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Uterine atony is a major contributor to postpartum hemorrhage. We previously proposed the novel histological concept of postpartum acute myometritis (PAM) to elucidate the pathophysiology of uterine atony. This concept involves the infiltration of macrophages and neutrophils, as well as mast cell and complement activation in the myometrium. However, the pathological mechanism underlying uterine atony in the context of PAM remains unclear. Herein, we focused on uterine contraction-associated proteins (CAPs) including connexin 43 (Cx43), oxytocin receptors (OXR), prostaglandin receptors EP1, EP3, FP, and protease-activated receptor (PAR)-1. This follow-up study aimed to compare CAP expression between PAM and control groups. We selected 38 PAM subjects from the cases enrolled in our amniotic fluid embolism registry between 2011 and 2018. Control tissues from 10 parturients were collected during cesarean section. We stained the myometrial tissues with the following CAP markers, inflammatory cell markers, and other markers: Cx43, OXR, EP1, EP3, FP, PAR-1, C5a receptor, tryptase, neutrophil elastase, CD68, β-actin, and Na + /K + -ATPase. The immunostaining-positive areas of Cx43, OXR, EP1, EP3, and FP standardized by β-actin in the PAM tissue were significantly smaller than in the control group, whereas those of PAR-1 and Na + /K + -ATPase increased significantly in the PAM group. The Cx43- and OXR-positive areas correlated negatively with the immunostaining-positive cell numbers of CD68 and tryptase with halo, respectively. PAM may impair individual and synchronized myocyte contraction, leading to uterine atony refractory to uterotonics. Further cell-based studies are needed to elucidate the molecular mechanism by which inflammatory cells suppress CAP expression., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tomoaki Oda, Naoaki Tamura, Naomi Furuta-Isomura, Naohiro Kanayama, and Hiroaki Itoh report financial support was provided by Japan Society for the Promotion of Science. Hiroaki Itoh reports financial support was provided by Japan Agency for Medical Research and Development. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background/aim: Intensity-modulated radiation therapy can deliver a highly conformal dose to a target while minimizing the dose to the organs at risk (OARs). Delineating the contours of OARs is time-consuming, and various automatic contouring software programs have been employed to reduce the delineation time. However, some software operations are manual, and further reduction in time is possible. This study aimed to automate running atlas-based auto-segmentation (ABAS) and software operations using a scripting function, thereby reducing work time., Materials and Methods: Dice coefficient and Hausdorff distance were used to determine geometric accuracy. The manual delineation, automatic delineation, and modification times were measured. While modifying the contours, the degree of subjective correction was rated on a four-point scale., Results: The model exhibited generally good geometric accuracy. However, some OARs, such as the chiasm, optic nerve, retina, lens, and brain require improvement. The average contour delineation time was reduced from 57 to 29 min (p<0.05). The subjective revision degree results indicated that all OARs required minor modifications; only the submandibular gland, thyroid, and esophagus were rated as modified from scratch., Conclusion: The ABAS model and scripted automation in head and neck cancer reduced the work time and software operations. The time can be further reduced by improving contour accuracy., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: In Japan, unlike Western countries, tocolytic agents are administered in long-term protocols to treat threatened preterm labor. Evaluating the side effects of this practice is crucial. We examined whether ritodrine hydrochloride had been administered in cases of maternal death, aiming to investigate any relationship between ritodrine administration and maternal death., Methods: This retrospective cohort study used reports of maternal deaths from multiple institutions in Japan between 2010 and 2020. Data on the reported cases were retrospectively analyzed, and data on the route of administration, administered dose, and clinical findings, including causes of maternal death, were extracted. The amount of tocolytic agents was compared between maternal deaths with ritodrine administration and those without., Results: A total of 390 maternal deaths were reported to the Maternal Death Exploratory Committee in Japan during the study period. Ritodrine hydrochloride was administered in 32 of these cases. The frequencies (n) and median doses (range) of oral or intravenous ritodrine hydrochloride were 34.4% (11) and 945 (5-2100) mg and 84.4% (27) and 4032 (50-18 680) mg, respectively. Frequencies of perinatal cardiomyopathy, cerebral hemorrhage, diabetic ketoacidosis, and pulmonary edema as causes of maternal death were significantly higher with ritodrine administration than without it., Conclusions: Our results suggest a relationship between long-term administration of ritodrine hydrochloride and an increased risk of maternal death due to perinatal cardiomyopathy, cerebral hemorrhage, diabetic ketoacidosis, and pulmonary edema. In cases where ritodrine should be administered to prevent preterm labor, careful management and monitoring of maternal symptoms are required., (© 2024 Japan Society of Obstetrics and Gynecology.)

Purpose: The study aimed to investigate the optimal isodose line (IDL) in linear accelerator-based stereotactic radiotherapy for single brain metastasis, using HyperArc. We compared the dosimetric parameters for target and normal brain tissue among six plans with different IDLs., Methods: This study included 30 patients with single brain metastasis. We retrospectively generated six plans for each tumor with different IDLs (80%, 70%, 60%, 50%, 40%, and 33%) using HyperArc. All treatment plans were normalized to the prescription dose of 35 Gy in five fractions which was covered by 95% of the planning target volume (PTV), defined by adding a 1.0 mm margin to the gross tumor volume (GTV). The dosimetric parameters were compared among the six plans., Results: For GTV > 0.1 cm 3 , the ratio of brain-GTV volumes receiving 25 Gy to PTV (V 25Gy /PTV) was significantly lower at IDL 40%-70% than at IDL 80% and 33% (p < 0.01, retrospectively). For GTV < 0.1 cm 3 , V 25Gy /PTV decreased continuously as IDL decreased. The values of D 99% and D 80% for GTV increased with decreasing IDL. An IDL of 50% or less was required to achieve D 99% of greater than 43 Gy and D 80% of greater than 50 Gy. The mean values of D 99% and D 80% for IDL 50% were 44.3 and 51.9 Gy., Conclusion: The optimal IDL is 40%-50% for GTV > 0.1 cm 3 . These lower IDLs could increase D 99% and D 80% of GTV while lowering V 25Gy of normal brain tissue, which may help reduce the risk of radiation necrosis and improve local control., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

In linear accelerator-based stereotactic irradiation (STI) for brain metastasis, cone-beam computed tomography (CBCT) image quality is essential for ensuring precise patient setup and tumor localization. However, CBCT images may be degraded by the deviation of the CBCT isocenter from the brain center. This study aims to investigate the effects of the distance from the brain center to the CBCT isocenter (DBI) on the image quality in STI. An anthropomorphic phantom was scanned with varying DBI in right, anterior, superior, and inferior directions. Thirty patients undergoing STI were prospectively recruited. Objective metrics, utilizing regions of interest included contrast-to-noise ratio (CNR) at the centrum semiovale, lateral ventricle, and basal ganglia levels, gray and white matter noise at the basal ganglia level, artifact index (AI), and nonuniformity (NU). Two radiation oncologists assessed subjective metrics. In this phantom study, objective measures indicated a degradation in image quality for non-zero DBI. In this patient study, there were significant correlations between the CNR at the centrum semiovale and lateral ventricle levels (r s = - 0.79 and - 0.77, respectively), gray matter noise (r s = 0.52), AI (r s = 0.72), and NU (r s = 0.91) and DBI. However, no significant correlations were observed between the CNR at the basal ganglia level, white matter noise, and subjective metrics and DBI (r s  < ± 0.3). Our results demonstrate the effects of DBI on contrast, noise, artifacts in the posterior fossa, and uniformity of CBCT images in STI. Aligning the CBCT isocenter with the brain center can aid in improving image quality., (© 2024. Australasian College of Physical Scientists and Engineers in Medicine.)

