Published papers

© 2017 The Japanese Society of Child Neurology Occipital lobe epilepsy of childhood includes two entities: Panayiotopoulos syndrome in pre-school children, and idiopathic childhood occipital epilepsy of Gastaut (ICOEG) in school-age children. The typical initial manifestation of the former is vomiting, and that of the latter is visual hallucinations. Ictal cardiopulmonary arrest at initial presentation has been reported for Panayiotopoulos syndrome, but not for ICOEG. We document a 7-year-old previously healthy girl who experienced an acute elemental visual hallucination of seeing insects, followed by a new-onset generalized seizure. Upon arrival at the local hospital, she was unconscious and soon thereafter, developed respiratory arrest. She was resuscitated and initiated on mechanical ventilation. An electroencephalogram taken three days after seizure cessation showed frequent occipital spikes, consistent with the diagnosis of ICOEG. The sequence of acute elementary visual hallucination followed by a motor seizure, and then witnessed respiratory arrest illustrated occurrence of life-threatening autonomic involvement at initial onset in ICOEG. We speculate that the epileptic propagation from the occipital lobes eventually compromised the respiratory center in the brainstem. The possibility of occipital lobe epilepsy should be considered in school-age children presenting with acute visual hallucination followed by respiratory arrest. Such a presentation should prompt an urgent electroencephalogram and initiation of antiepileptic treatment if indicated.

© 2018 Loss-of-function mutations in coagulation cascade proteins lead to bleeding diasthesis. In contrast, gain-of-function mutations in these proteins, which are exceptionally rare, lead to hereditary thrombosis. This is best exemplified by Factor V (i.e., Factor V Leiden) and Factor II (i.e., p.Arg596Leu). Here, we report a family with hereditary thrombosis. The proposita presented with cerebral venous thrombosis accompanied by infarction at the age of 12 years. Despite anticoagulation therapy with oral warfarin, she later developed deep venous thrombosis in her hepatic portal veins at the age of 27 years. A medical exome analysis identified a de novo heterozygous mutation p.Tyr434His in Factor II, which was segregated within the family. A retrospective molecular diagnosis was made using a preserved surgical specimen from the proposita's mother, who had died 10 years earlier. The p.Tyr434 residue, which was substituted in the presently reported family, was located in “exosite I” of thrombin, a critical recognition site for fibrinogen, protein C, and thrombin aptamer. Therefore, the mutant thrombin likely exerted its thrombophilic effect by altering the affinity of thrombin to downstream substrates. Furthermore, the “exosite I” domain of thrombin was inhibited by the arthropod bleeding toxin Triabin (a protein discovered from the saliva of the blood-sucking triatomine bug Triatoma pallidipennis). Our observation that patients with a p.Tyr434His mutation exhibited recurrent thrombosis provides the first proof-of-concept in humans that a pharmacologic agent targeting “exosite I” could be an effective means of specifically modulating the thrombogenic-side of the coagulation system via the inhibition of factor II.

© 2017 Wiley Periodicals, Inc. Loss-of function mutations in NALCN on chromosome 13q, a sodium leak channel that maintains baseline neuronal excitability, cause infantile hypotonia with psychomotor retardation and characteristic faces 1 (IHPRF1, OMIM #615419). Here, we document two individuals with early onset hypotonia with poor feeding and intellectual disability who were compatible with a diagnosis of IHPRF1. The two patients had bi-allelic mutations in NALCN through two different genetic mechanisms: Patient 1 had bi-allelic splice site mutations, that is c.1267-2A>G, derived from heterozygous parents, while Patient 2 had a partial maternal uniparental isodisomy that harbored a frameshift mutation, that is c.2022_2023delAT, in chromosome 13 that was detected through a dedicated algorithm for homozygosity data mapping in whole exome sequencing. The delineation of the exact pattern of inheritance provided vital information regarding the risk of recurrence. In animal models with Nalcn mutations, two behavioral phenotypes, that are, postnatal dyspnea and sleep disturbance, have been reported. Our observations of the two patients with postnatal dyspnea and one patient with sleep disturbance support an association between these two behavioral phenotypes and NALCN mutations in humans. The routine use of a detection algorithm for homozygosity data mapping might improve the diagnostic yields of next-generation sequencing.

