Exploring factors of successful transition to elementary school among children with autism spectrum disorder in Japan: a focus group study.

Introduction: Children with autism spectrum disorder (ASD) face numerous challenges in transitioning to elementary school, which can cause confusion for the children and concern among their parents. Aims: This study aimed to identify the process of school transition from kindergarten to elementary school for children with autism spectrum disorder in Japan, by evaluating the effectiveness of a school transition program. Methods: A focus group interview was conducted with seven parents who participated in a transition program. They were asked about communication with the teachers, support obtained from the school, and their experiences after their children entered elementary school. After the group interview was recorded and transcribed, the data were analyzed using inductive content analysis to determine the parents' experiences of the school transition process. Findings: Six main themes emerged from the focus group interview: acquisition of prerequisite skills, adjustment in dealing with children with ASD, communication between school and home, communication between peers and children with autism spectrum disorder, collaboration with special needs education teachers, and the principal's understanding of special needs education. Conclusion: These findings provide an overview of the challenges and possible solutions to support school transitions for children with autism spectrum disorder in inclusive educational environments.

Reliability and validity of eye-hand coordination pointing tests for older adults.

To examine the reliability and validity of eye-hand coordination pointing with pencil test (EHCPPT), which evaluates the spatial and temporal displacement of rhythmic movements. One hundred and thirty-five older adults participated in our study. Reproducibility of the EHCPPT was assessed by the participants tapping on the center of the circles using a tablet pen in response to 2 types of stimulus sound sequences (Test A and B) across 2 separate trials, the first and second half. Construct validity was assessed by comparison in the distances between ultimate and current processing abilities, based on the spatial and temporal displacement relationship across Test A and Test B. Concurrent validity was assessed by examining the relationship between the distances between ultimate and current processing abilities and the motor and cognitive functions. Spatial and temporal displacements showed an excellent intraclass correlation coefficient in both Tests A and B of EHCPPT. The distance between ultimate and current processing ability, based on the relationship of spatial and temporal displacement, was significantly shorter in Test A compared to Test B. Spatial and temporal displacements were correlated with motor and cognitive functions. The spatial and temporal displacements of EHCPPT indicated reproducibility and validity in older adults. The EHCPPT may serve as a rhythmic movement reflecting motor and cognitive functions.

Baseline Variability Affects N-of-1 Intervention Effect: Simulation and Field Studies.

The simulation study investigated the relationship between the local linear trend model's data-comparison accuracy, baseline-data variability, and changes in level and slope after introducing the N-of-1 intervention. Contour maps were constructed, which included baseline-data variability, change in level or slope, and percentage of non-overlapping data between the state and forecast values by the local linear trend model. Simulation results showed that baseline-data variability and changes in level and slope after intervention affect the data-comparison accuracy based on the local linear trend model. The field study investigated the intervention effects for actual field data using the local linear trend model, which confirmed 100% effectiveness of previous N-of-1 studies. These results imply that baseline-data variability affects the data-comparison accuracy using a local linear trend model, which could accurately predict the intervention effects. The local linear trend model may help assess the intervention effects of effective personalized interventions in precision rehabilitation.

Effects of Paired Associative Stimulation on Cortical Plasticity in Agonist-Antagonist Muscle Representations.