Postoperative radiotherapy for breast cancer reportedly increases the risk of thoracic soft tissue sarcomas, particularly angiosarcomas; however, the risk in the Japanese population remains unknown. Therefore, this study aimed to investigate the incidence of thoracic soft tissue sarcoma among patients with breast cancer in Japan and determine its association with radiotherapy. This retrospective cohort study used data from the population-based cancer registry of the Osaka Prefecture. The inclusion criteria were female sex, age 20-84 years, diagnosis of breast cancer between 1990 and 2010, no supraclavicular lymph node or distant metastasis, underwent surgery and survived for at least 1 year. The primary outcome was the occurrence of thoracic soft tissue sarcomas 1 year or later after breast cancer diagnosis. Among the 13 762 patients who received radiotherapy, 15 developed thoracic soft tissue sarcomas (nine angiosarcomas and six other sarcomas), with a median time of 7.7 years (interquartile range, 4.0-8.6 years) after breast cancer diagnosis. Among the 27 658 patients who did not receive radiotherapy, four developed thoracic soft tissue sarcomas (three angiosarcomas and one other sarcoma), with a median time of 11.6 years after diagnosis. The 10-year cumulative incidence was higher in the radiotherapy cohort than in the non-radiotherapy cohort (0.087 vs. 0.0036%, P < 0.001). Poisson regression analysis revealed that radiotherapy increased the risk of thoracic soft tissue sarcoma (relative risk, 6.8; 95% confidence interval, 2.4-24.4). Thus, although rare, breast cancer radiotherapy is associated with an increased risk of thoracic soft tissue sarcoma in the Japanese population., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Rationale: Amniotic fluid embolism (AFE) is a fatal obstetric condition that often rapidly leads to severe respiratory and circulatory failure. It is complicated by obstetric disseminated intravascular coagulation (DIC) with bleeding tendency; therefore, the introduction of venoarterial extracorporeal membrane oxygenation (VA-ECMO) is challenging. We report the case of a patient with AFE requiring massive blood transfusion, rescued using VA-ECMO without initial anticoagulation., Patients Concerns: A 39-year-old pregnant patient was admitted with a complaint of abdominal pain. An emergency cesarean section was performed because a sudden decrease in fetal heart rate was detected in addition to DIC with hyperfibrinolysis. Intra- and post-operatively, the patient had a bleeding tendency and required massive blood transfusions. After surgery, the patient developed lethal respiratory and circulatory failure, and VA-ECMO was introduced., Diagnosis: Based on the course of the illness and imaging findings, the patient was diagnosed with AFE., Interventions: By controlling the bleeding tendency with a massive transfusion and tranexamic acid administration, using an antithrombotic ECMO circuit, and delaying the initiation of anticoagulation and anti-DIC medication until the bleeding tendency settled, the patient was managed safely on ECMO without complications., Outcomes: By day 5, both respiration and circulation were stable, and the patient was weaned off VA-ECMO. Mechanical ventilation was discontinued on day 6. Finally, she was discharged home without sequelae., Lessons: VA-ECMO may be effective to save the lives of patients who have AFE with lethal circulatory and respiratory failure. For safe management without bleeding complications, it is important to start VA-ECMO without initial anticoagulants and to administer anticoagulants and anti-DIC drugs after the bleeding tendency has resolved., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The aim of this study was to evaluate the effectiveness of intensity-modulated radiation therapy in combination with long-term androgen deprivation therapy for high-risk and very high-risk localized prostate cancer while also investigating factors associated with the therapeutic effect., Methods: Men who fulfilled criteria for the National Comprehensive Cancer Network high-risk or very high-risk localized prostate cancer and were treated with definitive intensity-modulated radiation therapy (74-78 Gy) of the prostate and the seminal vesicle combined with androgen deprivation therapy in our institution from 2007 to 2016 were identified (n = 197). In principle, patients received androgen deprivation therapy for 3-6 months before radiation, concurrently, and for 2 years after completion of intensity-modulated radiation therapy., Results: The median follow-up period was 96 months. The 5-year and 10-year overall survival rates in the overall population were 96.9% and 89.3%, respectively. The 5-year and 10-year cumulative incidence rates of biochemical failure were 2.5% and 16.3% in the high-risk group, and 8.6% and 32.0% in the very high-risk group, respectively, indicating a significant difference between the two groups (P = 0.023). Grade Group 5 and younger age (cutoff: 70 years old) were independent predictors of recurrence (P = 0.016 and 0.017, respectively). Patients exhibiting biochemical failure within <18 months after completion of androgen deprivation therapy displayed an increased risk of cancer-specific mortality (P = 0.039) when contrasted with those who had a longer interval to biochemical failure., Conclusions: Patients with the National Comprehensive Cancer Network very high-risk prostate cancer, particularly those with Grade Group 5 and younger age, showed worse outcomes following intensity-modulated radiation therapy and long-term androgen deprivation therapy., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The involvement of the human amygdala in facial mimicry remains a matter of debate. We investigated neural activity in the human amygdala during a task in which an imitation task was separated in time from an observation task involving facial expressions. Neural activity in the amygdala was measured using functional magnetic resonance imaging in 18 healthy individuals and using intracranial electroencephalogram in six medically refractory patients with epilepsy. The results of functional magnetic resonance imaging experiment showed that mimicry of negative and positive expressions activated the amygdala more than mimicry of non-emotional facial movements. In intracranial electroencephalogram experiment and time-frequency analysis, emotion-related activity of the amygdala during mimicry was observed as a significant neural oscillation in the high gamma band range. Furthermore, spectral event analysis of individual trial intracranial electroencephalogram data revealed that sustained oscillation of gamma band activity originated from an increased number and longer duration of neural events in the amygdala. Based on these findings, we conclude that during facial mimicry, visual information of expressions and feedback from facial movements are combined in the amygdalar nuclei. Considering the time difference of information approaching the amygdala, responses to facial movements are likely to modulate rather than initiate affective processing in human participants., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Amniotic fluid embolism (AFE) and placental abruption (PA) are typical obstetric diseases associated with disseminated intravascular coagulation (DIC). AFE is more likely to be complicated with enhanced fibrinolysis than PA. AFE may have an additional mechanism activating fibrinolytic cascade. We aimed to compare the coagulation/fibrinolysis factors among AFE, PA, and peripartum controls. We assessed AFE cases registered in the Japanese AFE Registry, and PA cases complicated with DIC (severe PA) and peripartum controls recruited at our hospital. The following factors in plasma were compared: prothrombin fragment 1 + 2 (PF1 + 2), plasmin α2-plasmin inhibitor complex (PIC), tissue factor (TF), tissue plasminogen activator (tPA), annexin A2 (AnnA2), total thrombin activatable fibrinolysis inhibitor (TAFI) including its activated form (TAFIa), and plasminogen activator inhibitor-type 1 (PAI-1). PF1 + 2 and PIC were markedly increased in both AFE (n = 27) and severe PA (n = 12) compared to controls (n = 23), without significant difference between those disease groups; however, PIC in AFE showed a tendency to elevate relative to PF1 + 2, compared with severe PA. AFE had significantly increased tPA and decreased total TAFI levels compared with severe PA and controls, which might be associated with further plasmin production in AFE and underlie its specific fibrinolytic activation pathway., (© 2024. The Author(s).)

