University of Fukui Hospital

Panayiotidis P., Hayslip J., Mendes W., Jiang Q., Gopalakrishnan S., Chyla B., McDonald A., Yamauchi T., Murthy V., Hou J., Bergeron J., Anagnostopoulos A., Hu Y., Samoilova O., Pagoni M., et. al.

Abstract Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. Adults age ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international phase 3 randomized double-blind placebo-controlled trial. Patients (N = 211) were randomized 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1 to 10. Primary end point was overall survival (OS); secondary end points included response rate, transfusion independence, and event-free survival. Median age was 76 years (range, 36-93 years), 38% had secondary AML, and 20% had received prior hypomethylating agent treatment. Planned primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs LDAC alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.52-1.07; P = .11), although not statistically significant; median OS was 7.2 vs 4.1 months, respectively. Unplanned analysis with additional 6-month follow-up demonstrated median OS of 8.4 months for the venetoclax arm (HR, 0.70; 95% CI, 0.50-0.98; P = .04). Complete remission (CR) plus CR with incomplete blood count recovery rates were 48% and 13% for venetoclax plus LDAC and LDAC alone, respectively. Key grade ≥3 adverse events (venetoclax vs LDAC alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs 16%), and thrombocytopenia (45% vs 37%). Venetoclax plus LDAC demonstrates clinically meaningful improvement in remission rate and OS vs LDAC alone, with a manageable safety profile. Results confirm venetoclax plus LDAC as an important frontline treatment for AML patients unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352.

Egi M., Ogura H., Yatabe T., Atagi K., Inoue S., Iba T., Kakihana Y., Kawasaki T., Kushimoto S., Kuroda Y., Kotani J., Shime N., Taniguchi T., Tsuruta R., Doi K., et. al.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.

Mizuno Y., Kagitani-Shimono K., Jung M., Makita K., Takiguchi S., Fujisawa T.X., Tachibana M., Nakanishi M., Mohri I., Taniike M., Tomoda A.

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) share high rates of comorbidity, with the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition now acknowledging the comorbid diagnosis of ASD and ADHD. Although structural abnormalities in the prefrontal cortex, cerebellum, and basal ganglia occur in both ASD and ADHD, no structural studies have focused exclusively on patients with comorbid ASD and ADHD. We thus aimed to clarify the structural features and developmental changes in patients with comorbid ASD and ADHD in a relatively large sample from two sites. Ninety-two patients were age-matched to 141 typically developing (TD) controls (age range: 5–16 years) and assessed for volumetric characteristics using structural magnetic resonance imaging (i.e. surface-based morphometry). While there were no significant differences in prefrontal cortex, cerebellum, and basal ganglia volumes, patients with ASD and ADHD exhibited significantly lower left postcentral gyrus volumes than TD controls. We observed significantly lower postcentral gyrus volumes exclusively in children and preadolescents, and not in adolescents. Our findings suggest that abnormal somatosensory, attributed to delayed maturation of the left postcentral gyrus, leads to the core symptoms experienced by patients with comorbid ASD and ADHD.

Egi M., Ogura H., Yatabe T., Atagi K., Inoue S., Iba T., Kakihana Y., Kawasaki T., Kushimoto S., Kuroda Y., Kotani J., Shime N., Taniguchi T., Tsuruta R., Doi K., et. al.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.

Nishitani S., Isozaki M., Yao A., Higashino Y., Yamauchi T., Kidoguchi M., Kawajiri S., Tsunetoshi K., Neish H., Imoto H., Arishima H., Kodera T., Fujisawa T.X., Nomura S., Kikuta K., et. al.

