Molecular Dynamics Simulation of Cumulative Microscopic Damage in a Thermosetting Polymer under Cyclic Loading.

To develop durable composite materials, it is crucial to elucidate the correlation between nanoscale damage in thermosetting resins and the degradation of their mechanical properties. This study aims to investigate this correlation by performing cyclic loading tests on the cross-linked structure of diglycidyl ether bisphenol A (DGEBA) and 4,4'-diaminodiphenyl sulfone (44-DDS) using all-atom molecular dynamics (MD) simulations. To accurately represent the nanoscale damage in MD simulations, a bond dissociation algorithm based on interatomic distance criteria is applied, and three characteristics are used to quantify the microscopic damage: stress-strain curves, entropy generation, and the formation of voids. As a result, the number of covalent bond dissociations increases with both the cyclic loading and its amplitude, resulting in higher entropy generation and void formation, causing the material to exhibit inelastic behavior. Furthermore, our findings indicate the occurrence of a microscopic degradation process in the cross-linked polymer: Initially, covalent bonds align with the direction of the applied load. Subsequently, tensioned covalent bonds sequentially break, resulting in significant void formation. Consequently, the stress-strain curves exhibit nonlinear and inelastic behavior. Although our MD simulations employ straightforward criteria for covalent bond dissociation, they unveil a distinct correlation between the number of bond dissociations and microscale damage. Enhancing the algorithm holds promise for yielding more precise predictions of material degradation processes.

Survey on diagnosis of post-brain injury "higher brain dysfunction" in patients with cognitive impairment. Family/caregiver response.

In Japan, the diagnostic criteria for the higher brain dysfunction (HBD) emerged in 2005 in response to social needs for support for the patients and their families. The issue of cognitive dysfunction after brain trauma is not unique to Japan. The purpose of this study was to reveal the current status of family members of HBD patients from their perspective, focusing on the changes before and after the establishment of diagnostic criteria in Japan. We conducted a questionnaire survey for family members supporting the HBD patients. The questionnaire included the causative condition, explanation on HBD by health professionals, and problems/difficulties they encountered. This research involved family members of 278 HBD cases (males = 211, age 49 years). The major underlying cause was head injury (n = 139). Compared to patients diagnosed pre-2005, a significantly larger proportion of family members after 2005 received information on the condition during the acute phase (within one month) (p < 0.001), including that from physicians (p < 0.001). Nearly half of the families cited a lack of awareness of HBD among the professionals as a problem. In Japan, awareness of HBD in the society is gradually increasing especially after the current diagnostic criteria were implemented, and there has been a steady increase over time in early diagnosis. Yet, there still remain those not appropriately diagnosed. To salvage those patients and the families left behind, we are suggesting several recommendations to further augment clinical practice and the healthcare systems in Japan.

Click3D: Click reaction across deep tissues for whole-organ 3D fluorescence imaging.

Click chemistry offers various applications through efficient bioorthogonal reactions. In bioimaging, pretargeting strategies have often been used, using click reactions between molecular probes with a click handle and reporter molecules that make them observable. Recent efforts have integrated tissue-clearing techniques with fluorescent labeling through click chemistry, allowing high-resolution three-dimensional fluorescence imaging. Nevertheless, these techniques have faced a challenge in limited staining depth, confining their use to imaging tissue sections or partial organs. In this study, we introduce Click3D, a method for thoroughly staining whole organs using click chemistry. We identified click reaction conditions that improve staining depth with our custom-developed assay. The Click3D protocol exhibits a greater staining depth compared to conventional methods. Using Click3D, we have successfully achieved whole-kidney imaging of nascent RNA and whole-tumor imaging of hypoxia. We have also accomplished whole-brain imaging of hypoxia by using the clickable hypoxia probe, which has a small size and, therefore, has high permeability to cross the blood-brain barrier.

Characteristics of malignant brain tumor-associated epileptic spasms.