Independent component analysis (ICA) is widely used today for scalp-recorded EEG analysis. One of the limitations of ICA-based analysis is polarity indeterminacy. It is not easy to find detailed documentations that explains engineering solutions of how the polarity indeterminacy is addressed in a given implementation. We investigated how it is implemented in the case of EEGLAB and also the relation between the outcome of the polarity determination and classification of independent components (ICs) in terms of the estimated nature of the sources (brain, muscle, eye, etc.) using an open database of n = 212 EEG dataset of resting state recordings. We found that (1) about 91% of ICs showed positive-dominant IC scalp topographies; (2) positive-dominant ICs were more associated with brain-originated signals; (3) positive-dominant ICs showed more radial (peaked at 10-30 degrees deviations from the radial axis) dipolar projection pattern with less residual variance from fitting the equivalent current dipole. In conclusion, using the EEGLAB's default ICA algorithm, one out of 10 ICs results in flipping its polarity to negative, which is associated with non-radial dipole orientation with higher residual variance. Thus, we determined EEGLAB biases toward positive polarity in decomposing high-quality brain ICs., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Purpose: The geometric distortion related to magnetic resonance (MR) imaging in a diagnostic radiology (MR DR ) and radiotherapy (MR RT ) setup is evaluated, and the dosimetric impact of MR distortion on fractionated stereotactic radiotherapy (FSRT) in patients with brain metastases is simulated., Materials and Methods: An anthropomorphic skull phantom was scanned using a 1.5‑T MR scanner, and the magnitude of MR distortion was calculated with (MR DR -DC and MR RT -DC) and without (MR DR -nDC and MR RT -nDC) distortion-correction algorithms. Automated noncoplanar volumetric modulated arc therapy (HyperArc, HA; Varian Medical Systems, Palo Alto, CA, USA) plans were generated for 53 patients with 186 brain metastases. The MR distortion at each gross tumor volume (GTV) was calculated using the distance between the center of the GTV and the MR image isocenter (MIC) and the quadratic regression curve derived from the phantom study (MR RT -DC and MR RT -nDC). Subsequently, the radiation isocenter of the HA plans was shifted according to the MR distortion at each GTV (HA DC and HA nDC )., Results: The median MR distortions were approximately 0.1 mm when the distance from the MIC was < 30 mm, whereas the median distortion varied widely when the distance was > 60 mm (0.23, 0.47, 0.37, and 0.57 mm in MR DR -DC, MR DR -nDC, MR RT -DC, and MR RT -nDC, respectively). The dose to the 98% of the GTV volume (D 98% ) decreased as the distance from the MIC increased. In the HA DC plans, the relative dose difference of D 98% was less than 5% when the GTV was located within 70 mm from the MIC, whereas the underdose of GTV exceeded 5% when it was 48 mm (-26.5% at maximum) away from the MIC in the HA nDC plans., Conclusion: Use of a distortion-correction algorithm in the studied MR diagnoses is essential, and the dosimetric impact of MR distortion is not negligible, particularly for tumors located far away from the MIC., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: With category II fetal heart rate tracings, the preferred timing of interventions to prevent fetal hypoxic brain damage while limiting operative interventions remains unclear. We aimed to estimate fetal extracellular base deficit (BD ecf ) during labor with category II tracings to quantify the timing of potential interventions to prevent severe fetal metabolic acidemia., Material and Methods: A longitudinal study was conducted using the database of the Recurrence Prevention Committee, Japan Obstetric Compensation System for Cerebral Palsy, including infants with severe cerebral palsy born at ≥34 weeks' gestation between 2009 and 2014. Cases included those presumed to have an intrapartum onset of hypoxic-ischemic insult based on the fetal heart rate pattern evolution from reassuring to an abnormal pattern during delivery, in association with category II tracings marked by recurrent decelerations and an umbilical arterial BD ecf  ≥ 12 mEq/L. BD ecf changes during labor were estimated based on stages of labor and the frequency/severity of fetal heart rate decelerations using the algorithm of Ross and Gala. The times from the onset of recurrent decelerations to BD ecf 8 and 12 mEq/L (Decels-to-BD8, Decels-to-BD12) and to delivery were determined. Cases were divided into two groups (rapid and slow progression) based upon the rate of progression of acidosis from onset of decelerations to BD ecf 12 mEq/L, determined by a finite-mixture model., Results: The median Decels-to-BD8 (28 vs. 144 min, p < 0.01) and Decels-to-BD12 (46 vs. 177 min, p < 0.01) times were significantly shorter in the rapid vs slow progression. In rapid progression cases, physicians' decisions to deliver the fetus occurred at ~BD ecf 8 mEq/L, whereas the "decisions" did not occur until BD ecf reached 12 mEq/L in slow progression cases., Conclusions: Fetal BD ecf reached 12 mEq/L within 1 h of recurrent fetal heart rate decelerations in the rapid progression group and within 3 h in the slow progression group. These findings suggest that cases with category II tracings marked by recurrent decelerations (i.e., slow progression) may benefit from operative intervention if persisting for longer than 2 h. In contrast, cases with sudden bradycardia (i.e., rapid progression) represent a challenge to prevent severe acidosis and hypoxic brain injury due to the limited time opportunity for emergent delivery., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

To explore predictors of the histopathological response to preoperative chemoradiotherapy (CRT) in patients with pancreatic cancer (PC) using dual-energy computed tomography-reconstructed images. This retrospective study divided 40 patients who had undergone preoperative CRT (50-60 Gy in 25 fractions) followed by surgical resection into two groups: the response group (Grades II, III and IV, evaluated from surgical specimens) and the nonresponse group (Grades Ia and Ib). The computed tomography number [in Hounsfield units (HUs)] and iodine concentration (IC) were measured at the locations of the aorta, PC and pancreatic parenchyma (PP) in the contrast-enhanced 4D dual-energy computed tomography images. Logistic regression analysis was performed to identify predictors of histopathological response. Univariate analysis did not reveal a significant relation between any parameter and patient characteristics or dosimetric parameters of the treatment plan. The HU and IC values in PP and the differences in HU and IC between the PP and PC (ΔHU and ΔIC, respectively) were significant predictors for distinguishing the response (n = 24) and nonresponse (n = 16) groups (P < 0.05). The IC in PP and ΔIC had a higher area under curve values [0.797 (95% confidence interval, 0.659-0.935) and 0.789 (0.650-0.928), respectively] than HU in PP and ΔHU [0.734 (0.580-0.889) and 0.721 (0.562-0.881), respectively]. The IC value could potentially be used for predicting the histopathological response in patients who have undergone preoperative CRT., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

This study aimed to compare dosimetric parameters for targets and organs at risk (OARs) between volumetric modulated arc therapy (VMAT) and automated VMAT (HyperArc, HA) plans in stereotactic radiotherapy for patients with cervical metastatic spine tumors. VMAT plans were generated for 11 metastases using the simultaneous integrated boost technique to deliver 35 to 40 and 20 to 25 Gy for high dose and elective dose planning target volume (PTVHD and PTVED), respectively. The HA plans were retrospectively generated using 1 coplanar and 2 noncoplanar arcs. Subsequently, the doses to the targets and OARs were compared. The HA plans provided significantly higher (p < 0.05) D min (77.4 ± 13.1%), D 99% (89.3 ± 8.9%), and D 98% (92.5 ± 7.7%) for gross tumor volume (GTV) than those of the VMAT plans (73.4 ± 12.2%, 84.2 ± 9.6 and 87.3 ± 8.8% for D min , D 99% and D 98% , respectively). In addition, D 99% and D 98% for PTVHD were significantly higher in the HA plans, whereas dosimetric parameters were comparable between the HA and VMAT plans for PTVED. The D max values for the brachial plexus, esophagus, and spinal cord were comparable, and no significant difference was observed in the D mean for the larynx, pharyngeal constrictor, thyroid, parotid grand (left and right), and Submandibular gland (left and right). The HA plans provided significantly higher target coverage of GTV and PTVHD, with a comparable dose for OARs with VMAT plans. The results of this study may contribute to the improvement of local control in clinical practice., (Copyright © 2023 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

The sex of the conceived child is a significant concern for parents. To verify whether there women have pregnancy bias toward boys or girls, we investigated whether the history of continuous same-sex pregnancy was associated with the subsequent child's sex. We prospectively analyzed data from the Japan Environment and Children's Study, a birth cohort study. We included all cases of singleton live births (n = 98 412). Women with pregnancy due to infertility treatment were excluded (n = 6255); Similarly, women with a history of miscarriage, artificial abortion, stillbirth, and multiple pregnancies, and those with missing data on the sex of the previous child were excluded. Altogether, 62 718 women were included. For the first live birth, a male-biased sex ratio of 1.055 was observed. Further, no significant difference was found in the sex ratio of the conceived child between women with one boy and those with one girl previously. However, when there were more than two children previously, the subsequently conceived child's male/female sex ratio was significantly higher among boy-only mothers than among girl-only mothers. The results indicated that several pregnant women are biased toward conceiving either boys or girls., Competing Interests: Shuhei So is affiliated with the funded laboratory of Tawara IVF Clinic. Fumiko Tawara, Yu Taniguchi, and Naohiro Kanayama declare that they have no conflict of interest. The funder provided support in the form of salaries for authors [S.S]. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 So et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

