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Abstract Selective vulnerability offers a conceptual framework for understanding neurodegenerative disorders such as Parkinson’s disease, where specific neuronal types are selectively affected and adjacent ones are spared. However, the applicability of this framework to neurodevelopmental disorders, particularly those characterized by atypical social behaviors, such as autism spectrum disorder, remains uncertain. Here we show that an embryonic disturbance, known to induce social dysfunction in male mice, preferentially impaired the gene expression crucial for neural functions in parvocellular oxytocin (OT) neurons—a subtype linked to social rewards—while neighboring cell types experienced a lesser impact. Chemogenetic stimulation of OT neurons at the neonatal stage ameliorated social deficits in early adulthood, concurrent with cell-type-specific sustained recovery of pivotal gene expression within parvocellular OT neurons. Collectively, our data shed light on the transcriptomic selective vulnerability within the hypothalamic social behavioral center and provide a potential therapeutic target through specific neonatal neurostimulation.

Abstract We report an Arase‐all sky imager (ASI) conjugate event in which the pulsating aurora (PsA) has a one‐to‐one correspondence with chorus bursts. Wavelet analysis displayed three peaks at ∼0.3 Hz, 4 Hz, and >10 Hz, corresponding to the main pulsation, internal modulation, and fast modulation, respectively. These correspond to the old terms of ∼5–15 s pulsations, chorus risers/elements and subelements/subpackets, respectively. Electron “microbursts” correspond to the 4‐Hz peak. The internal and fast modulations are further verified by the analysis based on fast Fourier transform analyses. Moreover, the spatial distributions of the Fourier spectral amplitude show that the internal and fast modulations are well‐structured within auroral patches. The above results indicate a paradigm shift away from quasilinear theory which implicitly assumes diffuse wave generation. The three time‐scale modulations are consistent with coherent chorus which has been theoretically argued to lead to pitch angle transport three orders of magnitude faster.

Abstract We evaluated the effectiveness of a mobile health (mHealth) intervention for diabetic kidney disease patients by conducting a 12-month randomized controlled trial among 126 type 2 diabetes mellitus patients with moderately increased albuminuria (urinary albumin-to-creatinine ratio (UACR): 30-299 mg/g creatinine) recruited from eight clinical sites in Japan. Using a Theory of Planned Behavior (TPB) behavior change theory framework, the intervention provides patients detailed information in order to improve patient control over exercise and dietary behaviors. In addition to standard care, the intervention group received DialBetesPlus, a self-management support system allowing patients to monitor exercise, blood glucose, diet, blood pressure, and body weight via a smartphone application. The primary outcome, change in UACR after 12 months (used as a surrogate measure of renal function), was 28.8% better than the control group’s change (P = 0.029). Secondary outcomes also improved in the intervention group, including a 0.32-point better change in HbA1c percentage (P = 0.041). These improvements persisted when models were adjusted to account for the impacts of coadministration of drugs targeting albuminuria (GLP-1 receptor agonists, SGLT-2 inhibitors, ACE inhibitors, and ARBs) (UACR: −32.3% [95% CI: −49.2%, −9.8%] between-group difference in change, P = 0.008). Exploratory multivariate regression analysis suggests that the improvements were primarily due to levels of exercise. This is the first trial to show that a lifestyle intervention via mHealth achieved a clinically-significant improvement in moderately increased albuminuria.

Plasma aldosterone concentration (PAC) was routinely measured using radioimmunoassay (RIA); however, the RIA kit was discontinued in March 2021 in Japan. This study examined PAC conversion in adrenal venous sampling (AVS) and AVS criteria when measured using chemiluminescent enzyme immunoassay (CLEIA). PAC of 415 adrenal venous blood samples from AVS (including segmental AVS) of 63 patients with primary aldosteronism was measured using RIA (Spac-S aldosterone kit; Fujirebio Inc.) and CLEIA (Lumipulse Presto Aldosterone; Fujirebio Inc.). PAC of 70 AVS samples was also measured using liquid chromatography-mass spectrometry (LC-MS/MS, ASKA Pharma Medical Co., Ltd.). PAC conversion formulas were determined for each AVS sample assay. PAC measured using CLEIA was significantly correlated with that measured using RIA (correlation coefficient = 0.971). The PAC conversion formula was PAC (CLEIA) = PAC (RIA) × 0.772 – 1,199 pg/mL. The PAC of 14,000 pg/mL in RIA was equivalent to 9,613 pg/mL in CLEIA. PAC measured using CLEIA was also correlated with that measured using LC-MS/MS, and the PAC conversion formula was PAC (CLEIA, pg/mL) = 0.97 × PAC (LC-MS/MS, pg/mL) + 211. The inter-assay coefficient of variability (CV) was 1.1–1.3% and intra-assay CV was 1.0–1.7%, measured using CLEIA. The PAC conversion formula for AVS samples was obtained using CLEIA and RIA, and the conversion formula was different from that for peripheral blood. PAC values measured by CLEIA showed preferable accuracy and high concordance with those measured by LC-MS/MS, even in AVS samples. The study outcomes are useful for interpreting AVS results using non-RIA measurement methods.

