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Ozoralizumab is a bispecific NANOBODY compound that binds tumor necrosis factor alpha (TNFα) and human serum albumin. Ozoralizumab inhibits the TNFα physiological activity while maintaining long‐term plasma retention owing to its human serum albumin–binding ability. A population pharmacokinetic (PK) model was developed using data from 494 Japanese patients with rheumatoid arthritis in Phase II/III and Phase III trials to assess the effects of potential PK covariates. The ozoralizumab PK after subcutaneous administration was described using a 1‐compartment model with first‐order absorption and first‐order elimination processes. A proportional error model was used for inter‐ and intra‐individual variabilities, with covariance set between inter‐individual variabilities of the apparent clearance and apparent distribution volume. Body weight, sex, antidrug antibody status, estimated glomerular filtration rate, and concomitant methotrexate use were identified as covariates for apparent clearance, while body weight and sex were covariates for apparent distribution volume in the final model. Body weight had the greatest effect on the PK of ozoralizumab, while the other covariates had minor effects. When administered at 30 mg every 4 weeks, the predicted steady‐state plasma trough concentration in a patient weighing 83.2 kg exceeded the trough concentration required to maintain efficacy of ozoralizumab, and the estimated exposure in a patient weighing 42.5 kg did not exceed the mean exposure at 80 mg, a well‐tolerated dose, throughout 52 weeks. We developed a population PK model that adequately described the ozoralizumab PK in Japanese patients with rheumatoid arthritis, and none of the evaluated covariates showed clinically relevant effects on the PK of ozoralizumab. [ABSTRACT FROM AUTHOR]

The pharmacokinetics, pharmacodynamics and safety profile of vornorexant were investigated in healthy Japanese participants in three double‐blind studies: a single ascending dose of 1–30 mg (Study 101; n = 6) and multiple ascending doses of 10–30 mg (Study 102; n = 6). Study 202 consisted of two steps: an open‐label, 20 mg repeated‐dose in non‐elderly individuals (Step 1; n = 12) and a double‐blind, 20 mg repeated‐dose in elderly individuals (Step 2; n = 8/3 for vornorexant/placebo). Vornorexant was rapidly absorbed and eliminated under fasting conditions, with a time to maximum plasma concentration of 0.500–3.00 h (range) and elimination half‐life of 1.32–3.25 h. The area under the plasma concentration‐time curve (AUC) of vornorexant increased proportionally with dose increments. Sleepiness‐related pharmacodynamic outcome changes (Karolinska sleepiness scale, digit symbol substitution test and psychomotor vigilance task) were generally increased with dose increments at 1 and 4 h post‐dose, whereas no consistent dose‐related changes were detected the next morning. Food intake did not affect the maximum observed plasma concentration of vornorexant but increased the AUC0–inf. Exposure in elderly individuals was generally comparable to that in non‐elderly individuals. Altogether, vornorexant may have a favourable profile for insomnia treatment, including rapid onset of action and minimal next‐day residual effects. [ABSTRACT FROM AUTHOR]

Special processes recruited during the recognition of personally familiar people have been assumed to reflect the rich episodic and semantic information that selectively represents each person. However, the processes may also include person nonselective ones, which may require interpretation in terms beyond the memory mechanism. To examine this possibility, we assessed decrease in differential activation during the second presentation of an identical face (repetition suppression) as an index of person selectivity. During fMRI, pictures of personally familiar, famous, and unfamiliar faces were presented to healthy subjects who performed a familiarity judgment. Each face was presented once in the first half of the experiment and again in the second half. The right inferior temporal and left inferior frontal gyri were activated during the recognition of both types of familiar faces initially, and this activation was suppressed with repetition. Among preferentially activated regions for personally familiar over famous faces, robust suppression in differential activation was exhibited in the bilateral medial and anterior temporal structures, left amygdala, and right posterior STS, all of which are known to process episodic and semantic information. On the other hand, suppression was minimal in the posterior cingulate, medial prefrontal, right inferior frontal, and intraparietal regions, some of which were implicated in social cognition and cognitive control. Thus, the recognition of personally familiar people is characterized not only by person-selective representation but also by nonselective processes requiring a research framework beyond the memory mechanism, such as a social adaptive response.

