A pragmatic randomised controlled trial of the effectiveness and cost-effectiveness of Well Parent Japan in routine care in Japan: The training and nurturing support for mothers (TRANSFORM) study.

BACKGROUND: Well Parent Japan (WPJ) is a new hybrid group parent training programme combining sessions to improve mothers' psychological well-being with a culturally adapted version of the New Forest Parenting Programme (NFPP). This study investigates the effectiveness and cost-effectiveness of WPJ against treatment as usual (TAU) within Japanese child mental health services. METHODS: TRANSFORM was a pragmatic multi-site randomised controlled trial (RCT) with two parallel arms. Altogether 124 mothers of 6-12-year-old children with DSM-5 ADHD were randomised to WPJ (n = 65) or TAU (n = 59). Participants were assessed at baseline, post-treatment and three-month follow-up. The primary outcome was parent-domain stress following intervention. Secondary outcomes included maternal reports of child-domain stress, parenting practices, parenting efficacy, mood, family strain, child behaviour and impairment. Objective measures of the parent-child relationship were collected at baseline and post-treatment. Data analysis was intention to treat (ITT) with treatment effects quantified through analysis of covariance (ANCOVA) via multilevel modelling. An incremental cost-effectiveness ratio (ICER) assessed WPJ's cost-effectiveness. RESULTS: WPJ was superior to TAU in reducing parent-domain stress post-treatment (adjusted mean difference = 5.05, 95% CI 0.33 to 9.81, p = .036) and at follow-up (adjusted mean difference 4.82, 95% CI 0.09 to 9.55, p = .046). Significant WPJ intervention effects were also observed for parenting practices, parenting efficacy and family strain. WPJ and TAU were not significantly different post-intervention or at follow-up for the other secondary outcomes. The incremental cost of WPJ was 34,202 JPY (315.81 USD). The probability that WPJ is cost-effective is 74% at 10,000 JPY (USD 108.30) per one-point improvement in parenting stress, 92% at 20,000 JPY (216.60 USD). The programme was delivered with high fidelity and excellent retention. CONCLUSIONS: WPJ can be delivered in routine clinical care at modest cost with positive effects on self-reported well-being of the mothers, parenting practices and family coping. WPJ is a promising addition to psychosocial interventions for ADHD in Japan.

Lateral Mass Intrapedicular Screw Fixation for Subaxial Cervical Spines: A Short- to Medium-Term Retrospective Follow-Up Study of 20 Cases.

BACKGROUND: Lateral mass intrapedicular screw(LMIS) fixation was introduced in 2021 as an alternative method for the fixation of subaxial cervical spines for the treatment of various cervical spine disease. The objective of this study is to provide a short- to medium-term result of the 20 patients who underwent cervical spine fixation using LMIS. METHODS: Twenty patients with varying cervical spine pathology who underwent cervical spine fixation using LMIS in a 21-month period were included in the study. Postoperative computed tomography (CT) imaging was used to evaluate the screw placement. RESULTS: A total of 105 screws were used. The average screw size used was 3.5 × 14 mm. The average screw angle in the axial plane was 18 degrees. Five screws had breached the inner cortex of the vertebral canal. None of the patients had any postsurgical neurologic deficit. Fifteen screws did not reach the pedicle. Intraoperative fixation was excellent and no screw showed signs of loosening in the subsequent follow-up imaging. CONCLUSION: LMIS is a good alternative to the commonly used methods for subaxial cervical spine fixation and is worth considering in many patients.

Enhancing Fingertip Tactile Sensitivity by Vibrotactile Noise and Cooling Skin Temperature Effect.

This article discusses a method to enhance fingertip tactile sensitivity by applying a vibrotactile noise at the wrist. This is an application of stochastic resonance to the field of haptics. We consider that the tactile sensitivity of the fingertip improves when a sufficiently large noise is propagated to it from the wrist. However, fingertip tactile sensitivity decreases when a large noise that humans can perceive is applied to the wrist. Therefore, in this article, we cool the wrist skin to reduce the wrist's tactile sensitivity to noise. This allows us to apply noise that is large, but still imperceptible, at the wrist and thus to propagate it to the fingertip. On the basis of these procedures, we propose a method to enhance fingertip tactile sensitivity. Further, we carry out several experiments and confirm that the proposed method improves fingertip tactile sensitivity.

