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Emicizumab is a bispecific antibody to factor (F) IX/IXa and FX/FXa, which mimics FVIIIa cofactor function. Emicizumab prophylaxis significantly decreases bleeding events for patients with hemophilia A (PwHA). However, global hemostatic monitoring in emicizumab-treated PwHA remains poorly investigated. Using rotational thromboelastometry (ROTEM), we evaluated coagulation potentials of whole blood samples from seven emicizumab-treated PwHA who participated in ACE001JP/ACE002JP studies. Dose-dependent coagulation-enhancing effects of emicizumab to whole blood from PwHA mixed with an anti-FVIII C2 antibody in vitro were evident by non-activated ROTEM analysis (NATEM). The relationship between FVIII levels and NATEM parameters in PwHA not participating in the clinical trials demonstrated that CT + CFT inversely correlated with FVIII levels. These parameters were defined as NATEM-based grading of coagulation potential; ‘T1’ (FVIII < 1 IU/dL), ‘T2’ (1 ≤ , < 12 IU/dL) and ‘T3’ (12 ≤ , < 60 IU/dL). Coagulation function in emicizumab-treated PwHA was determined to be ‘T2’ or ‘T3,’ and was dependent on plasma emicizumab concentration. Improvement of NATEM-based grades corresponded with significant reduction of bleeding episodes, except for target joints, and differences were due to the time to reach the coagulation-steady state in individual patients. The NATEM analysis may be useful for intra- and inter-individual evaluation of coagulation function in emicizumab-treated PwHA.

Background Emicizumab (ACE910) is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII. In phase I–I/II studies, emicizumab reduced the bleeding frequency in patients with severe hemophilia A, regardless of the presence of factor VIII inhibitors, at once-weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. Methods Using the phase I–I/II study data, population pharmacokinetic and repeated time-to-event (RTTE) modeling were performed to quantitatively characterize the relationship between the pharmacokinetics of emicizumab and reduction in bleeding frequency. Simulations were then performed to identify the minimal exposure expected to achieve zero bleeding events for 1 year in at least 50% of patients and to select the dosing regimens to be tested in phase III studies. Results The RTTE model adequately predicted the bleeding onset over time as a function of plasma emicizumab concentration. Simulations suggested that plasma emicizumab concentrations of ≥  45 μg/mL should result in zero bleeding events for 1 year in at least 50% of patients. This efficacious exposure provided the basis for selecting previously untested dosing regimens of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks for phase III studies. Conclusions A pharmacometric approach guided the phase III dose selection of emicizumab in hemophilia A, without conducting a conventional dose-finding study. Phase III studies with the selected dosing regimens are currently ongoing. This case study indicates that a pharmacometric approach can substitute for a conventional dose-finding study in rare diseases and will streamline the drug development process.

Near-infrared spectroscopy (NIRS) is commonly used for studying human brain function. However, several studies have shown that superficial hemodynamic changes such as skin blood flow can affect the prefrontal NIRS hemoglobin (Hb) signals. To examine the criterion-related validity of prefrontal NIRS-Hb signals, we focused on the functional signals during a working memory (WM) task and investigated their similarity with blood-oxygen-level-dependent (BOLD) signals simultaneously measured by functional magnetic resonance imaging (fMRI). We also measured the skin blood flow with a laser Doppler flowmeter (LDF) at the same time to examine the effect of superficial hemodynamic changes on the NIRS-Hb signals. Correlation analysis demonstrated that temporal changes in the prefrontal NIRS-Hb signals in the activation area were significantly correlated with the BOLD signals in the gray matter rather than those in the soft tissue or the LDF signals. While care must be taken when comparing the NIRS-Hb signal with the extracranial BOLD or LDF signals, these results suggest that the NIRS-Hb signal mainly reflects hemodynamic changes in the gray matter. Moreover, the amplitudes of the task-related responses of the NIRS-Hb signals were significantly correlated with the BOLD signals in the gray matter across participants, which means participants with a stronger NIRS-Hb response showed a stronger BOLD response. These results thus provide supportive evidence that NIRS can be used to measure hemodynamic signals originating from prefrontal cortex activation. •Simultaneous NIRS, fMRI and LDF measurements to validate prefrontal NIRS signals•Significant correlation between NIRS and BOLD signals from the prefrontal cortex•Higher NIRS correlation with brain BOLD signal than with extracranial signals•Task-related signal amplitudes of NIRS were proportional to those of fMRI.•Validity of prefrontal NIRS signals was supported by comparable fMRI results.