Background: Research has shown that some microbiomes are linked to cancer. Hence, we hypothesize that alterations in the respiratory microbiome might be associated with lung cancer. Methods: Through droplet digital polymerase chain reaction analysis, we investigated the abundance of Acidovorax in surgically resected primary tumors and corresponding nontumor lung tissues obtained from 50 Japanese patients with non‐small cell lung cancer. Results: The rate of positivity for Acidovorax in tumor and nontumor tissues was 44 and 26%, respectively. The abundance of Acidovorax in tumor tissues was significantly higher in patients with nonsquamous cell carcinoma complicated by chronic obstructive pulmonary disease (COPD) and those who relapsed after surgical resection (p < 0.05). In tumor tissues, the results of the univariate and multivariate analyses revealed that only COPD exerted a direct effect on the abundance of Acidovorax (p < 0.05). Furthermore, the presence of Acidovorax was high in lung cancer patients with COPD comorbidity (65%) and TP53 gene mutation; only one of the nontumor tissues was positive for Acidovorax. In patients with lung cancer complicated by COPD, Acidovorax tended to be present in both the tumor and nontumor areas. Conclusions: This study identified novel microbiota involved in lung cancer with COPD comorbidity. The results suggested that Acidovorax may be a useful biomarker in the screening for lung cancer. Further studies are warranted to validate the clinical significance of the microbiome in a larger independent patient cohort. [ABSTRACT FROM AUTHOR]

We evaluated the in vitro drug–drug interaction (DDI) potential of enerisant (TS-091), a histamine H3 receptor antagonist/inverse agonist, mediated by cytochrome P450 (CYP) and transporters, as well as the pharmacokinetics of enerisant in healthy male subjects. Enerisant did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 and did not induce CYP1A2, CYP2B6, or CYP3A4. Enerisant inhibited organic cation transporter 2, multidrug and toxin extrusion protein (MATE) 1, and MATE2-K, but not P-glycoprotein (P-gp), breast cancer resistance protein, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, or OAT3. Enerisant was a substrate for P-gp, but not for eight other transporters. In healthy male subjects, enerisant was rapidly absorbed after oral administration, and the plasma concentration increased dose-dependently. The urinary excretion of enerisant within 48 h after administration was 64.5% to 89.9% of the dose, indicating that most of the absorbed enerisant was excreted in the urine without being metabolized. Based on the plasma concentrations at the estimated clinical dose, enerisant is unlikely to cause CYP-mediated, clinically relevant DDI. Although the possibility of transporter-mediated, clinically relevant DDI cannot be ruled out, there is little or no risk of side effects. [ABSTRACT FROM AUTHOR]

Background: Analyses of resting-state functional magnetic resonance imaging (rs-fMRI) have been performed to investigate pathophysiological changes in the brains of patients with autism spectrum disorder (ASD) relative to typically developing controls (CTLs). However, the results of these previous studies, which have reported mixed patterns of hypo- and hyperconnectivity, are controversial, likely due to the small sample sizes and limited age range of included participants. Methods: To overcome this issue, we analyzed multisite neuroimaging data from a large sample (n = 626) of male participants aged between 5 and 29 years (mean age = 13 years). The rs-fMRI data were preprocessed using SPM12 and DPARSF software, and signal changes in 90 brain regions were extracted. Multiple linear regression was used to exclude the effect of site differences in connectivity data. Subcortical–cortical connectivity was computed using connectivities in the hippocampus, amygdala, caudate nucleus, putamen, pallidum, and thalamus. Eighty-eight connectivities in each structure were compared between patients with ASD and CTLs using multiple linear regression with group, age, and age × group interactions, head movement parameters, and overall connectivity as variables. Results: After correcting for multiple comparisons, patients in the ASD group exhibited significant increases in connectivity between the thalamus and 19 cortical regions distributed throughout the fronto-parietal lobes, including the temporo-parietal junction and posterior cingulate cortices. In addition, there were significant decreases in connectivity between the amygdala and six cortical regions. The mean effect size of hyperconnectivity (0.25) was greater than that for hypoconnectivity (0.08). No other subcortical structures showed significant group differences. A group-by-age interaction was observed for connectivity between the thalamus and motor-somatosensory areas. Conclusions: These results demonstrate that pathophysiological changes associated with ASD are more likely related to thalamocortical hyperconnectivity than to amygdala-cortical hypoconnectivity. Future studies should examine full sets of clinical and behavioral symptoms in combination with functional connectivity to explore possible biomarkers for ASD. [ABSTRACT FROM AUTHOR]