Although epilepsy is the most common comorbidity of brain tumors, epileptic spasms rarely occur. Brain tumors associated with epileptic spasms are mostly low-grade gliomas. To date, few studies in the literature have reported on malignant (Grades 3-4) brain tumors associated with epileptic spasms. Thus, we aimed to investigate the characteristics of malignant brain tumor-associated epileptic spasms. We retrospectively reviewed patients with malignant brain tumors and epileptic spasms in our institution. Data on demographics, tumor histology, magnetic resonance imaging, epileptic spasm characteristics, electroencephalography, and treatment responsiveness were also collected. Six patients were included. In all cases, the brain tumors occurred in infancy in the supratentorial region and epileptic spasm onset occurred after the completion of brain tumor treatment. Anti-seizure medication did not control epileptic spasms; two patients were seizure-free after epileptic surgery. Although all patients had developmental delays caused by malignant brain tumors and their treatment, developmental regression proceeded after epileptic spasm onset. Two patients who achieved seizure-free status showed improved developmental outcomes after cessation of epileptic spasms. This is the first report of the characteristics of malignant brain tumor-associated epileptic spasms. Our report highlights a difficulties of seizure control and possibillity of efficacy of epileptic surgery in this condition. In malignant brain tumor-associated epileptic spasms, it is important to proceed with presurgical evaluation from an early stage, bearing in mind that epileptic spasms may become drug-resistant.

Successful Hemispherotomy in a Patient With 22q11.2 Deletion Syndrome Who Had Developmental and Epileptic Encephalopathy With Spike-and-Wave Activation During Sleep.

We report a case of developmental and epileptic encephalopathy with spike-and-wave activation during sleep with 22q11.2 deletion syndrome in a patient who had undergone hemispherotomy and achieved developmental improvement. A four-year-old male child with paralysis on the left side of his body since birth had a mild developmental delay. An MRI of the brain revealed polymicrogyria diffusely throughout the right hemisphere. He was diagnosed with the 22q11.2 deletion syndrome at one year of age. Focal impaired awareness seizure in the right hemisphere origin and focal to bilateral tonic-clonic seizure appeared by two years of age. At three years of age, myoclonic seizures occurred, which induced frequent falls. Simultaneously, developmental and epileptic encephalopathy with spike-and-wave activation during sleep were observed. At four years and seven months of age, the patient underwent a right hemispherotomy. Epileptic seizures and spike-and-wave activation during sleep disappeared, and cognitive improvement was observed one year after surgery. In spite of chromosomal abnormalities being present, drug-resistant epilepsy with localized regions on MRI should be evaluated to determine surgical options to improve cognitive function and development.

A 10-Year Study of the Trend of Accidental Falls in the Elderly in a Japanese Hospital.

Elderly people are prone to falls. We established the Falls Prevention Working Group (FPWG) at our hospital in 2015 to reduce the number of falls during hospitalization. This study compared the trend of in-hospital falls in the elderly in two time periods (2008/9 and 2018/9) and determined the effects of FPWG-implemented measures. Using medical records, we counted the monthly number of falls suffered by patients during hospitalization in April 2008-March 2009 and April 2018-March 2019. We also categorized the falls according to the severity of fall-related complications.A total of 3609 hospital falls were recorded during the 2008-2019 period (2008/9: n = 433, 2018/9: n = 324). Falls were more common in patients aged 70-79 in 2008/9 but were noted in those aged ≥ 80 in 2018/9. The mean number of falls/month (27.3 ± 6.4, range: 12-45) was stable throughout the year. The incidence of falls in 2018/9 (1.90/1000 per persons per day) was significantly lower than in 2008/9 (2.30/1000, p = 0.006). Level ≥ 3b accidents, reflecting serious accidents with complications, were encountered in 12 of 433 accidents in 2008/9 compared with significantly fewer accidents (2 of the same severity among 324 accidents) in 2018/9 (p = 0.030).Our results showed a decrease in in-hospital falls in 2018/9 and that the sufferers were older relative to 10 years earlier. A multidisciplinary team should recommend measures to prevent falls and an environment "resilient" to falls, and encourage patients to be aware of possible falls.

Pimonidazole-alkyne conjugate for sensitive detection of hypoxia by Cu-catalyzed click reaction.

