Development of a rapid detection method for the macrolide resistance gene in Mycobacterium avium using the amplification refractory mutation system-loop-mediated isothermal amplification method.

Macrolide antibiotics such as clarithromycin (CLR) and azithromycin are the key drugs used in multidrug therapy for Mycobacterium avium complex (MAC) diseases. For these antibacterial drugs, drug susceptibility has been correlated with clinical response in MAC diseases. We have previously demonstrated the correlation between drug susceptibility and mutations in the 23S rRNA gene, which confers resistance to macrolides. Herein, we developed a rapid detection method using the amplification refractory mutation system (ARMS)-loop-mediated isothermal amplification (LAMP) technique to identify mutations in the 23S rRNA gene of M. avium. We examined the applicability of the ARMS-LAMP method to genomic DNA extracted from six genotypes of M. avium clinical isolates. The M. avium isolates were classified into 21 CLR-resistant and 9 CLR-susceptible strains based on the results of drug susceptibility tests; the 23S rRNA genes of these strains were sequenced and analyzed using the ARMS-LAMP method. Sequence analysis revealed that the 9 CLR-sensitive strains were wild-type strains, whereas the 21 CLR-resistant strains comprised 20 mutant-type strains and one wild-type strain. Using ARMS-LAMP, no amplification from genomic DNAs of the 10 wild-type strains was observed using the mutant-type mismatch primer sets (MTPSs); however, amplification from the 20 mutant-type strain DNAs was observed using the MTPSs. The rapid detection method developed by us integrates ARMS-LAMP with a real-time turbidimeter, which can help determine drug resistance in a few hours. In conclusion, ARMS-LAMP might be a new clinically beneficial technology for rapid detection of mutations.IMPORTANCEMultidrug therapy for pulmonary Mycobacterium avium complex disease is centered on the macrolide antibiotics clarithromycin and azithromycin, and resistance to macrolides is an important prognosticator for clinical aggravation. Therefore, it is important to develop a quick and easy method for detecting resistance to macrolides. Drug resistance is known to be correlated with mutations in macrolide resistance genes. We developed a rapid detection method using amplification refractory mutation system (ARMS)-loop-mediated isothermal amplification (LAMP) to identify a mutation in the 23S rRNA gene, which is a macrolide resistance gene. Furthermore, we examined the applicability of this method using M. avium clinical isolates. The rapid method developed by us for detection of the macrolide resistance gene by integrating ARMS-LAMP and a real-time turbidimeter can help in detection of drug resistance within a few hours. Since this method does not require expensive equipment or special techniques and shows high analytical speed, it would be very useful in clinical practice.

Major HBV splice variant encoding a novel protein important for infection.

BACKGROUND & AIMS: HBV expresses more than 10 spliced RNAs from the viral pregenomic RNA, but their functions remain elusive and controversial. To address the function of HBV spliced RNAs, we generated splicing-deficient HBV mutants and conducted experiments to assess the impact of these mutants on HBV infection. METHODS: HepG2-NTCP cells, human hepatocyte chimeric FRG mice (hu-FRG mice), and serum from patients with chronic hepatitis B were used for experiments on HBV infection. Additionally, SHifter assays and cryo-electron microscopy were performed. RESULTS: We found the infectivity of splicing-deficient HBV was decreased 100-1,000-fold compared with that of wild-type HBV in hu-FRG mice. Another mutant, A487C, which loses the most abundant spliced RNA (SP1), also exhibits severely impaired infectivity. SP1 hypothetically encodes a novel protein HBcSP1 (HBc-Cys) that lacks the C-terminal cysteine from full-length HBc. In the SHifter assay, HBcSP1 was detected in wild-type viral particles at a ratio of about 20-100% vs. conventional HBc, as well as in the serum of patients with chronic hepatitis B, but not in A487C particles. When infection was conducted with a shorter incubation time of 4-8 h at lower PEG concentrations in HepG2-NTCP cells, the entry of the A487C mutant was significantly slower. SP1 cDNA complementation of the A487C mutant succeeded in rescuing its infectivity in hu-FRG mice and HepG2-NTCP cells. Moreover, cryo-electron microscopy revealed a disulfide bond between HBc cysteine 183 and 48 in the HBc intradimer of the A487C capsid, leading to a locked conformation that disfavored viral entry in contrast to the wild-type capsid. CONCLUSIONS: Prior studies unveiled the potential integration of the HBc-Cys protein into the HBV capsid. We confirmed the proposal and validated its identity and function during infection. IMPACT AND IMPLICATIONS: HBV SP1 RNA encodes a novel HBc protein (HBcSP1) that lacks the C-terminal cysteine from conventional HBc (HBc-Cys). HBcSP1 was detected in cell culture-derived HBV and confirmed in patients with chronic infection by both immunological and chemical modification assays at 10-50% of capsid. The splicing-deficient mutant HBV (A487C) impaired infectivity in human hepatocyte chimeric mice and viral entry in the HepG2-NTCP cell line. Furthermore, these deficiencies of the splicing-deficient mutant could be rescued by complementation with the SP1-encoded protein HBcSP1. We confirmed and validated the identity and function of HBcSP1 during infection, building on the current model of HBV particles.

