 4-week switching period with further titration (1-4 mg/day) allowed during the 52-week, open-label period. Major assessment items: total/low-density lipoprotein (LDL)-/high-density lipoprotein (HDL)-cholesterol, triglycerides, blood glucose, body weight and prolactin. Secondary evaluations were related to efficacy, treatment emergent adverse events (TEAEs), extrapyramidal symptoms, and corrected QT interval (QTc). RESULTS: 84/186 (45.2%) patients (aripiprazole, 32.9%; non-aripiprazole, 54.8%) discontinued treatment over 56 weeks mainly because of consent withdrawal/adverse events. From baseline to Week 56, both groups showed minimal mean changes in total/LDL-/HDL-cholesterol, triglycerides, and glucose levels and a slight increase in mean (SD) body weight (aripiprazole, 1.1 [4.4] kg; non-aripiprazole, 0.4 [4.6] kg). Mean prolactin levels increased slightly in the aripiprazole group, but decreased in the non-aripiprazole group. Symptom severity scores decreased similarly in both groups. TEAEs occurred in 161/186 (86.6%) patients (aripiprazole, 84.1% [serious, 9.8%]; non-aripiprazole, 88.5% [serious, 14.4%]). Few changes occurred in extrapyramidal symptom scales or QTc interval. CONCLUSIONS: Switching to brexpiprazole is associated with a low long-term risk for metabolic abnormalities (including weight gain), hyperprolactinemia, extrapyramidal symptoms and QTc changes and minimal changes in psychiatric symptoms.

Two-temperature Navier-Stokes equations for a polyatomic gas derived from kinetic theory.

A polyatomic gas with slow relaxation of the internal modes is considered, and the Navier-Stokes equations with two temperatures, the translational and internal temperatures, are derived for such a gas on the basis of the ellipsoidal-statistical (ES) model of the Boltzmann equation for a polyatomic gas, proposed by Andries et al. [Eur. J. Mech. B, Fluids 19, 813 (2000)10.1016/S0997-7546(00)01103-1], by the Chapman-Enskog procedure. Then, the derived equations are applied to numerically investigate the structure of a plane shock wave in CO_{2} gas, which is known to have slowly relaxing internal modes. The results show good agreement with those obtained by the direct numerical analysis of the ES model for moderately strong shock waves. In particular, the results perfectly reproduce the double-layer structure of the shock profiles consisting of a thin front layer with rapid change and a thick rear layer with slow relaxation of the internal modes.

Kinetic model of adsorption on crystal surfaces.

A kinetic theory model describing physisorption and chemisorption of gas particles on a crystal surface is introduced. A single kinetic equation is used to model gas and physisorbed particles interacting with a crystal potential and colliding with phonons. The phonons are assumed to be at equilibrium and the physisorbate-gas equation is coupled to similar kinetic equations describing chemisorbed particles and crystal atoms on the surface. A kinetic entropy is introduced for the coupled system and the H theorem is established. Using the Chapman-Enskog method with a fluid scaling, the asymptotic structure of the adsorbate is investigated and fluid boundary conditions are derived from the kinetic model.

Genetic and Environmental Risk Factors, Sleeping Environment, for Allergic Diseases in Infant: Analysis of a Data Subset from the South Kyushu and Okinawa Study Area of Japan Environment and Children's Study.