The child-parent relationship is a significant factor in an adolescent’s well-being and functional outcomes. Epidemiological evidence indicates that relationships with the father and mother are differentially associated with specific psychobehavioral problems that manifest differentially between boys and girls. Neuroimaging is expected to bridge the gap in understanding such a complicated mapping between the child-parent relationships and adolescents’ problems. However, possible differences in the effects of child-father and child-mother relationships on sexual dimorphism in children’s brains and psychobehavioral problems have not been examined yet. This study used a dataset of 10- to 13-year-old children (N ​= ​93) to reveal the triad of associations among child-parent relationship, brain, and psychobehavioral problems by separately estimating the respective effects of child-father and child-mother relationships on boys and girls. We first fitted general linear models to identify the effects of paternal and maternal relationships in largely different sets of children’s resting-state functional connectivity, which we term paternal and maternal functional brain connectomes (FBCs). We then performed connectome-based predictive modeling (CPM) to predict children’s externalizing and internalizing problems from these parental FBCs. The models significantly predicted a range of girls’ internalizing problems, whereas the prediction of boys’ aggression was also significant using a more liberal uncorrected threshold. A series of control analyses confirmed that CPMs using FBCs associated with peer relationship or family socioeconomic status failed to make significant predictions of psychobehavioral problems. Lastly, a causal discovery method identified causal paths from daughter-mother relationship to maternal FBC, and then to daughter’s internalizing problems. These observations indicate sex-dependent mechanisms linking child-parent relationship, brain, and psychobehavioral problems in the development of early adolescence. •Child-father and child-mother relationships were associated with sets of adolescent functional brain connectomes (FBCs).•Connectome-based predictive modeling with parental FBCs significantly predicted a range of girls’ internalizing problems.•A causal discovery method identified causal paths from daughter-mother relationship to FBC, and to internalizing problems.

The limited efficacy of available antidepressant therapies may be due to how they affect the underlying brain network. The purpose of this study was to develop a melancholic MDD biomarker to identify critically important functional connections (FCs), and explore their association to treatments. Resting state fMRI data of 130 individuals (65 melancholic major depressive disorder (MDD) patients, 65 healthy controls) were included to build a melancholic MDD classifier, and 10 FCs were selected by our sparse machine learning algorithm. This biomarker generalized to a drug-free independent cohort of melancholic MDD, and did not generalize to other MDD subtypes or other psychiatric disorders. Moreover, we found that antidepressants had a heterogeneous effect on the identified FCs of 25 melancholic MDDs. In particular, it did impact the FC between left dorsolateral prefrontal cortex (DLPFC)/inferior frontal gyrus (IFG) and posterior cingulate cortex (PCC)/precuneus, ranked as the second ‘most important’ FC based on the biomarker weights, whilst other eight FCs were normalized. Given that left DLPFC has been proposed as an explicit target of depression treatments, this suggest that the limited efficacy of antidepressants might be compensated by combining therapies with targeted treatment as an optimized approach in the future.

A serious problem in psychiatric practice is the lack of specific, objective biomarker-based assessments to guide diagnosis and treatment. The use of such biomarkers could assist clinicians in establishing differential diagnosis, which may improve specific individualised treatment. This multi-site study sought to develop a clinically suitable neuroimaging-guided diagnostic support system for differential diagnosis at the single-subject level among multiple psychiatric disorders with depressive symptoms using near-infrared spectroscopy, which is a compact and portable neuroimaging method. We conducted a multi-site, case–control replication study using two cohorts, which included seven hospitals in Japan. The study included 673 patients (women/men: 315/358) with psychiatric disorders (major depressive disorder, bipolar disorder, or schizophrenia) who manifested depressive symptoms, and 1007 healthy volunteers (530/477). We measured the accuracy of the single-subject classification in differential diagnosis among major psychiatric disorders, based on spatiotemporal characteristics of fronto-temporal cortical haemodynamic response patterns induced by a brief (<3min) verbal fluency task. Data from the initial site were used to determine an optimal threshold, based on receiver-operator characteristics analysis, and to generate the simplest and most significant algorithm, which was validated using data from the remaining six sites. The frontal haemodynamic patterns detected by the near-infrared spectroscopy method accurately distinguished between patients with major depressive disorder (74.6%) and those with the two other disorders (85.5%; bipolar disorder or schizophrenia) that presented with depressive symptoms. These results suggest that neuroimaging-guided differential diagnosis of major psychiatric disorders developed using the near-infrared spectroscopy method can be a promising biomarker that should aid in personalised care in real clinical settings. Potential confounding effects of clinical (e.g., age, sex) and systemic (e.g., autonomic nervous system indices) variables on brain signals will need to be clarified to improve classification accuracy. •No imaging-guided differential diagnosis has yet been established in psychiatry.•We measured fronto-temporal NIRS signals induced by a brief verbal fluency task.•We examined the accuracy of single-subject classification among major disorders.•NIRS distinguished unipolar depression from schizophrenia and bipolar depression.•Our results suggest a potential role for NIRS in guiding personalised care.

