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Abstract Dexamethasone is an antiemetic drug widely used to prevent nausea and vomiting caused by anticancer drugs. However, dexamethasone can cause several side effects even after short-term administration. Therefore, the development of dexamethasone-free antiemetic therapies has been recognized as an important challenge. The objective of this study was to investigate the efficacy and safety of palonosetron, aprepitant, and olanzapine. Patients who were chemotherapy-naïve and scheduled to receive highly emetogenic chemotherapy for breast cancer were enrolled and assessed for nausea and vomiting occurring within 120 h after the start of chemotherapy. The primary endpoint was the total control (TC) rate of overall phases. Secondary endpoints included the complete response (CR) rate, which was evaluated during the acute, delayed, and overall phases. A total of 88 patients were enrolled from eight centers in Japan, of whom 84 were included in the analysis. The proportion of patients achieving TC throughout the overall period was 17.1%. Similarly, CR and CC rates for the overall period were 43.4% and 39.5%, respectively. Frequently reported adverse events were loss of appetite and constipation, with rates of 52.4% and 50.0%, respectively. The primary endpoint was not achieved. Therefore, antiemetic therapy without dexamethasone shows an inadequate effect on nausea, and it is generally advisable to avoid omitting dexamethasone. However, in the overall period, both CR and CC were comparable to conventional three-drug combination therapy. Thus, in patients unable to use dexamethasone, replacing it with olanzapine could be an option. Trial registration number: UMIN 000038644, November 20, 2019. The date of first trial registration: 13/03/2020.

Abstract Aims/Introduction Severe diabetic macular edema (DME) is often resistant to anti‐vascular endothelial growth factor therapy. Steroids are particularly effective at reducing edema by suppressing inflammation; they are also used as an alternative to expensive anti‐vascular endothelial growth factor therapy in some patients. Therefore, the use of steroids in DME reflects an unmet need for anti‐vascular endothelial growth factor therapy. Notably, triamcinolone acetonide (TA) injections are widely used in Japan. Here, we evaluated the frequency of TA as an indicator of the efficacy of sodium–glucose cotransporter 2 inhibitors (SGLT2is) in DME treatment using a health insurance claims database. Materials and Methods In this cohort study, we retrospectively analyzed the health insurance claims data of 11 million Japanese individuals from 2005 to 2019. The frequency and duration of TA injection after the initiation of SGLT2is or other antidiabetic drugs were analyzed. Results Among the 2,412 matched patients with DME, the incidence rate of TA injection was 63.8 times per 1,000 person‐years in SGLT2i users and 94.9 times per 1,000 person‐years in non‐users. SGLT2is reduced the risk for the first (P = 0.0024, hazard ratio 0.66, 95% confidence interval 0.50–0.87), second (P = 0.0019, hazard ratio 0.53, 95% confidence interval 0.35–0.80) and third TA (P = 0.0053, hazard ratio 0.44, 95% confidence interval 0.25–0.80) injections. A subanalysis of each baseline characteristic of the patients showed that SGLT2is were effective regardless of the background factors. Conclusions The use of SGLT2is reduced the frequency of TA injection in patients with DME. Therefore, SGLT2i therapy might be a novel, noninvasive and low‐cost adjunctive therapy for DME.

BackgroundThe rise in internet addiction, including web-based gaming and social networking services, is a serious concern. Even with access to medical institutions and counseling services, individuals with internet addiction, particularly adolescents, often refuse medical treatment or counseling. Parent-focused psychological intervention may lead to positive outcomes by improving the parent-adolescent relationship and helping parents identify and modify their adolescent’s problematic behaviors, including internet addiction. ObjectiveThis study was a pilot randomized controlled trial to test the feasibility of remote cognitive behavioral therapy via videoconferencing for parents of adolescents with internet addiction. MethodsA total of 13 parents of adolescents aged 12-20 years with internet addiction were recruited and randomly assigned to either 12 sessions of the videoconference-delivered cognitive behavioral therapy (vCBT) group (n=6, 46%) or the waitlist control group (n=7, 54%). The study period was from March 1, 2018, to March 31, 2022. The primary outcome was the scores of the Young Internet Addiction Test reported by the adolescents. The secondary outcomes were adolescents’ hours of internet use per day (Internet Addiction Test), reported by the adolescents and by their parents; the Young Diagnostic Questionnaire, completed by the parents; and the quality of life of the adolescents and the parents, measured by the EQ-5D-5L. These were evaluated at weeks 0 and 13. ResultsAs the primary outcome, the mean total Internet Addiction Test score decreased from 67.7 (SD 18.3; 6/13, 46%) at week 0 to 56.2 (SD 25.1; 5/9, 56%) at week 13 in the vCBT group, compared to an increase from 66.9 (SD 21.9; 7/13, 54%) to 68.0 (SD 18.7; 4/9, 44%) in the control group. For all outcomes, no significant differences were found between the 2 groups (all P>.05). ConclusionsThis study suggested the practical feasibility of vCBT for parents of adolescents with internet addiction. Further large-scale, multicenter randomized controlled trials are necessary to examine the effectiveness. Trial RegistrationUMIN Clinical Trials Registry UMIN000032483; https://tinyurl.com/yuhen6c9

ABSTRACTThe selection of the sowing date is one of the most important decisions in soybean production. It is important for farmers to know the expected seed yield when developing a sowing plan. The objective of this study was to quantitatively reveal the decreased seed yield ratio during late sowing in southwestern Japan under irrigated conditions. Total above ground dry matter and distribution were measured from July to August sowing in 2018 and 2019 in Fukuyama, Hiroshima, Japan. The harvest index in the August sowing did not decrease compared to the July sowing under irrigated conditions. The decrease in yield was related to the total aboveground dry matter rather than to the harvest index. The decrease in total aboveground dry matter was related to the total amount of solar radiation intercepted rather than to radiation use efficiency. A significant regression equation was obtained for the relative yield, which was calculated from the maximum seed yield observed from early to mid-July. When seeds were sown after mid-July, our result showed that the seed yield will decrease by 0.60% per day for Sachiyutaka A1 and by 0.64% for Akimaro, even under conditions of 100% seedling establishment and controlled soil water conditions. This regression equation can be used in fields as an indicator of seed yield where irrigation is possible.

Abstract Background Individuals on the preclinical Alzheimer's continuum, particularly those with both amyloid and tau positivity (A + T +), display a rapid cognitive decline and elevated disease progression risk. However, limited studies exist on brain atrophy trajectories within this continuum over extended periods. Methods This study involved 367 ADNI participants grouped based on combinations of amyloid and tau statuses determined through cerebrospinal fluid tests. Using longitudinal MRI scans, brain atrophy was determined according to the whole brain, lateral ventricle, and hippocampal volumes and cortical thickness in AD-signature regions. Cognitive performance was evaluated with the Preclinical Alzheimer's Cognitive Composite (PACC). A generalized linear mixed-effects model was used to examine group × time interactions for these measures. In addition, progression risks to mild cognitive impairment (MCI) or dementia were compared among the groups using Cox proportional hazards models. Results A total of 367 participants (48 A + T + , 86 A + T − , 63 A − T + , and 170 A − T − ; mean age 73.8 years, mean follow-up 5.1 years, and 47.4% men) were included. For the lateral ventricle and PACC score, the A + T − and A + T + groups demonstrated statistically significantly greater volume expansion and cognitive decline over time than the A − T − group (lateral ventricle: β = 0.757 cm3/year [95% confidence interval 0.463 to 1.050], P

Introduction: Low-back pain causes sleep disorders, which impairs the quality of life (QOL) of patients. Sleep disorders are associated with lumbar spinal stenosis (LSS); however, the postoperative effects of LSS surgery on sleep disorders are unknown. This study aimed to assess sleep disorders in patients with LSS using wearable activity trackers and determine whether surgery improves sleep quality. Methods: A total of 39 patients scheduled for LSS surgery (mean age 71.1±8.7 years; 22 men and 17 women) were studied. Sleep disorders in the participants were objectively evaluated using a wearable Motionlogger Micro system. Sleep efficiency (SEf), mean active count (MAC), and wake after sleep onset (WASO) were measured before and 6 months following surgery. Furthermore, the patient-based outcomes of pain and QOL-related scores were measured and compared with those of healthy participants. The group with improved SEf following surgery was designated as “nonpoor sleepers,” whereas the group that did not exhibit improvements was designated as “poor sleepers.” The two groups were compared based on patient factors, patient-based questionnaires, and sleep disorder measurements. Results: The SEf and WASO were significantly worse in patients with LSS compared with healthy participants (P