Disrupted interoceptive awareness by auditory distractor: Difficulty inferring the internal bodily states?

Recent studies have associated interoceptive awareness, the perception of internal bodily sensations, with a predictive mechanism of perception across all sensory modalities. According to the framework, volitional attention plays a pivotal role in interoceptive awareness by prioritizing interoceptive sensations over exteroceptive ones. Consequently, it is hypothesized that the presence of irrelevant stimuli would disrupt the attentional modulation and interoceptive awareness, which remains untested. In this study, we investigated if interoceptive awareness is diminished by unrelated auditory distractors to validate the proposed perceptual framework. A total of 30 healthy human volunteers performed the heartbeat counting task both with and without auditory distractors. Additionally, we measured participant's psychophysiological traits related to interoception, including the high-frequency component of heart rate variability (HF-HRV) and trait interoceptive sensibility. The results showed that interoceptive accuracy, confidence, and heartbeat intensity decreased in the presence of distractor sound. Moreover, individuals with higher HF-HRV and a greater tendency to worry about bodily states experienced a more pronounced distractor effect on interoceptive awareness. These results provide support for the perceptual mechanism of interoceptive awareness in terms of the predictive process, highlighting the impact of relative precision across interoceptive and exteroceptive signals on perceptual experiences.

Revisiting the relationship between illusory hand ownership induced by visuotactile synchrony and cardiac interoceptive accuracy.

Multisensory integration plays an important role in the experience of the bodily self. Recently, the relationship between exteroception and interoception has been actively debated. The first evidence was a report that the susceptibility of the sense of ownership over a fake hand (i.e., illusory hand ownership: IHO) in the typical rubber hand illusion is negatively modulated by the accuracy of the heartbeat perception (i.e., cardiac interoceptive accuracy: CIA). If reliable, this would suggest an antagonism between the exteroceptive and interoceptive cues underlying the bodily self. However, some inconsistent data have been reported, raising questions about the robustness of the initial evidence. To investigate this robustness, we estimated the extent of the modulatory effect of CIA on IHO susceptibility by applying Bayesian hierarchical modeling to two independent datasets. Overall, our results did not support that IHO susceptibility is modulated by CIA. The present estimates with high uncertainty cannot exclude the hypothesis that the relationship between IHO susceptibility and CIA is so weak as to be negligible. Further studies with larger sample sizes are needed to reach a conclusion about the extent of the modulatory effect. These findings highlight the lack of robustness of key evidence supporting the "antagonism hypothesis".

UBL3 Interaction with α-Synuclein Is Downregulated by Silencing MGST3.

Ubiquitin-like 3 (UBL3) is a membrane-anchored protein that plays a crucial role in sorting proteins into small extracellular vesicles. Aggregations of alpha-synuclein (α-syn) are associated with the pathology of neurodegenerative diseases such as Parkinson's disease. Recently, the interaction between UBL3 and α-syn was discovered, with potential implications in clearing excess α-syn from neurons and its role in disease spread. However, the regulator that can mediate the interaction between UBL3 and α-syn remains unclear. In this study, using the split gaussian luciferase complementation assay and RNA interference technology, we identified that QSOX2, HTATIP2, UBE3C, MGST3, NSF, HECTD1, SAE1, and ATG3 were involved in downregulating the interaction between UBL3 and α-syn. Notably, silencing MGST3 had the most significant impact. Immunocytochemistry staining confirmed the impact of MGST3 silencing on the co-localization of UBL3 and α-syn in cells. MGST3 is a part of the antioxidant system, and silencing MGST3 is believed to contribute to oxidative stress. We induced oxidative stress with hydrogen peroxide, observing its effect on the UBL3-α-syn interaction, and showing that 800 µM of H2O2 downregulated this interaction. In conclusion, silencing MGST3 downregulates the interaction between UBL3 and α-syn.

