Autologous concentrated bone marrow injection for precollapse osteonecrosis of the femoral head concurrent with contralateral total hip arthroplasty: protocol for a clinical trial.

INTRODUCTION: The femoral head contralateral to the collapsed femoral head requiring total hip arthroplasty (THA) often manifests in the precollapse stage of osteonecrosis of the femoral head (ONFH). It is not yet demonstrated how autologous concentrated bone marrow injection may prevent collapse of the femoral head concurrent with contralateral THA. The primary objective is to evaluate the efficacy of autologous concentrated bone marrow injection for the contralateral, non-collapsed, femoral head in patients with bilateral ONFH, with the ipsilateral collapsed femoral head undergoing THA. METHODS AND ANALYSIS: This is a multicentre, prospective, non-randomised, historical-data controlled study. We will recruit patients with ONFH who are scheduled for THA and possess a non-collapsed contralateral femoral head. Autologous bone marrow will be collected using a point-of-care device. After concentration, the bone marrow will be injected into the non-collapsed femoral head following the completion of THA in the contralateral hip. The primary outcome is the percentage of femoral head collapse evaluated by an independent data monitoring committee using plain X-rays in two directions 2 years after autologous concentrated bone marrow injection. Postinjection safety, adverse events, pain and hip function will also be assessed. The patients will be evaluated preoperatively, and at 6 months, 1 year and 2 years postoperatively. ETHICS AND DISSEMINATION: This protocol has been approved by the Certified Committee for Regenerative Medicine of Tokyo Medical and Dental University and Japan's Ministry of Healthy, Labour and Welfare and will be performed as a class III regenerative medicine protocol, in accordance with Japan's Act on the Safety of Regenerative Medicine. The results of this study will be submitted to a peer-review journal for publication. The results of this study are expected to provide evidence to support the inclusion of autologous concentrated bone marrow injections in the non-collapsed femoral head in Japan's national insurance coverage. TRIAL REGISTRATION NUMBER: jRCTc032200229.

Internet of things-based approach for glycemic control in people with type 2 diabetes: A randomized controlled trial.

AIMS: The utilization of long-term effect of internet of things (IoT) on glycemic control is controversial. This trial aimed to examine the effect of an IoT-based approach for type 2 diabetes. MATERIALS AND METHODS: This randomized controlled trial enrolled 1,159 adults aged 20-74 years with type 2 diabetes with a HbA1c of 6.0-8.9% (42-74 mmol/mol), who were using a smartphone on a daily basis were randomly assigned to either the IoT-based approach group (ITG) or the control group (CTG). The ITG were supervised to utilize an IoT automated system that demonstrates a summary of lifelogging data (weight, blood pressure, and physical activities) and provides feedback messages that promote behavioral changes in both diet and exercise. The primary end point was a HbA1c change over 52 weeks. RESULTS: Among the patients, 581 were assigned to the ITG and 578 were in the CTG. The changes in HbA1c from baseline to the final measurement at 52 weeks [mean (standard deviation)] were -0.000 (0.6225)% in ITG and - 0.006 (0.6449)% in CTG, respectively (P = 0.8766). In the per protocol set, including ITG using the IoT system almost daily and CTG, excluding those using the application almost daily, the difference in HbA1c from baseline to 52 weeks were -0.098 (0.579)% and 0.027 (0.571)%, respectively (P = 0.0201). We observed no significant difference in the adverse event profile between the groups. CONCLUSIONS: The IoT-based approach did not reduce HbA1c in patients with type 2 diabetes. IoT-based intervention using data on the daily glycemic control and HbA1c level may be required to improve glycemic control.

Neuropathic pain development and maintenance and its association with motor recovery after cervical spinal cord injury.