Abstract Background No effective treatment for NAION with strong evidence has been established till date. The aim of this investigator-led, prospective, non-randomized, open-label, uncontrolled multi-center exploratory clinical trial is to evaluate the efficacy and safety of transdermal electrical stimulation (TdES) using skin electrodes in patients with NAION. Methods Five patients with monocular NAION underwent TdES (10-ms biphasic pulses, 1.0 mA, 20 Hz, 30 min) of the affected eye six times at 2-week intervals. The primary endpoint was the logarithm of the mini-mum angle of resolution (logMAR) visual acuity at 12 weeks compared with 0 weeks. The secondary endpoints were changes in the best-corrected logMAR visual acuity, Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity, and mean deviation (MD) of the Humphrey field analyzer (HFA) 10–2 and HFA Esterman test scores. Additionally, the safety of TdES was evaluated. Results LogMAR visual acuity improved by ≥ 0.1 in two eyes, and ETDRS visual acu-ity improved by ≥ 5 characters in one eye. The mean change in logMAR visual acuity from week 0 showed an increasing trend. The mean MD of HFA 10–2 showed no obvious change, while HFA Esterman score improved in four eyes. All patients completed the study according to the protocol, and no treatment-related adverse events were observed. Conclusions TdES treatment may have improved visual acuity and visual field in some patients. Further sham-controlled study in larger cohort is needed on its effectiveness. Trial registration UMIN, UMIN000036220. Registered 15 March, 2019, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000041261 .

Introduction: We investigated the effect of preoperative joint position sense in the big toe on the postoperative recovery of gait function after spinal tumor surgery. Methods: Seventy-three patients with spinal tumors who underwent surgery at our hospital between 2014 and 2019 and could be followed for at least 6 months after surgery were included. The patients were divided into the cervical spinal (41 cases) and thoracic spinal (32 cases) groups according to the localization of the tumor. These groups were further classified into an Impaired group (cervical spinal, 34 cases; thoracic spinal, 19 cases) and an Intact group (cervical spinal, 7 cases; thoracic spinal, 13 cases) according to the presence or absence of preoperative joint position sense in the big toe. The amount of change in ambulatory function from the preoperative period to 3 and 6 months postoperatively was compared between the Impaired and Intact groups within each tumor localization category. Results: Impaired preoperative joint position sense in the big toe in patients undergoing thoracic spinal tumor surgery delayed the recovery of gait function in the early postoperative period. Conclusions: In patients with thoracic spinal tumor surgery, the absence of preoperative joint position sense in the big toe delayed the recovery of postoperative gait function.

Abstract Background Autistic people demonstrate focused interests, sensitivity to sensory stimulation, and, compared with the general population, differences in social communication and interaction. We examined whether a combination of the Awareness and Care for My Autistic Traits (ACAT) program and treatment-as-usual is more effective than only treatment-as-usual in increasing the understanding of autistic attributes, reducing treatment stigma, and improving mental health and social adaptation among autistic adolescents and their parents/guardians. Methods Forty-nine adolescents and their parents/guardians were randomly assigned to either a combination of ACAT and treatment-as-usual or only treatment-as-usual. The combined group received six weekly 100-minute ACAT sessions, while the treatment-as-usual group received no additional intervention. The primary outcome was the change in understanding of autistic attributes (Autism Knowledge Quiz-Child), administered from pre- to post-intervention. The secondary outcomes included the change in Autism Knowledge Quiz-Parent, reduced treatment stigma, and improved mental health and social adaptation among autistic adolescents and their parents/guardians. A primary outcome measure scale was scored by assessors who were blind to the group assignment. Results The combined group (both autistic adolescents and their parents/guardians) showed an increase in Autism Knowledge Quiz scores compared to those in the treatment-as-usual group. Autistic adolescents in the combined group also demonstrated a decrease in treatment-related stigma and an improvement in general mental health compared to those in the treatment-as-usual group, while there were no group differences in the change in social adaptation. For parents/guardians, there were no group differences in the change in treatment-related stigma, general mental health, adaptive skills, or attitudes toward their children. Conclusions The ACAT program could be an effective treatment modality to increase the understanding of autistic attributes among both autistic adolescents and their parents/guardians. The ACAT program positively affects self-understanding, reduces treatment stigma, and stabilizes behavioral issues for autistic adolescents as a part of mental health measures, but it does not effectively reduce treatment barriers or improve mental health for parents/guardians. Further research should consider whether additional support for parents/guardians could be beneficial. Trial registration : The study was registered in UMIN (UMIN000029851, 06/01/2018).

Objectives This study documents the time elapsed from the diagnosis of osteonecrosis of the femoral head (ONFH) to surgery, exploring the factors that influence ONFH severity.Design Retrospective observational study of a nationwide database.Setting The Kaplan-Meier method with log-rank tests was applied to examine the period from definitive diagnosis of ONFH to surgery using any surgery as the end point. For bilateral cases, the date of the first surgery was the endpoint.Participants This study included 2074 ONFH cases registered in 34 university hospitals and highly specialised hospitals of the multicentre sentinel monitoring system of the Japanese Investigation Committee between 1997 and 2018.Main outcome measure The primary outcome was the time from diagnosis to surgery. The secondary outcome was the proportion of subjects remaining without surgery at 3, 6 and 9 months, and at 1, 2 and 5 years after diagnosis.Results The median time to surgery was 9 months (IQR 4–22 months) after diagnosis of ONFH. The time to surgery was significantly shorter in the alcohol alone group and the combined corticosteroid and alcohol group than in the corticosteroid alone group (p=0.018 and p

BackgroundCognitive behavioral therapy (CBT) is effective in treating anxiety disorders. Accessibility to CBT has been limited in Japan due to the shortage of therapists. While an open-source e-learning system can be used to create a simple internet-based cognitive behavioral therapy (ICBT) program, the safety and outpatient acceptance of this treatment approach have not been explored in Japan. ObjectiveThe aim of this study was to investigate whether outpatients with anxiety disorders could accept and successfully complete the ICBT program with guidance by CBT therapists when implementing therapeutic modules and CBT tasks. Due to being in the initial phase of a novel treatment in Japan, this study was intended for verification with a small sample size. MethodsIn total, 6 adults, including 4 male participants and 2 female participants, were enrolled in a single-arm trial. The intervention involved guided ICBT comprising 12 sessions, including CBT text, comprehension confirmation tests, and explanatory videos about cognitive behavioral models, accessible through a website. The therapist guided the participants in accessing the ICBT program and answering their questions using a chat tool. The primary outcome was anxiety severity assessed using the State-Trait Anxiety Inventory-Trait. Secondary outcomes included the Panic Disorder Severity Scale, Liebowitz Social Anxiety Scale (LSAS), Beck Anxiety Inventory (BAI), Patient Health Questionnaire–9, Generalized Anxiety Disorder–7, and Working Alliance Inventory–Short Form (WAI-SF). Statistical analyses were performed using paired 2-tailed t tests to assess the changes in clinical symptoms. The total WAI-SF score at the final session was used to evaluate the therapeutic alliance. For statistical analyses, mean changes for total State-Trait Anxiety Inventory-Trait, BAI, Panic Disorder Severity Scale, LSAS, Patient Health Questionnaire–9, and Generalized Anxiety Disorder–7 scores were analyzed using the paired 2-tailed t test. The 2-sided significance level for hypothesis testing was set at 5%, and 2-sided 95% CIs were calculated. ResultsMost participants diligently engaged with the ICBT program. No adverse events were reported. The mean total scores for the primary outcome decreased by 11.0 (SD 9.6) points (95% CI –22.2 to 0.20; Hedges g=0.95), but it was not statistically significant. The mean total scores for the secondary outcomes that assess clinical symptoms decreased, with a significant reduction observed in the BAI of 15.7 (SD 12.1) points (95% CI –28.4 to –3.0; P=.03; Hedges g=1.24). The mean total scores for PDSS and LSAS decreased significantly, by 12.0 (SD 4.24) points (95% CI –50.1 to 26.1; P=.16; Hedges g=1.79) and 32.4 (SD 11.1) points (95% CI –59.7 to –4.3; P=.04; Hedges g=1.38), respectively. Of the participants, 67% (n=4) showed treatment response, and 50% (n=3) achieved remission after the intervention. The therapeutic alliance, measured using the WAI-SF, was moderate. ConclusionsGuided ICBT may be feasible for the treatment of outpatients with panic disorder and social anxiety disorder in Japan. Trial RegistrationUniversity Hospital Medical Information Network Clinical Trials Registry UMIN0000038118; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000043439

