Drug-drug interaction potential and clinical pharmacokinetics of enerisant, a novel potent and selective histamine H3 receptor antagonist.

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.

In vitro evaluation of potential drug interactions mediated by cytochrome P450 and transporters for luseogliflozin, an SGLT2 inhibitor.

1. We evaluated potential in vitro drug 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 IC50 value 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. An in vitro transport 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 IC50 value 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.

Cultural influences on neural basis of inhibitory control.

Research on neural basis of inhibitory control has been extensively conducted in various parts of the world. It is often implicitly assumed that neural basis of inhibitory control is universally similar across cultures. Here, we investigated the extent to which culture modulated inhibitory-control brain activity at both cultural-group and cultural-value levels of analysis. During fMRI scanning, participants from different cultural groups (including Caucasian-Americans and Japanese-Americans living in the United States and native Japanese living in Japan) performed a Go/No-Go task. They also completed behavioral surveys assessing cultural values of behavioral consistency, or the extent to which one's behaviors in daily life are consistent across situations. Across participants, the Go/No-Go task elicited stronger neural activity in several inhibitory-control areas, such as the inferior frontal gyrus (IFG) and anterior cingulate cortex (ACC). Importantly, at the cultural-group level, we found variation in left IFG (L-IFG) activity that was explained by a cultural region where participants lived in (as opposed to race). Specifically, L-IFG activity was stronger for native Japanese compared to Caucasian- and Japanese-Americans, while there was no systematic difference in L-IFG activity between Japanese- and Caucasian-Americans. At the cultural-value level, we found that participants who valued being "themselves" across situations (i.e., having high endorsement of behavioral consistency) elicited stronger rostral ACC activity during the Go/No-Go task. Altogether, our findings provide novel insight into how culture modulates the neural basis of inhibitory control.

Molecular analysis of the integrons of metallo-ß-lactamase-producing Pseudomonas aeruginosa isolates collected by nationwide surveillance programs across Japan.

BACKGROUND: We investigate the evolving molecular epidemiology of metallo-ß-lactamase (MBL)-producing Pseudomonas aeruginosa isolates collected in a 100 institution, nationwide surveillance study in Japan from 2004 to 2006. RESULTS: MBL-producers were detected in 23/996 isolates (2.3%) in 2004 and 21/992 (2.1%) in 2006. Antimicrobial resistance (specifically, carbapenem resistance) rates between two periods did not differ significantly. MBL-producers were more prevalent in urinary tract isolates. bla IMP-1 group was the most predominant (38 isolates, 80%), followed by 3 bla IMP-7, 2 bla IMP-11 group, and 1 bla VIM-1. All MBL genes were identified in 16 different class 1 integrons, most of which were novel to INTEGRALL database. A total of 17 isolates of sequence type (ST) 235, a recognized worldwide drug-resistant lineage, were distributed in 5 geographic regions across Japan. ST235 isolates included a sublineage associated with In113-like integron. ST357 was identified in 14 isolates, 9 of which harboring a sole bla IMP-1 gene cassette (In994) were recovered from Chugoku region in 2004. ST357 isolates with bla IMP-11 group or ST235 with bla IMP-7 emerged in 2006. We also report for the first time the presence of novel fosI gene cassette in strains other than Mycobacterium spp. CONCLUSIONS: Our data give an important "snapshot" of the molecular characteristics and dynamics of MBL-producing lineages in P. aeruginosa in Japan. The significant association of specific genotypes and integrons implies that dissemination and transmission of the preexisting resistant lineage, rather than horizontal gene transfer in situ, might largely explain their endemicity.

Population Pharmacokinetics of Ozoralizumab in Patients with Rheumatoid Arthritis.

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.

Pharmacokinetics, pharmacodynamics and safety profile of the dual orexin receptor antagonist vornorexant/TS-142 in healthy Japanese participants following single/multiple dosing: Randomized, double-blind, placebo-controlled phase-1 studies.

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.