Paired associative stimulation (PAS) increases and decreases cortical excitability in primary motor cortex (M1) neurons, depending on the spike timing-dependent plasticity, i.e., long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity, respectively. However, how PAS affects the cortical circuits for the agonist and antagonist muscles of M1 is unclear. Here, we investigated the changes in the LTP- and LTD-like plasticity for agonist and antagonist muscles during PAS: 200 pairs of 0.25-Hz peripheral electric stimulation of the right median nerve at the wrist, followed by a transcranial magnetic stimulation of the left M1 with an interstimulus interval of 25 ms (PAS-25 ms) and 10 ms (PAS-10 ms). The unconditioned motor evoked potential amplitudes of the agonist muscles were larger after PAS-25 ms than after PAS-10 ms, while those of the antagonist muscles were smaller after PAS-25 ms than after PAS-10 ms. The γ-aminobutyric acid A (GABAA)- and GABAB-mediated cortical inhibition for the agonist and antagonist muscles were higher after PAS-25 ms than after PAS-10 ms. The cortical excitability for the agonist and antagonist muscles reciprocally and topographically increased and decreased after PAS, respectively; however, GABAA and GABAB-mediated cortical inhibitory functions for the agonist and antagonist muscles were less topographically decreased after PAS-10 ms. Thus, PAS-25 ms and PAS-10 ms differentially affect the LTP- and LTD-like plasticity in agonist and antagonist muscles.

Use of intravenous cangrelor in the treatment of ruptured and unruptured cerebral aneurysms: an updated single-center analysis and pooled analysis of current studies.

BACKGROUND: Intracranial stent placement for the treatment of cerebral aneurysms is increasingly utilized in both ruptured and unruptured scenarios. Intravenous (IV) cangrelor is a relatively new antiplatelet agent that was initially approved for coronary interventions. In addition to our institution, five other centers have published their results using IV cangrelor in neurointerventional procedures. This article combines the aneurysm treatment data from all prior studies to provide insight into the safety and efficacy of cangrelor for intracranial aneurysm treatment. METHODS: A prospectively maintained database was reviewed to identify all cases of IV cangrelor administration during aneurysm embolization. 20 additional patients were identified who had not been previously published. In addition, a literature search was performed to identify prior publications regarding cangrelor in neurointervention. The data from these were combined with our institutional results in a pooled-analysis. RESULTS: Overall, 85 patients who received IV cangrelor during aneurysm embolization were identified, including 46 ruptured and 39 unruptured cases. The asymptomatic and symptomatic intracranial hemorrhage rates were 4% (2/46) for ruptured cases and 2.6% (1/39) for unruptured cases. The rate of retroperitoneal hematoma and gastrointestinal bleeding was 0%. There were no incidents of intraprocedural thromboembolic complication or intraprocedural in-stent thrombosis in either cohort. One subject suffered an ischemic stroke at 24 hours secondary to in-stent thrombosis in a ruptured case. CONCLUSIONS: IV cangrelor during aneurysm embolization appears to be safe, with a symptomatic intracranial hemorrhage rate of 4% in ruptured cases and 2.6% in unruptured cases. More research is needed to determine the ideal dosing regimen.

IMiD/CELMoD-induced growth suppression of adult T-cell leukemia/lymphoma cells via cereblon through downregulation of target proteins and their downstream effectors.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasia associated with human T-cell leukemia virus type 1 (HTLV-1) infection and has an extremely poor prognosis. Lenalidomide (LEN; a second-generation immunomodulatory drug [IMiD]) has been employed as an additional therapeutic option for ATL since 2017, but its mechanism of action has not been fully proven, and recent studies reported emerging concerns about the development of second primary malignancies in patients treated with long-term IMiD therapy. Our purpose in this study was to elucidate the IMiD-mediated anti-ATL mechanisms. Thirteen ATL-related cell lines were divided into LEN-sensitive or LEN-resistant groups. CRBN knockdown (KD) led to a loss of LEN efficacy and IKZF2-KD-induced LEN efficacy in resistant cells. DNA microarray analysis demonstrated distinct transcriptional alteration after LEN treatment between LEN-sensitive and LEN-resistant ATL cell lines. Oral treatment of LEN for ATL cell-transplanted severe combined immunodeficiency (SCID) mice also indicated clear suppressive effects on tumor growth. Finally, a novel cereblon modulator (CELMoD), iberdomide (IBE), exhibited a broader and deeper spectrum of growth suppression to ATL cells with efficient IKZF2 degradation, which was not observed in other IMiD treatments. Based on these findings, our study strongly supports the novel therapeutic advantages of IBE against aggressive and relapsed ATL.

