Comparisons of in-hospital fee and surgical outcomes between robot-assisted, laparoscopic, and open radical cystectomy: a Japanese nationwide study.

OBJECTIVE: To evaluate in-hospital fees and surgical outcomes of robot-assisted radical cystectomy (RARC), laparoscopic radical cystectomy (LRC) and open radical cystectomy (ORC) using a Japanese nationwide database. METHODS: All data were obtained from the Diagnosis Procedure Combination database between April 2020 and March 2022. Basic characteristics and perioperative indicators, including in-hospital fees, were compared among the RARC, LRC and ORC groups. Propensity score-matched comparisons were performed to assess the differences between RARC and ORC. RESULTS: During the study period, 2931, 1311 and 2435 cases of RARC, LRC and ORC were identified, respectively. The RARC group had the lowest in-hospital fee (median: 2.38 million yen), the shortest hospital stay (26 days) and the lowest blood transfusion rate (29.5%), as well as the lowest complication rate (20.9%), despite having the longest anesthesia time (569 min) among the three groups (all P < 0.01). The outcomes of LRC were comparable with those of RARC, and the differences in these indicators between the RARC and ORC groups were greater than those between the RARC and LRC groups. In propensity score-matched comparisons between the RARC and ORC groups, the differences in the indicators remained significant (all P < 0.01), with an ~50 000 yen difference in in-hospital fees. CONCLUSIONS: RARC and LRC were considered to be more cost-effective surgeries than ORC due to their superior surgical outcomes and comparable surgical fees in Japan. The widespread adoption of RARC and LRC is expected to bring economic benefits to Japanese society.

Imaging of 17O-labeled Water Using Fast T2 Mapping with T2-preparation: A Phantom Study.

17O-labeled water is a T2-shortening contrast agent used in proton MRI and is a promising method for visualizing cerebrospinal fluid (CSF) dynamics because it provides long-term tracking of water molecules. However, various external factors reduce the accuracy of 17O-concentration measurements using conventional signal-intensity-based methods. In addition, T2 mapping, which is expected to provide a stable assessment, is generally limited to temporal-spatial resolution. We developed the T2-prepared based on T2 mapping used in cardiac imaging to adapt to long T2 values and tested whether it could accurately measure 17O-concentration in the CSF using a phantom. The results showed that 17O-concentration in a fluid mimicking CSF could be evaluated with an accuracy comparable to conventional T2-mapping (Carr-Purcell-Meiboom-Gill multi-echo spin-echo method). This method allows 17O-imaging with a high temporal resolution and stability in proton MRI. This imaging technique may be promising for visualizing CSF dynamics using 17O-labeled water.

Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton's Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies.

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies. We report the discovery and characterization of NX-2127, a BTK degrader with concomitant immunomodulatory activity. By design, NX-2127 mediates the degradation of transcription factors IKZF1 and IKZF3 through molecular glue interactions with the cereblon E3 ubiquitin ligase complex. NX-2127 degrades common BTK resistance mutants, including BTKC481S. NX-2127 is orally bioavailable, exhibits in vivo degradation across species, and demonstrates efficacy in preclinical oncology models. NX-2127 has advanced into first-in-human clinical trials and achieves deep and sustained degradation of BTK following daily oral dosing at 100 mg.

Prognostic nutritional index after introduction of atezolizumab with bevacizumab predicts prognosis in advanced hepatocellular carcinoma: A multicenter study.