Efficacy and pharmacokinetics of ozoralizumab, an anti-TNFα NANOBODY® compound, in patients with rheumatoid arthritis: 52-week results from the OHZORA and NATSUZORA trials.

INTRODUCTION: Ozoralizumab (OZR), a tumor necrosis factor alpha (TNFα) inhibitor, is a NANOBODY® compound that binds to TNFα and human serum albumin. The main objective of this study was to analyze the pharmacokinetics (PK) of the drug and its correlation with clinical efficacy in patients with rheumatoid arthritis (RA). METHODS: Efficacy data were analyzed from the OHZORA trial, in which OZR 30 or 80 mg was administered to Japanese patients with RA at 4-week intervals for 52 weeks in combination with methotrexate (MTX; n = 381), and the NATSUZORA trial, in which OZR 30 or 80 mg was administered without concomitant MTX (n = 140). Effects of patient baseline characteristics and anti-drug antibodies (ADAs) on the PK and efficacy of OZR were investigated, and a post hoc analysis of PK effects on drug efficacy was performed. RESULTS: The maximum plasma concentration (Cmax) was reached in 6 days in both the 30 and 80 mg groups, with an elimination half-life of 18 days. The Cmax and area under the plasma concentration-time curve increased in a dose-dependent manner, and the trough concentration reached steady state by week 16. The exposure of OZR correlated negatively with patient body weight and was not affected by other patient baseline characteristics. Effects of ADAs on the exposure and efficacy of OZR were limited in both trials. However, antibodies that neutralize the binding to TNFα had some effect on the exposure and efficacy of OZR in the NATSUZORA trial. The receiver operating characteristic analysis of the effect of trough concentration on the American College of Rheumatology 20% and 50% improvement rates was retrospectively performed, and a cutoff trough concentration of approximately 1 µg/mL at week 16 was obtained in both trials. The efficacy indicators in the subgroup with trough concentration ≥ 1 µg/mL were higher than those in the < 1 µg/mL subgroup at week 16, while no clear cutoff was obtained at week 52 in both trials. CONCLUSIONS: OZR showed a long half-life and favorable PK properties. A post hoc analysis suggested sustained efficacy independent of trough concentration by subcutaneous administration of OZR 30 mg at 4-week intervals for 52 weeks. TRIAL REGISTRATION: JapicCTI, OHZORA trial: JapicCTI-184029, registration date July 9, 2018; NATSUZORA trial: JapicCTI-184031, registration date July 9, 2018.

Comparison of four reading methods of broth microdilution based on the clinical and laboratory standards institute M27-A3 method for Candida spp.

This study aimed to compare the susceptibilities of 5 reference strains and 28 isolates of Candida spp., to micafungin, amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole, and miconazole, obtained by visually determined minimum inhibitory concentration (MIC) using the agitation method (V-A), as described in the Clinical and Laboratory Standards Institute M27-A3 document; visual determinations without agitation (V-NA); and spectrophotometric determinations for the presence or absence of agitation (SP-A and SP-NA, respectively). Our results indicate that when the V-NA, SP-A, and SP-NA-the 3 alternative microdilution procedures for MIC endpoint determinations-were compared with the V-A, excellent agreements were observed between the V-NA and V-A rather than with the spectrophotometric methods (between the SP-A or SP-NA, and V-A). Furthermore, many errors occurred while using the SP-A method in the presence of agitation and some isolates showed major errors. Three of 5 isolates that showed very major errors between the spectrophotometric SP-A or SP-NA, and the reference V-A method were trailing isolates. Therefore, it was suggested that the MICs of Candida spp. obtained by the V-NA method were more precise than those by the conventional SP-A method.

The respiratory microbiome associated with chronic obstructive pulmonary disease comorbidity in non-small cell lung cancer.

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.

Beyond the memory mechanism: person-selective and nonselective processes in recognition of personally familiar faces.

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.

The representation of social interaction in episodic memory: a functional MRI study.