OBJECTIVES: The incidence of infant allergic diseases have increased recently, and it may be caused by multiple influences of both genetic and environmental factors from the fetal stage through infancy. In this study, we analyzed a data subset from the South Kyushu and Okinawa (SKO) Study Area of Japan Environment and Children's Study (JECS) to determine the relationship of allergic diseases in infants with mothers' characteristics and/or infants' life habits, especially sleeping. METHODS: A total of 3873 mother-infant pairs from the SKO Regional Center of JECS were included. The mothers responded to questionnaires in the first trimester of their pregnancy and the self-reported questionnaire when their infants were 1 year old. Student's t-test, chi-square test, trend test, and logistic regression analysis were carried out to analyze the associations between the infants' allergic diseases and the mothers' genetic characteristics and/or sleeping habits of infants. RESULTS: Maternal allergic diseases were significantly associated with increased infant allergy risk (OR: 1.93, 95% CI: 1.63-2.27). The number of allergic diseases of mothers was also significantly associated with infant allergy, and the trend test showed an increasing risk of infant allergy (p<0.001). Regarding infants' life habits, the infants who sleep in the prone position had a higher allergic disease risk than those who sleep in other positions (OR: 1.46, 95% CI: 1.17-1.83). These significant associations were observed regardless of the presence of allergy in mothers. CONCLUSIONS: This study suggests that the development of allergic diseases in infants may be caused by the multiple participation of both genetic and environmental factors.

Motion of an array of plates in a rarefied gas caused by radiometric force.

In a rarefied gas in an infinitely long channel between two parallel plates, an array of infinitely many plates, arranged longitudinally with uniform interval, is placed along the channel. The array is assumed to be freely movable along the channel. If one side of each plate is heated, the radiometric force acts on it, and the array starts moving toward the cold sides of the plates. The final steady motion of the array, as well as the corresponding behavior of the gas, is investigated numerically on the basis of kinetic theory using the ellipsoidal statistical model of the Boltzmann equation. As the solution method, a finite-difference method, with a method of characteristics incorporated, that is able to capture the discontinuity in the velocity distribution function is employed. As the result, the local flow field near the edges of the plates and the terminal velocity of the array are obtained accurately for relatively small Knudsen numbers.

Decay of a linear pendulum in a collisional gas: spatially one-dimensional case.

An infinitely wide plate, subject to an external force in its normal direction obeying Hooke's law, is placed in an infinite expanse of a rarefied gas. When the plate is displaced from its equilibrium position and released, it starts in general an oscillatory motion in its normal direction. This is the one-dimensional setting of a linear pendulum considered previously for a collisionless gas and a special Lorentz gas by the present authors [T. Tsuji and K. Aoki, J. Stat. Phys. 146, 620 (2012)]. The motion decays as time proceeds because of the drag force on the plate exerted by the surrounding gas. The long-time behavior of the unsteady motion of the gas caused by the motion of the plate is investigated numerically on the basis of the Bhatnagar-Gross-Krook (BGK) model of the Boltzmann equation with special interest in the rate of the decay of the oscillatory motion of the plate. The result provides numerical evidence that the displacement of the plate decays in proportion to an inverse power of time for large time.

Differences in the levels of gastric cancer risk factors between Nanjing and Minqing counties, China.

OBJECTIVES: In Fujian Province, China, gastric cancer is one of the leading causes of mortality among all malignant tumors. Nanjing county and Minqing county are located in inland Fujian and have similar general demographics. However, the adjusted mortality rate of gastric cancer in Minqing was found to be much higher than that in Nanjing. We sought to explore factors associated with this increased risk of gastric cancer between the two counties. METHODS: We recruited 231 and 224 residents from Nanjing and Minqing, respectively, and analyzed differences between their dietary habits, Helicobacter pylori infection rates, and concentrations of serum pepsinogen I, pepsinogen II, gastrin-17, and ratio of pepsinogen I:II. RESULTS: Subjects in Minqing had more first-degree relatives who had been diagnosed with upper gastrointestinal tumor, more unhealthy dietary habits, a higher Helicobacter pylori positive rate, and greater proportion of abnormal serum gastrin-17 than those in Nanjing did. CONCLUSIONS: The factors that differed between these two counties might indicate that residents in Minqing have a higher risk for developing gastric cancer than those in Nanjing do.