INTRODUCTION: Atezolizumab plus bevacizumab (Atez/Bev) is the preferred treatment for advanced hepatocellular carcinoma (HCC). However, biomarkers of therapeutic efficacy have remained unclear. We took a retrospective approach to explore the role of prognostic nutritional index (PNI) for predicting the outcomes of Atez/Bev treatment. METHODS: One hundred twenty-five HCC patients were enlisted; these patients received Atez/Bev treatment and underwent dynamic computerized tomography/magnetic resonance imaging to determine the treatment response on at least one occasion between October 2020 and January 2023, and their PNI before treatment and at the beginning of the second cycle (PNI-2c) was evaluated. RESULTS: During the initial evaluation, 2 (2%), 28 (22%), 70 (56%), and 25 (20%) patients exhibited a complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), respectively. Patients with non-PD tended to have higher PNI at baseline and PNI-2c than those with PD (p = 0.245 and 0.122, respectively), with optimal baseline PNI and PNI-2c cut-off values of 42.6 and 40.4, respectively. PNI at baseline could not be used to predict overall survival (OS) or progression-free survival (PFS). However, PNI-2c predicted OS and PFS (PNI-2c ≥ 40.4 vs. < 40.4: 25.3 vs. 16.2 months, P = 0.008 for OS; 12.7 vs. 8.4 months, P = 0.036 for PFS). A multivariate analysis showed a significant association between PNI-2c and OS. CONCLUSIONS: PNI-2c is a predictor of prognosis in HCC patients treated with Atez/Bev therapy.

Post hoc analysis of patients with rheumatoid arthritis under clinical remission in two Japanese Phase 3 trials of peficitinib treatment (RAJ3 and RAJ4).

OBJECTIVE: We evaluated remission rates and their relationship with baseline characteristics in patients with rheumatoid arthritis treated with the oral Janus kinase inhibitor peficitinib. METHODS: This post hoc analysis of data from two Phase 3 studies (RAJ3 and RAJ4) of peficitinib (100 and 150 mg/day) in Asian rheumatoid arthritis patients investigated clinical disease activity index (CDAI) remission and low disease activity rates from baseline to Week 52. CDAI, Health Assessment Questionnaire-Disability Index, and van der Heijde-modified total Sharp score remission/low disease activity rates at Week 52 were evaluated among patients achieving CDAI remission at Weeks 12/28. Logistic regression analyses explored the relationship between baseline characteristics and CDAI remission/low disease activity rates. RESULTS: CDAI remission rates increased over time in a dose-dependent manner in both peficitinib-treated groups. Most patients achieving CDAI remission at Weeks 12/28 also achieved remission at Week 52. Following the multivariate analysis of demographic and baseline characteristics, factors associated with the achievement of CDAI remission at Week 28 included male sex, low baseline prednisone dose (RAJ3 only), and low baseline Disease Activity Score 28-C-reactive protein (RAJ4 only). CONCLUSIONS: Peficitinib demonstrated persistent efficacy in clinical remission to Week 52. Baseline characteristics associated with CDAI remission were mostly consistent with previous studies using other disease-modifying antirheumatic drugs.

Magnetic Resonance Water Tracer Imaging Using 17 O-Labeled Water.

ABSTRACT: Magnetic resonance imaging (MRI) is a crucial imaging technique for visualizing water in living organisms. Besides proton MRI, which is widely available and enables direct visualization of intrinsic water distribution and dynamics in various environments, MR-WTI (MR water tracer imaging) using 17 O-labeled water has been developed, benefiting from the many advancements in MRI software and hardware that have substantially improved the signal-to-noise ratio and made possible faster imaging. This cutting-edge technique allows the generation of novel and valuable images for clinical use. This review elucidates the studies related to MRI water tracer techniques centered around 17 O-labeled water, explaining the fundamental principles of imaging and providing clinical application examples. Anticipating continued progress in studies involving isotope-labeled water, this review is expected to contribute to elucidating the pathophysiology of various diseases related to water dynamics abnormalities and establishing novel imaging diagnostic methods for associated diseases.

Development of an Immunochromatography Assay to Detect Marburg Virus and Ravn Virus.

The recent outbreaks of Marburg virus disease (MVD) in Guinea, Ghana, Equatorial Guinea, and Tanzania, none of which had reported previous outbreaks, imply increasing risks of spillover of the causative viruses, Marburg virus (MARV) and Ravn virus (RAVV), from their natural host animals. These outbreaks have emphasized the need for the development of rapid diagnostic tests for this disease. Using monoclonal antibodies specific to the viral nucleoprotein, we developed an immunochromatography (IC) assay for the rapid diagnosis of MVD. The IC assay was found to be capable of detecting approximately 102-4 50% tissue culture infectious dose (TCID50)/test of MARV and RAVV in the infected culture supernatants. We further confirmed that the IC assay could detect the MARV and RAVV antigens in the serum samples from experimentally infected nonhuman primates. These results indicate that the IC assay to detect MARV can be a useful tool for the rapid point-of-care diagnosis of MVD.