AbstractNeuroepigenetics considers genetic sequences and the interplay with environmental influences to elucidate vulnerability risk for various neurological and psychiatric disorders. However, evaluating DNA methylation of brain tissue is challenging owing to the issue of tissue specificity. Consequently, peripheral surrogate tissues were used, resulting in limited progress compared with other epigenetic studies, such as cancer research. Therefore, we developed databases to establish correlations between the brain and peripheral tissues in the same individuals. Four tissues, resected brain tissue, blood, saliva, and buccal mucosa (buccal), were collected from 19 patients (aged 13–73 years) who underwent neurosurgery. Moreover, their genome-wide DNA methylation was assessed using the Infinium HumanMethylationEPIC BeadChip arrays to determine the cross-tissue correlation of each combination. These correlation analyses were conducted with all methylation sites and with variable CpGs, and with when these were adjusted for cellular proportions. For the averaged data for each CpG across individuals, the saliva–brain correlation (r = 0.90) was higher than that for blood–brain (r = 0.87) and buccal–brain (r = 0.88) comparisons. Among individual CpGs, blood had the highest proportion of CpGs correlated to the brain at nominally significant levels (19.0%), followed by saliva (14.4%) and buccal (9.8%). These results were similar to the previous IMAGE-CpG results; however, cross-database correlations of the correlation coefficients revealed a relatively low (brain vs. blood: r = 0.27, saliva: r = 0.18, and buccal: r = 0.24). To the best of our knowledge, this is the fifth study in the literature initiating the development of databases for correlations between the brain and peripheral tissues in the same individuals. We present the first database developed from an Asian population, specifically Japanese samples (AMAZE-CpG), which would contribute to interpreting individual epigenetic study results from various Asian populations.

Wei A.H., Panayiotidis P., Montesinos P., Laribi K., Ivanov V., Kim I., Novak J., Stevens D.A., Fiedler W., Pagoni M., Bergeron J., Ting S.B., Hou J., Anagnostopoulos A., McDonald A., et. al.

VIALE-C compared the safety and efficacy of venetoclax or placebo plus low-dose cytarabine (+LDAC) in patients with untreated AML ineligible for intensive chemotherapy. Overall, 211 patients were enrolled (n = 143, venetoclax; n = 68, placebo). At the primary analysis, the study did not meet its primary endpoint of a statistically significant improvement in overall survival (OS), however, ~60% of patients had been on study for ≤6-months. Here, we present an additional 6-months of follow-up of VIALE-C (median follow-up 17.5 months; range 0.1–23.5). Median OS was (venetoclax +LDAC vs. placebo +LDAC) 8.4 vs. 4.1 months (HR = 0.70, 95% CI 0.50,0.99; P = 0.040); a 30% reduction in the risk of death with venetoclax. Complete response (CR)/CR with incomplete hematologic recovery (CRi) rates were 48.3% vs. 13.2%. Transfusion independence rates (RBC) were 43% vs.19% and median event-free survival was 4.9 vs. 2.1 months (HR = 0.61; 95% CI 0.44,0.84; P = 0.002). These results represent improved efficacy over the primary analysis. Incidence of grade ≥3 adverse events were similar between study arms and overall safety profiles were comparable to the primary analysis. These data support venetoclax +LDAC as a frontline treatment option for patients with AML ineligible for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352.

Fujioka T., Tsuchiya K.J., Saito M., Hirano Y., Matsuo M., Kikuchi M., Maegaki Y., Choi D., Kato S., Yoshida T., Yoshimura Y., Ooba S., Mizuno Y., Takiguchi S., Matsuzaki H., et. al.

Elucidating developmental changes in the symptoms of autism spectrum disorder (ASD) is important to support individuals with ASD. However, no report has clarified the developmental changes in attention to social information for a broad age range. The aim of this study was to investigate the developmental changes in attention to social information from early childhood to adolescence in individuals with ASD and typically developed (TD) children. We recruited children with ASD (n = 83) and TD participants (n = 307) between 2 and 18 years of age. Using the all-in-one-eye-tracking system, Gazefinder, we measured the percentage fixation time allocated to areas of interest (AoIs) depicted in movies (the eyes and mouth in movies of a human face with/without mouth motion, upright and inverted biological motion in movies showing these stimuli simultaneously, people and geometry in preference paradigm movies showing these stimuli simultaneously, and objects with/without finger-pointing in a movie showing a woman pointing toward an object). We conducted a three-way analysis of variance, 2 (diagnosis: ASD and TD) by 2 (sex: male and female) by 3 (age group: 0–5, 6–11, and 12–18 years) and locally weighted the scatterplot smoothing (LOESS) regression curve on each AoI. In the face stimuli, the percentage fixation time to the eye region for the TD group increased with age, whereas the one for the ASD group did not. In the ASD group, the LOESS curves of the gaze ratios at the eye region increased up to approximately 10 years of age and thereafter tended to decrease. For the percentage fixation time to the people region in the preference paradigm, the ASD group gazed more briefly at people than did the TD group. It is possible that due to the cross-sectional design, the degree of severity and of social interest might have differed according to the subjects’ age. There may be qualitative differences in abnormal eye contact in ASD between individuals in early childhood and those older than 10 years.