A comprehensive evaluation of human papillomavirus positive status and p16INK4a overexpression as a prognostic biomarker in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) patients with human papillomavirus (HPV) infection have better prognosis than those without HPV infection. Although p16(INK4a) expression is used as a surrogate marker for HPV infection, there is controversy as to whether p16(INK4a) reliably indicates HPV infection. Here, to evaluate the accuracy of p16(INK4a) expression for determining HPV infection and the prognostic value of HPV infection and p16(INK4a) expression for HNSCC survival, especially oropharyngeal squamous cell carcinoma (OPSCC) survival, 150 fresh-frozen HNSCC samples were analyzed for HPV DNA, E6/E7 mRNA and p16(INK4a) expression by polymerase chain reaction and immunohistochemistry. p16(INK4a) expression was scored from 0 to 4 according to the percentage of p16(INK4a)-positive cells, with overexpression defined as >40% positive cells. Of the 150 tumor samples tested, 10 tumors were nasopharyngeal, 53 oropharyngeal, 39 hypopharyngeal, 24 laryngeal and 24 were located in the oral cavity. HPV DNA was detected in 47 (31.3%) samples, but only 21 also exhibited HPV mRNA expression. Inter-rater agreement was low between p16(INK4a) expression and HPV DNA presence and between p16(INK4a) expression and HPV mRNA expression, but was good between the combination of HPV DNA status and p16(INK4a) overexpression and HPV mRNA expression. Three-year recurrence-free survival was significantly higher for OPSCC patients who were HPV DNA-positive than for OPSCC patients who were HPV DNA-negative (P=0.008) and for OPSCC patients overexpressing p16(INK4a) than for without overexpressing p16(INK4a) (P=0.034). Multivariate analysis revealed that T1-3 stage and the combination of HPV DNA positivity and p16(INK4a) overexpression predicted significantly better recurrence-free survival. This combination is a more accurate marker for active HPV infection in HNSCC than HPV DNA status or general p16(INK4a)-positive status alone and offers a useful and reliable method for detecting and determining the prognosis of HPV-related HNSCC.

Predicting pharmacokinetic stability by multiple oral administration of atypical antipsychotics.

Lower fluctuation, i.e., lower peak-to-trough plasma-concentration variation at steady-state pharmacokinetics, has several advantages for the treatment of schizophrenia with antipsychotics. The reduction of peak concentration can decrease the risk of dose-dependent side effects, such as extrapyramidal symptom and somnolence, and by contrast the increase in trough concentration can decrease the incidence of lack of efficacy due to subtherapeutic drug concentration. Using a one-compartment simulation technique with pharmacokinetic parameters of each atypical antipsychotic collected from package inserts, the fluctuation index was calculated. Among the antipsychotics, the indices varied from 0.018 to 1.9, depending on dosing regimens, formulations and several pharmacokinetic properties. The order of simulated fluctuation index is active-moiety aripiprazole (b.i.d.)

Serum pepsinogens, gastrin-17 and Helicobacter pylori antibody in the residents of two cities in china with distinct mortality rates of gastric cancer.

Gastric cancer is one of the most common malignant tumors causing death in Fujian Province, China. However, the mortality of gastric cancer is greatly varied in different areas in Fujian; for example, the mortality in Changle City is 7.4 times higher than that in Fuan City. In this study, we compared the differences in serological parameters, pepsinogen (PG) I, PG II, gastrin-17 (G-17), and Helicobacter pylori (H. pylori) antibody, between the two cities. It has been reported that low serum PG I is correlated with atrophic gastritis, a high-risk condition for developing gastric cancer, while high serum G-17 has been used for serological detection of atrophic corpus gastritis. We recruited 224 healthy subjects in Changle and 229 healthy subjects in Fuan, matched in age and sex. The serum levels of PG II and G-17 were significantly higher in Changle than those in Fuan. Importantly, the frequency of the subjects with low serum PG I (< 25 µg/L) was significantly higher in Changle than in Fuan, although the serum PG I levels were similar between the two cities. Moreover, the percentage of the subjects with high serum G-17 (≥ 2 pmol/L) and the positive rate of serum IgG antibody against H. pylori were significantly higher in Changle than those in Fuan. The detected differences in these serological parameters are consistent with the notion that the prevalence of atrophic gastritis may be higher in Changle than in Fuan, which results in a higher risk condition for developing gastric cancer in Changle.

