Ramucirumab for advanced hepatocellular carcinoma in the current real world: a Japanese single-arm study post-REACH-2 (The R-evolution study).

This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study.

Two onset types of achalasia and the long-term course to diagnosis.

BACKGROUND: Recently, the incidence of achalasia has been increasing, but its cause remains unknown. This study aimed to examine the initial symptoms and the course of symptoms and to find new insights into the cause and course of the disease. METHODS: Altogether, 136 patients diagnosed with achalasia by high-resolution manometry (HRM) were enrolled. Questionnaires and chart reviews were conducted to investigate the initial symptoms, time from onset to diagnosis, and comorbidities, as well as the relationship between HRM results, time to diagnosis, and symptom severity. RESULTS: In total, 67 of 136 patients responded to the questionnaire. The median ages of onset and diagnosis were 42 and 58 years, respectively. The median time from onset to diagnosis was 78.6 months, with 25 cases (37.3%) taking > 10 years to be diagnosed. The symptom onset was gradual and sudden in 52 (77.6%) and 11 (16.4%) patients, respectively. Of the 11 patients with acute onset, three (27.3%) developed anhidrosis at the same time. There was no correlation between the time from onset to diagnosis and esophageal dilatation, resting LES pressure, or mean integrated relaxation pressure (IRP). No correlation was also found between the degree of symptoms and resting LES pressure or IRP. CONCLUSION: Esophageal achalasia can have acute or insidious onsets. This finding may help to elucidate the cause of achalasia.

Treatment Effects of Switching to Faricimab in Eyes with Diabetic Macular Edema Refractory to Aflibercept.

Background and Objectives: Faricimab is a vascular endothelial growth factor A and angiopoietin-2 bispecific antibody. It is a novel therapeutic approach distinct from previous anti-vascular endothelial growth factor agents. This study aimed to evaluate the efficacy of switching from aflibercept to faricimab in the treatment of diabetic macular edema (DME) refractory to aflibercept, with a specific focus on the resolution of macular edema. Materials and Methods: The medical records of 29 eyes of 21 patients with DME that were refractory to intravitreal injections of aflibercept (IVAs) and who had completed the clinical follow-up of at least four intravitreal injections of faricimab (IVFs) were reviewed. The central retinal thickness (CRT), best-corrected visual acuity (BCVA), and the mean period (weeks) until the next injection were measured after the second-to-last IVA, first-to-last IVA, last IVA, and first to fourth IVFs following the transition to IVF. Results: The mean time from the first IVF to the assessment of effectiveness was significantly shorter than the time to the last IVA; however, no significant difference was found in the time from the second, third, and fourth IVFs to the assessment. The mean CRTs after the first and second IVFs were not significantly different from the CRT after the last IVA, but the mean CRT after the third and fourth IVFs was significantly thinner than that after the last IVA (p = 0.0025 and p = 0.0076, respectively). The mean BCVAs after the third and fourth IVFs significantly improved compared with that after the last IVA (p = 0.0050 and p = 0.0052, respectively). Conclusions: When switching the treatment to IVF for eyes with IVA-resistant DME, better treatment outcomes are achieved if IVF is performed three or more times.

Feasibility of Guided Internet-Based Cognitive Behavioral Therapy for Panic Disorder and Social Anxiety Disorder in Japan: Pilot Single-Arm Trial.

BACKGROUND: Cognitive 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. OBJECTIVE: The 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. METHODS: In 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. RESULTS: Most 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. CONCLUSIONS: Guided ICBT may be feasible for the treatment of outpatients with panic disorder and social anxiety disorder in Japan. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN0000038118; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000043439.

Differences in Mucosal Permeability Among Patients With Ulcerative Colitis Classified Based on the Colonic Location and Disease Activity.