Microglial process dynamics depend on astrocyte and synaptic activity.

Microglial processes survey the brain parenchyma, but it is unknown whether this process is influenced by the cell activity of nearby microglia under physiological conditions. Herein, we showed that microglial process dynamics differ when facilitated by astrocytic activity and pre-synaptic activity. The results revealed distinct microglial process dynamics associated with the activity of other brain cells.

Activity-dependent oligodendrocyte calcium dynamics and their changes in Alzheimer's disease.

Oligodendrocytes (OCs) form myelin around axons, which is dependent on neuronal activity. This activity-dependent myelination plays a crucial role in training and learning. Previous studies have suggested that neuronal activity regulates proliferation and differentiation of oligodendrocyte precursor cells (OPCs) and myelination. In addition, deficient activity-dependent myelination results in impaired motor learning. However, the functional response of OC responsible for neuronal activity and their pathological changes is not fully elucidated. In this research, we aimed to understand the activity-dependent OC responses and their different properties by observing OCs using in vivo two-photon microscopy. We clarified that the Ca2+ activity in OCs is neuronal activity dependent and differentially regulated by neurotransmitters such as glutamate or adenosine triphosphate (ATP). Furthermore, in 5-month-old mice models of Alzheimer's disease, a period before the appearance of behavioral abnormalities, the elevated Ca2+ responses in OCs are ATP dependent, suggesting that OCs receive ATP from damaged tissue. We anticipate that our research will help in determining the correct therapeutic strategy for neurodegenerative diseases beyond the synapse.

Astrocytic NKCC1 inhibits seizures by buffering Cl- and antagonizing neuronal NKCC1 at GABAergic synapses.

OBJECTIVE: A pathological excitatory action of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) has been observed in epilepsy. Blocking the Cl- importer NKCC1 with bumetanide is expected to reduce the neuronal intracellular Cl- concentration ([Cl- ]i ) and thereby attenuate the excitatory GABA response. Accordingly, several clinical trials of bumetanide for epilepsy were conducted. Although NKCC1 is expressed in both neurons and glial cells, an involvement of glial NKCC1 in seizures has not yet been reported. Astrocytes maintain high [Cl- ]i with NKCC1, and this gradient promotes Cl- efflux via the astrocytic GABAA receptor (GABAA R). This Cl- efflux buffers the synaptic cleft Cl- concentration to maintain the postsynaptic Cl- gradient during intense firing of GABAergic neurons, thereby sustaining its inhibitory action during seizure. In this study, we investigated the function of astrocytic NKCC1 in modulating the postsynaptic action of GABA in acute seizure models. METHODS: We used the astrocyte-specific conditional NKCC1 knockout (AstroNKCC1KO) mice. The seizurelike events (SLEs) in CA1 pyramidal neurons were triggered by tetanic stimulation of stratum radiatum in acute hippocampus slices. The SLE underlying GABAA R-mediated depolarization was evaluated by applying the GABAA R antagonist bicuculline. The pilocarpine-induced seizure in vivo was monitored in adult mice by the Racine scale. The SLE duration and tetanus stimulation intensity threshold and seizure behavior in AstroNKCC1KO mice and wild-type (WT) mice were compared. RESULTS: The AstroNKCC1KO mice were prone to seizures with lower threshold and longer duration of SLEs and larger GABAA R-mediated depolarization underlying the SLEs, accompanied by higher Racine-scored seizures. Bumetanide reduced these indicators of seizure in AstroNKCC1KO mice (which still express neuronal NKCC1), but not in the WT, both in vitro and in vivo. SIGNIFICANCE: Astrocytic NKCC1 inhibits GABA-mediated excitatory action during seizures, whereas neuronal NKCC1 has the converse effect, suggesting opposing actions of bumetanide on these cells.