© 2017 The Authors. Developmental Psychobiology Published by Wiley Periodical, Inc. While the influence of the mother's voice on neonatal heart-rate response and its relevant activity on cerebral cortex and the autonomic nervous system (ANS) are well known, few studies have assessed its influence on respiratory activity. We investigated the relationship among the respiration rate, the delta wave amplitudes through electroencephalography, and the basal state of ANS through the respiratory variability index while 22 full-term neonates hear their mother's voice and an unknown voice. It was found that when respiratory variability was large, a transient (<5 s) change in respiration rates was observed in response to an unknown voice, while a greater increase in the delta wave amplitude was observed in the frontal lobe than the parietal one in response to the mother's voice. Conversely, when respiratory variability was small, a sustained increase (>10 s) in respiration rates was observed in response to the mother's voice, while a greater increase in the delta wave amplitude was found in both the frontal and parietal lobes. These results suggest that the basal state of ANS influences the latency of increases in respiration rates. Furthermore, induced by the mother's voice, transient increases in respiration rates are reduced in association with frontal lobe activity, and sustained increases in respiration rates are promoted in association with frontal and parietal lobe activities.

© 2019 Elsevier Ltd Objectives: We assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) by vaccine dose in children aged 6 months to 12 years for whom two doses are recommended in Japan to ascertain the appropriate vaccine doses. Methods: VE was assessed according to a test-negative case-control design based on rapid influenza diagnostic test (RIDT) results. Children aged 6 months to 12 years with a fever ≥38 °C who had received an RIDT in outpatient clinics of 24 hospitals were enrolled for all five seasons since 2013/14. VE by vaccine dose (none vs. once or twice, and once vs. twice) was analyzed. Results: In the dose analysis, 20,033 children were enrolled. Both one- and two-dose regimens significantly reduced cases in preventing any influenza, influenza A, and influenza B, but there was no significant difference in adjusted VE between one- and two-dose regimens overall (adjusted OR, 0.560 [95% CI, 0.505–0.621], 0.550 [95% CI, 0.516–0.586]), 0.549 [95% CI, 0.517–0.583], and 1.014 [95% CI, 0.907–1.135], for none vs. once, none vs. twice, none vs. once or twice, and once vs. twice for any influenza, respectively). Both one- and two-dose regimens significantly reduced cases with any influenza and influenza A every season. Also, both regimens significantly reduced cases of any influenza, influenza A, and influenza B among children aged 1–12 years, especially among those aged 1–5 years. In the 2013/14, 2015/16, and 2016/17 seasons, however, only the two-dose regimen was significantly effective in preventing influenza B. Both one- and two-dose regimens significantly reduced cases involving hospitalization due to any influenza and influenza A. Conclusions: Both one- and two-doses regimens of IIV were effective in preventing influenza for children aged 6 months to 12 years. The two-dose regimen was more effective against influenza B in some seasons.

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Both traditional case-control studies (TCCSs) and test-negative case-control studies (TNCCSs) are commonly used to assess influenza vaccine effectiveness (VE). To compensate for the fact that observational studies are susceptible to bias, we combined both methods to assess VE in one geographical area during the 2015/2016 season, when influenza A (H1N1)pdm was dominant. Our TNCCS covered 331 children aged 6 months to 15 years who visited our hospital with fever, including 182 with influenza, and our TCCS covered 812 pediatric outpatients aged 6 months to 15 years, including 214 with influenza. Influenza infection and vaccination history were reviewed, and VE was calculated as (1 − odds ratio) × 100. In the TNCCS, VE against influenza A was 68% (95% CI 47–81) overall, and 70% (48–83) for those given two doses; against influenza B, VE was 37% (− 12–64) overall and 49% (2–74) for two doses. In the TCCS, VE against influenza A was 44% (15–63) overall and 44% (13–64) for two doses, and VE against influenza B was 24% (− 19–52) overall and 41% (3–64) for two doses. Conclusion: Both studies confirmed significant VE against influenza A, significant two-dose VE against influenza B, and better two-dose VE than one-dose VE.What is Known:• Influenza vaccine effectiveness (VE) varies from year to year.• Observational studies are conventionally used for VE assessment. However, they are inherently susceptible to bias and confounding.What is New:• This is the first report of influenza VE assessment using more than one observational study and performed in a specific area during the same season.• VE estimates obtained in our traditional case-control study were lower than those in our test-negative case-control study, but both studies found significant VE against influenza.