Hypoxia is involved in various diseases, such as cancers. Pimonidazole has often been used as the gold-standard marker to visualize hypoxic regions. Pimonidazole labels hypoxic regions by forming a covalent bond with a neighboring protein under hypoxic conditions in the body, which is detected by immunohistochemistry performed on tissue sections. To date, some pimonidazole-fluorophore conjugates have been reported as fluorescent probes for hypoxia imaging that do not require immunostaining. They are superior to pimonidazole because immunostaining can produce high background signals. However, large fluorophores in the conjugates may alter the original biodistribution and reactivity. Here, we report a new hypoxia marker, Pimo-yne, as a pimonidazole-alkyne conjugate. Pimo-yne has a similar hypoxia detection capability as pimonidazole because the alkyne tag is small and can be detected by Cu-catalyzed click reaction with azide-tagged fluorescent dyes. We successfully visualized hypoxic regions in tumor tissue sections using Pimo-yne with reduced background signals. The detected regions overlapped well with those detected by pimonidazole immunohistochemistry. To further reduce the background, we employed a turn-on azide-tagged fluorescent dye.

Whole-Body and Whole-Organ 3D Imaging of Hypoxia Using an Activatable Covalent Fluorescent Probe Compatible with Tissue Clearing.

Elucidation of biological phenomena requires imaging of microenvironments in vivo. Although the seamless visualization of in vivo hypoxia from the level of whole-body to single-cell has great potential to discover unknown phenomena in biological and medical fields, no methodology for achieving it has been established thus far. Here, we report the whole-body and whole-organ imaging of hypoxia, an important microenvironment, at single-cell resolution using activatable covalent fluorescent probes compatible with tissue clearing. We initially focused on overcoming the incompatibility of fluorescent dyes and refractive index matching solutions (RIMSs), which has greatly hindered the development of fluorescent molecular probes in the field of tissue clearing. The fluorescent dyes compatible with RIMS were then incorporated into the development of activatable covalent fluorescent probes for hypoxia. We combined the probes with tissue clearing, achieving comprehensive single-cell-resolution imaging of hypoxia in a whole mouse body and whole organs.

Pneumococcal vaccination coverage and vaccination-related factors among older adults in Japan: LIFE Study.

PURPOSE: To investigate individual and environmental vaccination-related factors among the older adults in Japan, using administrative data. METHODS: We conducted a cohort study and included people who reached the relevant age (≥65 years) for routine pneumococcal vaccination of older adults between April 2015 and March 2020. Monthly data of residents in the two municipalities from April 2014 to March 2020 and vaccination records from April 2015 to March 2020 were used. We defined five cohorts according to the year in which routine vaccinations were available. Each cohort was followed for a total of two years, with the first year being the "baseline period" and second year being the "vaccine follow-up period." Pneumococcal vaccination data was extracted from vaccination records at "first dose." Age, sex, socioeconomic status, comorbidities, hospital visit history, hospitalization history, Specific Health Check-ups participation, and information on contracted hospitals for pneumococcal vaccination were used as covariates. A multivariate logistic regression model was used to investigate the relationship between pneumococcal vaccination and vaccination-related factors. Odds ratios (OR) and 95 % confidence intervals (95 % CI) were calculated. RESULTS: Analysis included 17,991 patients. Vaccination coverage was 33.6 % for all subjects. Multivariate analysis found the following as significant vaccination-related factors: female (OR: 1.18, 95 % CI: 1.11-1.26), not low income (1.76, 1.17-2.76), hospital visits: ≥once/month (1.27, 1.19-1.35), and Specific Health Check-ups participation (2.10, 1.95-2.27). No significant results were found for hospitals that contracted pneumococcal vaccination. CONCLUSIONS: Individual factors, such as sex and Specific Health Check-ups participation, were found to be important factors affecting pneumococcal vaccination among older adults in Japan. Environmental factors, such as the characteristics of residential areas, should be evaluated in further investigations.

Capturing temperature changes on the ocular surface along with estrus and ovulation using infrared thermography in Japanese Black cows.

Pre-ovulatory follicles are cooler than the neighboring reproductive organs in cows. Thus, measuring the temperature of reproductive organs could be a useful method for predicting estrus and ovulation in cows, and the establishment of a non-invasive technique is required. In this study, we used infrared thermography (IRT) to measure ocular surface temperature as a potential surrogate for reproductive organ temperature. Five Japanese Black cows with synchronized estrus were subjected to temperature measurements in five regions of the ocular surface, including the nasal conjunctiva, nasal limbus, center cornea, temporal limbus, and temporal conjunctiva, twice a day (0800 h and 1600 h) during the experimental period. The temperatures in the five regions significantly declined in cows from estrus to ovulation. To the best of our knowledge, this study is the first to use IRT to show a temperature decrease in the ocular surface along with estrus to ovulation in Japanese Black cows.