Segment-Unit Reading Comprehension Training for Japanese Students with Autism Spectrum Disorder and Learning Disabilities.

Students with autism spectrum disorder (ASD) and learning disabilities (LDs) often experience reading difficulties. In particular, reading long passages can cause comprehension problems. We examined whether 8 Japanese students with ASD, 7 students with LDs, and 13 typically developing (TD) students improved their reading comprehension through two types of repeated reading training: whole-sentence-unit reading (WSUR) training and segment-unit reading (SUR) training. Participants undergoing WSUR training read whole sentences repeatedly. In SUR training, they repeatedly read a segment of a sentence in its correct spatial location. Results indicated that students with ASD and LDs showed greater improvement in reading comprehension after SUR training than after WSUR training, whereas both procedures were equally effective for TD students. Moreover, students with ASD showed only negligible reading comprehension improvements, whereas students with LDs showed intermediate improvements after WSUR training. These results suggest that sequentially presenting word segments can improve the reading comprehension of students with ASD and specific LDs.

Evaluation of a Telehealth Parent-Training Program in Japan: Collaboration with Parents to Teach Novel Mand Skills to Children Diagnosed with Autism Spectrum Disorder.

This study developed a telehealth parent-training program to teach parents of children with autism spectrum disorder the process of mand-training implementation in Japan, and to further the international dissemination of evidence-based training strategies. Parent-training sessions were based on a behavioral skills training (BST) model, combined with weekly graphic and video feedback. The sessions were conducted by a board-certified behavior analyst-doctoral residing in Japan. Four parents with children with autism spectrum disorder participated in this study. The results preliminarily support the effectiveness and social validity of the program. This study extends previous parent-training research conducted in Japan by comprising all of the following features: (1) online program design; (2) mand training; (3) BST model; (4) session-by-session data on children's behavioral changes and procedural integrity; (5) within-subject experimental design; and (6) social validity evaluation.

Infants' Prefrontal Hemodynamic Responses and Functional Connectivity During Joint Attention in an Interactive-Live Setting.

The present study examined cerebral hemodynamic responses and functional connectivity during joint attention either initiated by infants (Initiating Joint Attention, IJA condition) or by their partner (Responding to Joint Attention, RJA condition). To capture responses to natural social cues in infants aged 7-12 months using functional near-infrared spectroscopy (fNIRS), we employed an interactive-live paradigm for IJA and RJA. During the measurement, an adult sat facing an infant, and objects, such as small stuffed animals, paired with sound toys were presented to the right or left side of the screen. In the RJA condition, the adult gazed at the infants' eyes and then to the objects to encourage the infants to follow the adult's gaze. On the other hand, in the IJA condition, the adult followed the infant's gaze as it shifted to the presented object. Our results indicate that the concentration of oxy-Hb in the bilateral ventral prefrontal region had significantly decreased, then followed by an increase in the right dorsal prefrontal region in the RJA. In addition, a selective activation in the bilateral dorsal prefrontal region was seen in the IJA condition. Moreover, the infants exhibited increased functional connectivity especially within the right ventral prefrontal region during RJA condition when compared with IJA conditions. These findings suggest that RJA and IJA recruit specific brain networks localized in the prefrontal cortex of infants.

Discovery of CRBN as a target of thalidomide: a breakthrough for progress in the development of protein degraders.

Progress in strategies aimed at breaking down therapeutic target proteins has led to a paradigm shift in drug discovery. Thalidomide and its derivatives are the only protein degraders currently used in clinical practice. Our understanding of the molecular mechanism of action of thalidomide and its derivatives has advanced dramatically since the identification of cereblon (CRBN) as their direct target. The binding of thalidomide derivatives to CRBN, a substrate recognition receptor for Cullin 4 RING E3 ubiquitin ligase (CRL4), induces the recruitment of non-native substrates to CRL4CRBN and their subsequent degradation. This discovery was a breakthrough in the current rapid development of protein-degrading agents because clarification of the mechanism of action of thalidomide derivatives has demonstrated the clinical value of these compounds. This review provides an overview of the mechanism of action of thalidomide and its derivatives and describes perspectives for protein degraders.