[Microglial regulation of brain function and pathological changes].

Microglia are the only immune cells in the central nervous system. It has been shown that microglia actively regulate the number of neurons by participating in the cell death of neural stem cells during development and maturation. In addition, recent optical techniques have enabled in vivo imaging, which has revealed the function of microglia on synapses. Microglia regularly monitor synaptic activity and remove synapses that show abnormal activity in the event of brain infarction or other disorders. During development, microglia contribute to the formation of immature synapses by contacting dendrites during early synapse formation, and they are also involved in the de-synaptic process by selectively removing weakly active synapses through the use of classical complement cascade signaling. Furthermore, these abnormalities are known to contribute to the development of autism during development and to the development of Alzheimer's disease during maturation. In addition to this, microglia also contribute to plastic changes in synapses during the learning process in maturation. Furthermore, by modifying synaptic activity, microglia are known to be involved in changes in the activity of neuronal circuits. In addition to these synaptic functions, microglia are also known to be involved in the permeability of the blood-brain barrier. In this chapter, these functions will be summarized and discussed.

Regulation of lipid synthesis in myelin modulates neural activity and is required for motor learning.

Brain function relies on both rapid electrical communication in neural circuitry and appropriate patterns or synchrony of neural activity. Rapid communication between neurons is facilitated by wrapping nerve axons with insulation by a myelin sheath composed largely of different lipids. Recent evidence has indicated that the extent of myelination of nerve axons can adapt based on neural activity levels and this adaptive myelination is associated with improved learning of motor tasks, suggesting such plasticity may enhance effective learning. In this study, we examined whether another aspect of myelin plasticity-changes in myelin lipid synthesis and composition-may also be associated with motor learning. We combined a motor learning task in mice with in vivo two-photon imaging of neural activity in the primary motor cortex (M1) to distinguish early and late stages of learning and then probed levels of some key myelin lipids using mass spectrometry analysis. Sphingomyelin levels were elevated in the early stage of motor learning while galactosylceramide levels were elevated in the middle and late stages of motor learning, and these changes were correlated across individual mice with both learning performance and neural activity changes. Targeted inhibition of oligodendrocyte-specific galactosyltransferase expression, the enzyme that synthesizes myelin galactosylceramide, impaired motor learning. Our results suggest regulation of myelin lipid composition could be a novel facet of myelin adaptations associated with learning.

Association between Undergraduate Education for Community-Based Medicine and General Practice Majors: A Longitudinal Study in Japan.

BACKGROUND: There is a shortage of general practitioners in Japan. With the revision of educational guidelines, general practice (GP) education has improved. However, the amount of education on GP in medical schools remains inconsistent. This study examined the relationship between medical students' amount of GP-related education and their subsequent choice of GP majors. METHODS: A retrospective cohort study was conducted in a teaching hospital in Japan. Participants were residents in the hospital. The exposure comprised compulsory lectures and training time for community-based medicine in medical schools. The outcome included participants choosing GP majors after their initial 2-year junior residency. RESULTS: Fifty-one participants were included in the final analysis. Of these, 14 majored in GP and 37 in non-GP after their initial 2-year junior residency. Of the participants who took GP lectures for 18 hours or more, 11 chose GP majors, and 18 chose non-GP majors (risk ratio, 2.78; 95% confidence interval [CI], 0.88-8.79). Of the participants who underwent training for 12 days or more, 10 chose GP majors, and 16 chose non-GP majors (risk ratio, 2.40; 95% CI, 0.87-6.68). CONCLUSION: The results do not support the association between the amount of compulsory undergraduate education for community-based medicine and the subsequent increase in the number of residents choosing GP majors in Japan. Educators would do well to explore different approaches, such as improving the quality of education to increase the number of GP residents. Further research is needed to reach more definitive conclusions.

Blockage of CSF Outflow in Rats after Deep Cervical Lymph Node Ligation Observed Using Gd-based MR Imaging.