© 2018 Elsevier Masson SAS Among the many regulators of microRNA formation, Argonaute 1 (AGO1) plays critical roles in RNA interference, which controls a wide range of biological activities. Recent large-scale genomic studies have identified at least five patients with intellectual disability/autism spectrum disorder who had de novo mutations in AGO1, but detailed clinical information was not available. The recognizable clinical features that are associated with AGO1 mutations remain to be determined. The proposita was a 15-year-old girl with diffuse hypotonia, infrequent seizures, and intellectual disability with an intelligence quotient of 41. She had characteristic facial features consisting of telecanthus, wide nasal bridge with bulbous nasal tip, and a round face with downslanted palpebral fissures. Serial computed tomography scans showed progressive calcification in the globus pallidus that became evident during childhood. A whole exome analysis in trio revealed a de novo heterozygous mutation in AGO1, i.e., c.595G > A p.(Gly199Ser). The distinctive facial features, i.e., telecanthus, wide nasal bridge with bulbous nasal tip, and a round face with downslanted palpebral fissures, closely resembled previously reported patients who had a chromosomal microdeletion encompassing AGO1 locus. The combinatory phenotype of such characteristic facial features and radiographic features, i.e. progressive calcification in the globus pallidus, in the presently reported patient suggest that AGO1 mutations lead to a syndromic form of intellectual disability/autism spectrum disorder. Distinctive facial features with early and progressive calcification in the globus pallidus may be suggestive of the presence of AGO1 mutations.

© 2018 Objectives: We assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) in children 6 months to 15 years of age during the 2016/17 season. In addition, we estimated the impact of repeated vaccination in children on VE. Methods: Our study for VEs in preventing influenza and admission due to influenza were conducted according to a test-negative case-control design (TNCC) based on influenza rapid diagnostic test results. We also analyzed the VE by vaccine status in the current and previous seasons for the impact of repeated vaccination. Results: During the 2016/17 season, the quadrivalent IIV was used in Japan. The adjusted VE in preventing influenza illness was 38% (95% CI, 29–46) against influenza A and 39% (95% CI, 18–54) against influenza B. Infants showed no significant VE. The VE in preventing hospitalization was not demonstrated. For the analysis of repeated vaccination, the vaccine was effective only when immunization occurred in the current season. The children who were immunized in two consecutive seasons were more likely to develop influenza compared to those immunized in the current season only (odds ratio, 1.58 [95% CI, 1.05–2.38], adjusted odds ratio, 1.53 [95% CI, 0.99–2.35]). However, the odds ratio of repeated vaccination was not significant when the analysis excluded those who developed influenza in the previous season. Conclusions: VE in children in the 2016/17 season was similar to values previously reported. Repeated vaccination interfered with the VE against any influenza infection in the 2016/17 season. The results of our study suggest that decreased VE by repeat vaccination phenomenon was associated with immunity by influenza infection in the previous season. However, the influenza vaccine should be recommended every season for children.

© 2019 Shibata, Iseda, Mitsuhashi, Oka, Shindo, Moritoki, Nagai, Otsubo, Inoue, Sasaki, Akazawa, Takahashi, Schalek, Lichtman and Okano. Recent improvements in correlative light and electron microscopy (CLEM) technology have led to dramatic improvements in the ability to observe tissues and cells. Fluorescence labeling has been used to visualize the localization of molecules of interest through immunostaining or genetic modification strategies for the identification of the molecular signatures of biological specimens. Newer technologies such as tissue clearing have expanded the field of observation available for fluorescence labeling; however, the area of correlative observation available for electron microscopy (EM) remains restricted. In this study, we developed a large-area CLEM imaging procedure to show specific molecular localization in large-scale EM sections of mouse and marmoset brain. Target molecules were labeled with antibodies and sequentially visualized in cryostat sections using fluorescence and gold particles. Fluorescence images were obtained by light microscopy immediately after antibody staining. Immunostained sections were postfixed for EM, and silver-enhanced sections were dehydrated in a graded ethanol series and embedded in resin. Ultrathin sections for EM were prepared from fully polymerized resin blocks, collected on silicon wafers, and observed by multibeam scanning electron microscopy (SEM). Multibeam SEM has made rapid, large-area observation at high resolution possible, paving the way for the analysis of detailed structures using the CLEM approach. Here, we describe detailed methods for large-area CLEM in various tissues of both rodents and primates.