INTRODUCTION: Factors affecting mucosal permeability (MP) in ulcerative colitis (UC) are largely unknown. We aimed to investigate the difference in MP among patients with UC classified according to the colonic locations and to evaluate the correlations between local MP and endoscopic or histological activity of UC. METHODS: The transepithelial electrical resistance (TER), which is inversely proportional to permeability, of tissue samples from the mucosa of the ascending colon, descending colon, and rectum of patients with UC and healthy individuals (HIs) was measured by using the Ussing chamber. TERs were compared between patients with UC and HIs and evaluated according to colonic locations and disease activity of UC. RESULTS: Thirty-eight patients with UC and 12 HIs were included in this study. Both in HIs and patients with UC, MP tends to be higher in the anal side. TER in the ascending colon was significantly lower in patients with UC than in HIs (45.3 ± 9.0 Ω × cm 2 vs 53.5 ± 9.7 Ω × cm 2 , P = 0.01). The increased permeability in UC was observed also in the descending colon, only when the inflammation involved the location. A significant correlation between TER and endoscopic activity was found in the rectum only ( r = -0.49, P = 0.002). There were no significant correlations between TERs and UC histology. DISCUSSION: The MP in the colon differs according to the colonic location. The ascending colon among patients with UC showed disease-specific changes in MP, whereas the MP is increased in proportion to the endoscopic activity in the rectum.

Risk factors of unintentional piecemeal resection in endoscopic mucosal resection for colorectal polyps ≥ 10 mm.

This study aimed to investigate the lesion and endoscopist factors associated with unintentional endoscopic piecemeal mucosal resection (uniEPMR) of colorectal lesions ≥ 10 mm. uniEPMR was defined from the medical record as anything other than a preoperatively planned EPMR. Factors leading to uniEPMR were identified by retrospective univariate and multivariate analyses of lesions ≥ 10 mm (adenoma including sessile serrated lesion and carcinoma) that were treated with endoscopic mucosal resection (EMR) at three hospitals. Additionally, a questionnaire survey was conducted to determine the number of cases treated by each endoscopist. A learning curve (LC) was created for each lesion size based on the number of experienced cases and the percentage of uniEPMR. Of 2557 lesions, 327 lesions underwent uniEPMR. The recurrence rate of uniEPMR was 2.8%. Multivariate analysis showed that lesion diameter ≥ 30 mm (odds ratio 11.83, 95% confidence interval 6.80-20.60, p < 0.0001) was the most associated risk factor leading to uniEPMR. In the LC analysis, the proportion of uniEPMR decreased for lesion sizes of 10-19 mm until 160 cases. The proportion of uniEPMR decreased with the number of experienced cases in the 20-29 mm range, while there was no correlation between the number of experienced cases and the proportion of uniEPMR ≥ 30 mm. These results suggest that 160 cases seem to be the minimum number of cases needed to be proficient in en bloc EMR. Additionally, while lesion sizes of 10-29 mm are considered suitable for EMR, lesion sizes ≥ 30 mm are not applicable for en bloc EMR from the perspective of both lesion and endoscopist factors.

Efficacy and safety of transdermal electrical stimulation in patients with nonarteritic anterior ischemic optic neuropathy.

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 .

Cognitive behavior therapy for autistic adolescents, awareness and care for my autistic traits program: a multicenter randomized controlled trial.

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).

Postoperative hormonal therapies reduce the recurrence of thoracic endometriosis-related pneumothorax.

OBJECTIVES: Thoracic endometriosis-related pneumothorax (TERP) frequently recurs even after surgery. Meanwhile, postoperative hormonal therapies (HTx) are believed to be effective for pelvic endometriosis. Therefore, we evaluated the relationship between postoperative TERP recurrence and postoperative HTx in a retrospective observational study. METHODS: We retrospectively reviewed the data of patients with TERP who underwent the first video-assisted thoracoscopic surgery between January 2011 and February 2022. RESULTS: Of the 248 patients eligible for this study, 67 (27.0%) experienced postoperative TERP recurrence. Postoperative HTx were administered to 70 patients (28.2%). Dienogest was the most frequently administered drug, given to 56.7% of patients. Following univariable analysis, postoperative hormonal therapies was closely related to reduce postoperative recurrence (P = 0.003). Likewise, the multivariable analysis revealed postoperative hormonal therapies were significantly associated with the risk reduction of recurrence (hazard ratio 0.28, P < 0.001). CONCLUSIONS: Postoperative HTx reduced TERP recurrence. We hypothesize that HTx may control residual endometrial tissues to avoid TERP if pleural endometrial tissues are resected as much as possible.

Effects of BL 23 (Shenshu) acupuncture on serum cytokine levels in healthy adults: A randomized double-blind sham-controlled phase 1 study.