Developing a fast-track discharge protocol for patients with cerebral aneurysms treated via neuroendovascular techniques.

INTRODUCTION: As we emerge from the current pandemic, hospitals, staff, and resources will need to continue to adjust to meet ongoing healthcare demands. Lessons learned during past shortages can be used to optimize peri-procedural protocols to safely improve the utilization of hospital resources. METHODS: Retrospective review of patients who underwent elective endovascular intracranial aneurysm treatment was performed. Multivariable logistic regression was used to identify factors associated with patients who were able to be discharged within 24 h of elective procedures. Rates of complications (particularly readmission) were determined. RESULTS: 330 patients underwent elective endovascular aneurysm treatment with 86 (26.1%) discharged within 24 h. Factors associated with earlier discharge included procedure years (2019-2021) and male sex. Patients were more likely to be discharged later (after 24 h) if they underwent stent-coil embolization or flow-diversion. There was no association between discharge timing and likelihood of readmission. DISCUSSION: Our review highlights the safety of earlier discharge and allowed us to prepare a fast-track protocol for same-day discharge in these patients. This protocol will be studied prospectively in the next phase of this study. As we gain more comfort with emerging, minimally invasive endovascular therapies, we hope to safely achieve same-day discharge on a protocolized and routine basis, reducing the demand of elective aneurysm treatments on our healthcare system. CONCLUSION: We retrospectively demonstrate that early discharge following elective aneurysm treatment is safe in our cohort and provide a fast-track pathway based on these findings for other centers developing similar protocols.

EEG Oscillations in Specific Frequency Bands Are Differently Coupled with Angular Joint Angle Kinematics during Rhythmic Passive Elbow Movement.

Rhythmic passive movements are often used during rehabilitation to improve physical functions. Previous studies have explored oscillatory activities in the sensorimotor cortex during active movements; however, the relationship between movement rhythms and oscillatory activities during passive movements has not been substantially tested. Therefore, we aimed to quantitatively identify changes in cortical oscillations during rhythmic passive movements. Twenty healthy young adults participated in our study. We placed electroencephalography electrodes over a nine-position grid; the center was oriented on the transcranial magnetic stimulation hotspot of the biceps brachii muscle. Passive movements included elbow flexion and extension; the participants were instructed to perform rhythmic elbow flexion and extension in response to the blinking of 0.67 Hz light-emitting diode lamps. The coherence between high-beta and low-gamma oscillations near the hotspot of the biceps brachii muscle and passive movement rhythms was higher than that between alpha oscillation and passive movement rhythm. These results imply that alpha, beta, and gamma oscillations of the primary motor cortex are differently related to passive movement rhythm.

Comparison of hydrogel coils versus bare platinum coils for the treatment of anterior communicating artery aneurysms.

INTRODUCTION: While endovascular coiling has been shown to be a safe treatment option for intracranial aneurysms, there remains concern regarding increased recurrence and retreatment rates. Preliminary studies evaluating hydrogel coated coils have demonstrated decreased recurrence rates compared to bare metal coils. METHODS: A retrospective chart review was done on all patients with anterior communicating artery aneurysms (ACoAAs) treated with endovascular coiling between 2014 and 2018. Treatment groups were divided into hydrogel coated coils or bare metal coils. Patients were categorized into the hydrogel group when ≥ 70% of the coil length was hydrogel coated. RESULTS: Eighty-four ACoAAs were treated with coil embolization between 2014 and 2018. Postoperative imaging was available for 68 patients. Twenty-six patients were categorized into the hydrogel treatment group. Aneurysm recurrence was seen in 7.7% (2/26) of patients treated with hydrogel coated coils compared to 33.3% (14/42) of those treated with bare metal coils (P = 0.03). Subanalysis of patients with ruptured aneurysms revealed decreased recurrence rates in patients treated with hydrogel coated coils at 5.9% (1/17) compared to patients treated with bare metal coils at 39.4% (13/33) (P = 0.01). CONCLUSIONS: Hydrogel-coated coils may reduce recurrence rates in the treatment of both ruptured and unruptured ACoAAs.