Mikami D., Kobayashi M., Uwada J., Yazawa T., Kamiyama K., Nishimori K., Nishikawa Y., Nishikawa S., Yokoi S., Kimura H., Kimura I., Taniguchi T., Iwano M.

Short-chain fatty acids (SCFAs), including acetate, butyrate, and propionate, are produced when colonic bacteria in the human gastrointestinal tract ferment undigested fibers. Free fatty acid receptor 2 (FFA2) and FFA3 are G-protein-coupled receptors recently identified as SCFA receptors that may modulate inflammation. We previously showed through in vitro experiments that SCFAs activate FFA2 and FFA3, thereby mitigating inflammation in human renal cortical epithelial cells. This study used a murine model of adenine-induced renal failure to investigate whether or not SCFAs can prevent the progression of renal damage. We also examined whether or not these FFA2 and FFA3 proteins have some roles in this protective mechanism in vivo. Immunohistochemical analyses of mouse kidneys showed that FFA2 and FFA3 proteins were expressed mainly in the distal renal tubules and collecting tubules. First, we observed that the administration of propionate mitigated the renal dysfunction and pathological deterioration caused by adenine. Consistent with this, the expression of inflammatory cytokines and fibrosis-related genes was reduced. Furthermore, the mitigation of adenine-induced renal damage by the administration of propionate was significantly attenuated in FFA2-/- and FFA3-/- mice. Therefore, the administration of propionate significantly protects against adenine-induced renal failure, at least in part, via the FFA2 and FFA3 pathways. Our data suggest that FFA2 and FFA3 are potential new therapeutic targets for preventing or delaying the progression of chronic kidney disease.

Suzuki S., Fujisawa T.X., Sakakibara N., Fujioka T., Takiguchi S., Tomoda A.

Child maltreatment (CM) is a major risk factor for various psychopathologies but also adversely affects social development. Research on oxytocin (OT) is currently drawing attention as an endocrine basis for social development. In this study, we investigated the relationship between visual attention to social cues and salivary OT levels in children exposed to CM. The results revealed that the CM group had a significantly lower percentage of gaze fixation for the human face eye area and lower salivary OT levels compared to the typical development group. Moreover, a path analysis suggested that gaze fixation for the eye area was a mediator of the relationship between salivary OT levels and social-emotional problems in the CM group. These results suggest that lower endogenous OT levels in maltreated children may lead to atypical development of their visual attention to eyes as a social cue, resulting in social-emotional problems.

Takahashi A., Naruse H., Kitade I., Shimada S., Tsubokawa M., Kokubo Y., Matsumine A.

Osteoporotic hip fracture is a major public health issue. Estimation of the outcome and maximization of functional recovery after fracture is very important in the treatment of older patients. The purposes of this study were to clarify the functional outcomes after the treatment of hip fracture and to identify the factors that influence functional recovery. In the present study, 228 patients admitted to an acute-care hospital from January 2016 to June 2018 were evaluated. The patients were categorized into a trochanteric fracture group (n = 128) and a neck fracture group (n = 100). We retrospectively reviewed their ambulation ability 6 months after fracture using the Functional Ambulation Category (FAC) score. The other survey items were the presurgical duration, length of hospital stay, time until beginning to walk using parallel bars, complications affecting treatment, and mortality rate. The 6-month follow-up rate was 54.4% (n = 124). The results showed that the patients with trochanteric fracture were significantly older than those with neck fracture (86 vs. 82 years, respectively; p = 0.03). In total, 85.0% of patients with trochanteric fracture and 92.2% of patients with neck fracture were independent ambulators before injury (FAC score of 4 or 5). The FAC score 6 months after fracture was positively correlated with the FAC score before fracture and at discharge (all p