The purpose of this study was to evaluate the safety and efficacy of BL 23 (Shenshu) acupuncture on serum cytokine levels. Sixteen healthy adults were randomized into the BL 23 acupuncture group or pseudo-acupuncture group and changes of serum cytokines were analyzed. The changes in IL-13, TNF-α, and GM-CSF levels were different between the BL 23 acupuncture group and pseudo-acupuncture group (P < 0.05). No adverse events associated with acupuncture were observed. In conclusion, BL 23 acupuncture can suppress immune responses via decreases in TNF-α and suppression of increases in IL-13 and GM-CSF. This study elucidated some of the mechanisms of the acupuncture effect.

A Multicenter Randomized Controlled Trial To Evaluate the Efficacy and Safety of Nelfinavir in Patients with Mild COVID-19.

Nelfinavir, an orally administered inhibitor of human immunodeficiency virus protease, inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. We conducted a randomized controlled trial to evaluate the clinical efficacy and safety of nelfinavir in patients with SARS-CoV-2 infection. We included unvaccinated asymptomatic or mildly symptomatic adult patients who tested positive for SARS-CoV-2 infection within 3 days before enrollment. The patients were randomly assigned (1:1) to receive oral nelfinavir (750 mg; thrice daily for 14 days) combined with standard-of-care or standard-of-care alone. The primary endpoint was the time to viral clearance, confirmed using quantitative reverse-transcription PCR by assessors blinded to the assigned treatment. A total of 123 patients (63 in the nelfinavir group and 60 in the control group) were included. The median time to viral clearance was 8.0 (95% confidence interval [CI], 7.0 to 12.0) days in the nelfinavir group and 8.0 (95% CI, 7.0 to 10.0) days in the control group, with no significant difference between the treatment groups (hazard ratio, 0.815; 95% CI, 0.563 to 1.182; P = 0.1870). Adverse events were reported in 47 (74.6%) and 20 (33.3%) patients in the nelfinavir and control groups, respectively. The most common adverse event in the nelfinavir group was diarrhea (49.2%). Nelfinavir did not reduce the time to viral clearance in this setting. Our findings indicate that nelfinavir should not be recommended in asymptomatic or mildly symptomatic patients infected with SARS-CoV-2. The study is registered with the Japan Registry of Clinical Trials (jRCT2071200023). IMPORTANCE The anti-HIV drug nelfinavir suppresses the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. However, its efficacy in patients with COVID-19 has not been studied. We conducted a multicenter, randomized controlled trial to evaluate the efficacy and safety of orally administered nelfinavir in patients with asymptomatic or mildly symptomatic COVID-19. Compared to standard-of-care alone, nelfinavir (750 mg, thrice daily) did not reduce the time to viral clearance, viral load, or the time to resolution of symptoms. More patients had adverse events in the nelfinavir group than in the control group (74.6% [47/63 patients] versus 33.3% [20/60 patients]). Our clinical study provides evidence that nelfinavir, despite its antiviral effects on SARS-CoV-2 in vitro, should not be recommended for the treatment of patients with COVID-19 having no or mild symptoms.

Guided parent-delivered cognitive behavioural therapy for Japanese children and parents: a single-arm uncontrolled study.

BACKGROUND: Guided parent-delivered cognitive behavioural therapy (GPD-CBT) is an effective low-intensity treatment for childhood anxiety disorder in Western countries and can increase access to evidence-based psychological therapies. AIM: This study aimed to examine its feasibility in a Japanese sample. METHOD: Twelve children with anxiety disorders and their parents participated in the study, and ten children and parents completed the program. Participants were assessed at pre-, post- and one-month follow-up using a diagnostic interview for anxiety disorders, self- and parent-report measures for anxiety, depression, parental behaviour, and parental anxiety. RESULTS: Four children (40% of completers) were free from their primary diagnoses immediately following the brief treatment, and seven children (70%) at the one-month follow-up. Changes in disorder severity, child and parent reported anxiety symptoms, and child reported depression symptoms were consistent with those found in Western trials of GPD-CBT and of Japanese trials of more intensive CBT for child anxiety disorders that involves both the child and the parent. Moderate increases were also found in child reported parental autonomy behaviours; however, there were only small changes in parent self-reported anxiety. CONCLUSION: These results support the potential of GPD-CBT to increase access to evidence-based treatments for anxiety disorders in Japanese children.

Exploratory clinical trial to evaluate the efficacy and safety of transdermal electrical stimulation in patients with central retinal artery occlusion.