The representation of social interaction in episodic memory is a critical factor for the successful navigation of social relationships. In general, it is important to separate episodic memory during social interaction from episodic memory during the self-generation of action events. Different cortical representations have been associated with social interaction vs. self-generated episodic memory. Here we clarified the cortical representation of the effect of context (social vs. solitary) on episodic memory by comparing it with the generation effect (self vs. other) on episodic memory. Each participant learned words while engaged in a sentence generation and a reading task, and subsequently each participant was scanned with functional magnetic resonance imaging (fMRI) while they performed a recognition task using the words that had been learned. The experiment was comprised of four conditions and we looked at two situations that involved a social context and non-social (solitary) context task. In the learning session before entering the MRI, two participants collaborated in a social context either generating (social-contextual self-generation condition: SS) or reading (social-contextual other-generation condition: SO) a sequence of sentences alternately to construct a meaningful story narrative. In the non-social context, the participants generated (non-social-contextual self-generation condition: NS) or read (non-social-contextual other-generation condition: NO) a sequence of sentences individually. The stimuli for the recognition session consisted of learned words and novel words. Activation for social context retrieval was identified in the right medial prefrontal cortex (mPFC), and activation for self-generated retrieval was identified in the left mPFC and the left middle cingulate cortex. These results indicate that dissociable regions within the medial prefrontal cortices contribute to the processes involved in the representation of social interaction, including social context and self-generation in the retrieval of episodic memory.

Transient neural activation in human amygdala involved in aversive conditioning of face and voice.

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.

Dissociable roles of the anterior temporal regions in successful encoding of memory for person identity information.

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.

Dynamic cultural influences on neural representations of the self.

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.

In vitro potentiation of carbapenems with ME1071, a novel metallo-beta-lactamase inhibitor, against metallo-beta-lactamase- producing Pseudomonas aeruginosa clinical isolates.

ME1071, a maleic acid derivative, is a novel specific inhibitor for metallo-beta-lactamases (MBL). In this study, the potentiation of ME1071 in combination with several beta-lactams was evaluated using MBL-producing Pseudomonas aeruginosa isolates. The rates of susceptibility of MBL producers to carbapenems (imipenem, biapenem, and doripenem) and ceftazidime were increased by 8 to 27% in the presence of 32 microg/ml of ME1071. The corresponding resistance rates were decreased by 13 to 46%, respectively. On the other hand, ME1071 showed weaker or no potentiation with non-MBL producers. The K(i) value of ME1071 for IMP-1 was 0.4 microM, significantly lower than the K(m) values of carbapenems for the IMP-1 enzyme. On the other hand, the K(i) value of ME1071 for VIM-2 was 120 microM, higher than the K(m) values of carbapenems for the VIM-2 enzyme. Results of this study indicate that ME1071 can potentiate the activity of ceftazidime and carbapenems against MBL-producing strains of P. aeruginosa.

Cultural influences on neural systems of intergroup emotion perception: An fMRI study.

Cultural factors, such as cultural group membership, have been shown to affect neural bases of face and emotion perception. However, little is known about how cultural factors influence neural processing of emotional faces expressed by in-group and out-group members. In this study, we examined cultural influences on neural activation during the intergroup perception of negative emotional faces. We used functional magnetic resonance imaging to compare neural activation during intergroup emotion processing across cultures in three participants groups; two monocultural groups (i.e. Caucasian-Americans and native Japanese) and a bicultural group (i.e. Japanese-Americans). During scanning, the participants completed an emotional match-to-sample task consisting of negative facial expressions of Japanese and Caucasians. Our results show cultural modulation of neural response in the bilateral amygdala as a function of in-group biases and collectivistic values. Additionally, bicultural Japanese-Americans showed enhanced neural responses in the ventral medial prefrontal and posterior cingulate cortices, which had been related to self-related processing, during the perception of negative facial expression of Japanese. Neural activation in the ventral and posterior cingulate cortices reflected individuals' collectivistic tendencies only in the Japanese-American group, possibly due to greater sensitivity to ingroup biases in bicultural individuals. Our results demonstrate the influence of culture on neural responses during the perception of intergroup emotion from faces.