Bioavailability, safety and tolerability of intravenous brivaracetam in healthy Japanese participants.

We characterised the bioavailability, safety, and tolerability of brivaracetam 100 mg intravenous bolus and 15-min infusion versus oral reference tablet in 24 healthy Japanese participants.In this randomised, open-label, three-period crossover study, participants received three 100 mg single doses of brivaracetam, intravenous bolus, infusion, and oral tablets. Maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (AUCt), and area under the plasma concentration-time curve extrapolated to infinity (AUCinf), were compared using analysis of variance following logarithmic transformation. Bioavailability comparisons were based on the 90% confidence intervals (CIs) around the geometric least squares means ratios (intravenous:oral). Safety and tolerability were monitored throughout the study.The 90% CIs around AUCt and AUCinf ratios were entirely contained within the bioequivalence limits (0.80-1.25), but Cmax was outside the limits (90% CI: 1.77-2.08 and 1.44-1.70 for intravenous bolus and infusion, respectively). All participants completed the study. Brivaracetam was well tolerated.Because response to brivaracetam in epilepsy is related to exposure (AUC), no dose adjustment is warranted when switching from oral to intravenous dosing. However, investigations are needed to assess the safety and tolerability of intravenous administration in Japanese patients with epilepsy.

PLZF and its fusion proteins are pomalidomide-dependent CRBN neosubstrates.

Pomalidomide and lenalidomide are immunomodulatory agents that were derived from thalidomide. Cereblon (CRBN) is a common direct target of thalidomide and related compounds and works as a Cullin Ring 4 E3 ubiquitin ligase (CRL4) with DDB1, CUL4, and ROC1. The substrate specificity of CRL4CRBN is modulated by thalidomide-related compounds. While lenalidomide is approved for the treatment of several diseases including multiple myeloma, 5q- syndrome, mantle cell lymphoma, and follicular lymphoma, pomalidomide is approved only for the treatment of lenalidomide-resistant multiple myeloma. Here we show that PLZF/ZBTB16 and its fusion proteins are pomalidomide-dependent neosubstrates of CRL4CRBN. PLZF joins to RARα or potentially other partner genes, and the translocation causes leukemias, such as acute promyelocytic leukemia and T-cell acute lymphoblastic leukemia. We demonstrate that pomalidomide treatment induces PLZF-RARα degradation, resulting in antiproliferation of leukemic cells expressing PLZF-RARα. This study highlights a potential therapeutic role of pomalidomide as a degrader of leukemogenic fusion proteins.

Characterization of antiplatelet response to low-dose cangrelor utilizing platelet function testing in neuroendovascular patients.