Neural substrates of top-down processing during perceptual duration-based timing and beat-based timing.

Temporal context is a crucial factor in timing. Previous studies have revealed that the timing of regular stimuli, such as isochronous beats or rhythmic sequences (termed beat-based timing), activated the basal ganglia, whereas the timing of single intervals or irregular stimuli (termed duration-based timing) activated the cerebellum. We conducted a functional magnetic resonance imaging (fMRI) experiment to determine whether top-down processing of perceptual duration-based and beat-based timings affected brain activation patterns. Our participants listened to auditory sequences containing both single intervals and isochronous beats and judged either the duration of the intervals or the tempo of the beats. Whole-brain analysis revealed that both duration judgments and tempo judgments activated similar areas, including the basal ganglia and cerebellum, with no significant difference in the activated regions between the two conditions. In addition, an analysis of the regions of interest revealed no significant differences between the activation levels measured for the two tasks in the basal ganglia as well as the cerebellum. These results suggested that a set of common brain areas were involved in top-down processing of both duration judgments and tempo judgments. Our findings indicate that perceptual duration-based timing and beat-based timing are driven by stimulus regularity irrespective of top-down processing.

UBL3 Interacts with Alpha-Synuclein in Cells and the Interaction Is Downregulated by the EGFR Pathway Inhibitor Osimertinib.

Ubiquitin-like 3 (UBL3) acts as a post-translational modification (PTM) factor and regulates protein sorting into small extracellular vesicles (sEVs). sEVs have been reported as vectors for the pathology propagation of neurodegenerative diseases, such as α-synucleinopathies. Alpha-synuclein (α-syn) has been widely studied for its involvement in α-synucleinopathies. However, it is still unknown whether UBL3 interacts with α-syn, and is influenced by drugs or compounds. In this study, we investigated the interaction between UBL3 and α-syn, and any ensuing possible functional and pathological implications. We found that UBL3 can interact with α-syn by the Gaussia princeps based split luciferase complementation assay in cells and immunoprecipitation, while cysteine residues at its C-terminal, which are considered important as PTM factors for UBL3, were not essential for the interaction. The interaction was upregulated by 1-methyl-4-phenylpyridinium exposure. In drug screen results, the interaction was significantly downregulated by the treatment of osimertinib. These results suggest that UBL3 interacts with α-syn in cells and is significantly downregulated by epidermal growth factor receptor (EGFR) pathway inhibitor osimertinib. Therefore, the UBL3 pathway may be a new therapeutic target for α-synucleinopathies in the future.

Heterogeneity of social cognition between visual perspective-taking and theory of mind in the temporo-parietal junction.

Visual perspective taking (VPT), particularly level 2 VPT (VPT2), which allows an individual to understand that the same object can be seen differently by others, is related to the theory of mind (ToM), because both functions require a decoupled representation from oneself. Although previous neuroimaging studies have shown that VPT2 and ToM activate the temporo-parietal junction (TPJ), it is unclear whether common neural substrates are involved in both functions. To clarify this point, we directly compared the TPJ activation patterns of individual participants performing VPT2 and ToM tasks using functional magnetic resonance imaging and within-subjects design. A whole-brain analysis revealed that VPT2 and ToM activated overlapping areas in the posterior part of the TPJ. In addition, we found that both the peak coordinates and activated regions for ToM were located significantly more anteriorly and dorsally within the bilateral TPJ than those measured during the VPT2 task. We further confirmed that these activated areas were spatially distinct from the nearby extrastriate body area (EBA), visual motion area (MT+), and the posterior superior temporal sulcus (pSTS) using independent localizer scans. Our findings revealed that VPT2 and ToM have gradient representations, indicating the functional heterogeneity of social cognition within the TPJ.

Factors associated with adverse drug reactions or death in very elderly hospitalized patients with pulmonary tuberculosis.