Neural basis of individualistic and collectivistic views of self.

Individualism and collectivism refer to cultural values that influence how people construe themselves and their relation to the world. Individualists perceive themselves as stable entities, autonomous from other people and their environment, while collectivists view themselves as dynamic entities, continually defined by their social context and relationships. Despite rich understanding of how individualism and collectivism influence social cognition at a behavioral level, little is known about how these cultural values modulate neural representations underlying social cognition. Using cross-cultural functional magnetic resonance imaging (fMRI), we examined whether the cultural values of individualism and collectivism modulate neural activity within medial prefrontal cortex (MPFC) during processing of general and contextual self judgments. Here, we show that neural activity within the anterior rostral portion of the MPFC during processing of general and contextual self judgments positively predicts how individualistic or collectivistic a person is across cultures. These results reveal two kinds of neural representations of self (eg, a general self and a contextual self) within MPFC and demonstrate how cultural values of individualism and collectivism shape these neural representations.

Perspective-taking as part of narrative comprehension: a functional MRI study.

During narrative comprehension, readers understand the emotions of the protagonist by taking the perspective of the character, which is an essential component of empathy. Spatial perspective-taking is crucial to understanding the standpoints and perceptions of others, and gives clues as to what the protagonist knows. As a default, a "here and now" point-of-view is adopted to make sense of the narrative. If the protagonist is in a different location while an event takes place ("there and now"), in order to comprehend the narrative the reader must take an allocentric perspective, which places greater demands on spatial perspective-taking. Utilizing this phenomenon, we evaluated the neural substrates of perspective-taking in emotional narrative comprehension using functional MRI in 18 normal adults. The subjects read short stories followed by a target sentence, which described an event that might evoke an emotional response in the protagonist if the character were present. The stories involved a scenario in which the character was either present at the same location ("here and now") or at a distant location ("there and now") during the event. The "there and now" scenario activated the posterior cingulate cortex and the right temporo-parietal junction more prominently than the "here and now" condition. In contrast to the control tasks, both scenarios activated the well-known mentalizing network including the dorsomedial prefrontal cortex, temporal pole, posterior cingulate cortex and temporo-parietal junction. Along with the mentalizing network, the posterior cingulate cortex and the right temporo-parietal junction are involved in spatial perspective-taking during emotional narrative comprehension.

Thalamocortical Hyperconnectivity and Amygdala-Cortical Hypoconnectivity in Male Patients With Autism Spectrum Disorder.

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.

Acinetobacter baumannii can be transferred from contaminated nitrile examination gloves to polypropylene plastic surfaces.

BACKGROUND: Several observational studies suggest that gloves of health care workers are major routes of multidrug-resistant Acinetobacter baumannii transmission. However, limited experimental data are available assessing Acinetobacter transmission from gloves to environmental surfaces. This study determined whether A baumannii was easily transferred from nitrile gloves to polypropylene plastic compared with other gram-negative bacteria that cause health care-associated infections in laboratory-controlled experiments. METHODS: Gloved fingerpad-to-fomite transfer efficiency was determined for drug-resistant and -sensitive strains of A baumannii, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa. RESULTS: Only A baumannii transferred from gloves to fomites 3 minutes after the bacterial transfer event. Transfer efficiency of A baumannii was 0.1%-33% at that time point. DISCUSSION: Bacterial transfer from contaminated gloves to the hospital environment may be related to the type of contaminating bacteria, inoculated bacterial level, fomites, and glove materials. Therefore, it is important to need a comprehensive assessment of the transfer efficiency. CONCLUSIONS: A baumannii can transfer easily from nitrile gloves to fomite compared with other gram-negative bacteria that cause health care-associated infections. These findings support data from previous observational studies that gloves of health care workers can be major routes of A baumannii transmission in clinical settings.