To compare dosimetric parameters for the hippocampus, organs at risk (OARs), and targets of volumetric modulated arc therapy (VMAT), noncoplanar VMAT (NC-VMAT), and HyperArc (HA) plans in patients undergoing postoperative radiotherapy for primary brain tumors. For 20 patients, HA plans were generated to deliver 40.05 to 60 Gy for the planning target volume (PTV). In addition, doses for the hippocampus and OARs were minimized. The VMAT and NC-VMAT plans were retrospectively generated using the same optimization parameters as those in the HA plans. For the hippocampus, the equivalent dose to be administered in 2 Gy fractions (EQD 2 ) was calculated assuming α/β = 2. Dosimetric parameters for the PTV, hippocampus, and OARs in the VMAT, NC-VMAT, and HA plans were compared. For PTV, the HA plans provided significantly lower D max and D 1% than the VMAT and NC-VMAT plans (p < 0.05), whereas the D 99% and D min were significantly higher (p < 0.05). For the contralateral hippocampus, the dosimetric parameters in the HA plans (8.1 ± 9.6, 6.5 ± 7.2, 5.6 ± 5.8, and 4.8 ± 4.7 Gy for D 20% , D 40% , D 60% and D 80% , respectively) were significantly smaller (p < 0.05) than those in the VMAT and NC-VMAT plans. Except for the optic chiasm, the D max in the HA plans (brainstem, lens, optic nerves, and retinas) was the smallest (p < 0.05). In addition, the doses in the HA plans for the brain and skin were the smallest (p < 0.05) among the 3 plans. HA planning, instead of coplanar and noncoplanar VMAT, significantly reduces the dosage to which the contralateral hippocampus as well as other OARs are exposed without compromising on target coverage., Competing Interests: Conflict of Interest The authors declare no conflicts of interest in relation to this study., (Copyright © 2022 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.)

To compare the dosimetric parameters of automated noncoplanar volumetric modulated arc therapy plans using single-isocentric (SIC) and multi-isocentric (MIC) techniques for patients with two brain metastases (BMs) in stereotactic irradiation and to evaluate the robustness of rotational errors. The SIC and MIC plans were retrospectively generated (35 Gy/five fractions) for 58 patients. Subsequently, a receiver operating characteristic curve analysis between the tumor surface distance (TSD) and V 25Gy was performed to determine the thresholds for the brain tissue. The SIC and MIC plans were recalculated based on the rotational images to evaluate the dosimetric impact of rotational error. The MIC plans showed better brain tissue sparing for TSD > 6.6 cm. The SIC plans provided a significantly better conformity index for TSD ≤ 6.6 cm, while significantly lower gradient index was obtained (3.22 ± 0.56vs. 3.30 ± 0.57, p < 0.05) in the MIC plans with TSD > 6.6 cm. For organs at risk (OARs) (brainstem, chiasm, lens, optic nerves, and retinas), D 0.1 cc was significantly lower (p < 0.05) in the MIC plans than in the SIC plans. The prescription dose could be delivered (D 99% ) to the gross tumor volume (GTV) for patients with TSD ≤ 6.6 cm when the rotational error was < 1°, whereas 31% of the D 99% of GTV fell below the prescription dose with TSD > 6.6 cm. MIC plans can be an optimal approach for reducing doses to OARs and providing robustness against rotational errors in BMs with TSD > 6.6 cm., (© 2023. The Author(s), under exclusive licence to Japanese Society of Radiological Technology and Japan Society of Medical Physics.)

Background: Data on acute toxicities after stereotactic radiotherapy (SRT) for brain metastases, including multiple and large lesions, are lacking. We aimed to evaluate the incidence and nature of toxicities immediately after SRT using a linear accelerator., Methods: This retrospective study reviewed the medical records of 315 patients with brain metastases treated with SRT at our institution between May 2019 and February 2022. In total, 439 SRT sessions were performed for 2161 brain metastases. The outcome of interest was immediate side effects (ISEs), defined as new or worsening symptoms occurring during SRT or within 14 days after the end of SRT., Results: Grade ≥ 2 and ≥ 3 ISEs occurred in 16 (3.6%) and 7 (1.6%) cases, respectively. Among 63 treatments for 10 or more lesions (range: 10-40), 1 (1.6%) ISE occurred. Among 22 treatments for lesions with a maximum tumor volume of > 10 cc, 2 (9.1%) ISEs occurred. Grade ≥ 3 ISEs included 1, 4, 1, and 1 cases of grade 3 nausea, grade 3 new-onset partial and generalized seizures, grade 3 obstructive hydrocephalus, and grade 5 intracranial hemorrhage, respectively. ISEs were more common in patients with a larger maximum tumor volume, primary sites other than lung and breast cancer, and pre-treatment neurological symptoms., Conclusion: SRT using a linear accelerator for brain metastases, including multiple and large lesions, is safe, with a low incidence of ISEs. Serious complications immediately after SRT are rare but possible; therefore, careful follow-up is necessary after treatment initiation., (© 2023. The Author(s).)