The effects of instruction regarding sleep posture on the postural changes and sleep quality among middle-aged and elderly men: a preliminary study.

The purpose of this study was to examine whether instruction to sleep in a lateral posture prior to falling asleep could increase the frequency of instructed posture and sleep quality, as evaluated by sleep parameters and a questionnaire for subjective assessment of sleep. The participants were comprised of 8 middle-aged and elderly men who had an awareness of their habitual snoring during sleep. Data were gathered from observations of sleep posture, sleep polysomnography and a subjective sleep quality questionnaire. As a result of the instruction, the frequency of the instructed posture was significantly increased, and there were no significant effects on sleep parameters or the frequency of postural changes. The subjective sleep quality during the instructed sleep showed worse scores than free postural-sleep for all factors. Our findings suggest that the instructed sleep posture could be increased during sleep without substantially worsening the sleep parameters and the frequency of postural changes. Future studies will therefore be required to clarify the mechanism and the long-term effects of such instruction on sleep posture, including the influence on subjective sleep quality.

Long-term administration of the fungus toxin, sterigmatocystin, induces intestinal metaplasia and increases the proliferative activity of PCNA, p53, and MDM2 in the gastric mucosa of aged Mongolian gerbils.

OBJECTIVE: The causal agents of gastric cancer could include fungus toxins. Sterigmatocystin (ST), a fungus toxin, is a risk factor of gastric cancer. We investigated the effects of ST on the stomach tissues of Mongolian gerbils. METHODS: Seventy-five-week-old male Mongolian gerbils received ST ad libitum at a concentration of 0 ppb (non-treated, n = 11), 100 ppb (n = 7), or 1000 ppb (n = 13) dissolved in drinking water for a period of 24 weeks. After administration, we tested the histopathological changes and immunostaining for proliferating cell nuclear antigen (PCNA), p53, and MDM2 expression. RESULTS: We investigated the histopathological changes and determined the incidence of histopathological changes in animals with various gastric diseases after ST administration at a dose of 0 ppb (non-treated control), 100, or 1,000 ppb as follows: firstly, indices for gastritis were 18.2, 100, and 100%, those for erosion events were 9.1, 100, and 92.3%, and those for polyps were 0, 71.4, and 61.5%, respectively. These incidences in the ST-administered groups (100 or 1000 ppb) showed significant increases compared with those in the non-treated control group. And, lastly, indices for intestinal metaplasia were 0, 100, and 15.4%, respectively. Furthermore, immunostaining for PCNA, p53, and MDM2 expression showed significantly greater rates in the ST-administered groups (100 or 1000 ppb) than in the non-treated control group. CONCLUSION: The histopathological and immunohistopathological findings of this study indicate that ST exerts a marked influence on gastric mucus and gland cells, showing dominant gastritis, erosion events, polyps, and intestinal metaplasia in these animals.

Approach to steady motion of a plate moving in a free-molecular gas under a constant external force.

A thin plate accelerated or decelerated in a free-molecular gas at rest by a constant external force is considered. The force is in the direction perpendicular to the plate. In this situation, the plate velocity approaches its final constant velocity as time goes on. It is shown numerically that, under the diffuse-reflection boundary condition, the difference between the plate velocity and its final value decreases in proportion to an inverse power of time. This agrees with the previous theoretical result obtained under the assumption that the initial plate velocity is sufficiently close to the final one.

Effects of cow's milk on reproduction in ICR male mice.

OBJECTIVE: To study the effects of Cow's milk on the reproduction in male mice. METHODS: Twenty-four male mice were divided randomly into two groups: milk group (M) and control group (C). Each mouse was given 10 mL milk per day from 4 to 16 weeks in the group M. At the age of 17 weeks, all the mice were sacrificed. RESULTS: Serum testosterone was decreased in the group M (P=0.037). No significant difference was found in weight of testes, seminal vesicle or adrenal gland of mice between the groups C and M. However, the weight of seminal vesicle decreased when expressed in g/100 g body weight in the group M. Epididymal sperm concentration, motility, morphology, and sperm head number were not affected by milk. CONCLUSION: Cow's milk has adverse effects on the reproductive system in ICR male mice. Further studies are needed to clarify the specific effects of milk on reproductive health.