BACKGROUND: In our published randomized controlled trial, we revealed that patients with acute ASIA Grade C incomplete cervical spinal cord injury (SCI) who underwent early surgery (within 24 h post-injury) had accelerated motor recovery at six months than those with delayed surgery (>2 weeks post-injury); however, neuropathic pain (NeP) worsened regardless of surgery timing. Here, we conducted post-hoc analyses to intensively assess NeP development and maintenance. METHODS: Of 44 patients (median 64.5 years; three female; early intervention, n = 26), NeP was categorized into at-level and below-level pain and evaluated at  two weeks and one year after injury using the Neuropathic Pain Symptom Inventory (NPSI). We compared the two groups based on background characteristics. A mixed-design analysis of variance with sex as a covariate was conducted to analyze motor recovery and Health-related quality of life (HRQOL) in groups with severe (NPSI ≥ 10) or mild (NPSI < 10) pain. RESULTS: Upper and lower limb motor impairments were comparable between both groups regardless of pain severity. Severe at-level pain remained stable and worsened at one year than mild at-level pain; however, the upper- and lower-limb motor scores and HRQOL had comparable recovery. Background characteristics did not affect severity or time course of NeP. Patients with severe below-level pain demonstrated slower lower-limb motor recovery than those with mild below-level pain, whereas HRQOL improved regardless of pain severity. CONCLUSIONS: Both at-level and below-level NeP developed and persisted relatively early in the course of traumatic SCI with incomplete motor paralysis; their severities worsened over time or remained severe since onset.

Comparative effectiveness of tocilizumab vs standard care in patients with severe COVID-19-related pneumonia: a retrospective cohort study utilizing registry data as a synthetic control.

BACKGROUND: The severity of coronavirus disease 2019 (COVID-19) infections has led to the development of several therapeutic agents, with tocilizumab becoming increasingly used to treat patients with COVID-19-related pneumonia. This study compared the use of tocilizumab treatment with the standard of care (SOC) to determine its efficacy against severe COVID-19-related pneumonia in Japan. METHODS: This retrospective cohort study was designed to evaluate the efficacy of tocilizumab in two different databases: the JA42434 single-arm study and COVID-19 Registry Japan (COVIREGI-JP), with a synthetic control group from the COVIREGI-JP cohort as a benchmark for the tocilizumab group. The study's primary objective was to evaluate the efficacy of tocilizumab in treating severe COVID-19-related pneumonia compared to the SOC among patients included in the above two databases. The SOC group was extracted as the synthetic control group using exact matching and a propensity score matching in sequence per subject. As a secondary objective, the efficacy of tocilizumab compared to the SOC was evaluated exclusively among patients included in the COVIREGI-JP database. In each objective, the primary endpoint was defined as the time to discharge or the status of awaiting discharge. RESULTS: For the primary endpoint, the hazard ratio (HR) of the tocilizumab group against the SOC group was 1.070 (95% confidence interval [CI]: 0.565-2.028). The median time from Study Day 1 to discharge or the state of awaiting discharge was 15 days in the tocilizumab group and 16 days in the SOC group. The HRs for the secondary endpoints, namely, time to improvement in the clinical state, time to clinical failure, and time to recovery, were 1.112 (95% CI: 0.596-2.075), 0.628 (95% CI: 0.202-1.953), and 1.019 (95% CI: 0.555-1.871), respectively. Similarly, the HR of the primary endpoint for the secondary objective was 0.846 (95% CI: 0.582-1.230). CONCLUSIONS: Tocilizumab did not demonstrate a positive effect on time to discharge or the state of awaiting discharge. Furthermore, no statistically significant differences in other clinical outcomes, such as time to improvement in the clinical state, time to clinical failure, and time to recovery, were observed among the groups.

Efficacy and Safety of Treatment with Plasma from COVID-19-Recovered Individuals.

Convalescent plasma therapy, which involves administering plasma from recovered coronavirus disease 2019 (COVID-19) patients to infected individuals, is being explored as a potential treatment for severe cases of COVID-19. This study aims to evaluate the efficacy and safety of convalescent plasma therapy in COVID-19 patients with moderate to severe illness. An open-label, single-arm intervention study was conducted without a control group. Plasma collected from recovered COVID-19 patients was administered to eligible participants. The primary endpoint was the proportion of patients who were placed on artificial ventilation or died within 14 days of transfusion. Secondary endpoints included clinical improvement, viral load measurements, and adverse event monitoring. A total of 59 cases were included in the study. The primary endpoint was evaluated by comparing the rate obtained in the study to an existing rate of 25%. The study also assessed clinical improvement, viral load changes, and safety endpoints through adverse event monitoring. Convalescent plasma therapy shows potential as a treatment option for COVID-19. This study aimed to provide evidence for the efficacy and safety of this therapy and may contribute to its future use in treating severe cases of COVID-19.