CD98 is a marker of cancer stem cells, and it regulates radiosensitivity in head and neck squamous cell carcinoma (HNSCC). The current study aimed to investigate whether CD98 can be used as a prognostic factor and marker of radioresistance. CD98 immunostaining was performed using biopsy specimens collected from patients diagnosed with HNSCC. The average period of postoperative monitoring was 31.6 months. The treatment options were radiation therapy with either cisplatin or cetuximab, and surgery. The participants were divided into groups of low and high fluorescence intensity. CD98 was an independent prognostic factor of radioresistance. In total, 103 patients were treated with chemoradiotherapy or bioradiotherapy. The overall survival rates of patients receiving chemoradiotherapy or bioradiotherapy were 69.2% in the low group and 36.2% in the high group. The progression-free survival rates were 60.0% and 24.6%, respectively. CD98 expression was considered an independent prognostic factor of overall survival and progression-free survival. In total, 99 patients underwent surgical treatment. The surgery group did not differ according to CD98 expression. Via CD98 immunostaining, sensitivity to radiotherapy can be determined in advance. In HNSCC, knowledge about sensitivity to radiotherapy can significantly improve prognosis.

Abstract Background This study aimed to clarify the clinical outcomes of surgical treatment for end-stage ankle osteoarthritis in patients aged ≥ 75 years and compare these outcomes with those of patients aged

Cancer stem cells (CSCs) are proposed to be involved in tumor initiation and play important roles in cancer relapse, metastasis, and drug resistance. Therefore, the targeting of CSCs has potential for effective anticancer therapies. Curcumin is one of the most widely characterized phytochemicals with tumor‐suppressive potential. GO‐Y030 is a novel curcumin analogue exhibiting a much stronger growth‐inhibitory effect than curcumin. In the present study, we verified the potency of GO‐Y030 against a CSC population. We observed that GO‐Y030 suppressed CSC sphere‐forming ability in several cancer cell lines. Interestingly, a specific inhibitor of heat shock protein (HSP) 70 also exhibited effects similar to GO‐Y030 (i.e. inhibition of CSC sphere formation and upregulation of HSP70 and HSP40 protein expression), suggesting that HSP70 and/or HSP40 might be target molecules of GO‐Y030. We then performed an in vitro HSP70/HSP40‐mediated refolding activity assay and observed that chaperone activity was efficiently inhibited by GO‐Y030. Finally, we performed a substrate‐binding assay to show that GO‐Y030 reduced the binding of both HSP70 and HSP40 with their substrates. HSPs prevent denaturation or unfolding of client proteins under stressful conditions such as high temperature. Because CSCs by nature adapt to various stresses by reinforcing protein‐folding activity, the function of HSP70/HSP40 is important for the maintenance of CSC population. Our data suggest that GO‐Y030 may impair stress tolerance in CSCs by inhibiting the interaction of HSP70/HSP40 with their substrate proteins and disrupting the function of HSP70/HSP40, thereby contributing to a reduction of the CSC population.

Abstract Background Nutritional support influences the growth and development of late preterm infants (LPIs) and their long-term health status. However, healthy LPIs have a shorter hospital stay and may not receive adequate care after discharge. In this study, we developed and evaluated the effectiveness of an educational program for nurses and midwives to enable them to support breastfeeding of healthy LPIs. Methods A randomized controlled trial was conducted in Japan from July 2018 to April 2019. The participant pool consisted of nurses and midwives working at midwiferies and obstetric centers in Tokyo, Japan. A total of 395 candidates were recruited for participation across 79 facilities. The final participants were assigned to two groups: the breastfeeding support for LPIs program (BSLPI group; n = 36) or the non-technical skills program (NTS group; n = 33). The measures included the Self-Efficacy of Breastfeeding Support scale (SBS), the Social Skills in Nursing Interactions with Mothers (SS) scale, and the Knowledge and Skills Necessary for Breastfeeding Support for LPIs test (K-S). Scores for each measure were collected before, after, and one-month after the intervention. Repeated-measures ANOVA was used to identify differences (main effects) according to program (BSLPI and NTS) and time (before, immediately after, and one month after intervention). Results All 69 participants attended the program. Main effects of the program were observed only for K-S scores (F[1,58] = 78.57, p = 0.01). No significant differences were found for SBS (F[1,58] = 0.63, p = 0.43) or SS scores (F[1,58] = 1.51, p = 0.23). Conclusions Participation in the BSLPI was related to improved breastfeeding support knowledge and skills but was not related to improvements in nurses’ self-efficacy or social skills. Trial registration Registered 12 December 2018, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000040145 (UMIN: UMIN000035227).

Abstract Green stem disorder (GSD) of soybean is characterized by delayed leaf and stem maturation despite normal pod maturation. Previous studies have suggested that GSD occurrence is promoted by a high source–sink ratio, which is produced by thinning or shade removal at the R5 growth stage (the beginning of seed filling). Here the effects of different times and durations of shade removal after the R5 stage on GSD severity were analyzed. First, shade removal for more than 28 days after R5 increased GSD severity by more than 0.4 point in GSD score. Thinning treatment at R5 increased specific leaf weight by 23%, suppressed stem dry weight reduction, and upregulated 19 genes including those encoding vegetative storage proteins at R5 + 28d, indicating excess source ability relative to sink size. On the contrary, shade removal for 14 days after R5 decreased GSD severity by 0.5 point in GSD score. In this treatment, seed size was smaller, while seed number was significantly larger than control, suggesting that shortage of source ability relative to sink size. These results implied that soybean plants regulate GSD occurrences either positively or negatively according to a source-sink ratio during the R5 to R5 + 28d growth stages.

Abstract To compare the efficacy and safety of intravitreal aflibercept with three loading doses + pro re nata regimen combined with subthreshold laser application to that of IVA monotherapy on eyes with diabetic macular edema. This was a phase 4 clinical trial with a prospective, randomized, and parallel investigator-driven protocol. Patients with DME were randomly assigned to the IVA monotherapy group (n = 25) or the IVA + SL combination therapy group (n = 26). The main outcome measures were the number of IVA injections and the changes in the best-corrected visual acuity (BCVA) and the central retinal thickness (CRT) at the final evaluation at 96 weeks. The mean number of IVA injections in the monotherapy group was 5.86 ± 2.43 and it was 6.05 ± 2.73 in the IVA + SL group at 96 weeks, and this difference was not significant (P = 0.83). The differences in the mean changes of the CRT (P = 0.17) and the BCVA (P = 0.31) were also not significant between the two groups throughout the follow-up period. We conclude that adjunct of SL to anti-VEGF therapy does not reduce the number of necessary intravitreal injections.

Abstract Background The development of computer-assisted technologies to diagnose anterior cruciate ligament (ACL) injury by analyzing knee magnetic resonance images (MRI) would be beneficial, and convolutional neural network (CNN)-based deep learning approaches may offer a solution. This study aimed to evaluate the accuracy of a CNN system in diagnosing ACL ruptures by a single slice from a knee MRI and to compare the results with that of experienced human readers. Methods One hundred sagittal MR images from patients with and without ACL injuries, confirmed by arthroscopy, were cropped and used for the CNN training. The final decision by the CNN for intact or torn ACL was based on the probability of ACL tear on a single MRI slice. Twelve board-certified physicians reviewed the same images used by CNN. Results The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of the CNN classification was 91.0%, 86.0%, 88.5%, 87.0%, and 91.0%, respectively. The overall values of the physicians’ readings were similar, but the specificity was lower than the CNN classification for some of the physicians, thus resulting in lower accuracy for the human readers. Conclusions The trained CNN automatically detected the ACL tears with acceptable accuracy comparable to that of human readers.