The Effectiveness and Cost-effectiveness of Well Parent Japan for Japanese Mothers of Children With ADHD: Protocol for a Randomized Controlled Trial.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder associated with numerous functional deficits and poor long-term outcomes. Internationally, behavioral interventions are recommended as part of a multimodal treatment approach for children with ADHD. Currently, in Japan, there are limited interventions available to target ADHD. Well Parent Japan (WPJ), a new hybrid parent-training program, provides a culturally acceptable and effective way to help support Japanese children with ADHD and their parents. OBJECTIVE: This pragmatic multicenter randomized controlled trial aims to provide preliminary evidence about the effectiveness and cost-effectiveness of WPJ evaluated against treatment as usual (TAU) within routine Japanese mental health services. METHODS: Mothers of children (aged 6-12 years) diagnosed with ADHD were recruited from child and adolescent mental health care services at three hospital sites across Japan (Fukui, Fukuoka, and Okinawa). The mothers were randomized to receive immediate treatment or TAU. The effectiveness and cost-effectiveness of WPJ over TAU at the end of the intervention and at 3-month follow-up will be evaluated. The primary outcome is maternal parent domain stress in the parenting role. The following secondary outcomes will be explored: child behavior, including severity of ADHD symptoms; parenting practices; emotional well-being; and the parent-child relationship and maternal child domain parenting stress. Data analysis will follow intention-to-treat principles with treatment effects quantified through analysis of covariance using multilevel modeling. An incremental cost-effectiveness ratio will be used to analyze the cost-effectiveness of the WPJ intervention. RESULTS: Study funding was secured through a proof-of-concept grant in July 2018. Approval by the institutional review board for the data collection sites was obtained between 2017 and 2019. Data collection began in August 2019 and was completed in April 2022. Participant recruitment (N=124) was completed in May 2021. Effectiveness and cost-effectiveness analyses are expected to be completed by July 2022 and December 2022, respectively. These timelines are subject to change owing to the COVID-19 pandemic. CONCLUSIONS: This is the first multisite pragmatic trial of WPJ based on the recruitment of children referred directly to routine clinical services in Japan. This multisite randomized trial tests the effectiveness of WPJ in children and families by comparing WPJ directly with the usual clinical care offered for children diagnosed with ADHD in Japan. We also seek to assess and compare the cost-effectiveness of WPJ with TAU in Japan. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number ISRCTN66978270; https://www.isrctn.com/ISRCTN66978270. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/32693.

Lateral mass intra-pedicular screw fixation for subaxial cervical spines - An alternative surgical technique.

BACKGROUND: Lateral mass screw (LMS) and transpedicular screw (TPS) techniques are the two major options for performing posterior cervical fusion of the subaxial cervical spine. Although these two techniques can cover the vast majority of patients who require posterior fixation of the cervical spine, they are not without their limitations. OBJECTIVE: The objective of this study is to introduce a novel technique, lateral mass intrapedicular screw (LMIS) fixation, for posterior subaxial cervical spine (C3-C6) fixation. MATERIALS AND METHODS: The starting point of the screw is defined as the midpoint of the lateral mass. In the axial plane, the screw is angled at 20-25 with respect to the midline of the spinous process. In the sagittal plane, the screw is directed toward the rostral quarter (zone 1) of the vertebral body and placed within the pedicle. A preliminary, proof-of-concept experiment was performed using a bone model created with synthetic bone and computed tomography images before performing the operation on a patient. RESULTS: During the preliminary experiment, insignificant breaching of the inner cortex of the pedicle was observed with one of the screws. However, no other screws breached the inner cortex in the same manner during the preliminary experiment or during the operation, and the intraoperative fixation was strong. CONCLUSION: LMIS is a relatively simple and safe technique that can be performed for the fixation of subaxial cervical spines with screws that are longer than those used in LMS. We believe that this technique may join the two existing techniques to become a common alternative technique, particularly for patients with poor bone quality.