Background: Cerebral palsy is more common among preterm infants than among full-term infants. Although there is still no clear evidence that fetal heart rate monitoring effectively reduces cerebral palsy incidence, it is helpful to estimate the timing of brain injury leading to cerebral palsy and the causal relationship with delivery based on the fetal heart rate evolution patterns. Understanding the relationship between the timing and the type of brain injury can help to identify preventive measures in obstetrical care., Objective: This study aimed to examine the relationship between the timing of insults and the type of brain injury in preterm infants with severe cerebral palsy., Study Design: This longitudinal study was based on a nationwide database for cerebral palsy. The data of infants with severe cerebral palsy (equivalent to levels 3-5 of the Gross Motor Function Classification System-Expanded and Revised), born between 2009 and 2014 at 28 to 33 weeks of gestation, were included. The intrapartum fetal heart rate evolution patterns were evaluated by 3 obstetricians blinded to clinical information other than gestational age at birth, and these were categorized after agreement by at least 2 of the 3 reviewers into (1) continuous bradycardia, (2) persistently nonreassuring (prenatal onset), (3) reassuring-prolonged deceleration, (4) Hon's pattern (intrapartum onset), (5) persistently reassuring (pre- or postnatal onset), and (6) unclassified. Infant brain magnetic resonance imaging findings at term-equivalent age were assessed by a pediatric neurologist blinded to the background details, except for gestational age at birth and corrected age at image acquisition, and these were categorized as (1) basal ganglia-thalamus, (2) white matter, (3) watershed cortex or subcortex, (4) stroke, (5) normal, and (6) unclassified based on the predominant site involved. The risk factors for the basal ganglia-thalamus group were compared with those of the combined white matter and watershed injuries group., Results: Among 1593 infants with severe cerebral palsy, 231 were born at 28 to 33 weeks of gestation, and 140 met the eligibility criteria. Fetal heart rate evolution patterns were categorized as bradycardia (17% [24]); persistently nonreassuring (40% [56]); reassuring-prolonged deceleration (7% [10]); reassuring-Hon (6% [8]); persistently reassuring (7% [10]); and unclassified (23% [32]). Cerebral palsy was presumed to have an antenatal onset in 57% of infants and to have been caused by intrapartum insult in 13% of infants. Magnetic resonance imaging showed that 34% (n=48) of infants developed basal ganglia-thalamus-dominant brain injury. Of the remaining 92 infants, 43% (60) showed white matter injuries, 1% (1) showed watershed injuries, 4% (5) showed stroke, 1% (1) had normal findings, and 18% (25) had unclassified findings. Infants with continuous bradycardia (adjusted odds ratio, 1033.06; 95% confidence interval, 15.49-68,879.92) and persistently nonreassuring fetal heart rate patterns (61.20; 2.09-1793.12) had a significantly increased risk for basal ganglia-thalamus injury., Conclusion: Severe cerebral palsy was presumed to have an antenatal onset in 57% of infants and to have been caused by intrapartum insult in only 13% of infants born at 28 to 33 weeks of gestation. Although the white matter-watershed injury was predominant in the study populations, severe acute hypoxia-ischemia may be an important prenatal etiology of severe cerebral palsy in preterm infants., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Immunohistochemical analysis of formalin-fixed paraffin-embedded (FFPE) tissue blocks is routinely used to identify virus-infected cells. However, detecting virus particles in FFPE sections using light microscopy is difficult because of the light diffraction resolution limitations of an optical microscope. In this study, light microscopy and field emission scanning electron microscopy were performed to observe 3-dimensional virus particles in FFPE sections in a nondestructive manner using NanoSuit or osmium conductive treatment methods. The virus particles in FFPE sections were immunostained with specific antibodies against the surface antigens of the viral particles and stained with 3,3'-diaminobenzidine. A metal solution (0.2% gold chloride or 2% osmium tetroxide) was applied to enhance the 3,3'-diaminobenzidine-stained area. This procedure is nondestructive for FFPE sections and is a simpler method than transmission electron microscopy. To validate the applicability of this technique, we performed 3-dimensional imaging of the virus particles of different sizes, such as human papillomavirus, cytomegalovirus, and varicella-zoster virus. Furthermore, ultrathin sections from the FFPE sections that were observed to harbor viral particles using field emission scanning electron microscopy were prepared and assessed using transmission electron microscopy. In the correlative areas, transmission electron microscopy confirmed the presence of large numbers of virus particles. These results indicated that the combination of marking viral particles with 3,3'-diaminobenzidine/metal staining and conductive treatment can identify active progeny virus particles in FFPE sections using scanning electron microscopy. This easy correlative imaging of field emission scanning electron microscopy of the identical area of FFPE in light microscopy may help elucidate new pathological mechanisms of virus-related diseases., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/aim: Dosimetric parameters in volumetric modulated arc therapy (VMAT), non-coplanar VMAT (NC-VMAT), and automated NC-VMAT (HyperArc, HA) were compared for patients with maxillary sinus carcinoma (MSC)., Patients and Methods: Twenty HA plans were generated to deliver 70.4, 64, and 46 Gy for planning target volumes with high (PTV1), intermediate (PTV2), and low risk (PTV3), respectively. The VMAT and NC-VMAT plans were retrospectively generated using the same optimized parameters as those used in the HA plans., Results: For PTV1, the three treatment plans provided comparable target coverages. For PTV2, the D 95% , D 99% , and D min in the HA plans (64.7±1.2, 62.7±2.1 and 54.6±6.2 Gy, respectively) were significantly higher (p<0.05) than those in the VMAT plans (64.3±1.7, 61.9±2.4 and 52.9±6.4 Gy, respectively). The NC-VMAT and HA plans provided significantly higher (p<0.05) dosimetric parameters for PTV3 than those in the VMAT plans, and D 99% in the HA was significantly higher than that in the NC-VMAT plans (52.5±3.0 vs. 51.8±2.7 Gy, p<0.05). The doses to the brain and brainstem were lowest in the HA plans (p<0.05). Moreover, dosimetric parameters of the contralateral organs (lens, optic nerve, retina, and parotid) were lower in the HA plans than in the VMAT and NC-VMAT plans., Conclusion: The HA plans provided the best target coverage and OAR sparing compared with VMAT and NC-VMAT plans for patients with MSC., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: This nationwide study aimed to investigate the practical management of term premature rupture of membrane (PROM) and its relationship with maternal and neonatal outcomes., Methods: We conducted a questionnaire survey of 415 facilities participating in the Japan Perinatal Registry Network of the Japan Society of Obstetrics and Gynecology in 2016. The patients were women expecting vaginal birth after PROM at term without clinical chorioamnionitis. We classified the facilities into three groups based on duration of the expectant management after PROM (within 24, 24, and 48 h). Furthermore, we analyzed the association between perinatal outcomes and management protocol using the Japan Perinatal Registry Network Database 2016., Results: Of 415 facilities, 346 (83.4%) completed and returned the survey. Among 231 facilities with management protocols, an interval of 3 days from PROM to delivery was acceptable in 167 facilities (72.3%). One hundred forty-nine facilities (64.5%) responded that they did not perform mechanical cervical dilation, and 90 (39.0%) used oxytocin as a uterotonic irrespective of cervical maturation. The number of hospitals that had a policy to administer antibiotics to Group B streptococcus-positive patients was 211 (91.3%). Neonatal outcomes at birth and the frequency of cesarean section and postpartum fever did not differ among the three groups., Conclusions: Most facilities in the Japan Perinatal Registry Network managed women at term to delivery within 3 days after PROM with attention to bacterial infection. Expectant management up to 48 h after PROM did not increase the risk of postpartum fever, compared to labor induction immediately after PROM., (© 2022 Japan Society of Obstetrics and Gynecology.)

This study investigates whether decision-making under uncertainty is influenced by the cardiac cycle. To test this hypothesis, we examined the influence of the cardiac cycle on an individual's decision-making process in a gambling experiment. Participants were asked to choose one option with a sure payout or uncertain option with varying degrees of winning probability, ambiguity, and monetary amounts. The onset of presentation of the options is timed to coincide with either cardiac ventricular systole or diastole. The results show that, for most participants, the risk aversion score was lower in the systole trial than in the diastole trial. Model-based exploratory analysis revealed that the higher propensity to take risks in the systole trial compared with that in the diastole trial could be captured better by the change in the gambling bias against the utility of the risky options, rather than by a change in risk attitude. The results provide evidence that the natural fluctuation of cardiac afferent signals can affect risky decision-making., Competing Interests: Declaration of interests The authors have no competing interests to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Purpose: Few reports include volumetric measurements as endpoints after stereotactic radiotherapy (SRT) despite the importance of such measurements. This study aimed to (1) investigate the impact of the volumetric response (specifically, an over 65% and over 90% volume reduction in brain metastases) at 6 months post-SRT on local control and (2) identify the predictive factors for a volumetric response of over 65% and over 90%., Materials and Methods: This study included 250 unresected brain metastases (>0.3 cc) treated with SRT. Doses were stratified according to the biological effective dose (BED). The BED was calculated using four models: linear-quadratic (LQ): α/β = 10; LQ: α/β = 20; LQ cubic: α/β = 12; and LQ linear: α/β = 10. The median prescription dose was 30 Gy/3 fractions (BED20, 45). The median follow-up time after SRT was 18.6 months (range, 6.4-81.8 months)., Results: In the multivariate analysis, over 65% volume reduction and over 90% volume reduction were prognostic factors for local control (hazard ratio: 2.370, p = 0.011 and hazard ratio: 3.161, p = 0.014, respectively). A dose of 80% of the gross tumor volume (GTV) D80 > BED20 58 was a predictive factor for over 65% and over 90% volume reductions (odds ratio: 1.975, p = 0.023; odds ratio: 3.204, p < 0.001, respectively)., Conclusion: Robust volume reduction of brain metastases at 6 months post-SRT can predict local control. GTV D80 in the LQ model: α/β = 20 may be warranted for good volume reduction., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Follicular dendritic cells (FDCs) play a crucial role in generating high-affinity antibody-producing B cells during the germinal center (GC) reaction. Herein, we analysed the altered gene expression profile of a mouse FDC line, FL-Y, following lymphotoxin β receptor stimulation, and observed increased Slam-family member 8 (Slamf8) mRNA expression. Forced Slamf8 expression and SLAMF8-Fc addition enhanced the ability of FL-Y cells to induce FDC-induced monocytic cell (FDMC) differentiation. FDMCs accelerated GC-phenotype proliferation in cultured B cells, suggesting that they are capable of promoting GC responses. Furthermore, a pulldown assay showed that SLAMF8-Fc could bind to SLAMF8-His. Overall, the homophilic interaction of SLAMF8 promotes FDMC differentiation and SLAMF8 might act as a novel regulator of GC responses by regulating FDMC differentiation., (© 2022 Federation of European Biochemical Societies.)