STUDY OBJECTIVES: The optimal antiplatelet therapy for emergent neuroendovascular stenting is uncertain. Cangrelor is an intravenous P2Y12 inhibitor that is an attractive option due its favorable pharmacokinetic profile and ease of measurability but optimal dosing remains unclear. The primary objective of this study is to characterize the dose response of low dose cangrelor (<2 mcg/kg/min) with the utilization of platelet function testing (PFT). DESIGN: A retrospective review of all patients treated with cangrelor for either procedural stenting or bridging was conducted between January 1st, 2019 and October 31st, 2020. Seventy-two patients met inclusion criteria. An in-depth analysis of dose response to low dose cangrelor based on PFT was performed. PATIENTS: Neuroendovascular patients treated with cangrelor. SETTING: Albany Medical Center Hospital. INTERVENTION AND MAIN RESULTS: Patients who underwent procedural stenting were given a bolus of 5 mcg/kg and an initial infusion rate of either 0.75 mcg/kg/min or 1 mcg/kg/min. Patients who were bridged with cangrelor were administered an initial infusion rate of 0.75 mcg/kg/min or 1 mcg/kg/min. Twelve patient's doses were titrated to achieve a platelet reactivity unit (PRU) between 50-150; three patient's doses were titrated multiple times. Based on initial PFT results, utilizing the 1 mcg/kg/min maintenance dose resulted in more patients being in the acceptable (10-180) and desired (50-150) PRU range than the 0.75 mcg/kg/min dose (47% vs 56% and 70% vs 80%, respectively). Final recorded PRU results showed that 64% of patients had PRUs in the optimal range (50-150) and 88% of patients had PRUs in the desire range (10-180). CONCLUSIONS: Utilizing low doses of cangrelor with platelet function testing is an option during emergent neuroendovascular stenting and bridging. Cangrelor demonstrates significant variability in response at low doses and exhibits a dose response relationship when PFT is utilized.

Delayed hypersensitivity reaction to a dural repair substitute.

BACKGROUND: Modern neurosurgeons commonly rely on dural grafts to aid in obtaining watertight closures when the native dura itself cannot be approximated. CASE PRESENTATION: We present a patient who developed a symptomatic, delayed hypersensitivity reaction to a cellulose-based synthetic dural graft, which resolved after reoperation and removal of the graft. DISCUSSION: Dural grafts are a safe and common implant utilized in neurosurgery. Nevertheless, as with all implanted material, there is a chance for symptomatic immune reactions to occur. CONCLUSION: This type of response is exceedingly uncommon, but recognition of this rare presentation may help other providers recognize it in the future.

Stent-in-stent technique for the management of blood blister-like basilar apex aneurysms.

Blood blister-like basilar apex aneurysms are rare thin-walled vascular lesions with a poorly defined aneurysmal neck. We present two patients with ruptured blister aneurysms of the basilar apex who were treated using the stent-in-stent technique. Long-term follow-up showed persistent and complete occlusion of the aneurysms without radiographically or neurological complications. There is no optimal treatment of choice for the basilar apex blood blister-like aneurysms. Double- or triple-stent placement using the stent-in-stent technique can be a safe and feasible option for these uncommon and challenging intracranial aneurysms.

A pilot study of combining social skills training and parenting training for children with autism spectrum disorders and their parents in Japan.

The purpose of this study is to investigate the effects of a program containing a combination of social skills training (SST) and parenting training (PT) for the enrichment of social interaction skills and reduction of parenting stress for children with high-functioning autism spectrum disorder (HFASD) and their parents in Japan. Twenty-two patients with HFASD from second to fourth grade and their parents were assigned to a training group (TG) or treatment as usual (TAU) and compared. The children with HFASD and their parents who were assigned to the TG participated in the manualized program for over a period of five to six months. Subjects provided demographic and medical information and completed teacher and parent-rating scales for social competence (Social Responsiveness Scale-2: SRS-2) and parent-rating of parenting stress (Parental Stress Index: PSI) and mental health (General Health Questionnaire-28: GHQ-28). The participants exhibited some improvements pre-, middle-, and post-treatment, particularly regarding the GHQ, PSI and SRS-2, as reported by parents. However, the social skills improvement reported by teachers was not significant. At the three-month follow-up, parent-rated GHQ and PSI maintained improvement, and SRS-2 achieved the greatest improvement from the baseline rating. Although some findings indicate that a program combination of SST and PT might be useful for enhancing social skills and improving parental stress and mental health, some subscales did not show a sufficient effect. Future research should consider program contents and provide longitudinal follow-up data to test the durability of the treatment.