[A Case of a Massive Retropharyngeal Hematoma Associated with Traumatic Cervical Cord Injury].

Retropharyngeal hematomas are uncommon, but they may rarely cause occlusion of the upper airway and threaten life. Retropharyngeal hematomas often occur due to head or neck injury;they rarely occur due to iatrogenic causes such as insertion of a gastric tube or anticoagulant therapy. It has been found that patients receiving anticoagulant therapy are more likely to experience potentially severe retropharyngeal hematomas. We report the case of a patient with retropharyngeal hematoma with cervical cord damage. A 75-year-old man was transferred to our hospital after he sustained a fall and damaged his face. CT showed a massive retropharyngeal hematoma, but he did not complain of any breathing issues. Therefore, we selected conservative therapy. However, after approximately 4 hours, he suddenly complained of breathing problems and suffered from loss of consciousness. We performed intubation and provided sedation. After one week, his condition clearly improved and he was extubated.

Relationship between changes in the 7-day urticaria activity score after treatment with omalizumab and the responsiveness of basophils to FcεRI stimulation in patients with chronic spontaneous urticaria.

BACKGROUND: About one-half of all patients with chronic spontaneous urticaria have low or less reactivity of the basophils to FcεRI stimulation. However, the differences in the clinical characteristics between patients who show normal and attenuated basophil reactivities to FcεRI stimulation are still unclear. Furthermore, it also remains unknown as to what factors induce the poor reactivity of basophils to FcεRI stimulation. OBJECTIVE: The aim of the study is to investigate the differences in the clinical characteristics between patients who show normal and attenuated basophil reactivities to FcεRI stimulation. METHODS: We compared the clinical characteristics, including the autologous serum skin test-positive rates, serum concentrations of anti-IgE and anti-FcεRIα autoantibodies, and the FcεRI-crosslinking ability of these autoantibodies between patients with a negative basophil activation test (BAT) (≤10% CD203chigh basophils, n = 9) and positive BAT (>10% CD203chigh basophils, n = 13). We also monitored the changes in the 7-day urticaria activity scores after treatment with omalizumab, as compared to the score at the baseline, between the BAT-positive and BAT-negative patients. RESULTS: The BAT-negative patients showed a significantly higher urticaria control test score than the BAT-positive patients (p = 0.01). There were no significant differences in the autologous serum skin test-positive rates, concentrations of anti-IgE and anti-FcεRIα autoantibodies, and the FcεRI-crosslinking ability of these autoantibodies between the 2 groups. After treatment with omalizumab for 35 days, the score decreased to under 15 (corresponding to controlled or mild chronic spontaneous urticaria) in all of the BAT-negative patients, whereas in 6 out of the 13 BAT-positive patients, the scores remained over 16 (corresponding to moderate or severe chronic spontaneous urticaria). CONCLUSIONS: The weak reactivity of basophils to FcεRI stimulation may not be due to the desensitization of basophils by anti-IgE or anti-FcεRIα autoantibodies. The time to response to omalizumab might differ between BAT-negative and BAT-positive patients with chronic spontaneous urticaria.

Differentiation between control subjects and patients with chronic spontaneous urticaria based on the ability of anti-IgE autoantibodies (AAbs) to induce FcεRI crosslinking, as compared to anti-FcεRIα AAbs.