PURPOSE: To evaluate the efficacy and safety of transdermal electrical stimulation (TdES) using skin electrodes in patients with central retinal artery occlusion (CRAO). METHODS: Five 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. RESULTS: The 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. CONCLUSION: In 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.

[A Case of Locally Advanced Sigmoid Colon Cancer Invading the Urinary Bladder Treated with Neoadjuvant Chemotherapy and Robot Assisted Urinary Bladder-Conserving Surgery].

We report a case of 72s male with locally advanced sigmoid colon cancer. Colonoscopy revealed an advanced sigmoid colon cancer(AV 15 cm, type 2, semi-peripheral, deeper than T3). He was diagnosed as cT4bN2M0, cStage Ⅲc(Japanese Classification of Colorectal, appendiceal, and, Carcinoma, 9th edition), and was given chemotherapy as preoperative treatment. He was treated with CAPOX plus BEV as neoadjuvant chemotherapy. Preoperative diagnosis was ycT4bN0M0, ycStage Ⅱc. The robot assisted high anterior resection and partial bladder resection were performed. The bladder was sutured under robotic assistance. The residual bladder capacity was 100 mL. Postoperative diagnosis was ypT0N0M0, ypStage 0, TRG 0 (AJCC). We experienced a case of neoadjuvant chemotherapy for rectosigmoid colon cancer with bladder invasion, which resulted in pCR.

Long-term course of gastric submucosal tumors: growth speed and size-increasing factors.

BACKGROUND AND AIMS: Gastric submucosal tumors (SMTs) are treated or monitored according to GI stromal tumor guidelines, but the adequacy of the guidelines has not been thoroughly examined. We investigated the long-term course of gastric SMTs to determine the validity of guideline-based follow-up methods and the factors contributing to their size increase. METHODS: This study included gastric SMTs diagnosed as GI mesenchymal tumors (GIMTs) by using EUS and followed up with EUS. The percentage and speed of GIMT enlargement and factors associated with the enlargement were investigated by using the Cox proportional hazards model. RESULTS: From January 1994 to May 2022, a total of 925 gastric SMTs were evaluated with EGD, and 231 SMTs were diagnosed as GIMTs. Of the 231 GIMTs, 145 were examined by EUS more than twice and were followed up for >6 months. The mean ± standard deviation follow-up period was 5.20 ± 4.04 years (range, 0.5-17.3 years), with 39 (26.9%) of 145 GIMTs increasing in size with a mean doubling time of 3.60 ± 3.37 years. A multivariate analysis of factors influencing tumor growth revealed that irregular extraluminal borders were an increasing factor (hazard ratio, 3.65; 95% confidence interval, 1.26-10.52), initial tumor size ≤9.5 mm (hazard ratio, .23; 95% confidence interval, 0.07-0.77) was a nonincreasing factor, and GIMTs with calcification (n = 13) did not increase in size. CONCLUSIONS: Tumor growth in gastric GIMTs <9.5 mm in diameter and/or with calcification is rare. Follow-up intervals for these lesions could be extended.

Effects of the combination of atomoxetine and oxybutynin in Japanese patients with obstructive sleep apnoea: A randomized controlled crossover trial.

BACKGROUND AND OBJECTIVE: The possibility of combination therapy with atomoxetine (ATO) and oxybutynin (OXY) has been suggested for obstructive sleep apnoea (OSA). However, the effectiveness of this treatment remains uninvestigated in Japanese OSA patients. Therefore, we performed a randomized, crossover, phase II, single-centre prospective trial to examine the effects of ATO-OXY therapy in Japanese OSA patients. METHODS: In total, 17 OSA patients participated in this study. The effects of one night of 80-mg ATO plus 5-mg OXY administration were compared with those of no medication administered before sleep. The primary and secondary outcomes comprised the apnoea-hypopnoea index (AHI) and nadir SpO2 , SpO2 drop time and sleep architecture, respectively. The safety endpoints included drug side effects and adverse events. RESULTS: The values of AHI, nadir SpO2 , 3% oxygen desaturation index (ODI), 4% ODI, and SpO2 drop time of <90% did not significantly differ between patients receiving ATO-OXY administration and no medication. Sleep architecture exhibited a significant change: ATO-OXY increased sleep stage N1 (p < 0.0001) and decreased stage N2 (p = 0.03), rapid eye movement (p < 0.0001) and sleep efficiency (p = 0.02). However, the subanalysis demonstrated an obvious decrease in AHI in five responder patients. Total sleep time and basal sleep efficiency tended to be lower in the responders compared with nonresponders (p = 0.065). No patients experienced severe adverse events or side effects. CONCLUSION: Overall, ATO-OXY therapy does not reduce AHI in Japanese OSA patients, although AHI was decreased in a proportion of patients. Future studies for identifying treatment response group characteristics are warranted.

