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Microglia survey brain parenchyma, responding to injury and infections. Microglia also respond to systemic disease, but the role of blood–brain barrier (BBB) integrity in this process remains unclear. Using simultaneous in vivo imaging, we demonstrated that systemic inflammation induces CCR5-dependent migration of brain resident microglia to the cerebral vasculature. Vessel-associated microglia initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 and make physical contact with endothelial cells. During sustained inflammation, microglia phagocytose astrocytic end-feet and impair BBB function. Our results show microglia play a dual role in maintaining BBB integrity with implications for elucidating how systemic immune-activation impacts neural functions. Although it is known that microglia respond to injury and systemic disease in the brain, it is unclear if they modulate blood–brain barrier (BBB) integrity, which is critical for regulating neuroinflammatory responses. Here authors demonstrate that microglia respond to inflammation by migrating towards and accumulating around cerebral vessels, where they initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 before switching, during sustained inflammation, to phagocytically remove astrocytic end-feet resulting in impaired BBB function

Maternal infection or inflammation causes abnormalities in brain development associated with subsequent cognitive impairment and in an increased susceptibility to schizophrenia and autism spectrum disorders. Maternal immune activation (MIA) and increases in serum cytokine levels mediates this association via effects on the fetal brain, and microglia can respond to maternal immune status, but consensus on how microglia may respond is lacking and no-one has yet examined if microglial process motility is impaired. In this study we investigated how MIA induced at two different gestational ages affected microglial properties at different developmental stages. Immune activation in mid-pregnancy increased IL-6 expression in embryonic microglia, but failed to cause any marked changes in morphology either at E18 or postnatally. In contrast MIA, particularly when induced earlier (at E12), caused sustained alterations in the patterns of microglial process motility and behavioral deficits. Our research has identified an important microglial property that is altered by MIA and which may contribute to the underlying pathophysiological mechanisms linking maternal immune status to subsequent risks for cognitive disease.

Social isolation during the juvenile critical window is detrimental to proper functioning of the prefrontal cortex (PFC) and establishment of appropriate adult social behaviors. However, the specific circuits that undergo social experience-dependent maturation to regulate social behavior are poorly understood. We identify a specific activation pattern of parvalbumin-positive interneurons (PVIs) in dorsal-medial PFC (dmPFC) prior to an active bout, or a bout initiated by the focal mouse, but not during a passive bout when mice are explored by a stimulus mouse. Optogenetic and chemogenetic manipulation reveals that brief dmPFC-PVI activation triggers an active social approach to promote sociability. Juvenile social isolation decouples dmPFC-PVI activation from subsequent active social approach by freezing the functional maturation process of dmPFC-PVIs during the juvenile-to-adult transition. Chemogenetic activation of dmPFC-PVI activity in the adult animal mitigates juvenile isolation-induced social deficits. Therefore, social experience-dependent maturation of dmPFC-PVI is linked to long-term impacts on social behavior. Isolation during critical periods of development prevents development of normal social behaviours in mice, and this is thought to involve the prefrontal cortex. Here, the authors identify an activation pattern in parvalbumin-positive interneurons in the dorsal medial prefrontal cortex that when activated promotes sociability behaviours in mice.

To develop our proposed technology method to improve retinal pigment epithelium (RPE) detection in optical coherence tomography (OCT) images and compare its efficacy with Topcon’s automated segmentation algorithm across multiple retinal diseases and healthy eyes. OCT images from 88 patients with age-related macular degeneration (AMD) were used for our proposed technology model training and validation. For testing with separate images were obtained from patients with AMD (100), diabetic retinopathy (DR; 50), epiretinal membrane (ERM; 50), branch retinal vein occlusion (BRVO; 50), and healthy eyes (50). The proposed technology was used to identify RPE in OCT images using the Pyramid Scene Parsing Network on top of ResNet-50. The accuracy of the proposed technology method in RPE detection was measured using the mean absolute error (MAE) and compared with Topcon’s automated segmentation algorithm for each retinal condition. As compared with Topcon’s automated segmentation algorithm, the proposed technology showed significantly better MAEs across all conditions: AMD (2.18 vs. 4.79), DR (1.69 vs. 3.17), ERM (1.50 vs. 2.67), BRVO (1.86 vs. 2.98), and healthy eyes (1.59 vs. 2.28). Notably, the proposed technology’s superiority was most evident in the AMD group. The proposed technology method outperformed Topcon’s automated segmentation algorithm in accurately visualizing RPE in OCT images across all tested conditions, especially in AMD. Our results indicate the proposed technology’s potential to elevate the RPE segmentation which can lead to enhancing ophthalmology care by providing more accurate OCT imaging analyses.