© 2019 Wiley Periodicals, Inc. Subsets of mitochondrial transfer RNA (tRNA) contain the N6-isopentenyladenosine (i6A) or 2-methylthio-N6-isopentenyladenosine (ms2i6A) modification at position A37, which is adjacent to an anticodon. These modifications are essential for efficient protein translation in mitochondria and contribute to energy metabolism. The first step in i6A and ms2i6A modifications is catalyzed by tRNA isopentenyltransferase, which is encoded by the TRIT1 gene. Herein, we report a girl with a developmental delay, frequent episodes of seizures induced by febrile illness, and myoclonic epilepsy who had compound heterozygous missense mutations in TRIT1. A mass spectrometry analysis of RNA nucleoside obtained from the subject's peripheral blood and urine showed a marked decrease in both i6A and ms2i6A modifications. These results suggest that the mitochondrial disorder was caused by defective tRNA isopentenylation arising from a loss-of-function mutation in TRIT1. Furthermore, the present observations suggest that noninvasive biochemical analysis using peripheral blood and urine samples are sufficient for the diagnosis of TRIT1-related disorders, making muscle biopsy for the direct measurement of oxidative phosphorylation unnecessary. Such biochemical analyses before the start of antiepileptic medications would be beneficial to avoid hepatotoxicity in patients with possible mitochondrial disorders.

© 2019 The Healthcare Infection Society Background: Nosocomial infections by respiratory viruses undetected by rapid tests are not often diagnosed. For paediatric patients with background diseases, nosocomial infection could be fatal. Aim: To determine the relationship between developing symptoms by respiratory viruses undetectable by rapid tests and respiratory risks and to improve the management of infection control. Methods: Two episodes of nosocomial infection by human bocavirus (HBoV) and human rhinovirus (HRV) were retrospectively investigated in a tertiary hospital paediatric ward in Japan. Viruses were identified by polymerase chain reaction to determine infection control management. When viruses of the same species were detected from different patients, the virus homology was investigated. The relationship between respiratory risks and developing symptoms was statistically investigated. Findings: Three and four patients with respiratory risks in the HBoV and HRV outbreaks, respectively, developed respiratory symptoms. The nucleotide sequences of two patients in the HBoV outbreak and all four patients in the HRV outbreak were phylogenetically close. In both outbreaks, the patients with respiratory risks developed significantly more symptoms than those without any risk (P = 0.035 and 0.018, respectively). After the patients with respiratory infection were separated from those with respiratory risks, no additional nosocomial infection occurred. Conclusion: Patients with respiratory risks easily develop respiratory symptoms and acquire severe symptoms of nosocomial infection by those viruses. In a paediatric ward, we should adopt not only standard precautions but also isolation management of the patients with respiratory symptoms, even if they have negative results in rapid tests.