BACKGROUND: The reported prevalences of IgG autoantibodies (AAbs) to FcεRIα and IgE in sera from patients with chronic spontaneous urticaria (CSU) have varied, and these AAbs are also often observed in healthy control subjects. Regarding the histamine release activity of purified IgG from patients with CSU, the number of examined patients has been small. Thus, we sought to determine the prevalence and FcεRI crosslinking ability of these AAbs in a large number of patients with CSU and non-atopic control (NC) subjects. METHODS: We compared the concentrations of anti-IgE and anti-FcεRIα AAbs and the abilities of these AAbs to cause FcεRI aggregation in patients with CSU (n = 134) and NC subjects (n = 55) using ELISA and an in vitro elicitation test, respectively. RESULTS: The concentration of anti-IgE AAbs was significantly different between the NC subjects and the CSU patients (P < 0.0001, cutoff value: 0.558 µg/mL), whereas the concentration of anti-FcεRIα AAbs was not. A significant difference in the duration of illness was noted between patients with lower and those with higher concentrations of anti-IgE AAbs relative to the cutoff value. The abilities of anti-IgE AAbs, but not anti-FcεRIα AAbs, to induce FcεRI crosslinking were significantly higher in CSU patients than in NC subjects (P = 0.0106). CONCLUSIONS: In the Japanese population of CSU patients studied, the ability of the anti-IgE AAbs to induce FcεRI crosslinking differed significantly between NC subjects and CSU patients, suggesting the involvement of anti-IgE AAbs in the pathogenesis of CSU in the Japanese population.

Intra-articular Retention and Anti-arthritic Effects in Collagen-Induced Arthritis Model Mice by Injectable Small Interfering RNA Containing Hydrogel.

Small interfering RNAs (siRNAs) are expected to offer a means of treating rheumatoid arthritis (RA) because they allow the specific silencing of genes related to RA pathogenesis. In our previous study, we reported that the siRNA targeted against RelA (anti-RelA siRNA), an important nuclear factor-kappaB (NF-κB) subdomain, was an effective therapeutic in atopic dermatitis and RA model animals. In this study, to develop an intra-articular injectable gel formulation against RA, we prepared a hydrogel that contains anti-RelA siRNA, and determined the in vitro release profile (%) and in vivo intra-articular retention of fluorescence-labeled model siRNA, and the anti-arthritic effects of the anti-RelA siRelA containing hydrogel in RA model mice. We selected the silk protein, sericin (SC), as an aqueous gel base, as it is a biocompatible and useful for forming hydrogels without a cross-linker. We showed that fluorescence-labeled model siRNA was continuously released from SC hydrogel in vitro, and retained in the knee joint of rats after injection of siRNA hydrogel. In addition, the knee joint thickness, clinical severity and incidence (%) in collagen-induced arthritis (CIA) mice as RA model treated with anti-RelA siRNA containing hydrogel were more improved than untreated, anti-RelA siRNA solution and negative control siRNA containing hydrogel group. Therefore, the intra-articular injectable sericin hydrogel formulation containing of anti-RelA siRNA could be a great potential therapeutic in rheumatoid arthritis.

Regulation of mitosis-meiosis transition by the ubiquitin ligase ß-TrCP in male germ cells.

The mitosis-meiosis transition is essential for spermatogenesis. Specific and timely downregulation of the transcription factor DMRT1, and consequent induction of Stra8 expression, is required for this process in mammals, but the molecular mechanism has remained unclear. Here, we show that ß-TrCP, the substrate recognition component of an E3 ubiquitin ligase complex, targets DMRT1 for degradation and thereby controls the mitosis-meiosis transition in mouse male germ cells. Conditional inactivation of ß-TrCP2 in male germ cells of ß-TrCP1 knockout mice resulted in sterility due to a lack of mature sperm. The ß-TrCP-deficient male germ cells did not enter meiosis, but instead underwent apoptosis. The induction of Stra8 expression was also attenuated in association with the accumulation of DMRT1 at the Stra8 promoter in ß-TrCP-deficient testes. DMRT1 contains a consensus ß-TrCP degron sequence that was found to bind ß-TrCP. Overexpression of ß-TrCP induced the ubiquitylation and degradation of DMRT1. Heterozygous deletion of Dmrt1 in ß-TrCP-deficient spermatogonia increased meiotic cells with a concomitant reduction of apoptosis. Collectively, our data indicate that ß-TrCP regulates the transition from mitosis to meiosis in male germ cells by targeting DMRT1 for degradation.

Task-Space Synchronization of Networked Mechanical Systems With Uncertain Parameters and Communication Delays.