Abstract Background Monoiodoacetate (MIA)-induced arthritis models are used widely in osteoarthritis (OA) research to develop effective conservative treatments for hip OA, as an alternative to joint replacement surgery. In joint OA models, such as the MIA-induced knee OA model, various doses of MIA are utilized, depending on the purpose of the research. So far, only 2 mg of MIA has been used for MIA-induced hip OA research. We hypothesized that the amount of MIA should be adjusted according to the osteoarthritis model under investigation. We performed radiographic and histological evaluations in rats for hip OA models induced by different doses of MIA. Methods One hundred and eighty right hips of six-week-old, male Sprague–Dawley rats (n = 30 rats per group) were treated with either a single intra-articular injection of various doses of MIA (0.25, 0.5, 1.0, 2.0, and 4.0 mg) dissolved in 25 μl of sterile saline (MIA group), or with 25 μl of sterile saline alone (Sham group). Radiographic and histological evaluations of the hip joint were performed at one, two, four, eight, and 12 weeks after administration (n = 6 rats per group per time point). Results OA changes progressed from 1 week after administration in the 1.0-mg, 2.0-mg, and 4.0-mg MIA groups. The degree of OA changes increased as the dose of MIA increased. The 0.25-mg and 0.5-mg MIA groups presented fewer OA changes than the 2.0-mg and 4.0-mg MIA groups during the entire study period (up to 12 weeks). The administration of 0.25 mg and 0.5 mg of MIA-induced both radiographic and histological OA changes in a time-dependent manner, whereas more than 2 mg of MIA provoked end-stage OA at 8 weeks after injection. Absolute, dose-dependent histopathological OA changes were observed 4 weeks after MIA administration. Conclusions Intra-articular MIA injection to the hip joints of rats induced diverse OA changes dose-dependently. Research for developing novel conservative treatments for hip OA and intractable pain should consider the pathological condition when determining the dose of MIA to be employed.

Abstract Background The blood concentration of cyclosporine (CyA) is frequently elevated following the transfusion of red blood cell concentrate (RCC) to patients after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this retrospective study was to identify the variable factors affecting changes in the blood concentration of CyA before and after transfusion of RCC. Methods We enrolled 105 patients (age, 5–66 years) who received both CyA and transfusion after HSCT. The ratio of the measurement after transfusion to the measurement before transfusion was calculated for the hematocrit and blood concentration/dose ratio of CyA (termed the HCT ratio and the CyA ratio, respectively). Results The blood concentration/dose ratio of CyA was increased after transfusion compared with before transfusion (P

Abstract One of the complications of esophageal endoscopic submucosal dissection (ESD) is postoperative stricture formation. Stenosis formation is associated with inflammation and fibrosis in the healing process. We hypothesized that the degree of thermal damage caused by the device is related to stricture formation. We aimed to reveal the relationship between thermal damage and setting value of the device. We energized a resected porcine esophagus using the ESD device (Flush Knife 1.5). We performed 10 energization points for 1 s, 3 s, and 5 s at four setting values of the device. We measured the amount of current flowing to the conducted points and the temperature and evaluated the effects of thermal damage pathologically. As results, the mean highest temperatures for 1 s were I (SWIFT Effect3 Wat20): 61.19 °C, II (SWIFT Effect3 Wat30): 77.28 °C, III (SWIFT Effect4 Wat20): 94.50 °C, and IV (SWIFT Effect4 Wat30): 94.29 °C. The mean heat denaturation areas were I: 0.84 mm2, II: 1.00 mm2, III: 1.91 mm2, and IV: 1.54 mm2. The mean highest temperature and mean heat denaturation area were significantly correlated (P

Abstract Background Adult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disease which encompasses patients with heterogenous presentation and a wide range of clinical courses. In this study, we aimed to identify potential subgroups of AOSD and reveal risk factors for relapse. Methods We included a total of 216 AOSD patients who received treatment in nine hospitals between 2000 and 2019. All patients fulfilled the Yamaguchi classification criteria. We retrospectively collected information about baseline characteristics, laboratory tests, treatment, relapse, and death. We performed latent class analysis and time-to-event analysis for relapse using the Cox proportional hazard model. Results The median age at disease onset was 51.6 years. The median follow-up period was 36.8 months. At disease onset, 22.3% of the patients had macrophage activation syndrome. The median white blood cell count was 12,600/μL, and the median serum ferritin level was 7230 ng/mL. Systemic corticosteroids were administered in all but three patients (98.6%) and the median initial dosage of prednisolone was 40mg/day. Ninety-six patients (44.4%) were treated with concomitant immunosuppressants, and 22 (10.2%) were treated with biologics. Latent class analysis revealed that AOSD patients were divided into two subgroups: the typical group (Class 1: 71.8%) and the elderly-onset group (Class 2: 28.2%). During the follow-up period, 13 of 216 patients (6.0%) died (12 infections and one senility), and 76 of 216 patients (35.1%) experienced relapses. Overall and relapse-free survival rates at 5 years were 94.9% and 57.3%, respectively, and those rates were not significantly different between Class 1 and 2 (p=0.30 and p=0.19). Time-to-event analysis suggested higher neutrophil count, lower hemoglobin, and age ≥65 years at disease onset as risk factors for death and age ≥65 years at disease onset as a risk factor for relapse. Conclusions AOSD patients were divided into two subgroups: the typical group and the elderly-onset group. Although the survival of patients with AOSD was generally good, the patients often experienced relapses. Age ≥65 years at disease onset was the risk factor for relapse.

Introduction: Condoliase is a newly approved drug that improves symptoms associated with lumbar disk herniation (LDH) by intradiscal administration. This study aimed to evaluate the mid-term outcomes of condoliase injection, examine the adverse events, including cases that required surgery after condoliase administration, and verify cases in which condoliase could be effective. Methods: We enrolled patients with LDH who were treated conservatively for at least six weeks and received condoliase. We assessed the visual analog scale (VAS) score, Japanese Orthopaedic Association Back Pain Evaluation Questionnaire, Oswestry Disability Index, disk height, and disk degeneration for up to 6 months, and we examined the complications. Furthermore, a 50% or more improvement in leg pain VAS score was considered effective. Factors related to symptom improvement were investigated by determining whether lower limb pain improved in six months. Results: In total, 84 patients were recruited (52 men, 32 women; mean age, 44.2 ±> 17.1 [16-86 years]). The duration of illness was 6.7 ±> 6.8 (1.5-30) months. All patient-based outcomes significantly improved at 4 weeks after the administration compared with pretreatment. The intervertebral disc height decreased significantly at four weeks after condoliase administration compared with that before administration. Progression of intervertebral disc degeneration occurred in 50% of the patients. Eleven patients underwent herniotomy due to poor treatment effects. Moreover, treatment in 77.4% of the patients was considered effective. A logistic regression analysis revealed that L5/S1 disk administration (p = 0.029; odds ratio, 5.94; 95% confidence interval, 1.20-29.45) were significantly associated with clinical effectiveness. Conclusions: Condoliase disk administration improved pain and quality of life over time. Condoliase disk administration was more effective in L5/S1 intervertebral administration.

PurposeTo evaluate the efficacy and safety of transdermal electrical stimulation (TdES) using skin electrodes in patients with central retinal artery occlusion (CRAO).MethodsFive eyes of five patients with CRAO underwent TdES (10-ms biphasic pulses, 20 Hz, 30 min) six times at 2-week intervals. Only the affected eye was stimulated with 1.0-mA pulses in all patients. The primary endpoint was the best-corrected logMAR visual acuity. The secondary endpoints were changes in the best-corrected logMAR visual acuity, Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity, mean deviation of the Humphrey field analyzer (HFA) 10-2, and HFA Esterman test score. We also evaluated its safety.ResultsThe logMAR visual acuity at 12 weeks was improved by 0.1 or more in two patients and was maintained in two patients compared to the baseline. No obvious changes in the mean logMAR visual acuity, ETDRS visual acuity, mean deviation, and HFA Esterman score were observed at 12 weeks compared to the baseline. All five enrolled patients completed the study according to the protocol. No treatment-related adverse events were observed during this study.ConclusionIn this study, logMAR visual acuity was slightly improved in two patients, confirming the safety of TdES. Since CRAO has no established treatment method, further research into the effects of TdES treatment in CRAO patients may be beneficial.