Abstract Adrenal venous sampling (AVS) is crucial for subtyping primary aldosteronism (PA) to explore the possibility of curing hypertension. Because AVS availability is limited, efforts have been made to develop strategies to bypass it. However, it has so far proven unsuccessful in applying clinical practice, partly due to heterogeneity and missing values of the cohorts. For this purpose, we retrospectively assessed 210 PA cases from three institutions where segment-selective AVS, which is more accurate and sensitive for detecting PA cases with surgical indications, was available. A machine learning-based classification model featuring a new cross-center domain adaptation capability was developed. The model identified 102 patients with PA who benefited from surgery in the present cohort. A new data imputation technique was used to address cross-center heterogeneity, making a common prediction model applicable across multiple cohorts. Logistic regression demonstrated higher accuracy than Random Forest and Deep Learning [(0.89, 0.86) vs. (0.84, 0.84), (0.82, 0.84) for surgical or medical indications in terms of f-score]. A derived integrated flowchart revealed that 35.2% of PA cases required AVS with 94.1% accuracy. The present model enabled us to reduce the burden of AVS on patients who would benefit the most.

Fibromuscular dysplasia can cause renovascular hypertension. Since fibromuscular dysplasia may be underdiagnosed, precise diagnosis and management are crucial, especially for young women. A 20-year-old woman with hypertension and hypokalemia was referred to our hospital for further evaluation of secondary hypertension. At the previous hospital, her blood pressure was 160/110 mmHg and the serum potassium level was 2.9 mEq/L. The equilibrium phase on contrast-enhanced computed tomography revealed a low-density area in the upper median portion of the right kidney. On admission to our hospital, her blood pressure was 141/96 mmHg under 5 mg of amlodipine. Laboratory tests revealed plasma renin activity of 11.3 ng/mL/h and plasma aldosterone concentration of 117.1 pg/mL. Renal venous sampling of active renin concentration showed a right-to-left renin ratio of 3.13, confirming a significant increase in renin secretion from the right kidney. Selective reno-angiography detected focal stenosis with adjacent aneurysmal dilation and tortuosity in the proximal branch of the right renal artery. She was diagnosed with branch artery fibromuscular dysplasia and successfully treated with percutaneous transluminal angioplasty. After the treatment, she was free from hypertension and hypokalemia without any medications. Since branch artery fibromuscular dysplasia is sometimes difficult to diagnose, contrast-enhanced computed tomography can be a promising diagnostic tool as shown in this case. Concerning treatment, our patient was treated with percutaneous transluminal angioplasty, which should be considered for women of reproductive age because recommended antihypertensive medications can be teratogenic even in the first trimester of pregnancy.