Juvenile social isolation reduces sociability in adulthood, but the underlying neural circuit mechanisms are poorly understood. We found that, in male mice, 2 weeks of social isolation immediately following weaning leads to a failure to activate medial prefrontal cortex neurons projecting to the posterior paraventricular thalamus (mPFC→pPVT) during social exposure in adulthood. Chemogenetic or optogenetic suppression of mPFC→pPVT activity in adulthood was sufficient to induce sociability deficits without affecting anxiety-related behaviors or preference toward rewarding food. Juvenile isolation led to both reduced excitability of mPFC→pPVT neurons and increased inhibitory input drive from low-threshold-spiking somatostatin interneurons in adulthood, suggesting a circuit mechanism underlying sociability deficits. Chemogenetic or optogenetic stimulation of mPFC→pPVT neurons in adulthood could rescue the sociability deficits caused by juvenile isolation. Our study identifies a pair of specific medial prefrontal cortex excitatory and inhibitory neuron populations required for sociability that are profoundly affected by juvenile social experience.Yamamuro et al. show that juvenile social isolation disrupts prefrontal neurons projecting to the paraventricular thalamus and associated prefrontal somatostatin interneurons, and thereby impairs sociability in adulthood.

The clinical utility of antigen test using anterior nasal samples has not been well evaluated. We conducted a prospective study in a drive-through testing site located at a PCR center to evaluate the diagnostic performance of the antigen test QuickNavi-COVID19 Ag using anterior nasal samples and to compare the degrees of coughs or sneezes induction and the severity of pain between anterior nasal collection and nasopharyngeal collection. The study included a total of 862 participants, of which 91.6% were symptomatic. The median duration from symptom onset to sample collection was 2.0 days. Fifty-one participants tested positive for severe acute respiratory syndrome coronavirus 2 on reverse transcription PCR (RT-PCR) with nasopharyngeal samples, and all of them were symptomatic. In comparison to the findings of RT-PCR, the antigen test using anterior nasal samples showed 72.5% sensitivity (95% confidence interval [CI] 58.3–84.1%) and 100% specificity (95% CI 99.3–100%). Anterior nasal collection was associated with a significantly lower degree of coughs or sneezes induction and the severity of pain in comparison to nasopharyngeal collection ( p  < 0.001). The antigen test using anterior nasal samples showed moderate sensitivity in symptomatic patients who were at the early stages of the disease course but was less painful and induced fewer coughs or sneezes.

ObjectivesThere are limitations to defining multimorbidity (MM) based on a simple count of diseases. To address these limitations, the concept of complex MM (CMM) focuses on how many body systems are affected in a single patient, rather than counting comorbid conditions. This study compared the prediction of mortality among older Japanese adults between CMM and conventional MM.DesignA population-based prospective cohort study.SettingThe Japan Gerontological Evaluation Study, a nationwide longitudinal cohort study, which ran from 2010 to 2016.ParticipantsFunctionally independent individuals who were older than 65 and had complete illness data at the time of baseline survey were eligible.Outcomes measureCMM was defined as the coexistence of 3 or more body system disorders at baseline. We calculated the propensity for each individual to develop CMM based on a wide array of characteristics, including socioeconomic status and health behaviours. Individuals with and without CMM were then matched on their propensity scores before we estimated overall survival using a log-rank test.ResultsOur 6-year follow-up included 38 889 older adults: 20 233 (52.0%) and 7565 (19.5%) adults with MM and CMM, respectively. In the MM-matched cohort (n=15 666 pairs), the presence of MM was significantly associated with increased mortality (HR 1.07; 95% CI 1.01 to 1.14; p=0.02 by the log-rank test). A similar mortality association was found in the CMM-matched cohort (n=7524 pairs, HR, 1.07; 95% CI 0.99 to 1.16; p=0.08 by the log-rank test).ConclusionThis is the first study to report the association between CMM and mortality among older adults in Japan. MM and CMM predict mortality in older adults to a similar degree. This finding needs to be replicated with more precision in larger samples.