The aging of patients with tuberculosis and better therapeutic management for them are recent concerns. This study aimed to identify risk factors for adverse drug reactions (ADRs) or death in very elderly patients with pulmonary tuberculosis and to assess the association between the dosage of antituberculosis drugs and outcomes. We conducted a multicenter retrospective study at two hospitals. Hospitalized patients (≥ 80 years old) with pulmonary tuberculosis who were treated with antituberculosis drugs were enrolled. Multivariate analysis was performed to assess factors associated with ADRs or death within 60 days after treatment initiation. In total, 632 patients were included. The primary endpoint occurred in 268 patients (190 ADRs and 78 deaths). A serum albumin level < 2.5 g/dL, respiratory failure, and dependent activities of daily living were independent risk factors for ADRs or death. However, a low dosage (< 8 mg/kg/day) of rifampicin was associated with a lower risk of the primary outcomes. Delayed time to negative sputum culture conversion was not observed in the lower dosage of rifampicin group. Very elderly hospitalized tuberculosis patients with the aforementioned risk factors should be carefully monitored to receive safer treatment. Rifampicin dosage reduction may be considered for very elderly tuberculosis patients to prevent ADRs/death.

Lysine long-chain fatty acylation regulates the TEAD transcription factor.

TEAD transcription factors are responsible for the transcriptional output of Hippo signaling. TEAD activity is primarily regulated by phosphorylation of its coactivators, YAP and TAZ. In addition, cysteine palmitoylation has recently been shown to regulate TEAD activity. Here, we report lysine long-chain fatty acylation as a posttranslational modification of TEADs. Lysine fatty acylation occurs spontaneously via intramolecular transfer of acyl groups from the proximal acylated cysteine residue. Lysine fatty acylation, like cysteine palmitoylation, contributes to the transcriptional activity of TEADs by enhancing the interaction with YAP and TAZ, but it is more stable than cysteine acylation, suggesting that the lysine fatty-acylated TEAD acts as a "stable active form." Significantly, lysine fatty acylation of TEAD increased upon Hippo signaling activation despite a decrease in cysteine acylation. Our results provide insight into the role of fatty-acyl modifications in the regulation of TEAD activity.

Identification of a derivative of the alkaloid emetine as an inhibitor of the YAP-TEAD interaction and its potential as an anticancer agent.

TEAD is a transcription factor responsible for the output of the tumor suppressor Hippo pathway. The transcriptional activity of TEAD requires molecular interaction with its transcriptional coactivator, YAP. Aberrant activation of TEAD is deeply involved in tumorigenesis and is associated with poor prognosis, suggesting that inhibitors targeting the YAP-TEAD system are promising as antitumor agents. In this study, we identified NPD689, an analog of the natural product alkaloid emetine, as an inhibitor of the YAP-TEAD interaction. NPD689 suppressed the transcriptional activity of TEAD and reduced the viability of human malignant pleural mesothelioma and non-small cell lung cancer cells but not the viability of normal human mesothelial cells. Our results suggest that NPD689 is not only a new useful chemical tool for elucidating the biological role of the YAP-TEAD system but also has potential as a starting compound for developing a cancer therapeutic agent that targets the YAP-TEAD interaction.

Distinct neural representations of hand movement direction between motor imagery and execution in the presupplementary motor area.

Motor simulation theory proposes a functional equivalence between motor execution (ME) and its simulation, suggesting that motor imagery (MI) is the self-intentioned simulation of one's actions. This study used functional magnetic resonance imaging (fMRI) with multivoxel pattern analysis to test whether the direction of hand movement is represented with a similar neural code between ME and MI. In our study, participants used their right hand to move an on-screen cursor in the left-right direction with a joystick or imagined the same movement without execution. The results indicated that the left-right direction as well as their modality (ME or MI) could be decoded significantly above the chance level in the presupplementary motor area (pre-SMA) and primary visual cortex (V1). Next, we used activation patterns of ME as inputs to the decoder to predict hand move directions in MI sessions and found a significantly higher-than-chance accuracy only in V1, not in pre-SMA. Moreover, the representational similarity analysis showed similar activation patterns for the same directions between ME and MI in V1 but not in pre-SMA. This study's finding indicates distinct spatial activation patterns for movement directions between ME and MI in pre-SMA.

A Rapid Screening Assay for Clarithromycin-Resistant Mycobacterium avium Complex Using Melting Curve Analysis with Nonfluorescent Labeled Probes.