BackgroundIncreasing physical activity improves glycemic control in patients with type 2 diabetes (T2D). Mobile health (mHealth) interventions have been proven to increase exercise, but engagement often fades with time. As the use of health behavior theory in mHealth design can increase effectiveness, we developed StepAdd, an mHealth intervention based on the constructs of social cognitive theory (SCT). StepAdd improves exercise behavior self-efficacy and self-regulation through the use of goal-setting, barrier-identifying, and barrier-coping strategies, as well as automatic feedback functions. A single-arm pilot study of StepAdd among 33 patients with T2D showed a large increase in step count (mean change of 4714, SD 3638 daily steps or +86.7%), along with strong improvements in BMI (mean change of −0.3 kg/m2) and hemoglobin A1c level (mean change of −0.79 percentage points). ObjectiveIn this study, we aim to investigate the efficacy and safety of StepAdd, an mHealth exercise support system for patients with T2D, via a large, long, and controlled follow-up to the pilot study. MethodsThis is a randomized, open-label, multicenter study targeting 160 patients with T2D from 5 institutions in Japan with a 24-week intervention. The intervention group will record daily step counts, body weight, and blood pressure using the SCT-based mobile app, StepAdd, and receive feedback about these measurements. In addition, they will set weekly step count goals, identify personal barriers to walking, and define strategies to overcome these barriers. The control group will record daily step counts, body weight, and blood pressure using a non–SCT-based placebo app. Both groups will receive monthly consultations with a physician who will advise patients regarding lifestyle modifications and use of the app. The 24-week intervention period will be followed by a 12-week observational period to investigate the sustainability of the intervention’s effects. The primary outcome is between-group difference in the change in hemoglobin A1c values at 24 weeks. The secondary outcomes include other health measures, measurements of steps, measurements of other behavior changes, and assessments of app use. The trial began in January 2023 and is intended to be completed in December 2025. ResultsAs of September 5, 2023, we had recruited 44 patients. We expect the trial to be completed by October 8, 2025, with the follow-up observation period being completed by December 31, 2025. ConclusionsThis trial will provide important evidence about the efficacy of an SCT-based mHealth intervention in improving physical activities and glycemic control in patients with T2D. If this study proves the intervention to be effective and safe, it could be a key step toward the integration of mHealth as part of the standard treatment received by patients with T2D in Japan. Trial RegistrationJapan Registry of Clinical Trials (JRCT) jRCT2032220603; https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2032220603 International Registered Report Identifier (IRRID)DERR1-10.2196/53514

Abstract Therapeutic options for breast cancer patients with brain metastases (BM)/leptomeningeal carcinomatosis (LMC) are limited. Here, we report on the effectiveness and safety of trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2-positive breast cancer patients with BM. Data were analyzed for 104 patients administered T-DXd. Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), intracranial (IC)-ORR, and IC-PFS were evaluated. ORR by investigator assessment was 55.7% (total population). Median PFS was 16.1 months; 12-month OS rate was 74.9% (total population). Median time-to-treatment failure was 9.7 months. In 51 patients with BM imaging, IC-ORR and median IC-PFS by independent central review were 62.7% and 16.1 months, respectively. In 19 LMC patients, 12-month PFS and OS rates were 60.7% and 87.1%, respectively. T-DXd showed effectiveness regarding IC-ORR, IC-PFS, PFS, and OS in breast cancer patients with BM/active BM, and sustained systemic and central nervous system disease control in LMC patients. Trial Registration: UMIN000044995.

Background: Abemaciclib-induced diarrhea (AID) impairs quality of life (QOL) and treatment adherence in patients with breast cancer. Supportive treatment with loperamide is associated with constipation. We hypothesized that probiotics and trimebutine maleate (TM) would decrease the frequency of AID without causing constipation. Methods: Hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer patients were randomized into the probiotic Bifidobacterium (A) or probiotic Bifidobacterium and TM (B) groups. Endocrine therapy, Abemaciclib and probiotic Bifidobacterium three times a day for 28 days, was administered to both arms. Arm B was treated with TM upon the onset of diarrhea. The primary endpoint was the percentage of patients who experienced grade ≥2 diarrhea. The secondary endpoints were safety, frequency, and duration of all-grade diarrhea; frequency of emesis and constipation; usage of loperamide; and health-related QOL/patient-reported outcome during the study. We evaluated whether the primary endpoint of each arm exceeded the predetermined threshold. Results: Fifty-one patients completed treatment. Grade 2 diarrhea occurred in 52% and 50% of patients in Arm A and Arm B, respectively. One patient experienced grade 3 diarrhea in each arm. The median duration of grade2 diarrhea was 2 and 2.5day, and only one patient required dose reduction. Grade ≥2 constipation was observed in 4% of Arm A and 3.6% of Arm B. Conclusions: Probiotic Bifidobacterium or the combination of probiotic Bifidobacterium with TM did not decrease the incidence of grade 2 or greater diarrhea compared with historical control, although the grade 3 or greater diarrhea was reduced. Clinical trial registration: jRCT (Japan registry of clinical trials).jRCTs031190154.