Although immobility is a common cause of muscle atrophy, the mechanism underlying this causality is unclear. We here show that Krüppel-like factor 15 (KLF15) and IL-6 are upregulated in skeletal muscle of limb-immobilized mice and that mice with KLF15 deficiency in skeletal muscle or with systemic IL-6 deficiency are protected from immobility-induced muscle atrophy. A newly developed Ca2+ bioimaging revealed that the cytosolic Ca2+ concentration ([Ca2+]i) of skeletal muscle is reduced to below the basal level by immobilization, which is associated with the downregulation of Piezo1. Acute disruption of Piezo1 in skeletal muscle induced Klf15 and Il6 expression as well as muscle atrophy, which was prevented by antibodies against IL-6. A role for the Piezo1/KLF15/IL-6 axis in immobility-induced muscle atrophy was validated in human samples. Our results thus uncover a paradigm for Ca2+ signaling in that a decrease in [Ca2+]i from the basal level triggers a defined biological event.

Background Robot-assisted gait training (RAGT) is an effective method for treating gait disorders in individuals with stroke. However, no previous studies have demonstrated the effectiveness of RAGT in individuals with acute stroke. This study aimed to investigate the effects of RAGT initiation within 1 week after onset on degree of gait independence in individuals with hemiparetic stroke. Methods This retrospective cohort study used propensity-score matching. Individuals admitted to Fujita Health University Hospital after stroke onset and underwent RAGT between March 2017 and June 2023 were enrolled. Ninety-two individuals were eligible and grouped into the acute (≤ 7 days after the onset) and subacute groups (8–90 days after onset). RAGT was conducted using Welwalk, primarily comprising a knee–ankle–foot orthosis type robot worn on one paralyzed lower extremity, with training sessions lasting approximately 40 min/day, occurring 3–7 days/week. The primary outcome was the gait under supervision within 90 days of onset, which was compared between groups using the log-rank test. Results After propensity-score matching, 36 individuals were included in the analysis, including 18 each in the acute and subacute groups; the participant demographics were not significantly different between the groups. RAGT was initiated at a median of 6 and 25 days after onset in the acute and subacute groups, respectively. The Kaplan–Meier curves after the log-rank test showed a significantly higher percentage and shorter median days to achieve gait under supervision in the acute group than in the subacute group. The cumulative incidence of gait under supervision events at 90 days after onset was 82.2% and 55.6% in the acute and the subacute groups, respectively. Half of the individuals achieved gait under supervision within 49 days and 75 days in the acute and subacute groups, respectively ( p  = 0.038). No significant differences were observed in the dose of rehabilitation program and gait training per day from onset to achieving gait under supervision. Conclusion Initiation of RAGT within 1 week after stroke onset in individuals with hemiparesis may reduce the number of days required to achieve gait under supervision and increase the percentage of gait under supervision.

Japan's health system is well known for achieving one of the world's highest life expectancy with universal health coverage. However, the country now faces challenges of a rapidly aging population and changes in patterns and burden of disease. Primary care is an important component of a well‐functioning health system. In Japan, primary care services are provided in both the community and hospital settings. The distinction between primary and secondary care may not always be clear. This review is based on the framework from the 2015 WHO publication on primary care systems in Europe. Our aim is to describe the journey of primary care in Japan, with its past, present, and future as a valuable addition to the academic English literature. We also hope that this article would inspire readers outside of Japan who might face similar issues in their respective countries.