1. We evaluated potentialin vitrodrug interactions of luseogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, mediated by CYP inhibition, CYP induction and drug transporters using human liver microsomes, primary hepatocytes and recombinant cells-expressing efflux or uptake transporters, respectively. 2. Human CYP inhibition studies indicated that luseogliflozin was a weak inhibitor for CYP2C19 with an IC50value of 58.3 μM, whereas it was not an inhibitor of the other eight major isoforms that were tested. The exposure of primary hepatocytes to luseogliflozin for 72 hrs weakly induced CYP3A4 at a concentration of 10 μM, whereas it did not induce CYP1A2 or CYP2B6 at concentrations of 0.1–10 μM. 3. Anin vitrotransport study suggested that luseogliflozin is a substrate for human P-glycoprotein (P-gp), but not for breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1 and OATP1B3, organic anion transporter (OAT) 1 and OAT3, or organic cation transporter (OCT) 2. Luseogliflozin weakly inhibited OATP1B3 with an IC50value of 93.1 μM, but those for other transporters are greater than 100 μM. 4. Based on the therapeutic plasma concentration of the drug, clinically relevant drug interactions are unlikely to occur between luseogliflozin and coadministered drugs mediated by CYPs and/or transporters. [ABSTRACT FROM PUBLISHER]

Memory for person identity information consists of three main components: face-related information, name-related information, and person-related semantic information, such as the person's job title. Although previous studies have demonstrated the importance of the anterior temporal lobe (ATL) in the retrieval of associations between these kinds of information, there is no evidence concerning whether the ATL region contributes to the encoding of this memory, and whether ATL roles are dissociable between different levels of association in this memory. Using fMRI, we investigated dissociable roles within the ATL during successful encoding of this memory. During encoding, participants viewed unfamiliar faces, each paired with a job title and name. During retrieval, each learned face was presented with two job titles or two names, and participants were required to choose the correct job title or name. Successful encoding conditions were categorized by subsequent retrieval conditions: successful encoding of names and job titles (HNJ), names (HN), and job titles (HJ). The study yielded three main findings. First, the dorsal ATL showed greater activations in HNJ than in HN or HJ. Second, ventral ATL activity was greater in HNJ and HJ than in HN. Third, functional connectivity between these regions was significant during successful encoding. The results are the first to demonstrate that the dorsal and ventral ATL roles are dissociable between two steps of association, associations of person-related semantics with name and with face, and a dorsal-ventral ATL interaction predicts subsequent retrieval success of memory for person identity information. [ABSTRACT FROM AUTHOR]

Elucidating the neural mechanisms involved in aversive conditioning helps find effective treatments for psychiatric disorders such as anxiety disorder and phobia. Previous studies using fMRI and human subjects have reported that the amygdala plays a role in this phenomenon. However, the noxious stimuli that were used as unconditioned stimuli in previous studies (e.g., electric shock) might have been ecologically invalid because we seldom encounter such stimuli in daily life. Therefore, we investigated whether a face stimulus could be conditioned by using a voice that had negative emotional valence and was collected from a real-life environment. A skin conductance response showed that healthy subjects were conditioned by using these stimuli. In an fMRI study, there was greater amygdala activation in response to the faces that had been paired with the voice than to those that had not. The right amygdala showed transient activity in the early stage of acquisition. A psychophysiological interaction analysis indicated that the subcortical pathway from the medial geniculate body to the amygdala played a role in conditioning. Modulation of the subcortical pathway by voice stimuli preceded the transient activity in the amygdala. The finding that an ecologically valid stimulus elicited the conditioning and amygdala response suggests that our brain is automatically processing unpleasant stimuli in daily life. [ABSTRACT FROM AUTHOR]

People living in multicultural environments often encounter situations which require them to acquire different cultural schemas and to switch between these cultural schemas depending on their immediate sociocultural context. Prior behavioral studies show that priming cultural schemas reliably impacts mental processes and behavior underlying self-concept. However, less well understood is whether or not cultural priming affects neurobiological mechanisms underlying the self. Here we examined whether priming cultural values of individualism and collectivism in bicultural individuals affects neural activity in cortical midline structures underlying self-relevant processes using functional magnetic resonance imaging. Biculturals primed with individualistic values showed increased activation within medial prefrontal cortex (MPFC) and posterior cingulate cortex (PCC) during general relative to contextual self-judgments, whereas biculturals primed with collectivistic values showed increased response within MPFC and PCC during contextual relative to general self-judgments. Moreover, degree of cultural priming was positively correlated with degree of MPFC and PCC activity during culturally congruent self-judgments. These findings illustrate the dynamic influence of culture on neural representations underlying the self and, more broadly, suggest a neurobiological basis by which people acculturate to novel environments. [ABSTRACT FROM AUTHOR]