Correlation between the arsenic concentrations in the air and the SMR of lung cancer.

OBJECTIVES: To verify whether the concentrations of arsenic (As) and its compounds in the air (referred to here as arsenic concentrations) affect the standardized mortality ratio (SMR) associated with lung cancer. METHODS: Using monitoring survey data on arsenic concentrations published by the Ministry of the Environment, we classified the municipalities for which arsenic concentrations were measured (measured municipalities) into ten groups according to the average arsenic concentration. We then determined the SMR of lung cancer, stomach cancer, pneumonia, cerebrovascular disease and cardiac disease for each group using socio-demographic data, such as the national census and demographic trends. The relationships between these factors were compared and investigated by statistical means. RESULTS: No effect of arsenic concentrations on stomach cancer, cerebrovascular disease or cardiac disease was observed, and while significant differences in pneumonia were observed among several of the male subjects, there were no significant effects of arsenic concentration. However, lung cancer and arsenic concentration showed a significantly positive correlation for both males and females (males: Spearman r = 0.709, P < 0.05; females: Spearman r = 0.758, P < 0.05). The probability of type alpha error was less than 5% in areas with more than 1.77 ng As/m(3) (71st percentile) and less than 1% in areas with more than 2.70 ng As/m(3) (91st percentile). These results confirm that the SMR of lung cancer tends to be higher than the national average in areas of higher arsenic concentrations. CONCLUSIONS: The SMR of lung cancer is significantly higher in areas with arsenic concentrations of 1.77 ng/m(3) or more.

Linear stability of the cylindrical Couette flow of a rarefied gas.

A rarefied gas between two coaxial circular cylinders of infinite length, rotating with different angular velocities and kept at a common temperature, is considered. The stability of the circumferentially as well as axially uniform flow (cylindrical Couette flow) for circumferentially uniform small disturbances is investigated on the basis of kinetic theory. The linear-stability analysis is performed using the Bhatnagar-Gross-Krook model of the Boltzmann equation and the diffuse reflection condition on the cylinders. The maximum growth rate of the disturbances is determined numerically by solving the initial and boundary value problem for the disturbances for relatively small Knudsen numbers and wide ranges of angular velocities of the cylinders. As a result, the parameter range where the cylindrical Couette flow is unstable is clarified. The result is compared with the corresponding result based on the continuum model of the compressible Navier-Stokes type. A comparison is also made with the result of a direct numerical analysis of the original Boltzmann system, obtained by the direct simulation Monte Carlo method in previous papers as well as in the present study.

Sodium nitrite-induced cytotoxicity in cultured human gastric epithelial cells.

To investigate the effect of sodium nitrite on the viability of the human gastric adenocarcinoma epithelial cell line, AGS, cultured AGS cells were exposed to various concentrations of sodium nitrite for 24, 48 or 72 h. The cytotoxic response was assessed using a cell proliferation assay, and the extent of the response was evaluated on the basis of intracellular and extracellular levels of interleukin 1 beta (IL-1 beta), interleukin 6 (IL-6), interleukin 8 (IL-8) and tumor necrosis factor (TNF-alpha). Both mRNA and protein levels were measured for each cytokine. Sodium nitrite had a significant effect on AGS cell proliferation after a 72-h exposure. At low sodium nitrite concentrations (up to 6.25 mM), cell proliferation increased in a dose-dependent manner; however, exposure to higher concentrations resulted in a dose-dependent decrease in cell proliferation. Sodium nitrite at a low concentration (6.25 mM) increased IL-8 release, whereas IL-1 beta, IL-6, and TNF-alpha release increased only after exposure to high sodium nitrite concentration (25 mM). Our data demonstrate that sodium nitrite can induce the release of these inflammatory cytokines and that high concentrations of sodium nitrite decrease AGS cell proliferation.