Abnormal axonal development and severe epileptic phenotype in Dynamin-1 (DNM1) encephalopathy.

Dynamin-1 (DNM1) is involved in synaptic vesicle recycling, and DNM1 mutations can lead to developmental and epileptic encephalopathy. The neuroimaging of DNM1 encephalopathy has not been reported in detail. We describe a severe phenotype of DNM1 encephalopathy showing characteristic neuroradiological features. In addition, we reviewed previously reported cases who have DNM1 pathogenic variants with white matter abnormalities. Our case presented drug-resistant seizures from 1 month of age and epileptic spasms at 2 years of age. Brain MRI showed no progression of myelination, progression of diffuse cerebral atrophy, and a thin corpus callosum. Proton magnetic resonance spectroscopy showed a decreased N-acetylaspartate peak and diffusion tensor imaging presented with less pyramidal decussation. Whole-exome sequencing revealed a recurrent de novo heterozygous variant of DNM1. So far, more than 50 cases of DNM1 encephalopathy have been reported. Among these patients, delayed myelination occurred in two cases of GTPase-domain DNM1 encephalopathy and in six cases of middle-domain DNM1 encephalopathy. The neuroimaging findings in this case suggest inadequate axonal development. DNM1 is involved in the release of synaptic vesicles with the inhibitory transmitter GABA, suggesting that GABAergic neuron dysfunction is the mechanism of refractory epilepsy in DNM1 encephalopathy. GABA-mediated signaling mechanisms play important roles in axonal development and GABAergic neuron dysfunction may be cause of white matter abnormalities in DNM1 encephalopathy.

Cilostazol treats transient heart failure caused by ATP1A3 variant-associated polymicrogyria.

BACKGROUND: Some patients with ATP1A3 variant-associated polymicrogyria have recurrent transient heart failure. However, effective treatment for the transient cardiac condition remains to be elucidated. CASE REPORT: The patient started experiencing focal motor onset seizures in 12 h after birth, revealing bilateral diffuse polymicrogyria. The patient also experienced transient bradycardia (sinus bradycardia) attacks from 15 days old. Echocardiography revealed a reduced ejection fraction; however, no obvious electrocorticogram or electroencephalogram abnormalities were observed during the attacks. Initially, the attacks occurred in clusters daily. They later decreased in frequency, occurring at monthly intervals. Repeated episodes of transient bradycardia attacks and polymicrogyria indicated possible ATP1A3 gene abnormality and genetic testing revealed a novel heterozygous ATP1A3 variant (NM_152296: exon22:c.2977_2982del:p.(Glu993_Ile994del)), which was not found in the patient's parents. Cilostazol was administered at 3 months old for recurrent transient bradycardia attacks. Cilostazol significantly shortened the duration of bradycardia episodes and prolonged the interval between attacks. Cilostazol also effectively treats transient symptomatic bradycardia. CONCLUSION: Cilostazol could be a treatment option for recurrent transient bradycardia attacks associated with ATP1A3 gene abnormalities and polymicrogyria.

Surveys of eleven species of wild and zoo birds and feeding experiments in white-tailed eagles reveal differences in the composition of the avian gut microbiome based on dietary habits between and within species.

The composition of the gut microbiome varies due to dietary habits. We investigated influences of diet on the composition of the gut microbiome using the feces of 11 avian species, which consumed grain-, fish- and meat-based diets. We analyzed gut microbiome diversity and composition by next-generation sequencing (NGS) of 16S ribosomal RNA. The grain-diet group had higher gut microbiome diversity than the meat- and fish-diet group. The ratio of Bacteroidetes and Firmicutes phyla was higher in the grain-diet group than in the meat- and fish-diet groups. The grain-diet group had a higher ratio of Veillonellaceae than the meat-diet group and a higher ratio of Eubacteriaceae than the fish-diet habit group. To clarify the influence of diet within the same species, white-tailed eagles (Haliaeetus albicilla, n=6) were divided into two groups, and given only deer meat or fish for approximately one month. The composition of the gut microbiome of individuals in both groups were analyzed by NGS. There were indications of fluctuation in the levels of some bacteria (Lactobacillus, Coriobacteriales, etc.) in each diet group. Moreover, one individual for each group which switched each diet in last week changed to each feature of composition of bacterial flora. The above results show that the composition of the gut microbiome differ depending on diet, even within the same species.