PURPOSE: To investigate whether deep cervical lymph node (DCLN) ligation alters intracranial cerebrospinal fluid (CSF) tracer dynamics and outflow using a rat model with intrathecal dynamic contrast-enhanced (DCE) MRI. METHODS: Six bilateral DCLN-ligated and six sham-operated rats were subjected to DCE MRI with Gd-BTDO3A, and dynamic T1-weighted images were acquired. ROIs were collected from the CSF at the C1 level (CSF_C1), CSF between the olfactory bulbs (CSF_OB), CSF at the pituitary recess (CSF_PitR), and CSF at the pineal recess (CSF_PinR), upper nasal turbinate (UNT), olfactory bulbs, cerebrum, and the jugular region. Time-intensity curves were evaluated, and the maximum slope, peak timing, peak signal ratio, and elimination half-life for the four CSF ROIs and UNT were calculated and compared. RESULTS: Delayed tracer arrival in the rostral CSF space and the nasal cavity with tracer retention in the ventral CSF space were observed in the ligation group. The maximum slopes were smaller in the ligation group at UNT (sham: 0.075 ± 0.0061, ligation: 0.044 ± 0.0086/min, P = 0.011). A significant difference was not detected in peak timings. The peak signal ratio values were lower in the ligation group at UNT (sham: 2.12 ± 0.19, ligation: 1.72 ± 0.11, P = 0.011). The elimination half-life was delayed in the ligation group at CSF_C1 (sham: 30.5 ± 2.70, ligation: 44.4 ± 12.6 min, P = 0.043), CSF_OB (sham: 30.2 ± 2.67, ligation: 44.8 ± 7.47 min, P = 0.021), and CSF_PitR (sham: 30.2 ± 2.49, ligation: 41.3 ± 7.57 min, P = 0.021). CONCLUSION: The DCLN ligation in rats blocked CSF outflow into the nasal cavity and caused CSF retention.

Direct Enhancement Effect of Hippocampal Cholinergic Neurostimulating Peptide on Cholinergic Activity in the Hippocampus.

The cholinergic efferent network from the medial septal nucleus to the hippocampus is crucial for learning and memory. This study aimed to clarify whether hippocampal cholinergic neurostimulating peptide (HCNP) has a rescue function in the cholinergic dysfunction of HCNP precursor protein (HCNP-pp) conditional knockout (cKO). Chemically synthesized HCNP or a vehicle were continuously administered into the cerebral ventricle of HCNP-pp cKO mice and littermate floxed (control) mice for two weeks via osmotic pumps. We immunohistochemically measured the cholinergic axon volume in the stratum oriens and functionally evaluated the local field potential in the CA1. Furthermore, choline acetyltransferase (ChAT) and nerve growth factor (NGF) receptor (TrkA and p75NTR) abundances were quantified in wild-type (WT) mice administered HCNP or the vehicle. As a result, HCNP administration morphologically increased the cholinergic axonal volume and electrophysiological theta power in HCNP-pp cKO and control mice. Following the administration of HCNP to WT mice, TrkA and p75NTR levels also decreased significantly. These data suggest that extrinsic HCNP may compensate for the reduced cholinergic axonal volume and theta power in HCNP-pp cKO mice. HCNP may function complementarily to NGF in the cholinergic network in vivo. HCNP may represent a therapeutic candidate for neurological diseases with cholinergic dysfunction, e.g., Alzheimer's disease and Lewy body dementia.

Biological-Activity-Based Prioritization of Antidepressants in Wastewater in England and Japan.