Calcium/calmodulin-dependent protein kinase kinases (CaMKKs) activate CaMKI, CaMKIV, protein kinase B/Akt, and AMP-activated protein kinase (AMPK) by phosphorylating Thr residues in activation loops to mediate various Ca 2+ -signaling pathways. Mammalian cells expressing CaMKKα and CaMKKβ lacking Arg/Pro-rich insert domain (RP-domain) sequences showed impaired phosphorylation of AMPKα, CaMKIα, and CaMKIV, whereas the autophosphorylation activities of CaMKK mutants remained intact and were similar to those of wild-type CaMKKs. Liver kinase B1 (LKB1, an AMPK kinase) complexed with STRAD and MO25 and was unable to phosphorylate CaMKIα and CaMKIV; however, mutant LKB1 with the RP-domain sequences of CaMKKα and CaMKKβ inserted between kinase subdomains II and III acquired CaMKIα and CaMKIV phosphorylating activity in vitro and in transfected cultured cells. Furthermore, ionomycin-induced phosphorylation of hemagglutinin (HA)-CaMKIα at Thr177, HA-CaMKIV at Thr196, and HA-AMPKα at Thr172 in transfected cells was significantly suppressed by cotransfection of kinase-dead mutants of CaMKK isoforms, but these dominant-negative effects were abrogated with RP-deletion mutants, suggesting that sequestration of substrate kinases by loss-of-function CaMKK mutants requires the RP-domain. This was confirmed by pulldown experiments that showed that dominant-negative mutants of CaMKKα and CaMKKβ interact with target kinases but not RP-deletion mutants. Taken together, these results clearly indicate that both CaMKK isoforms require the RP-domain to recognize downstream kinases to interact with and phosphorylate Thr residues in their activation loops. Thus, the RP-domain may be a promising target for specific CaMKK inhibitors., (© 2022 Federation of European Biochemical Societies.)

Objective: To investigate the association between hypoxic-ischaemic insult timing and brain injury type in infants with severe cerebral palsy (CP)., Design: Longitudinal study., Setting: Database of the Recurrence Prevention Committee, Japan Obstetric Compensation System for Cerebral Palsy., Sample: Infants with severe CP born at ≥34 weeks of gestation., Methods: The intrapartum fetal heart rate (FHR) strips were categorised as continuous bradycardia; persistently non-reassuring (NR-NR); reassuring-prolonged deceleration (R-PD); Hon's pattern (R-Hon); persistently reassuring (R-R); and unclassified. The brain magnetic resonance imaging (MRI) scans were categorised based on the predominant site involved: basal ganglia-thalamus (BGT); white matter (WM); watershed (WS); stroke; normal; and unclassified., Main Outcome Measures: Manifestations of the brain MRI types and the association between FHR evolution pattern and MRI type were analysed., Results: Among 672 eligible infants, 76% had BGT-dominant injury, 5.4% WM, 1.2% WS, 1.6% stroke, 1.9% normal, and 14% unclassified. Placental abruption and small-for-gestational age were associated with an increased (adjusted odds ratio [aOR] 8.02) and decreased (aOR 0.38) risk of BGT injury, respectively. The majority of infants had BGT injury in most FHR groups (bradycardia, 97%; NR-NR, 75%; R-PD, 90%; R-Hon, 76%; and R-R, 45%). The risk profiles in case of BGT in the NR-NR group were similar to those in the R-PD and R-Hon groups., Conclusion: BGT-dominant brain damage accounted for three-fourths of the cases of CP in term or near-term infants, even in prenatal onset cases. Hypoxic-ischaemic insult has a major impact on CP development during the antenatal period., Tweetable Abstract: Basal ganglia-thalamus injury constitutes 76% of severe cerebral palsy cases, predominant even in antenatal-onset cases., (© 2022 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: The goal of this study is to find clues to improve perinatal outcomes in the case of cerebrovascular acute disorders during pregnancy., Study Design: We analyzed 35 cases of cerebrovascular diseases related to maternal deaths in Japan those that occurred during pregnancy and reported to the Committee of the Ministry of Health, Labor, and Welfare from 2010 to 2018., Results: Cerebrovascular acute disorders occurred at 34.6 ± 6.6 gestational weeks. There were seven intrauterine fetal deaths (IUFD), and eight cases showed neonatal asphyxia with umbilical arterial pH between 6.7 and 7.0 (asphyxia cases, n  = 15). In two of eight newborns, brain hypothermia therapy was given, and all survived without neurological sequelae. Maternal dyspnea was significantly related to severe prolonged decelerations of the fetus ( p  < .05), and asphyxia cases ( p  < .005). Median time from maternal onset to delivery (OD time) was significantly longer in asphyxia cases than in the non-asphyxia cases (84 vs 29 min, p  < .05). OD time over 30 min was significantly related to the antepartum occurrence, cervical dilatation <5 cm ( p  < .05), onset outside of the hospital ( p  < .001), and maternal transfer before delivery ( p  < .001)., Conclusion: More than 40% of cases experienced fetal asphyxia, and 20% ended in IUFD in maternal deaths related to cerebrovascular acute disorders. Maternal respiratory support and rapid delivery would be the keys to improve perinatal outcomes in case of cerebrovascular acute disorders during pregnancy.

This study aimed to investigate whether instrumental reward learning is affected by the cardiac cycle. To this end, we examined the effects of the cardiac cycle (systole or diastole) on the computational processes underlying the participants' choices in the instrumental learning task. In the instrumental learning task, participants were required to select one of two discriminative stimuli (neutral visual stimuli) and immediately receive reward/punishment feedback depending on the probability assigned to the chosen stimuli. To manipulate the cardiac cycle, the presentation of discriminative stimuli was timed to coincide with either cardiac systole or diastole. We fitted the participants' choices in the task with reinforcement learning (RL) models and estimated parameters involving instrumental learning (i.e., learning rate and inverse temperature) separately in the systole and diastole trials. Model-based analysis revealed that the learning rate for positive prediction errors was higher than that for negative prediction errors in the systole trials; however, learning rates did not differ between positive and negative prediction errors in the diastole trials. These results demonstrate that the natural fluctuation of cardiac afferent signals can affect asymmetric value updating in instrumental reward learning., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kimura, Kanayama, Toyama and Katahira.)

Ca 2+ /calmodulin-dependent protein kinase kinase (CaMKK), a Ca 2+ /CaM-dependent enzyme that phosphorylates and activates multifunctional kinases, including CaMKI, CaMKIV, protein kinase B/Akt, and 5'AMP-activated protein kinase, is involved in various Ca 2+ -signaling pathways in cells. Recently, we developed an ATP-competitive CaMKK inhibitor, TIM-063 (2-hydroxy-3-nitro-7 H -benzo[de]benzo[4,5]imidazo[2,1-a]isoquinolin-7-one, Ohtsuka et al. Biochemistry 2020, 59, 1701-1710). To gain mechanistic insights into the interaction of CaMKK with TIM-063, we prepared TIM-063-coupled sepharose (TIM-127-sepharose) for association/dissociation analysis of the enzyme/inhibitor complex. CaMKKα/β in transfected COS-7 cells and in mouse brain extracts specifically bound to TIM-127-sepharose and dissociated following the addition of TIM-063 in a manner similar to that of recombinant GST-CaMKKα/β, which could bind to TIM-127-sepharose in a Ca 2+ /CaM-dependent fashion and dissociate from the sepharose following the addition of TIM-063 in a dose-dependent manner. In contrast to GST-CaMKKα, GST-CaMKKβ was able to weakly bind to TIM-127-sepharose in the presence of EGTA, probably due to the partially active conformation of recombinant GST-CaMKKβ without Ca 2+ /CaM-binding. These results suggested that the regulatory domain of CaMKKα prevented the inhibitor from interacting with the catalytic domain as the GST-CaMKKα mutant (residues 126-434) lacking the regulatory domain (residues 438-463) interacted with TIM-127-sepharose regardless of the presence or absence of Ca 2+ /CaM. Furthermore, CaMKKα bound to TIM-127-sepharose in the presence of Ca 2+ /CaM completely dissociated from TIM-127-sepharose following the addition of excess EGTA. These results indicated that TIM-063 interacted with and inhibited CaMKK in its active state but not in its autoinhibited state and that this interaction is likely reversible, depending on the concentration of intracellular Ca 2+ .