IntroductionKawasaki disease (KD) is an acute systemic vasculitis that predominantly afflicts children. KD development is known to be associated with an aberrant immune response and abnormal platelet activation, however its etiology is still largely unknown. Myosin light chain 9 (Myl9) is known to regulate cellular contractility of both non-muscle and smooth muscle cells, and can be released from platelets, whereas any relations of Myl9 expression to KD vasculitis have not been examined.MethodsPlasma Myl9 concentrations in KD patients and children with febrile illness were measured and associated with KD clinical course and prognosis. Myl9 release from platelets in KD patients was also evaluated in vitro. Myl9 expression was determined in coronary arteries from Lactobacillus casei cell wall extract (LCWE)-injected mice that develop experimental KD vasculitis, as well as in cardiac tissues obtained at autopsy from KD patients.Results and discussionPlasma Myl9 levels were significantly higher in KD patients during the acute phase compared with healthy controls or patients with other febrile illnesses, declined following IVIG therapy in IVIG-responders but not in non-responders. In vitro, platelets from KD patients released Myl9 independently of thrombin stimulation. In the LCWE-injected mice, Myl9 was detected in cardiac tissue at an early stage before inflammatory cell infiltration was observed. In tissues obtained at autopsy from KD patients, the highest Myl9 expression was observed in thrombi during the acute phase and in the intima and adventitia of coronary arteries during the chronic phase. Thus, our studies show that Myl9 expression is significantly increased during KD vasculitis and that Myl9 levels may be a useful biomarker to estimate inflammation and IVIG responsiveness to KD.

ABSTRACT: Objective: To investigate changes in weight following the initiation of antiretroviral therapy in treatment-naïve Asian people living with human immunodeficiency virus (PLWH). Methods: This retrospective observational study evaluated adult treatment-naïve Asian PLWH who started antiretroviral therapy based on an integrase strand transfer inhibitor, a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor at the AIDS Clinical Centre, Tokyo between January 2005 and February 2019. Patients were followed-up until October 2019. Multi-variate linear mixed-effects models were used to generate marginal predictions of weight over time. Predicted weight was reported at 3-month intervals until censoring or for 5 years after treatment initiation. Results: Five years after treatment initiation, average weight gain in PLWH who started on dolutegravir-, darunavir- and elvitegravir-based treatment was 5.3 kg, 4.1 kg and 4.6 kg, respectively, while those who started on raltegravir-, lopinavir- and atazanavir-based treatment gained an average of 1.9 kg, 2.1 kg and 2.3 kg, respectively. Average weight gain in PLWH who started treatment with the backbone drugs, tenofovir alafenamide, abacavir and tenofovir disproxil fumarateb was 4.1 kg, 3.0 kg and 3.0 kg, respectively, and those treated with dolutegravir plus tenofovir alafenamide/emtricitabine gained an average of 6.7 kg. Conclusions: Antiretroviral-therapy-associated weight gain continued to increase for 5 years following treatment initiation. A combination of dolutegravir and tenofovir alafenamide/emtricitabine was associated with the greatest weight gain.

Background: In double-bundle anterior cruciate ligament reconstruction (ACLR), fixed-loop and adjustable-loop cortical suspensory devices are commonly used to fix the soft graft on the femoral side. However, few studies have compared in vivo elongation of the two devices. The purpose of this study was to determine whether EndoButton CL (EB) and TightRope RT (TR), the suspensory fixation devices used in ACLR, maintained their length in vivo from the time of surgery through the postoperative period in a randomized controlled trial. Methods: This study prospectively incorporated 30 patients undergoing initial ACLR at a single center. Participants were divided into two groups using a stratified randomization method with age and sex as assignment adjustment factors. EB or TR was used for fixation of the soft graft on the femoral side. The primary endpoint was to compare the elongation distance of the suspensory device. MRIs were taken within seven days after ACLR and 3,6,12 months postoperatively and measured by a radiologist in a blinded fashion. Secondary endpoints included the side-to-side difference in anterior translation, one leg hop test (HOP index), Lachman test, lateral pivot shift test, and Lysholm score one year postoperatively. Results: Twenty-eight patients (EB, n = 13; TR, n = 15) were followed for one year. There was no significant difference between EB and TR groups in elongation from the immediate postoperative period to 3, 6, 12 months after surgery. However, the non-inferiority of TR to EB (non-inferiority margin: 1.5 mm) was not proved by the difference in measured elongation between the two groups (TR – EB, lower 95% CI. AM: 1.80 mm; PL: 1.86 mm) at 6 months. There was no significant difference in anterior translation, HOP index, Lachman test, lateral pivot shift test, or Lysholm score. Conclusion: EB and TR had similar graft retaining ability in vivo for 12 months, but the non-inferiority of TR against EB was not verified statistically.

Objective: Despite the use of surgical and chemoradiation therapies, head and neck squamous cell carcinoma (HNSCC) still has a poor prognosis. Immune checkpoint inhibitors have been shown to prolong life expectancy but have limited efficacy. Glycoprotein nonmetastatic melanoma protein B (GPNMB) has received significant attention in breast cancer treatment, in which it has been associated with cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT); however, the function of GPNMB in HNSCC is completely unknown. This study aimed to clarify the characteristics of GPNMB-positive cells in vitro and their association with the prognosis by immunostaining clinical specimens.Methods: We examined the sphere formation, invasion, and migration ability of GPNMB-positive cells in four HNSCC cell lines in vitro. We also immunostained biopsy specimens with GPNMB from 174 patients with HNSCC diagnosed, treated, and followed-up in our institution to evaluate overall survival and progression-free survival.Results: GPNMB-positive cells showed enhanced sphere formation, invasion, and migration, suggesting that they could have CSC characteristics and the ability to induce EMT, as reported for breast cancer. Clinical specimens showed that overall survival was 39.4% and 57.8% (p = 0.045) and that progression-free survival was 27.6% and 51.6% (p = 0.013) for the high-expression and the low-expression groups, respectively, indicating poor prognosis for the high GPNMB group. The high GPNMB group was also more resistant to chemoradiation and bioradiotherapy. GPNMB was more highly expressed in metastatic lymph nodes than in the primary tumor.Conclusion: GPNMB-positive cells might have CSC characteristics and induce EMT. Detailed functional analyses of GPNMB in HNSCC and the establishment of therapies targeting GPNMB will lead to improved prognoses.

BackgroundSome attempts have been made to detect atrial fibrillation (AF) with a wearable device equipped with photoelectric volumetric pulse wave technology, and it is expected to be applied under real clinical conditions. ObjectiveThis study is the second part of a 2-phase study aimed at developing a method for immediate detection of paroxysmal AF, using a wearable device with built-in photoplethysmography (PPG). The objective of this study is to develop an algorithm to immediately diagnose AF by an Apple Watch equipped with a PPG sensor that is worn by patients undergoing cardiac surgery and to use machine learning on the pulse data output from the device. MethodsA total of 80 patients who underwent cardiac surgery at a single institution between June 2020 and March 2021 were monitored for postoperative AF, using a telemetry-monitored electrocardiogram (ECG) and an Apple Watch. AF was diagnosed by qualified physicians from telemetry-monitored ECGs and 12-lead ECGs; a diagnostic algorithm was developed using machine learning on the pulse rate data output from the Apple Watch. ResultsOne of the 80 patients was excluded from the analysis due to redness caused by wearing the Apple Watch. Of 79 patients, 27 (34.2%) developed AF, and 199 events of AF including brief AF were observed. Of them, 18 events of AF lasting longer than 1 hour were observed, and cross-correlation analysis showed that pulse rate measured by Apple Watch was strongly correlated (cross-correlation functions [CCF]: 0.6-0.8) with 8 events and very strongly correlated (CCF>0.8) with 3 events. The diagnostic accuracy by machine learning was 0.9416 (sensitivity 0.909 and specificity 0.838 at the point closest to the top left) for the area under the receiver operating characteristic curve. ConclusionsWe were able to safely monitor pulse rate in patients who wore an Apple Watch after cardiac surgery. Although the pulse rate measured by the PPG sensor does not follow the heart rate recorded by telemetry-monitored ECGs in some parts, which may reduce the accuracy of AF diagnosis by machine learning, we have shown the possibility of clinical application of using only the pulse rate collected by the PPG sensor for the early detection of AF.