Multimodal treatment, including extracorporeal shock wave therapy, for refractory chronic tension-type headache: a case report.

BACKGROUND: Few reports have described multidisciplinary treatment, including extracorporeal shock wave therapy, for patients with refractory chronic tension-type headache. In this study, we conducted multidisciplinary treatment for a patient with chronic tension-type headache who suffered from chronic headache refractory to treatment. CASE PRESENTATION: The patient was a 45-year-old Japanese male suffering from 20 years of headache. As his headache had worsened recently, he visited a local clinic. With the diagnosis of suspected tension-type headache, its treatment was unsuccessful and he was referred to our hospital. The neurology department confirmed the tension-type headache and prescribed another medication, but he showed no improvement. Then, the patient was referred to the rehabilitation medicine department for consultation. At the initial visit, we identified multiple myofascial trigger points in his bilateral posterior neck and upper back regions. At the initial visit, he was prescribed 10 mL of 1% lidocaine injected into the muscles in these areas. In addition, he received 2000 extracorporeal shock wave therapy into bilateral trapezius muscles, and was instructed to take oral Kakkonto extract granules, benfotiamine, pyridoxine hydrochloride, and cyanocobalamin. Cervical muscle and shoulder girdle stretches and exercises were also recommended. At follow-up treatment visits, we used extracorporeal shock wave therapy to bilateral trapezius muscles, which led to immediate pain relief. After 11 weeks, he was not taking any medication and his headache was subjectively improved and his medical treatment ended. CONCLUSION: A patient with chronic tension-type headache refractory to regular treatment was successfully treated with a multimodal approach including extracorporeal shock wave therapy in addition to standard treatment. For patients with tension-type headache accompanied by myofascial trigger points, it may be recommended to promptly consider aggressive multimodal treatment that includes extracorporeal shock wave therapy.

Transvascular delivery of talaporfin sodium to subcutaneous tumors in mice by nanosecond pulsed laser-induced photomechanical waves.

BACKGROUND: We previously developed a site-specific transvascular drug delivery system (DDS) based on photomechanical waves (PMWs) or laser-induced stress/shock waves (LISWs). In this study, we investigated the validity of this method to deliver a clinical photosensitizer, talaporfin sodium (TS), to subcutaneous tumors in mice and to enhance the efficacy of photodynamic therapy (PDT). METHODS: TS solution (2.5 mg/kg) was intravenously injected into mice. Immediately thereafter, PMWs were applied to the tumor by irradiating a laser target with a Q-switched ruby laser pulse (0.8 J/cm2). Five hours after TS administration, some tumors were excised to evaluate the depth distribution of the delivered TS under a fluorescence microscope. Other tumors were subjected to PDT by irradiating the tissues with a 665 nm continuous-wave laser diode (75 mW/cm2, 667 s) at this timepoint. The effects of PDT were evaluated on the basis of the two primary therapeutic mechanisms of TS-mediated PDT: i) damage to tumor cells and ii) damage to endothelial cells of tumor vessels, i.e., the vascular shutdown effect on tumors. RESULTS: PMW application significantly increased the accumulation of TS in the tumor parenchyma but not in the tumor vessel walls; the endothelial cell junctions of tumor vessels should be the route of TS delivery enhanced by PMWs. Thus, as a result of PMW application followed by PDT, while the vascular shutdown effect on the tumors was not enhanced, direct damage to the tumor cells was increased, resulting in significant tumor growth retardation without body weight loss for 7 days after treatment.

Surgery for ventricular tachycardia originating from the left ventricular summit.