This paper addresses the adaptive synchronization problem of networked mechanical systems in task space with time-varying communication delays, where both kinematic and dynamic uncertainties are considered and the information flow in the networks is represented by a directed graph. Based on a novel coordination auxiliary system, we first extend existing feedback architecture to achieve synchronization of networked mechanical systems in task space with slow-varying delays. Given that abrupt turns arise for the delays sometimes, we then propose a delay-independent adaptive synchronization control scheme which removes the requirement of the slow-varying condition. Both of the two control schemes are established with time-domain approaches by using Lyapunov-Krasovskii functions. Simulation results are provided to demonstrate the effectiveness of the proposed control schemes.

Systemic delivery of small interfering RNA targeting nuclear factor κB in mice with collagen-induced arthritis using arginine-histidine-cysteine based oligopeptide-modified polymer nanomicelles.

This study aimed to build an innovative system to deliver a systemic small interfering RNA (siRNA) treatment for rheumatoid arthritis. We combined arginine-histidine-cysteine based oligopeptide-modified polymer micelles with siRNA targeting the nuclear factor κB subunit, RelA (siRelA). This is a key molecule in the control of inflammation. We tested the cellular uptake of siRNA and its effects on inflammatory cytokine levels in vitro using synoviocytes, and siRNA distribution and therapeutic effects in vivo in mice with collagen-induced arthritis (CIA). These studies showed that arginine-histidine based oligopeptide modified micelles produced effective cellular siRNA uptake and suppressed inflammatory cytokine levels in synoviocytes. In vivo, these micelles produced marked accumulation of siRNAs in arthritic paws in CIA mice, with much less accumulation in healthy mice. The siRelA-polymer micelle complexes also produced more effective suppression of RelA mRNA expression and inflammatory cytokine levels in the arthritic paws of CIA mice and reduced their clinical symptom scores and paw thickness.

Functional peptide nanocarriers for delivery of novel anti-RelA RNA interference agents as a topical treatment of atopic dermatitis.

Small interfering RNAs (siRNAs) are a potential treatment of atopic dermatitis (AD) because they can specifically silence the gene expression of AD-related factors. However, siRNA alone cannot exert a sufficiently strong therapeutic effect due to low delivery efficiency to the target tissues and cells; simply increasing the amount used is not possible due to the possibility of off-target effects. We previously reported a novel class of therapeutic RNA interference (RNAi) agents called nkRNA(®) and PnkRNA(®), which have been shown to be effective in several disease models, have greater resistance to nuclease degradation than canonical siRNAs, and do not induce any immunotoxicity. In the present study, we describe a non-invasive and effective transdermal RNAi therapeutic system for atopic dermatitis that uses the functional cell-penetrating stearoyl-oligopeptide OK-102 as a cytoplasm-responsive nanocarrier for nkRNA(®) and PnkRNA(®). The two RNAi agents were targeted against RelA, a subclass of NF-κB (nuclear factor kappa B), and, as part of OK-102 complexes, they strongly silenced RelA mRNA in macrophage cells and demonstrated a significant therapeutic effect in a mouse model of AD. It was shown that OK-102-complexed RNAi agents were an efficient therapeutic system for AD and caused no adverse reactions.

Reversible ion transportation switch by a ligand-gated synthetic supramolecular ion channel.

Inspired by the regulation of cellular activities found in the ion channel proteins, here we developed membrane-embedded synthetic chiral receptors 1 and 2 with different terminal structures, where receptor 1 has hydrophobic triisopropylsilyl (TIPS) groups and receptor 2 has hydrophilic hydroxy groups. The receptors have ligand-binding units that interact with cationic amphiphiles such as 2-phenethylamine (PA). Conductance study revealed that the receptors hardly show ion transportation at the ligand-free state. After ligand binding involving a conformational change, receptor 1 bearing TIPS termini displays a significant current enhancement due to ion transportation. The current substantially diminishes upon addition of ß-cyclodextrin (ßCD) that scavenges the ligand from the receptor. Importantly, the receptor again turns into the conductive state by the second addition of PA, and the activation/deactivation of the ion transportation can be repeated. In contrast, receptor 2 bearing the hydroxy terminal groups hardly exhibits ion transportation, suggesting the importance of terminal TIPS groups of 1 that likely anchor the receptor in the membrane.

Acute exacerbation of idiopathic pulmonary fibrosis: high-resolution CT scores predict mortality.