Backgrounds: Despite the absolute need for life-long treatment of inherited and genetic diseases, there has been little effort to develop such treatments for most of these conditions due to their rarity. Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is recognized as one such orphan disease. We have been developing an adipocyte-based ex vivo gene therapy/regenerative medicine, a novel methodology that differs from the adeno-associated virus-mediated in vivo gene therapy or ex vivo gene-transduced hematopoietic cell therapy, to treat familial LCAT deficiency. Recently, a first-in-human (FIH) clinical study was conducted under the Act on Securement of Safety of Regenerative Medicine, wherein a patient with familial LCAT deficiency was treated. To obtain approval to put this treatment into practical use, a clinical trial has been designed with reference to the FIH clinical study. Methods: An interventional, open-label, unblinded dose-escalation trial was planned, referring to previous FIH clinical study. The trial aims to evaluate the safety of the investigational product in relation to the characteristics of the investigational product (ex vivo gene/cell therapy product by retroviral vector-mediated LCAT gene transduction) using two doses, and the efficacy of the treatment will be evaluated exploratively. A total of three patients will be enrolled sequentially and followed for 24 weeks after administration. This study is designed as a multicenter trial, with Chiba University Hospital administering and evaluating the safety/efficacy of the investigational products at the prescribed visit. Conclusion: This clinical trial is expected to facilitate the provision of lifelong treatment to many patients with LCAT deficiency. Trial registration number: Japan Registry of Clinical Trials (jRCT2033200096).

Abstract Background The appropriate position of retractors to minimize the risk of femoral nerve palsy remains uncertain. The purpose of this imaging study was to evaluate the distance between the femoral nerve (FN) and anterior acetabulum (AA) in hip osteoarthritis (OA). Methods Forty-one patients with unilateral hip OA underwent magnetic resonance imaging. Three measurement levels were defined and the minimum distance between the femoral nerve (FN) margin and anterior acetabulum (AA) rim was measured on axial T1-weighted images on the OA and normal sides at each level, with reference to an advanced neurography view. The cross-sectional area (CSA) of the iliopsoas muscle was also measured at each level bilaterally by three observers. Distances and CSAs were compared between the OA and normal side. Multiple regression analysis was performed to identify variables associated with the distance in OA. Results The mean minimum FN to AA distances in OA were 19.4 mm at the top of the anterior inferior iliac spine (AIIS), 24.3 mm at the bottom of the AIIS, and 21.0 mm at the tip of the greater trochanter. These distances were significantly shorter than in normal hips at the top and bottom of the AIIS, with mean differences of 1.6 and 5.8 mm, respectively (p = 0.012, p

Abstract Background The evaluation of postoperative total knee arthroplasty (TKA) alignment mainly relies on measurement data obtained from plain radiographs. The aim of this retrospective observational study was to document the intra- and inter-observer reliability in assessment of TKA component positioning after surgery using a three-dimensional (3D) computed tomography (CT) image matching system. Methods Fourteen knees from 14 patients who received primary TKA were included, and images were analyzed by blinded readers not associated with the surgeries. The examiner digitized the reference points according to defined landmarks, and the designated size component was superimposed to the 3D reconstructed CT model for measurement. In addition to the evaluation of implant position against the coronal and sagittal lower limb mechanical axes that were defined based on bony landmarks, implant position against axes connecting implant-based reference points that are easier to indicate was evaluated. Results The overall intra- and inter-observer reliabilities determined by the intraclass correlation coefficients (ICC) of the implant alignment measurement for both femoral and tibial components were good (ICC > 0.60), except in the direction of femoral flexion and extension, for both mechanical and implant-based axes. The difference between implant alignment measurements according to the traditional mechanical axis and the implant-based axis ranged between means of 0.08o and 1.70o and were statistically significantly different. Conclusions The postoperative evaluation of implant position in the coronal and sagittal planes using 3D-CT image matching is reliable and has good reproducibility except for the sagittal alignment assessment of the femoral component. The measured implant position according to the traditional mechanical axis and the implant-based axis were slightly but significantly different.

Abstract Objectives The aim of this trial is to evaluate the antiviral efficacy, clinical efficacy, and safety of nelfinavir in patients with asymptomatic and mild COVID-19. Trial design The study is designed as a multicenter, open-label, blinded outcome assessment, parallel group, investigator-initiated, exploratory, randomized (1:1 ratio) controlled clinical trial. Participants Asymptomatic and mild COVID-19 patients will be enrolled in 10 university and teaching hospitals in Japan. The inclusion and exclusion criteria are as follows: Inclusion criteria: (1) Japanese male or female patients aged ≥ 20 years (2) SARS-CoV-2 detected from a respiratory tract specimen (e.g., nasopharyngeal swab or saliva) using PCR, LAMP, or an antigen test within 3 days before obtaining the informed consent (3) Provide informed consent Exclusion criteria: (1) Symptoms developed ≥ 8 days prior to enrolment (2) SpO2 < 96 % (room air) (3) Any of the following screening criteria: a) ALT or AST ≥ 5 × upper limit of the reference range b) Child-Pugh class B or C c) Serum creatinine ≥ 2 × upper limit of the reference range and creatinine clearance < 30 mL/min (4) Poorly controlled diabetes (random blood glucose ≥ 200 mg/dL or HbA1c ≥ 7.0%, despite treatment) (5) Unsuitable serious complications based on the assessment of either the principal investigator or the sub-investigator (6) Hemophiliac or patients with a marked hemorrhagic tendency (7) Severe diarrhea (8) Hypersensitivity to the investigational drug (9) Breastfeeding or pregnancy (10) With childbearing potential and rejecting contraceptive methods during the study period from the initial administration of the investigational drug (11) Receiving rifampicin within the previous 2 weeks (12) Participated in other clinical trials and received drugs within the previous 12 weeks (13) Undergoing treatment for HIV infection (14) History of SARS-CoV-2 vaccination or wishes to be vaccinated against SARS-CoV-2 (15) Deemed inappropriate (for miscellaneous reasons) based on the assessment of either the principal investigator or the sub-investigator Intervention and comparator Patients who meet the inclusion criteria and do not meet any of the exclusion criteria will be randomized to either the nelfinavir group or the symptomatic treatment group. The nelfinavir group will be administered 750 mg of nelfinavir orally, three times daily for 14 days (treatment period). However, if a participant tests negative on two consecutive PCR tests of saliva samples, administration of the investigational drug for that participant can be discontinued at the discretion of the investigators. The symptomatic treatment group will not be administered the investigational drug, but all other study procedures and conditions will be the same for both groups for the duration of the treatment period. After the treatment period of 14 days, each group will be followed up for 14 days (observational period). Main outcomes The primary endpoint is the time to negative conversion of SARS-CoV-2. During the study period from Day 1 to Day 28, two consecutive negative PCR results of saliva samples will be considered as the negative conversion of the virus. The secondary efficacy endpoints are as follows: For patients with both asymptomatic and mild disease: area under the curve of viral load, half decay period of viral load, body temperature at each time point, all-cause mortality, incidence rate of pneumonia, percentage of patients with newly developed pneumonia, rate of oxygen administration, and the percentage of patients who require oxygen administration. For asymptomatic patients: incidence of symptomatic COVID-19, incidence of fever (≥ 37.0 °C for two consecutive days), incidence of cough For patients with mild disease: incidence of defervescence (< 37.0 °C), incidence of recovery from clinical symptoms, incidence of improvement of each symptom The secondary safety endpoints are adverse events and clinical examinations. Randomization Patients will be randomized to either the nelfinavir group or the symptomatic treatment group using the electric data capture system (1:1 ratio, dynamic allocation based on severity [asymptomatic], and age [< 60 years]). Blinding (masking) Only the assessors of the primary outcome will be blinded (blinded outcome assessment). Numbers to be randomized (sample size) The sample size was determined based on our power analysis to reject the null hypothesis, S (t | z =1) = S (t | z = 0) where S is a survival function, t is time to negative conversion, and z denotes randomization group, by the log-rank test with a two-sided p value of 0.05. We estimated viral dynamic parameters by fitting a nonlinear mixed-effects model to reported viral load data, and simulated our primary endpoint from viral-load time-courses that were realized from sets of viral dynamics parameters sampled from the estimated probability distribution of the parameters (sample size: 2000; 1000 each for randomization group). From this estimation of the hazard ratio between the randomization groups for the event of negative conversion using this simulation dataset, the required number of events for rejecting our null hypothesis with a power of 0.80 felled 97.345 by plugging the estimated hazard ratio, 1.79, in Freedman’s equation. Therefore, we decided the required number of randomizations to be 120 after consideration of the frequency of censoring and the anticipated rate of withdrawal caused by factors such as withdrawal of consent. Trial Status Protocol version 6.0 of February 12, 2021. Recruitment started on July 22, 2020 and is anticipated to be completed by March 31, 2022. Trial registration This trial was registered in Japan Registry of Clinical Trials (jRCT) ( jRCT2071200023 ) on 21 July 21, 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Introduction Previously, we conducted a clinical trial to evaluate the safety and efficacy of transdermal electrical stimulation (TdES) with skin electrodes to improve the visual functions in patients with retinitis pigmentosa (RP). No adverse events were related to the treatment during follow-up examinations, and TdES significantly improved the mean visual acuity and visual field sensitivity.Methods and analysis We developed a study protocol for a prospective, multicentre, randomised, double-masked and sham-controlled clinical trial, planned to commence on June 2021. We intend to compare the maintenance or improvement in best-corrected visual acuity, and safety of TdES using skin electrodes between patients with RP and the sham group. The primary endpoint comprises the superiority of the logarithm of the minimum angle of resolution (logMAR) visual acuity change at week 24 from baseline in the treatment and sham groups. Secondary endpoints involve the comparison of the treatment and sham groups at week 24 for the logMAR visual acuity, early treatment diabetic retinopathy study visual acuity, the mean deviation value of Humphrey field analyser 10-2, monocular Humphrey Esterman visual field test score, ellipsoid zone length, central foveal thickness and 25-item National Eye Institute Visual Function Questionnaire score. We intend to enrol 50 patients from three Japanese institutions within 1 year and follow them up for 1 years.Ethics and dissemination The protocol was approved by the institutional review board at the Chiba University Hospital and two other institutions, and was registered with the Japan Registry of Clinical Trials on 17 May 2021. The trial will be conducted in accordance with the principles of the Declaration of Helsinki, and is in accordance with Good Clinical Practice standards. The findings will be published in a peer-reviewed journal.Trial registration number JRCT2032210094.