OBJECTIVES: Ventricular tachycardia (VT) originating from the left ventricular summit region, the most superior region of the left ventricle surrounded by the major coronary arteries and veins, is frequently refractory to pharmacological therapies and endocardial and epicardial catheter ablation. METHODS: Eleven patients with an age from 31 to 79 (median 56) years old, underwent map-guided surgery for left ventricular summit VT. All patients had undergone 1-5 unsuccessful sessions of catheter ablation for incessant VT, preoperatively. Five patients had suffered VT storm and 1 had a history of cardiopulmonary resuscitation. Four patients had implanted with a defibrillator. Epicardium to endocardium transmural cryothermia was applied at the VT origin determined by intraoperative epicardial mapping with electro-anatomical mapping system. Harmonic scalpel was used to remove the epicardial fat and cryothermia was applied directly to the myocardium, avoiding thermal or mechanical injuries to the coronary vessels. Additional endocardial cryothermia at the VT origin was performed by a cryoprobe introduced into the left ventricular cavity through an aortotomy. RESULTS: There was no surgical mortality or long-term mortality related to VT during a median follow-up period of 60 months (interquartile range: 34-82). Five-year freedom from preoperatively documented left ventricular summit VT and non-documented VT was 91% and 73%, respectively. All the patients with postoperative VT underwent successful catheter ablation. Other patients were free from VT during the follow-up period. CONCLUSIONS: Epicardial to endocardial transmural cryothermia at the VT origin guided by intraoperative electro-anatomical mapping with a close collaboration with electrophysiologists was crucial in successful surgery for left ventricular summit VT.

Effects of group therapy on jumping to conclusion bias in adolescents with autism spectrum disorder : An exploratory study.

BACKGROUND AND PURPOSE: Jumping to conclusion (JTC)-a cognitive bias in thinking processes-leads to drawing conclusions based on little information, and could be related to psychosis and paranoia. While it has recently been pointed out that it could accompany the autism spectrum disorder (ASD), no interventions targeting this bias in adolescents with ASD have been reported. Therefore, this exploratory study investigated the effects of a group social cognition program on JTC bias in adolescents with ASD. PATIENTS AND METHODS: Group rehabilitation using social cognition and interaction training (SCIT) was conducted for 12- to 18-year-old adolescents with ASD. An SCIT program comprehensively targets social cognitive functions, including interventions for JTC bias, and examines changes before and after the SCIT intervention, social cognitive functioning tasks, and subjective quality of life (QOL). RESULTS: Thirteen adolescents with ASD participated in this program ; 10 (76.9%) stayed through it. The proportion of participants with JTC bias decreased significantly before and after SCIT (before : 7/10 ; after : 1/10 ; p = 0.041), and subjective QOL increased significantly (p=0.014). CONCLUSION: The results show that a group social cognition program with a JTC bias approach improves the JTC bias and increases subjective QOL in adolescents with ASD. J. Med. Invest. 70 : 115-122, February, 2023.

Combination Psychotropic Use for Schizophrenia With Long-Acting Injectable Antipsychotics and Oral Antipsychotics: A Nationwide Real-World Study in Japan.

BACKGROUND: Although several guidelines recommend monotherapy with antipsychotics for the treatment of schizophrenia, patients who receive long-acting injectable antipsychotics (LAIs) are frequently treated with oral antipsychotics (OAPs). In the present study, we investigated the detailed use of psychotropic medications among patients throughout Japan with schizophrenia who received LAIs or OAPs. METHODS: The present study used data from the project for the Effectiveness of Guidelines for Dissemination and Education in psychiatric treatment from 94 facilities in Japan. The LAI group included patients who received any LAI, and the non-LAI group included patients who took only OAP medications at discharge. The participants of this study were 2518 schizophrenia patients (263 in the LAI group and 2255 in the non-LAI group) who received inpatient treatment and had prescription information at discharge between 2016 and 2020. RESULTS: This study revealed significantly higher rates of polypharmacy antipsychotics, number of antipsychotics, and chlorpromazine equivalents in the LAI group than in the non-LAI group. In contrast, the LAI group showed lower rate of concomitant use of hypnotic and/or antianxiety medication than the non-LAI group. CONCLUSIONS: Presenting these real-world clinical results, we want to encourage clinicians to keep monotherapy in mind for the treatment of schizophrenia, especially by reducing concomitant use of antipsychotics in the LAI group and reducing hypnotic and/or antianxiety medication in the non-LAI group.