Mycobacterium avium complex (MAC) thrives in various environments and mainly causes lung disease in humans. Because macrolide antibiotics such as clarithromycin or azithromycin are key drugs for MAC lung disease, the emergence of macrolide-resistant strains prevents the treatment of MAC. More than 95% of macrolide-resistant MAC strains are reported to have a point mutation in 23S rRNA domain V. This study successfully developed a melting curve assay using nonfluorescent labeled probes to detect the MAC mutation at positions 2058 to 2059 of the 23S rRNA gene (AA genotype, clarithromycin susceptible; TA, GA, AG, CA, AC, and AT genotypes, clarithromycin resistant). In the AA-specific probe assay, the melting peak of the DNA fragment of the AA genotype was higher than that of DNA fragments of other genotypes. Melting temperature (Tm) values of the AA genotype and the other genotypes were about 80°C and 77°C, respectively. DNA fragments of each genotype were identified correctly in six other genotype-specific probes (TA, GA, AG, CA, AC, and AT) assays. Using genomic DNA from six genotype strains of M. avium and four genotype strains of M. intracellulare, we confirmed that all genomic DNAs could be correctly identified as individual genotypes according to the highest Tm values among the same probe assays. These results indicate that this melting curve-based assay is able to determine MAC genotypes at positions 2058 to 2059 of the 23S rRNA gene. This simple method could contribute to the rapid detection of clarithromycin-resistant MAC strains and help to provide accurate drug therapy for MAC lung disease. IMPORTANCE Since macrolide antibiotics such as clarithromycin or azithromycin are key drugs in multidrug therapy for Mycobacterium avium complex (MAC) lung diseases, the rapid detection of macrolide-resistant MAC strains has important implications for the treatment of MAC. Previous studies have reported a correlation between drug susceptibility testing and the mutation of macrolide resistance genes. In this study, we developed a novel melting curve-based assay using nonfluorescent labeled probes to identify both clarithromycin-resistant M. avium and M. intracellulare with mutations in the 23S rRNA gene, which is the clarithromycin or azithromycin resistance gene. This assay contributed to not only the detection of MAC mutations but also the determination of all genotypes at positions 2058 to 2059 of the 23S rRNA gene. Furthermore, because nonfluorescent labeled probes are used, this assay is more easily and more immediately available than other methods.

Cardiac and Gastric Interoceptive Awareness Have Distinct Neural Substrates.

Interoceptive awareness, an awareness of the internal body state, guides adaptive behavior by providing ongoing information on body signals, such as heart rate and energy status. However, it is still unclear how interoceptive awareness of different body organs are represented in the human brain. Hence, we directly compared the neural activations accompanying attention to cardiac (related to heartbeat) and gastric (related to stomach) sensations, which generate cardiac and gastric interoceptive awareness, in the same population (healthy humans, N = 31). Participants were asked to direct their attention toward heart and stomach sensations and become aware of them in a magnetic resonance imaging (MRI) scanner. The results indicated that the neural activations underlying gastric attention encompassed larger brain regions, including the occipitotemporal visual cortices, bilateral primary motor cortices, primary somatosensory cortex, left orbitofrontal cortex, and hippocampal regions. Cardiac attention, however, selectively activated the right anterior insula extending to the frontal operculum compared with gastric attention. Moreover, our detailed analyses focusing on the insula, the most relevant region for interoceptive awareness, revealed that the left dorsal middle insula encoded cardiac and gastric attention via different activation patterns, but the posterior insula did not. Our results demonstrate that cardiac and gastric attention evoke different brain activation patterns; in particular, the selective activation may reflect differences in the functional roles of cardiac and gastric interoceptive awareness.

Supramodal Representation of the Sense of Body Ownership in the Human Parieto-Premotor and Extrastriate Cortices.