Purpose: To compare the intrafractional motion error (IME) during stereotactic irradiation (STI) in patients with brain metastases immobilized using open- (Encompass) and full-face (DSPS) clamshell-style immobilization devices., Methods: Encompass (38 patients) and DSPS (38 patients) were used for patient immobilization, and HyperArc plans with three to four non-coplanar beams were generated to deliver 25 to 35 Gy in three to five fractions. Cone-beam computed tomography (CBCT) was performed on patients before and after the treatment. Moreover, the difference in patient position between the two CBCT images was considered as the IME. The margins to compensate for IME were calculated using the van Herk margin formula., Results: For Encompass, the mean values of IME in the translational setup were 0.1, 0.2, and 0.0 mm in the anterior-posterior, superior-inferior, and left-right directions, respectively, and the mean values of IME about rotational axes were -0.1, 0.0, and 0.0° for the Pitch, Roll, and Yaw rotations, respectively. For DSPS, the mean values of IME in the translational setup were 0.2, 0.2, and 0.0 mm in the anterior-posterior, superior-inferior, and left-right directions, respectively, and the mean values of IME about rotational axes were -0.1, -0.1, and 0.0° for the Pitch, Roll, and Yaw rotations, respectively. No statistically significant difference was observed between the IME of the two immobilization systems except in the anterior-posterior direction (p = 0.02). Moreover, no statistically significant correlation was observed between three-dimensional IME and treatment time. The margin compensation for IME was less than 1 mm for both immobilization devices., Conclusions: The IME during STI using open- and full-face clamshell-style immobilization devices is approximately equal considering the adequate accuracy in patient positioning., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Purpose: This study introduced an A-mode portable ultrasound bladder scanner, the Lilium® α-200 (here after Lilium; Lilium Otsuka, Kanagawa, Japan), for the treatment of prostate cancer patients with hypofractionated volumetric modulated arc therapy to improve the reproducibility of bladder volume (BV)., Materials and Methods: Thirty patients were advised to maintain full BV prior to computed tomography (CT) simulation and daily treatment. Among these, the BV of 15 patients was measured using Lilium until a BV of 80% in the simulation was achieved (with the Lilium group). Daily cone-beam CT (CBCT) was performed for treatment. The correlation between BV measured by CBCT and Lilium was assessed. The differences in the BV and dosimetric parameters of the bladder in the CBCT versus planning CT were compared between the groups with and without Lilium., Results: There was a significantly strong relationship (r = 0.796, p < 0.05) between the BVs measured using CBCT and Lilium. The relative BV ratios to simulation CT < 0.5 and > 2 were observed in 10.3% and 12.7%, respectively, of treatment sessions without Lilium group, while these ratios were 1% and 2.8%, respectively, in the Lilium group. The mean absolute difference in the range of V 30Gy to V 40Gy without Lilium sessions was significantly larger (p < 0.05) than that in the Lilium group., Conclusion: The use of the A-mode portable ultrasound bladder scanner significantly improved the reproducibility of the BV, resulting in few variations in the dosimetric parameters for the bladder., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Background: The optimal radiation dose for treating non-metastatic superficial esophageal squamous cell carcinoma is unknown. In this retrospective observational study, we investigated the influence of radiation dose and pretreatment endoscopic prediction of tumor invasion depth on local recurrence after definitive chemoradiotherapy in patients with superficial esophageal squamous cell carcinoma., Methods: We analyzed 134 patients with clinical Tis-T1N0M0 esophageal squamous cell carcinoma who underwent chemoradiotherapy at our institution between 2006 and 2019. Patients were grouped into standard-dose (50.0-50.4 Gy) and high-dose (60.0 Gy) radiotherapy groups. The outcomes of interest were local recurrence and major local recurrence (endoscopically unresectable local recurrent tumors). Kaplan-Meier analysis and the log-rank test were used with propensity score and inverse probability of treatment weighting. Cox proportional hazards analysis was performed to identify predictors of local recurrence and major local recurrence., Results: The median follow-up times were 52 and 84 months for the standard-dose and high-dose groups, respectively. The adjusted 3-year local recurrence and major local recurrence rates in the standard-dose and high-dose groups were 33.8 and 9.6% (adjusted hazard ratio, 4.00 [95% confidence interval: 1.64-9.73]; adjusted log-rank p = 0.001) and 12.5 and 4.7% (adjusted hazard ratio, 3.13 [95% confidence interval: 0.91-10.81]; adjusted log-rank p = 0.098), respectively. Cox proportional hazards analysis showed that standard-dose radiotherapy and endoscopic findings of deep submucosal invasion are independently associated with local recurrence and major local recurrence., Conclusions: High-dose radiotherapy is more beneficial for local tumor control than standard-dose radiotherapy in patients with non-metastatic superficial esophageal squamous cell carcinoma. The use of high-dose radiotherapy may merit consideration for tumors with deep submucosal invasion., (© 2022. The Author(s).)

In recent years, with the advancement of next-generation sequencing (NGS) technology, gene panel tests have been approved in the field of cancer diseases, and approaches to prescribe optimal molecular target drugs to patients are being developed. In the field of rare diseases, whole-genome and whole-exome analysis has been used to identify the causative genes of undiagnosed diseases and to diagnose patients' diseases, and further progress in personalized medicine is expected. In order to promote personalized medicine in the future, we investigated the current status and progress of personalized medicine in disease areas other than cancer and rare diseases, where personalized medicine is most advanced. We selected rheumatoid arthritis and psoriasis as the inflammatory disease, in addition to Alzheimer's disease. These diseases have high unmet needs for personalized medicine from the viewpoints of disease mechanisms, diagnostic biomarkers, therapeutic drugs with diagnostic markers and treatment satisfaction. In rheumatoid arthritis and psoriasis, there are many therapeutic options; however, diagnostic methods have not been developed to select the best treatment for each patient. In addition, there are few effective therapeutic agents in Alzheimer's disease, although clinical trials of many candidate drugs have been conducted. In rheumatoid arthritis and psoriasis, further elucidation of the disease mechanism is desired to enable the selection of appropriate therapeutic agents according to the patient profile. In the case of Alzheimer's disease, progress in preventive medicine is desired through the establishment of an early diagnosis method as well as the research and development of innovative therapeutic agents. To this end, we hope for further research and development of diagnostic markers and new drugs through progress in comprehensive data analysis such as comprehensive genomic and transcriptomic information. Furthermore, new types of markers such as miRNAs and the gut microbiome are desired to be utilized in clinical diagnostics.

Ca 2+ /calmodulin-dependent protein kinase kinases (CaMKKα and β) are regulatory kinases for multiple downstream kinases, including CaMKI, CaMKIV, PKB/Akt, and AMP-activated protein kinase (AMPK) through phosphorylation of each activation-loop Thr residue. In this report, we biochemically characterize the oligomeric structure of CaMKK isoforms through a heterologous expression system using COS-7 cells. Oligomerization of CaMKK isoforms was readily observed by treating CaMKK transfected cells with cell membrane permeable crosslinkers. In addition, His-tagged CaMKKα (His-CaMKKα) pulled down with FLAG-tagged CaMKKα (FLAG-CaMKKα) in transfected cells. The oligomerization of CaMKKα was confirmed by the fact that GST-CaMKKα/His-CaMKKα complex from transiently expressed COS-7 cells extracts was purified to near homogeneity by the sequential chromatography using glutathione-sepharose/Ni-sepharose and was observed in a Ca 2+ /CaM-independent manner by reciprocal pulldown assay, suggesting the direct interaction between monomeric CaMKKα. Furthermore, the His-CaMKKα kinase-dead mutant (D293A) complexed with FLAG-CaMKKα exhibited significant CaMKK activity, indicating the active CaMKKα multimeric complex. Collectively, these results suggest that CaMKKα can self-associate in the cells, constituting a catalytically active oligomer that might be important for the efficient activation of CaMKK-mediated intracellular signaling., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Pulmonary thromboembolism (PTE) is one of the leading causes of maternal mortality. We previously reported that possible contamination of amniotic fluid (AF) into maternal circulation accelerated thrombin production and activated platelet function in maternal blood through the extrinsic pathway, which may be associated with the high incidence of PTE in early puerperium. However, it remains unclear whether the maternal anticoagulation system, e.g., the activated protein C (APC) pathway, contributes to the hypercoagulable condition induced by AF. Our previous study using an endogenous thrombin potential (ETP)-based assay revealed that sensitivity to APC was reduced during the postpartum first day, i.e., immediately after delivery, when parturients were supposed to be exposed to AF. Our aim is to investigate the susceptibility of maternal plasma to APC when mixed with AF. We collected plasma from 51 pregnant females and mixed with AF as well as APC. APC-sensitivity ratio (APC-sr) was calculated using the ETP-based assay. Addition of AF to maternal plasma showed a significant increase of ETP in the presence of APC. APC-sr was significantly increased, indicating decreased sensitivity to APC, after AF mixture to maternal plasma. The present APC-sr difference with AF contamination was smaller than that we reported previously in venous thromboembolism cases. The inhibitory effects of AF on the APC anticoagulation pathway may contribute, at least partly, to further promotion of thrombin production induced by AF. Combined with other classical thrombophilic risk factors, the present findings support possible involvements of AF exposure in the high incidence of PTE in early puerperium., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Several studies have reported the relation between the imaging dose and secondary cancer risk and have emphasized the need to minimize the additional imaging dose as low as reasonably achievable. The iterative cone-beam computed tomography (iCBCT) algorithm can improve the image quality by utilizing scatter correction and statistical reconstruction. We investigate the use of a novel iCBCT reconstruction algorithm to reduce the patient dose while maintaining low-contrast detectability and registration accuracy. Methods: Catphan and anthropomorphic phantoms were analyzed. All CBCT images were acquired with varying dose levels and reconstructed with a Feldkamp-Davis-Kress algorithm-based CBCT (FDK-CBCT) and iCBCT. The low-contrast detectability was subjectively assessed using a 9-point scale by 4 reviewers and objectively assessed using structure similarity index (SSIM). The soft tissue-based registration error was analyzed for each dose level and reconstruction technique. Results: The results of subjective low-contrast detectability found that the iCBCT acquired at two-thirds of a dose was superior to the FDK-CBCT acquired at a full dose (6.4 vs 5.4). Relative to FDK-CBCT acquired at full dose, SSIM was higher for iCBCT acquired at one-sixth dose in head and head and neck region while equivalent with iCBCT acquired at two-thirds dose in pelvis region. The soft tissue-based registration was 2.2 and 0.6 mm for FDK-CBCT and iCBCT, respectively. Conclusion: Use of iCBCT reconstruction algorithm can generally reduce the patient dose by approximately two-thirds compared to conventional reconstruction methods while maintaining low-contrast detectability and accuracy of registration.