Epidemiological studies have revealed that schizophrenia is highly heritable. However, genetic studies have not fully elucidated its etiology. Accumulating evidence suggests that epigenetic alterations may provide an additional explanation of its pathophysiology. We investigated the methylation profiles of DNA in peripheral blood cells from 18 patients with first-episode schizophrenia (FESZ) and from 15 normal controls. Schizophrenia patients were confined to those at the stage of first-episode psychosis. We analyzed the DNA methylation status of 27,578 CpG sites by means of the Illumina Infinium HumanMethylation27 BeadChip array. Differentially methylated CpG sites, which were particularly abundant within CpG islands, were enriched in genes related to the nuclear lumen, to transcription factor binding, and to nucleotide binding. We also observed differential methylation of the promoters of HTR1E and COMTD1, which are functionally related to genes found to be differentially methylated in schizophrenia patients in previous studies. Our results indicate the site-specific epigenetic alterations in patients with FESZ.

The objective of this study was to assess prospectively the diagnostic accuracy of computer-assisted computed tomographic colonography (CTC) in the detection of polypoid (pedunculated or sessile) and nonpolypoid neoplasms and compare the accuracy between gastroenterologists and radiologists. This nationwide multicenter prospective controlled trial recruited 1,257 participants with average or high risk of colorectal cancer at 14 Japanese institutions. Participants had CTC and colonoscopy on the same day. CTC images were interpreted independently by trained gastroenterologists and radiologists. The main outcome was the accuracy of CTC in the detection of neoplasms ≥6 mm in diameter, with colonoscopy results as the reference standard. Detection sensitivities of polypoid vs. nonpolypoid lesions were also evaluated. Of the 1,257 participants, 1,177 were included in the final analysis: 42 (3.6%) were at average risk of colorectal cancer, 456 (38.7%) were at elevated risk, and 679 (57.7%) had recent positive immunochemical fecal occult blood tests. The overall per-participant sensitivity, specificity, and positive and negative predictive values for neoplasms ≥6 mm in diameter were 0.90, 0.93, 0.83, and 0.96, respectively, among gastroenterologists and 0.86, 0.90, 0.76, and 0.95 among radiologists (P<0.05 for gastroenterologists vs. radiologists). The sensitivity and specificity for neoplasms ≥10 mm in diameter were 0.93 and 0.99 among gastroenterologists and 0.91 and 0.98 among radiologists (not significant for gastroenterologists vs. radiologists). The CTC interpretation time by radiologists was shorter than that by gastroenterologists (9.97 vs. 15.8 min, P<0.05). Sensitivities for pedunculated and sessile lesions exceeded those for flat elevated lesions ≥10 mm in diameter in both groups (gastroenterologists 0.95, 0.92, and 0.68; radiologists: 0.94, 0.87, and 0.61; P<0.05 for polypoid vs. nonpolypoid), although not significant (P>0.05) for gastroenterologists vs. radiologists. CTC interpretation by gastroenterologists and radiologists was accurate for detection of polypoid neoplasms, but less so for nonpolypoid neoplasms. Gastroenterologists had a higher accuracy in the detection of neoplasms ≥6 mm than did radiologists, although their interpretation time was longer than that of radiologists.

According to the operational diagnostic criteria, psychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and autism spectrum disorder (ASD) are classified based on symptoms. While its cluster of symptoms defines each of these psychiatric disorders, there is also an overlap in symptoms between the disorders. We hypothesized that there are also similarities and differences in cortical structural neuroimaging features among these psychiatric disorders. T1-weighted magnetic resonance imaging scans were performed for 5,549 subjects recruited from 14 sites. Effect sizes were determined using a linear regression model within each protocol, and these effect sizes were meta-analyzed. The similarity of the differences in cortical thickness and surface area of each disorder group was calculated using cosine similarity, which was calculated from the effect sizes of each cortical regions. The thinnest cortex was found in SZ, followed by BD and MDD. The cosine similarity values between disorders were 0.943 for SZ and BD, 0.959 for SZ and MDD, and 0.943 for BD and MDD, which indicated that a common pattern of cortical thickness alterations was found among SZ, BD, and MDD. Additionally, a generally smaller cortical surface area was found in SZ and MDD than in BD, and the effect was larger in SZ. The cosine similarity values between disorders were 0.945 for SZ and MDD, 0.867 for SZ and ASD, and 0.811 for MDD and ASD, which indicated a common pattern of cortical surface area alterations among SZ, MDD, and ASD. Patterns of alterations in cortical thickness and surface area were revealed in the four major psychiatric disorders. To our knowledge, this is the first report of a cross-disorder analysis conducted on four major psychiatric disorders. Cross-disorder brain imaging research can help to advance our understanding of the pathogenesis of psychiatric disorders and common symptoms.