The sense of body ownership, defined as the sensation that one's body belongs to oneself, is a fundamental component of bodily self-consciousness. Several studies have shown the importance of multisensory integration for the emergence of the sense of body ownership, together with the involvement of the parieto-premotor and extrastriate cortices in bodily awareness. However, whether the sense of body ownership elicited by different sources of signal, especially visuotactile and visuomotor inputs, is represented by common neural patterns remains to be elucidated. We used functional magnetic resonance imaging (fMRI) to investigate the existence of neural correlates of the sense of body ownership independent of the sensory modalities. Participants received tactile stimulation or executed finger movements while given synchronous and asynchronous visual feedback of their hand. We used multivoxel patterns analysis (MVPA) to decode the synchronous and asynchronous conditions with cross-classification between two modalities: the classifier was first trained in the visuotactile sessions and then tested in the visuomotor sessions, and vice versa. Regions of interest (ROIs)-based and searchlight analyses revealed significant above-chance cross-classification accuracies in the bilateral intraparietal sulcus (IPS), the bilateral ventral premotor cortex (PMv), and the left extrastriate body area (EBA). Moreover, we observed a significant positive correlation between the cross-classification accuracy in the left PMv and the difference in subjective ratings of the sense of body ownership between the synchronous and asynchronous conditions. Our findings revealed the neural representations of the sense of body ownership in the IPS, PMv, and EBA that is invariant to the sensory modalities.

Traumatic retropharyngeal hematoma without spinal cord injury or spinal fracture: a retrospective multicenter analysis.

BACKGROUND: Retropharyngeal hematoma can be a life-threatening injury due to progressive upper airway obstruction. It is common following spinal cord injury or spinal fracture, and the clinical course and outcome of such patients are determined by their primary injuries. However, the natural clinical course of retropharyngeal hematoma itself remains unclear. In this study, we aimed to examine the clinical characteristics of traumatic retropharyngeal hematoma without spinal cord injury or spinal fracture (TREWISS). METHODS: We performed a multicenter retrospective analysis of patients who were diagnosed in the emergency department with soft tissue swelling of the retropharyngeal space by neck CT, between April 2010 and April 2020. The inclusion criterion was thickness of the retropharyngeal space > 7 mm at C1-C4 or > 22 mm at C5-C7 on a CT image. The exclusion criteria were (1) age < 18 years, (2) cardiopulmonary arrest, (3) other causes of soft tissue swelling besides hematoma, (4) patients with cervical spinal cord injury or spine fractures. Baseline characteristics were compared between intubated and non-intubated patients. RESULTS: Twenty-two patients were included in the analysis. Among them, 16 patients needed intubation. Median patient age was 69 years, and 27% of the patients were on antiplatelet or anticoagulant medications. The width of the hematoma on sagittal CT images was significantly wider in the intubated group [median (interquartile range), 2.5 cm (2.0-3.4) vs. 1.2 cm (0.9-1.7), p = 0.002). More than half the intubated patients needed tracheotomy. Tracheotomy was performed around day 3, and endotracheal tube was placed about 3 weeks. Only 60% of patients were successfully discharged to their homes, and one patient (6.3%) died during hospitalization. CONCLUSION: Early intubation and subsequent intensive care are important for patients with TREWISS. The patients typically require several weeks of hospitalization, although their outcomes are usually poor.

Efficacy and safety of isavuconazole against deep-seated mycoses: A phase 3, randomized, open-label study in Japan.

OBJECTIVES: Isavuconazole is a convenient triazole antifungal agent with a broad antifungal spectrum. A randomized, open-label study (ClinicalTrials.gov, NCT03471988) was conducted to evaluate the efficacy and safety of isavuconazole in Japanese patients with deep-seated mycoses. PATIENTS AND METHODS: In Cohort A, patients with aspergillosis (chronic pulmonary aspergillosis and invasive aspergillosis) were randomized in a 2:1 ratio to isavuconazole or voriconazole, and in Cohort B, patients with cryptococcosis and mucormycosis were assigned to isavuconazole for up to 84 days of treatment. The overall outcome was evaluated according to the clinical, radiological, and mycological responses at Days 42 and 84 and at the end of treatment (EOT). RESULTS: A total of 103 participants were enrolled and received the study drug. The overall response rate of patients with chronic pulmonary aspergillosis in the isavuconazole (52 patients) and voriconazole (27 patients) groups was 82.7% and 77.8% at EOT, respectively. The response rate in patients with cryptococcosis (10 patients, isavuconazole group only) was 90.0%. One of three participants with invasive aspergillosis and one of three participants with mucormycosis responded in the isavuconazole group. In the safety evaluation, the incidence of adverse events in participants with chronic pulmonary aspergillosis was similar in both groups. Adverse drug reactions were reported in 32 (61.5%) patients receiving isavuconazole and 23 (85.2%) patients receiving voriconazole. CONCLUSIONS: Isavuconazole showed efficacy and safety in Japanese patients with chronic pulmonary aspergillosis and cryptococcosis, for which the drug is not currently indicated.