Antidepressants are one of the most commonly prescribed pharmaceuticals. Although they have been frequently detected in aquatic environments around the globe, little is known regarding their adverse effects on humans and aquatic organisms. Recently, an in vitro monoamine transporter inhibition assay was developed to detect transporter-inhibitory activities of antidepressants in wastewater in Japan. However, it was unclear which antidepressants were responsible for transporter-inhibitory activities in wastewater. Herein, the per capita consumption of 32 antidepressants, their excretion of unchanged parent compounds, per capita water consumption, removal rate during wastewater treatment processes, and potency values from the monoamine transporter inhibition assay were used to prioritize antidepressants of concern in effluent wastewater in England and Japan. In both countries, sertraline and O-desmethylvenlafaxine had the highest contribution to inhibitory activities against the human serotonin transporter (hSERT) and zebrafish SERT (zSERT), respectively. It was found that the antidepressants inhibited the zSERT more strongly than the hSERT. The inhibitory activities found against the zSERT in wastewater in England and Japan were higher than thresholds for abnormal behavior in fish. The antidepressants prioritized in this study provide insight into launching environmental monitoring and ecotoxicological studies of antidepressants.

Microglia enable cross-modal plasticity by removing inhibitory synapses.

Cross-modal plasticity is the repurposing of brain regions associated with deprived sensory inputs to improve the capacity of other sensory modalities. The functional mechanisms of cross-modal plasticity can indicate how the brain recovers from various forms of injury and how different sensory modalities are integrated. Here, we demonstrate that rewiring of the microglia-mediated local circuit synapse is crucial for cross-modal plasticity induced by visual deprivation (monocular deprivation [MD]). MD relieves the usual inhibition of functional connectivity between the somatosensory cortex and secondary lateral visual cortex (V2L). This results in enhanced excitatory responses in V2L neurons during whisker stimulation and a greater capacity for vibrissae sensory discrimination. The enhanced cross-modal response is mediated by selective removal of inhibitory synapse terminals on pyramidal neurons by the microglia in the V2L via matrix metalloproteinase 9 signaling. Our results provide insights into how cortical circuits integrate different inputs to functionally compensate for neuronal damage.

Diagnostic performance of microscopic stool examination in Campylobacter infection performed by different medical specialties.

Background: Microscopic examination of stool samples can contribute to the early diagnosis of Campylobacter gastroenteritis. However, it is unclear whether the diagnostic performance is reliable when performed by physicians. Methods: This prospective study included fresh stool samples collected from patients with gastroenteritis between August 2018 and March 2020. The samples were used for microscopic examination through Gram staining. Two physicians, a clinical laboratory technician, and microbiologists performed the examinations. In addition, antigen tests (QuickNavi-Campylobacter; Denka Co., Ltd.) were evaluated for the samples collected between May 2019 and March 2020. Infection with Campylobacter spp. was confirmed when stool cultures or polymerase chain reaction tests provided positive results. Results: Microscopic examination was performed on 205 samples, of which 46 (22.4%) were positive for Campylobacter spp. For the microscopic examination, the sensitivity and specificity were 53.5% and 98.1% for physician A, 46.7% and 96.2% for physician B, 63.0% and 100% for the clinical laboratory technician, and 67.4% and 100% for microbiologists, respectively. The antigen testing was evaluated in 131 of the 205 samples and showed a sensitivity of 93.3% and specificity of 99.0%. Conclusions: Microscopic examination of the stool samples showed high specificity. The sensitivity when the examinations were performed by the physicians was insufficient. The rapid antigen tests can reliably detect Campylobacter spp. in stool samples.

CD206+ macrophages transventricularly infiltrate the early embryonic cerebral wall to differentiate into microglia.

The relationships between tissue-resident microglia and early macrophages, especially their lineage segregation outside the yolk sac, have been recently explored, providing a model in which a conversion from macrophages seeds microglia during brain development. However, spatiotemporal evidence to support such microglial seeding in situ and to explain how it occurs has not been obtained. By cell tracking via slice culture, intravital imaging, and Flash tag-mediated or genetic labeling, we find that intraventricular CD206+ macrophages, which are abundantly observed along the inner surface of the mouse cerebral wall, frequently enter the pallium at embryonic day 12. Immunofluorescence of the tracked cells show that postinfiltrative macrophages in the pallium acquire microglial properties while losing the CD206+ macrophage phenotype. We also find that intraventricular macrophages are supplied transepithelially from the roof plate. This study demonstrates that the "roof plate→ventricle→pallium" route is an essential path for microglial colonization into the embryonic mouse brain.