Study Question: Does fibrin promote trophoblast growth in human and mouse blastocysts during early embryo implantation?, Summary Answer: Mouse blastocysts were unaffected by fibrin; however, human blastocysts were significantly suppressed by fibrin in trophoblast growth and then switched to growth promotion through increased fibrinolysis with urokinase-type plasminogen activator (uPA) activity., What Is Known Already: Fibrin(ogen) plays an important role in various physiological processes and is also critical for maintaining feto-maternal attachment during pregnancy. The addition of fibrin to embryo transfer media has been used to increase implantation rates in human ART; however, its mechanism of action' in vitro has not yet been characterized., Study Design, Size, Duration: Vitrified mouse and human blastocysts were warmed and individually cultured in vitro for up to 120 and 168 h, respectively, on a fibrin substrate. Blastocysts were cultured at 37°C in 6% CO2, 5% O2 and 89% N2. Blastocyst development and related fibrinolytic factors were analyzed., Participants/materials, Setting, Methods: ICR strain mouse embryos were purchased from a commercial supplier. Human blastocysts were donated with informed consent from two fertility centers. Mouse and human blastocysts cultured on fibrin-coated plates were compared to those on non-coated and collagen-coated plates in vitro. Trophoblast growth and fibrin degradation were assessed based on the cell area and fibrin-free area, respectively. Fibrinolytic factors were detected in supernatants using plasminogen-casein zymography. The fibrinolytic activity of blastocysts was investigated using a selective uPA inhibitor, exogenous uPA, plasminogen activator inhibitor-1 (PAI-1) inhibitor and fibrin degradation products (FDPs). Fibrinolysis-related mRNA expression level was detected using quantitative real-time PCR., Main Results and the Role of Chance: Fibrin did not affect the developmental speed or morphology of mouse blastocysts, and a large fibrin-degrading region was observed in the attachment stage. In contrast, fibrin significantly suppressed the outgrowth of trophoblasts in human blastocysts, and trophoblasts grew after the appearance of small fibrin-degrading regions. uPA was identified as a fibrinolytic factor in the conditioned medium, and uPA activity was significantly weaker in human blastocysts than in mouse blastocysts. The inhibition of uPA significantly reduced the outgrowth of trophoblasts in mouse and human blastocysts. Human blastocysts expressed PLAU (uPA), PLAUR (uPA receptor), SERPINE1 (PAI-1) and SERPINB2 (PAI-2), whereas mouse blastocysts were limited to Plau, Plaur and Serpine1. In a subsequent experiment on human blastocysts, the addition of exogenous uPA and the PAI-1 inhibitor promoted trophoblast growth in the presence of fibrin, as did the addition of FDPs., Limitations, Reasons for Caution: This model excludes maternal factors and may not be fully reproduced in vivo. Donated human embryos are surplus embryos that may inherently exhibit reduced embryonic development. In addition, donated ART-derived embryos may exhibit weak uPA activity, because women with sufficient uPA-active embryos may not originally require ART. The present study used orthodox culture methods, and results may change with the application of recently developed protocols for culture blastocysts beyond the implantation stage., Wider Implications of the Findings: The present results suggest that the distinct features of trophoblast outgrowth in human blastocysts observed in the presence of fibrin are regulated by a phenotypic conversion induced by contact with fibrin and FDPs. Mouse embryos did not exhibit the human phenomenon, indicating that the present results may be limited to humans., Study Funding/competing Interest(s): The present study was supported by the Department of Obstetrics and Gynecology at the Hamamatsu University School of Medicine and Kishokai Medical Corporation. None of the authors have any conflicts of interest to declare., Trial Registration Number: N/A., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. Several studies have demonstrated the beneficial effects of antithrombin replacement in patients with preeclampsia. Here, we describe the study protocol of KOUNO-TORI (KW-3357 randOmized, mUlti-center, double-bliNd, placebO-controlled phase 3 sTudy in patients with early Onset pReeclampsIa) to evaluate recombinant human antithrombin gamma (rhAT-gamma) for the treatment of early-onset severe de novo preeclampsia., Material and Methods: Patients with early-onset severe de novo preeclampsia who are ≥24 to <32 weeks pregnant at the time of registration and have an antithrombin activity of ≤100% at screening are included. The target population is selected based on a reanalysis of the data of a previous plasma-derived antithrombin phase 3 study. Primary endpoint is the prolongation of pregnancy from the initiation of rhAT-gamma treatment to the pregnancy termination. Secondary endpoints include gestational age in terms of achievement of 32- and 34-weeks'gestation, and gestational age in terms of achievement of 28 weeks' gestation for patients enrolled at <28 weeks' gestation. Maternal, fetal, and neonatal outcomes will be assessed., Discussion: As we have selected a specifically defined target population based on reanalysis of data of a previous plasma-derived antithrombin phase 3 study, the results of our study are expected to provide efficacy and safety data concerning rhAT-gamma treatment in Japanese patients. This study could help identify an effective novel treatment for such patients with early-onset severe preeclampsia for whom appropriate treatment is unavailable., (Copyright © 2021. Published by Elsevier Inc.)

The full body illusion (FBI) is a bodily illusion based on the application of multisensory conflicts that induce changes in bodily self-consciousness (BSC). This has been used to study cognitive brain mechanisms underlying body ownership and related aspects of self-consciousness. Typically, such paradigms employ external passive multisensory stimulation, thus neglecting the possible contributions of self-generated action and haptic cues to body ownership. In this article, the effects of both external and voluntary self-touch on BSC were examined with a robotics-based FBI paradigm. We compared the effects of classical passive visuotactile stimulation and active self-touch (in which experimental participants had a sense of agency over the tactile stimulation) on the FBI. We evaluated these effects using a questionnaire, crossmodal congruency task, and measurements of changes in self-location. The results indicated that both synchronous passive visuotactile stimulation and synchronous active self-touch induced illusory ownership over a virtual body, without significant differences in their magnitudes. However, the FBI induced by active self-touch was associated with a larger drift in self-location towards the virtual body. These results show that movement-related signals arising from self-touch impact the BSC not only for hand ownership but also for torso-centered body ownership and related aspects of BSC.