OBJECTIVES: To determine high-resolution computed tomography (HRCT) findings helpful in predicting mortality in patients with acute exacerbation of idiopathic pulmonary fibrosis (AEx-IPF). METHODS: Sixty patients with diagnosis of AEx-IPF were reviewed retrospectively. Two groups (two observers each) independently evaluated pattern, distribution, and extent of HRCT findings at presentation and calculated an HRCT score at AEx based on normal attenuation areas and extent of abnormalities, such as areas of ground-glass attenuation and/or consolidation with or without traction bronchiectasis or bronchiolectasis and areas of honeycombing. The correlation between the clinical data including the HRCT score and mortality (cause-specific survival) was evaluated using the univariate and multivariate Cox-regression analyses. RESULTS: Serum KL-6 level, PaCO(2), and the HRCT score were statistically significant predictors on univariate analysis. Multivariate analysis revealed that the HRCT score was an independently significant predictor of outcome (hazard ratio, 1.13; 95% confidence interval, 1.06-1.19, P = 0.0002). The area under receiver operating characteristics curve for the HRCT score was statistically significant in the classification of survivors or nonsurvivors (0.944; P < 0.0001). Survival in patients with HRCT score ≥245 was worse than those with lower score (log-rank test, P < 0.0001). CONCLUSION: The HRCT score at AEx is independently related to prognosis in patients with AEx-IPF.

Operative management of skull base malignant tumors arising from the nasal cavity and paranasal sinus: recent strategies used in 25 cases.

Cancers of the paranasal sinuses and nasal cavity are the most common malignant tumors of the anterior and anterolateral skull base. The treatment of these tumors affecting the skull base is complex due to the significant anatomical features. We examined 25 patients, 17 males and 8 females with mean age 61 +/- 2 years. En bloc resections using anterior skull base resection, orbital resection, middle fossa resection, and combined procedures of these three resections were performed. Using a combination of adjuvant radiation and chemotherapy, we have achieved a 2-year disease-free survival rate of 90% in these cases. However, potential complications include cerebrospinal fluid leakage, meningitis, abscess formation, pneumocephalus, frontal brain contusion, trismus, and dysphagia as a functional complication. We believe that the optimal management of such malignant tumors involves a multimodal and multidisciplinary team approach. Here we present our recent institutional experience and treatment policy employed during the past 3 years.

[Trends in antibiotic susceptibility and genetic beta-lactam resistance patterns among Haemophilus influenzae cases isolated from adult patients with respiratory tract infection].

Haemophilus influenzae, a major respiratory tract pathogen, is becoming increasingly resistant to beta-lactam antibiotics. Studying annual trends in antibiotic susceptibility and genetic patterns of H. influenzae beta-lactam resistance, we isolated 122 strains from the adult respiratory tract in 2007, determined MIC for different antibiotics, and analyzed TEM-1 beta-lactamase resistant genes and ftsI encoding PBP3 mutation compared to results in 2005 and 2007. We found that ABPC-susceptible strains with MIC <1 microg/mL (BLNAS) accounted for 71.0%, ABPC-resistant strains with MIC exceeding 2 microg/mL without beta-lactamase activity (BLNAR) for 25.3%, and beta-lactamase-positive strains (BLP) for 3.7%. The BLNAS ratio showed no significant change from 2002 and 2005. The BLP ratio decreased from those in 2002 and 2005. Genetic studies of resistant genes showed that gBLNAS with no resistant genes had increased in the last five years. The ratio of all strains with PBP3 mutation (gBLNAR and gLow-BLNAR) remained constant from 2002 to 2007. The proportion of gBLNAR with two PBP3 mutations had increased, however, while gLow-BLNAR with one mutation had decreased. LVFX showed constant strong antimicrobial potency for all mutation groups. Among beta-lactam antibiotics, the lowest MIC90 was observed in parenteral CTRX and oral CDTR-PI use. Although a new MIC peak generated by gBLNAR became obvious in the ABPC and CDTR-PI MIC distribution, the MIC of the new peak was still low enough to treat with high doses of those two antibiotics.