Risk factors for coronary artery abnormalities and resistance to immunoglobulin plus ciclosporin A therapy in severe Kawasaki disease: subanalysis of the KAICA trial, randomized trial for cicrosporin A as the first-line treatment.

Background: To investigate risk factors for coronary arterial abnormalities (CAAs) and resistance to treatment in patients with Kawasaki disease (KD) receiving intravenous immunoglobulin (IVIG) plus ciclosporin A (CsA) as the first-line treatment, we performed a subanalysis of baseline data of participants in the KAICA trial, a phase 3, randomized study (JMA-ILA00174). Methods: All data of the patients enrolled in the KAICA trial, who had a Gunma score ≥5 at diagnosis and had been randomly assigned to either IVIG (2 g/kg/24 h) plus CsA (5 mg/kg/day for 5 days) (n = 86) or IVIG alone (n = 87), were subjected to this study. CAA was defined by a Z score ≥2.5 observed within 4 weeks after treatment initiation. Baseline data including genotypes of KD susceptibility genes were compared between subgroups of patients for CAA or treatment response for each treatment group. Backword-forward stepwise logistic regression analyses were performed. Results: Pre-Z-max, defined as the maximum among Z scores on four coronary artery branches before treatment, was higher in patients with CAA in both treatment groups and was associated with CAA in IVIG plus CsA treatment group [odds ratio (OR) = 17.0]. High serum total bilirubin level was relevant to treatment resistance only in the IVIG plus CsA group (OR = 2.34). Conclusions: Coronary artery enlargement before treatment is a major determinant of CAA even in KD patients treated with initial IVIG treatment intensified by addition of CsA. Baseline serum total bilirubin level was a risk factor associated with resistance to IVIG plus CsA.

Recovery of Forearm Bone Strength After Plate Removal: A Finite Element Analysis Study.

PURPOSE: The purpose of this study was to estimate the bone strength after plate removal over time and to investigate the progression of bone strength recovery. METHODS: A consecutive series of 31 patients was investigated to evaluate bone strength before and after forearm plate removal. Patients who were included underwent plate fixation for forearm diaphyseal fractures and were scheduled for plate removal. Computed tomography (CT) scans of the entire length of the bilateral forearms were taken before plate removal and at 1, 3, and 6 months after surgery. Patient-specific CT-based finite element analysis was used to predict the forearm bone fracture strength against an axial load (N), defined as the bone strength. Bone strength was estimated by patient-specific CT-based finite element analysis at each time point. RESULTS: The mean age of the patients was 40.4 years. The mean time between plate fixation and removal was 27.5 months. Bone strength before the removal was estimated as reduced to 47% of that of the uninjured side. This was constant regardless of age group, involvement of the radius or ulna, Arbeitsgemeinschaft für Osteosynthesefragen (AO) classification, open fracture, or type of plate. Bone strength at 1, 3, and 6 months after removal was estimated to be 66%, 85%, and 97%, respectively. The bone strength of the distal ulna was weaker than that at the other sites in the forearm and showed delayed recovery. CONCLUSIONS: Bone strength after plate removal showed recovery within 3-6 months and was fully recovered by 6 months. The degree of recovery of bone atrophy varies from site to site, and patients should be careful about refracture after removal. CLINICAL RELEVANCE: Clinicians should be aware that bone strength may not be sufficiently restored even 6 months after plate removal of forearm fractures.

Diagnosis of Atrial Fibrillation Using Machine Learning With Wearable Devices After Cardiac Surgery: Algorithm Development Study.

BACKGROUND: Some 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. OBJECTIVE: This 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. METHODS: A 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. RESULTS: One 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. CONCLUSIONS: We 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.

LCAT-trial-24 weeks: Protocol for a clinical study to evaluate the safety of regenerative medicine and gene therapy by the autologous transplantation of human lecithin:cholesterol acyltransferase gene-transduced human pre-adipocytes.

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).