Introduction Advanced hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) has the worst prognosis among all phenotypes. This trial aims to evaluate whether treatment with durvalumab, alone or in combination with tremelimumab, plus particle therapy is a safe and synergistically effective treatment in patients with advanced HCC and MVI.Methods and analysis This phase Ib, multicentre (two sites in Japan), open-label, single-arm, investigator-initiated clinical trial will assess durvalumab monotherapy in combination with particle therapy (cohort A) and that of durvalumab plus tremelimumab in combination with particle therapy (cohort B) for patients with advanced HCC with MVI. Cohort A will receive 1500 mg durvalumab every 4 weeks. Cohort B will receive 1500 mg durvalumab every 4 weeks in principle and 300 mg tremelimumab only on day 1 of the first cycle. Carbon-ion radiotherapy will be administered after day 8 of the first cycle. The primary endpoints are rates of any and severe adverse events, including dose-limiting toxicities (DLTs); secondary endpoints are overall survival, 6-month survival, objective response, 6-month progression-free survival and time to progression. Patients are initially enrolled into cohort A. If cohort A treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), the trial proceeds to enrol more patients into cohort B. Similarly, if cohort B treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), a total of 15 patients will be enrolled into cohort B.Ethics and dissemination This study was approved by the ethics committees of the two participating institutions (Chiba University Hospital and National Institutes for Quantum (approval number: 2020040) and Radiological Science and Technology, QST Hospital (approval number: C20-001)). Participants will be required to provide written informed consent. Trial results will be reported in a peer-reviewed journal publication.Trial registration number jRCT2031210046.

Few studies have compared the effectiveness of internet-based cognitive behavior therapy (ICBT) for obsessive-compulsive disorder (OCD) with treatment as usual (TAU). We investigated the effectiveness of guided ICBT for patients with OCD. This prospective, randomized, controlled, assessor-blinded, multicenter clinical trial was conducted at three facilities in Japan from January 2020 to March 2021. Thirty-one patients with OCD as the primary diagnosis participated in the trial and were randomly assigned to either the intervention group or the control group. The primary outcome was the Yale–Brown obsessive-compulsive scale score; the assessors were blinded. Results of the analysis of covariance among the groups were significantly different between the groups (p

Background and purpose — Deep-learning approaches based on convolutional neural networks (CNNs) are gaining interest in the medical imaging field. We evaluated the diagnostic performance of a CNN to discriminate femoral neck fractures, trochanteric fractures, and non-fracture using antero-posterior (AP) and lateral hip radiographs. Patients and methods — 1,703 plain hip AP radiographs and 1,220 plain hip lateral radiographs were included in the total dataset. 150 images each of the AP and lateral views were separated out and the remainder of the dataset was used for training. The CNN made the diagnosis based on: (1) AP radiographs alone, (2) lateral radiographs alone, or (3) both AP and lateral radiographs combined. The diagnostic performance of the CNN was measured by the accuracy, recall, precision, and F1 score. We further compared the CNN’s performance with that of orthopedic surgeons. Results — The average accuracy, recall, precision, and F1 score of the CNN based on both anteroposterior and lateral radiographs were 0.98, 0.98, 0.98, and 0.98, respectively. The accuracy of the CNN was comparable to, or statistically significantly better than, that of the orthopedic surgeons regardless of radiographic view used. In the CNN model, the accuracy of the diagnosis based on both views was significantly better than the lateral view alone and tended to be better than the AP view alone. Interpretation — The CNN exhibited comparable or superior performance to that of orthopedic surgeons to discriminate femoral neck fractures, trochanteric fractures, and non-fracture using both AP and lateral hip radiographs.

Abstract Background One aim of an autism spectrum disorder (ASD) diagnosis is to obtain special support for the disorder, though this does not guarantee practical support. We developed a psychoeducational program using cognitive-behavioral therapy (CBT) and Aware and Care for my Autistic Traits (ACAT) for Japanese adolescents with high-functioning ASD and their parents. Methods This multisite study is a randomized controlled trial. In total, 24 participants will be assigned to the ACAT group and 24 to the treatment-as-usual (TAU) group. The ACAT group will receive a weekly 100-min session for 6 weeks, regular medical care, and one follow-up session. In this ongoing clinical trial, we will compare the scores of the measures recorded in the pre- and post-intervention stages between the ACAT and TAU groups. A total of 41 patients out of a target of 48 have participated in the trial to date. The primary outcome measure is the Autism Knowledge Questionnaire. Secondary outcome measures include Barriers to Access to Care Evaluation 3rd Edition, the Strengths and Difficulties Questionnaire, the Vineland Adaptive Behavior Scales second edition, the Parenting Resilience Elements Questionnaire, the General Health Questionnaire 12, and the Depression Self-Rating Scale for Children assessments, as well as an electroencephalographic recording. Discussion It is expected that participants in the ACAT group will significantly increase their self-understanding and awareness of ASD symptoms compared to those in the TAU group. Additionally, the ACAT group is expected to exhibit improved social adaptation and mental health if children and parents are able to better understand the ASD characteristics through sessions. This intervention will contribute to the establishment of an effective evidence-based treatment strategy for adolescents with ASD. Trial registration UMIN Register 000029851 . Registered on January 06, 2018