Decoding of Motor Imagery Involving Whole-body Coordination.

The present study investigated whether different types of motor imageries can be classified based on the location of the activation peaks or the multivariate pattern analysis (MVPA) of functional magnetic resonance imaging (fMRI) and compared the difference between visual motor imagery (VI) and kinesthetic motor imagery (KI). During fMRI scanning sessions, 25 participants imagined four movements included in the Motor Imagery Questionnaire-Revised (MIQ-R): knee lift, jump, arm movement, and waist bend. These four imagined movements were then classified based on the peak location or the patterns of fMRI signal values. We divided the participants into two groups based on whether they found it easier to generate VI (VI group, n = 10) or KI (KI group, n = 15). Our results show that the imagined movements can be classified using both the location of the activation peak and the spatial activation patterns within the sensorimotor cortex, and MVPA performs better than the activation peak classification. Furthermore, our result reveals that the KI group achieved a higher MVPA decoding accuracy within the left primary somatosensory cortex than the VI group, suggesting that the modality of motor imagery differently affects the classification performance in distinct brain regions.

Clinical manifestations of hospitalized influenza patients without risk factors: A prospective multicenter cohort study in Japan via internet surveillance.

INTRODUCTION: Influenza remains a clinically heavy burden worldwide. It is well known that some populations are at high risk of complications from influenza, whereas, even previously healthy people might suffer from severe influenza. The objective of this study was to clarify clinical manifestations of hospitalized patients without risk factors infected with influenza. METHODS: The clinical data for patients who were severely ill with influenza, and required hospitalization were gathered and analyzed between November 2014 and August 2020 (6 influenza seasons) using an internet-surveillance system. Among them, the patients who had no risk factors of complications from influenza were extracted. RESULTS: Finally, a total of 91 patients (9.0% of all influenza-related hospitalizations) without risk factors were analyzed. The no risk group was younger than the risk group, though other significant differences of clinical characteristics were not recognized between the groups. Pneumonia was the most common cause of hospitalization in the no risk group, and primary influenza viral pneumonia was the most common pneumonia. Antiviral drugs were administered in 96.7% of the no-risk group, and artificial ventilation was performed in 18.7%. In-hospital death was recorded for 3 patients without risk factors. CONCLUSIONS: Severe complications of influenza which required hospitalization may occur in a certain degree of patients with no risk factors. Efforts are needed to diagnose and treat influenza appropriately even in previously healthy younger patients. Continuous nationwide surveillance will be required to clarify risk factors for severe influenza even in previously healthy younger patients. (UMIN000015989).

Neuroimaging Examination of Driving Mode Switching Corresponding to Changes in the Driving Environment.

Car driving is supported by perceptual, cognitive, and motor skills trained through continuous daily practice. One of the skills that characterize experienced drivers is to detect changes in the driving environment and then flexibly switch their driving modes in response to the changes. Previous functional neuroimaging studies on motor control investigated the mechanisms underlying behaviors adaptive to changes in control properties or parameters of experimental devices such as a computer mouse or a joystick. The switching of multiple internal models mainly engages adaptive behaviors and underlies the interplay between the cerebellum and frontoparietal network (FPN) regions as the neural process. However, it remains unclear whether the neural mechanisms identified in previous motor control studies also underlie practical driving behaviors. In the current study, we measure functional magnetic resonance imaging (fMRI) activities while participants control a realistic driving simulator inside the MRI scanner. Here, the accelerator sensitivity of a virtual car is abruptly changed, requiring participants to respond to this change flexibly to maintain stable driving. We first compare brain activities before and after the sensitivity change. As a result, sensorimotor areas, including the left cerebellum, increase their activities after the sensitivity change. Moreover, after the change, activity significantly increases in the inferior parietal lobe (IPL) and dorsolateral prefrontal cortex (DLPFC), parts of the FPN regions. By contrast, the posterior cingulate cortex, a part of the default mode network, deactivates after the sensitivity change. Our results suggest that the neural bases found in previous experimental studies can serve as the foundation of adaptive driving behaviors. At the same time, this study also highlights the unique contribution of non-motor regions to addressing the high cognitive demands of driving.