© 2019 Elsevier B.V. Background: Although relatively rare among pediatric patients, acquired demyelinating syndromes of the central nervous system (ADS) is a potentially disabling condition that warrants hospitalization and long-term follow-up. As such, a better understanding of the epidemiology and hospital utilization for this condition could provide critical information for health care planning and resource allocation. Objective: To evaluate the trends of hospital utilization and resource use associated with pediatric ADS in the US. Method: We conducted a serial cross-sectional trend analysis with complex sampling and weighting using nationally representative hospital discharge records, from the Kids´ Inpatient Database (KID), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality coded with International Classification of Diseases (Healthcare Cost and Utilization Project (HCUP) 2018), Ninth Revision (ICD-9-CM) for the years 2003, 2006, 2009, and 2012. We also conducted a cross-sectional study for the KID2016 dataset coded with ICD10-CM to estimate the pediatric ADS-related hospital utilization for the year. Excluding transferring discharges: we evaluated the discharge records for those aged 0 to 19 years diagnosed with any of ADS of central nervous systems including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myelitis (TM) and demyelinating disease not specified (DDNS). For the trend analysis, we used variance-weighted regression and Poisson regression for the annual hospitalization rate, total hospital charges and hospital days associated with the ADS hospitalizations for the year 2003 to 2012. Results: We estimated a total of 1,292 ADS-related hospitalizations (95%CI: 1127–1,458) in 2003, 2104 hospitalizations (95%CI: 1823–2385) in 2006, 2851 hospitalizations (95%CI: 2499–3203) in 2009, and 3501 hospitalizations (95%CI: 3058–3945) in 2012 among those aged 19 years or younger with diagnoses of ADS. There was an increase in the proportion of the inpatient hospital cost attributed to ADS from 0.06% in 2003 to 0.20% in 2012. The annual hospitalization rates relative to pediatric ADS were 1.59/100,000 (95%CI: 1.51–1.68) in 2003 and 4.21/100,000 (95%CI: 4.07–4.35) in 2012. In the cross-sectional analysis for the year 2016 coded by ICD10-CM, the number of pediatric ADS related hospitalizations were 4,568, constituting 0.30% of the total pediatric hospitalization cost. The annual hospitalization rate for the year 2016 was estimated to be 5.51/100,000. Conclusion: Hospital utilization by pediatric patients with ADS increased during the period 2003 through 2012. The cross-sectional analysis for the year 2016 indicated that the trend could be ongoing, although the direct comparison was not feasible due to the changes in the coding system of the dataset from ICD9-CM to ICD10-CM. Although relatively rare, pediatric ADS warrant long-term follow-ups and hospitalizations, impacting the developmental trajectory of the affected children and the lives of their family members. Th potentially increasing trend of pediatric ADS hospital utilization should be acknowledged when allocating and planning future resources and supporting programs.

© 2018 IOP Publishing Ltd. Objective. Assessing an infant's brain development remains a challenge for neuroscientists and pediatricians despite great technological advances. As a non-invasive neuroimaging tool, functional near-infrared spectroscopy (fNIRS) has great advantages in monitoring an infant's brain activity. To explore the dynamic features of hemodynamic changes in infants, in-pattern exponent (IPE), anti-pattern exponent (APE), as well as permutation cross-mutual information (PCMI) based on symbolic dynamics are proposed to measure the phase differences and coupling strength in oxyhemoglobin (HbO) and deoxyhemoglobin (Hb) signals from fNIRS. Approach. First, simulated sinusoidal oscillation signals and four coupled nonlinear systems were employed for performance assessments. Hilbert transform based measurements of hemoglobin phase oxygenation and deoxygenation (hPod) and phase-locking index of hPod (hPodL) were calculated for comparison. Then, the IPE, APE and PCMI indices from resting state fNIRS data of preterm, term infants and adults were calculated to estimate the phase difference and coupling of HbO and Hb. All indices' performance was assessed by the degree of monotonicity (DoM). The box plots and coefficients of variation (CV) were employed to assess the measurements and robustness in the results. Main results. In the simulation analysis, IPE and APE can distinguish the phase difference of two sinusoidal oscillation signals. Both hPodL and PCMI can track the strength of two coupled nonlinear systems. Compared to hPodL, the PCMI had higher DoM indices in measuring the coupling of two nonlinear systems. In the fNIRS data analysis, similar to hPod, the IPE and APE can distinguish preterm, term infants, and adults in 0.01-0.05 Hz, 0.05-0.1 Hz, and 0.01-0.1 Hz frequency bands, respectively. PCMI more effectively distinguished the term and preterm infants than hPodL in the 0.05-0.1 Hz frequency band. As symbolic time series measures, the IPE and APE were able to detect the brain developmental changes in subjects of different ages. PCMI can assess the resting-state HbO and Hb coupling changes across different developmental ages, which may reflect the metabolic and neurovascular development. Significance. The symbolic-based methodologies are promising measures for fNIRS in estimating the brain development, especially in assessing newborns' brain developmental status.