Abstract Background If anaplastic lymphoma kinase (ALK) gene rearrangement in lung cancer is identified, ALK‐tyrosine kinase inhibitors (ALK‐TKIs) can be an effective treatment. However, the details of drug‐induced lung injury (DILI) caused by ALK‐TKI, which can be a serious side effect of ALK‐TKIs, remains unclear. This study aimed to investigate the clinical features and the onset risk factors of DILI by ALK‐TKIs in clinical practice. Methods The clinical features of 56 consecutive patients who received crizotinib, alectinib, and/or ceritinib at our hospital from 2012 to 2018 were retrospectively examined. Among these, patients diagnosed with DILI due to ALK‐TKIs were evaluated in terms of clinical features and parameters. Each clinical parameter before the administration of ALK‐TKIs was compared between the DILI onset group and the non‐onset group. Results A total of seven cases were diagnosed with DILI due to ALK‐TKIs; no DILI‐related deaths were observed. Chest computed tomography (CT) scan findings identified six patients with the organizing pneumonia (OP) pattern and one with the hypersensitivity pneumonia pattern. The onset of DILI was significantly different in patients age ≥ 64 years and with a creatinine clearance

Abstract Introduction Landiolol hydrochloride reduces the incidence of perioperative atrial fibrillation (AF) in cardiac surgery; however, little evidence is available regarding its effects in other types of surgery, including esophagectomy. We assessed the hypothesis that landiolol reduces perioperative AF and other complications associated with esophagectomy. Methods This single-center, randomized, double-blind, parallel-group study enrolled patients scheduled for esophagectomy. Patients were divided into those given landiolol at 3 μg/kg/min or placebo for 24 h. The primary outcome was the proportion of patients who developed AF within 96 h starting at 9:00 am on the day of surgery. The secondary outcomes were the proportion of patients whose AF appeared within 24 h, other complications based on the Clavien–Dindo classification, and the intensive care unit and hospital stays. Results Despite early study termination, 80 patients were screened, and 56 were enrolled (28/group) from September 2016 to June 2018. AF occurred within 96 h of surgery in six (21.4%) patients in the landiolol group and five (17.9%) patients in the placebo group (odds ratio, 1.26; 95% confidence interval, 0.33–4.7) and within 24 h of surgery in three (10.7%) patients in the landiolol group and two (7.1%) patients in the placebo group. There were no significant differences in the incidence of complications or in the number of intensive care unit or hospital stays between the groups. Conclusion Although our small sample size prevents definitive conclusions, landiolol might not reduce the occurrence of AF or other complications. Trial registration UMIN, UMIN000024040. Registered 13 September 2016, http://www.umin.ac.jp/ctr/index/htm

Introduction The prognosis of head and neck squamous cell carcinoma (HNSCC) is generally good in cases of high radiation sensitivity but poor in cases exhibiting radiation resistance; this resistance has been attributed to the presence of cancer stem cells. In recent years, CD98hc overexpression has been associated with poor prognosis in various types of cancers. CD98 is a heterodimer of heavy and light chains and is strongly involved in cell proliferation, survival, migration, and adhesion. We investigated whether CD98hc can be used as a cancer stem cell marker for HNSCC. Material and methods We exposed five HNSCC cell lines to a total radiation dose of 60 Gy administered in 2 Gy fractions on consecutive days to investigate changes in CD98hc expression. Furthermore, we separated CD98-positive and CD98-negative cell populations to comparatively investigate the properties of each. Results Radiation resistance was observed in all five cell lines, and resistant cells exhibited CD98hc overexpression, with enhanced spheroid formation, migratory, and invasive abilities. Radiation-resistant cell lines were separated into CD98-positive and CD98-negative populations. CD98hc-positive radiation-resistant cell lines exhibited enhanced spheroid formation, invasion, and plating efficiency as well as strong tumorigenicity in nude mice. Conclusions CD98hc-positive cells exhibited cancer stem cell-like properties in all cell lines. Thus, CD98hc is a potential marker of radiation sensitivity as well as a potential therapeutic target for improved survival rates of patients with HNSCC.

Abstract Background Lumbar spinal disease causes disabilities in performing daily activities. Operative treatments are aimed at pain relief and rapid return to routine activity. Patient-based outcome measures are used to evaluate pathologies and therapeutic effects associated with lumbar spinal disease. Nevertheless, it remains unknown as to how much such treatment improves activity levels. The purpose of the current study was to measure changes in activity levels before and after lumbar spinal surgery using a wearable activity tracker and to analyze the differences between results and patient-based outcomes. Methods Sixty patients who underwent lumbar surgery were studied. The physical activity of participants was objectively evaluated using a wearable Micro-Motion logger system (Actigraph). We measured the amount of activity before and at 1, 3, 6, and 12 months after the surgery to evaluate postoperative changes. The Japanese Orthopaedic Association Back Pain Evaluation Questionnaire, Oswestry Disability Index, Roland-Morris Disability Questionnaire and visual analog scale were used to assess patient-based outcomes of pain and activities of daily living-related scores; we analyzed the relationships between scores and actual activity levels. Results The amount of actual activity decreased significantly 1 month after the surgery compared to that during the preoperative period, which then improved after 3 months postoperatively (p

Abstract Background The indications for the surgical treatment of gastric cancer liver metastases (GCLMs) remain controversial. In addition, the outcome of surgery for the treatment of liver metastases of alpha-fetoprotein-producing gastric cancer (AFP-GC) has not yet been reported. We assessed the clinicopathologic features, including AFP-GC, and the surgical results of these patients. Methods This retrospective study analyzed 20 patients who underwent hepatectomy for GCLM at Odawara Municipal Hospital between April 2006 and January 2016. Results The actuarial 1-, 3-, and 5-year overall survival (OS) rates after primary hepatectomy were 80.0%, 55.5%, and 31.7%, respectively, with a median OS of 42 months. Four patients survived for more than 5 years after their final hepatectomy procedures. A multivariate analysis showed multiple metastases in the liver, the elevated level of carbohydrate antigen 19-9 (CA19-9), and an age of less than 70 years to be independently associated with a poor prognosis in terms of OS. No significant differences were noted between the AFP-GC and AFP-negative GC groups. Conclusion Surgical treatment is therefore considered to be a feasible option for GCLM. The findings of the present study showed the number of metastatic liver tumors, the level of CA19-9, and the patient age to be prognostic indicators for the surgical treatment of GCLM.

Introduction Concurrent chemoradiotherapy is considered the standard treatment strategy for locally advanced cervical cancer. Most recent reports indicate that patients with bulky tumours or adenocarcinoma subtypes have poorer local control. Carbon-ion radiotherapy (CIRT) with the concurrent use of chemotherapy has shown promising results in such cases of difficult-to-treat uterine cervical cancer. Programmed death-ligand 1 (PD-L1) upregulation was observed in tumour tissue samples from patients who had undergone CIRT. Thus, a combination of CIRT and anti-PD-L1 antibody may suppress metastasis by activating antitumour immune response, in addition to exhibiting strong local effects.Objective We will assess the safety and tolerability (primary endpoint) of the concomitant use of durvalumab, an anti-PD-L1 antibody, with CIRT and weekly cisplatin for locally advanced cervical cancer.Methods and analysis This study is a non-randomised, open-label, prospective phase 1b study. Up to 10 patients with histologically proven uterine cervical cancer at stage IIB, IIIA, IIIB, IIIC1 or IVA as per International Federation of Gynecology and Obstetrics (2018) staging will be enrolled. All patients will receive CIRT of 74.4 Gy relative biological effectiveness in 20 fractions over 5 weeks (four fractions per week). Weekly cisplatin at a dose of 40 mg/m2 will be administrated up to five times. Durvalumab at a dose of 1500 mg/body will be administrated at weeks 2 and 6. Safety and tolerability will be evaluated based on the frequency of dose-limiting toxicities until 92 days after CIRT starts. Patients will be followed-up strictly as per the scheduled protocol for 1 year after CIRT initiation.Ethics and dissemination The Human Research Ethics Committees of QST Hospital (#C21-002) and Chiba University (#2021006) have approved this study protocol. The findings will be published in peer-reviewed journals and presented at scientific conferences.Trial registration number Japan Registry of Clinical Trials (jRCT2031210083), registered on 12 May 2021.

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