Abstract Chorus subpackets/subelements are the wave packets occurring at intervals of ∼10–100 msec and are suggested to play a crucial role in the formation of substructures within pulsating aurora. In this study, we investigate the evolution of subpackets from the upstream to downstream regions. Using Van Allen Probe A measurements, we have found that the frequency of the upstream subpackets increases smoothly, but that of the downstream subpackets remains almost unchanged. Through a simulation in the real‐size magnetosphere, we have reproduced the subpackets with characteristics similar to those in observations, and revealed that the frequency chirping is influenced by both resonant current of electrons and wave amplitude due to nonlinear physics. Although the resonant currents in the upstream and downstream regions are comparable, the wave amplitude increases significantly during evolution, resulting in lower sweep rate in the downstream region. Our findings provide a fresh insight into the evolution of chorus subpackets.

Background Hormone receptor (HR)-positive breast cancer is a disease for which no immune checkpoint inhibitors have shown promise as effective therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors synergistically increased the effectiveness of antiprogrammed cell death protein-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibodies in preclinical studies.Methods This non-randomized, multicohort, phase II study evaluated the efficacy and safety of the anti-PD-1 antibody nivolumab 240 mg administered every 2 weeks in combination with the CDK4/6 inhibitor abemaciclib 150 mg twice daily and either fulvestrant (FUL) or letrozole (LET) as a first-line or second-line treatment for HR-positive HER2-negative metastatic breast cancer. The primary end point was the objective response rate (ORR), and secondary end points were toxicity, progression-free survival, and overall survival. Blood, tissue, and fecal samples were collected at multiple points for correlative studies to evaluate immunity biomarkers.Results From June 2019 to early study termination due to safety concerns on July 2020, 17 patients were enrolled (FUL: n=12, LET: n=5). One patient with a prior treatment history in the FUL cohort was excluded. ORRs were 54.5% (6/11) and 40.0% (2/5) in the FUL and LET cohorts, respectively. Treatment-emergent (TE) adverse events (AEs) of grade ≥3 occurred in 11 (92%) and 5 (100%) patients in the FUL and LET cohorts, respectively. The most common grade ≥3 TEAEs were neutropenia (7 (58.3%) and 3 (60.0%) in the FUL and LET cohorts, respectively), followed by alanine aminotransferase elevation (5 (41.6%) and 4 (80.0%)). One treatment-related death from interstitial lung disease occurred in the LET cohort. Ten patients developed liver-related grade ≥3 AEs. Liver biopsy specimens from 3 patients showed hepatitis characterized by focal necrosis with predominant CD8+ lymphocyte infiltration. Marked elevation of tumor necrosis factor-related cytokines and interleukin-11, and a decrease in peripheral regulatory T cells (Tregs), were observed in patients with hepatotoxicity. These findings suggest that treatment-related toxicities were immune-related AEs likely caused by proinflammatory cytokine production and suppression of Treg proliferation due to the addition of abemaciclib to nivolumab therapy.Conclusions Although the combination of nivolumab and abemaciclib was active, it caused severe and prolonged immune-related AEs.Trial registration number JapicCTI-194782, jRCT2080224706, UMIN000036970.

BackgroundTrastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.MethodsIn this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety.ResultsOverall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%).ConclusionsTrastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast01 ClinicalTrials.gov number, NCT03248492.).

Magnetospheric relativistic electrons are accelerated during substorms and strong convection events that occur during high-intensity long-duration continuous auroral electrojet activity (HILDCAA) events, associated with solar wind high-speed streams (coming from coronal holes). From an analysis of ∼2–20 MeV electrons at L ∼ 2–7 measured by the Van Allen Probe satellite, it is shown that ∼3.4–4.1 days long HILDCAA events are characterized by ∼7.2 MeV electron acceleration in the L ∼ 4.0–6.0 region, which occurs ∼2.9–3.4 days after the onset of HILDCAA. The dominant acceleration process is due to wave–particle interactions between magnetospheric electromagnetic chorus waves and substorm-injected ∼100 keV electrons. The longer the HILDCAA and chorus last, the higher the maximum energy of the accelerated relativistic electrons. The acceleration to higher and higher energies is due to a bootstrap mechanism.