© 2018 Higher brain dysfunction, such as language delay, is a major concern among preterm infants. Cerebral substrates of cognitive development in preterm infants remain elusive, partly because of limited methods. The present study focuses on hemodynamic response patterns for brain function by using near-infrared spectroscopy. Specifically, the study investigates gestational differences in the hemodynamic response pattern evoked in response to phonetic changes of speech and cerebral hemispheric specialization of the auditory area in preterm infants (n = 60) and term infants (n = 20). Eighty neonates born between 26 and 41 weeks of gestational age (GA) were tested from 33 to 41 weeks of postmenstrual age (PMA). We analyzed the hemodynamic response pattern to phonemic and prosodic contrasts for multiple channels on temporal regions and the laterality index of the auditory area. Preterm infants younger than 39 weeks of PMA showed significantly atypical hemodynamic patterns, with an inverted response shape. Partial correlation analysis of the typicality score of hemodynamic response revealed a significant positive correlation with PMA. The laterality index of preterm infants from 39 weeks of PMA demonstrated a tendency rightward dominance for prosodic changes similar to term infants. We provide new evidence that alterations in hemodynamic regulation and the functional system for phonemic and prosodic processing in preterm infants catch up by their projected due dates.

© 2018 Elsevier Ltd Objectives: We assessed the vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) in children 6 months to 15 years of age in 2015/16 season. In addition, based on the data obtained during the three seasons from 2013 to 2016, we estimated the three-season VE in preventing influenza illness and hospitalization. Methods: Our study was conducted according to a test-negative case-control design (TNCC) and as a case-control study based on influenza rapid diagnostic test results. Results: During 2015/16 season, the quadrivalent IIV was first used in Japan. The adjusted VE in preventing influenza illness was 49% (95% confidence interval [CI]: 42–55%) against any type of influenza, 57% (95% CI: 50–63%) against influenza A and 34% (95% CI: 23–44%) against influenza B. The 3-season adjusted VE was 45% (95% CI: 41–49%) against influenza virus infection overall (N = 12,888), 51% (95% CI: 47–55%) against influenza A (N = 10,410), and 32% (95% CI: 24–38%) against influenza B (N = 9232). An analysis by age groups showed low or no significant VE in infants or adolescents. By contrast, VE was highest in the young group (1–5 years old) and declined with age thereafter. The 3-season adjusted VE in preventing hospitalization as determined in a case-control study was 52% (95% CI: 42–60%) for influenza A and 28% (95% CI: 4–46%) for influenza B, and by TNCC design, it was 54% (95% CI: 41–65%) for influenza A and 34% (95% CI: 6–54%) for influenza B. Conclusion: We demonstrated not only VE in preventing illness, but also VE in preventing hospitalization based on much larger numbers of children than previous studies.

© 2018, Springer Japan KK, part of Springer Nature. Pulmonary arterial hypertension (PAH) is a progressive disease associated with vasoconstriction and remodeling. Intracellular Ca 2+ signaling regulates the contraction of pulmonary arteries and the proliferation of pulmonary arterial smooth muscle cells (PASMCs); however, it is not clear which molecules related to Ca 2+ signaling contribute to the progression of PAH. In this study, we found the specific expression of type 2 inositol 1,4,5-trisphosphate receptor (IP 3 R2), which is an intracellular Ca 2+ release channel, on the sarco/endoplasmic reticulum in mouse PASMCs, and demonstrated its inhibitory role in the progression of PAH using a chronic hypoxia-induced PAH mouse model. After chronic hypoxia exposure, IP 3 R2 −/− mice exhibited the significant aggravation of PAH, as determined by echocardiography and right ventricular hypertrophy, with significantly greater medial wall thickness by immunohistochemistry than that of wild-type mice. In IP 3 R2 −/− murine PASMCs with chronic hypoxia, a TUNEL assay revealed the significant suppression of apoptosis, whereas there was no significant change in proliferation. Thapsigargin-induced store-operated Ca 2+ entry (SOCE) was significantly enhanced in IP 3 R2 −/− PASMCs in both normoxia and hypoxia based on in vitro fluorescent Ca 2+ imaging. Furthermore, the enhancement of SOCE in IP 3 R2 −/− PASMCs was remarkably suppressed by the addition of DPB162-AE, an inhibitor of the stromal-interacting molecule (STIM)–Orai complex which is about 100 times more potent than 2-APB. Our results indicate that IP 3 R2 may inhibit the progression of PAH by promoting apoptosis and inhibiting SOCE via the STIM–Orai pathway in PASMCs. These findings suggest a previously undetermined role of IP 3 R in the development of PAH and may contribute to the development of targeted therapies.