Postoperative Adjuvant Anastrozole for 10 or 5 Years in Patients With Hormone Receptor-Positive Breast Cancer: AERAS, a Randomized Multicenter Open-Label Phase III Trial.

PURPOSE: Treatment with an aromatase inhibitor for 5 years is the standard treatment for postmenopausal hormone receptor-positive breast cancer. We investigated the effects of extending this treatment to 10 years on disease-free survival (DFS). PATIENTS AND METHODS: This prospective, randomized, multicenter open-label phase III study assessed the effect of extending anastrozole treatment for an additional 5 years in postmenopausal patients who were disease-free after treatment with either 5 years of anastrozole alone or 2-3 years of tamoxifen followed by 2-3 years of anastrozole. Patients were allocated randomly (1:1) to continue anastrozole for an additional 5 years or stop anastrozole. The primary end point was DFS, including breast cancer recurrence, second primary cancers, and death from any cause. This study is registered with University Hospital Medical Information Network, Japan (UMIN) clinical trials registry (UMIN000000818). RESULTS: We enrolled 1,697 patients from 117 facilities between November 2007 and November 2012. Follow-up information was available for 1,593 patients (n = 787 in the continue group, n = 806 in the stop group), who were defined as the full analysis set, including 144 patients previously treated with tamoxifen and 259 patients who underwent breast-conserving surgery without irradiation. The 5-year DFS rates were 91% (95% CI, 89 to 93) in the continue group and 86% (95% CI, 83 to 88) in the stop group (hazard ratio, 0.61; 95% CI, 0.46 to 0.82; P < .0010). Notably, extended anastrozole treatment reduced the incidence of local recurrence (continue group, n = 10; stop group, n = 27) and second primary cancers (continue group, n = 27; stop group, n = 52). There was no significant difference in overall or distant DFS. Menopausal or bone-related all-grade adverse events were more frequent among patients in the continue group than those in the stop group, but the incidence of grade ≥3 adverse events was <1% in both groups. CONCLUSION: Continuing adjuvant anastrozole for an additional 5 years after 5 years of initial treatment with anastrozole or tamoxifen followed by anastrozole was well tolerated and improved DFS. Although no difference in overall survival was observed as in other trials, extended anastrozole therapy could be one treatment choice in postmenopausal patients with hormone receptor-positive breast cancer.

Hypertensive Disorders of Pregnancy are Associated with Cardiovascular Disease in Middle- and Older-Aged Japanese Women.

AIM: Hypertensive disorders of pregnancy (HDP) are estimated to occur in up to 10% of all pregnancies and are associated with an increased risk of future cardiovascular disease (CVD) and chronic hypertension (HT). Therefore, we examined the impact of a history of HDP on CVD possibility in middle- and older-aged Japanese women. METHODS: We used the Tohoku Medical Megabank database to obtain the data of 26,024 menopausal women who were aged ≥ 50 years, had children, did not smoke, and did not have chronic kidney disease and to analyze the relationship between HDP history and CVD. RESULTS: A history of HDP was found in 4.6% of women. We divided the women into four groups according to the presence or absence of HDP and HT. The percentage of women with dyslipidemia, diabetes mellitus, and body mass index of ≥ 25 kg/m2 was the highest in the HDP＋ HT＋ group compared to the other groups (43.4%, 24.0%, and 45.2%, respectively). Adjusted odds ratio (OR) for the combined six CVD categories was higher for those with a history of HDP alone (OR [95% confidence interval [CI]]: 1.61 [1.03-2.53]). Moreover, the OR was significantly higher for those with combination with HDP history and HT (OR [95% CI]: 4.11 [3.16-5.35]). The prevalence of individual CVD was also the highest in the HT＋ HDP＋ group. CONCLUSION: An HDP history can influence the risk of CVD in Japanese women, indicating the importance of information about pregnancy outcomes in health management.

Highly accurate acoustical prediction using support vector machine algorithm for post-operative subsidence after cementless total hip arthroplasty.

PURPOSE: Acoustic analysis has recently been applied to cementless total hip arthroplasty (THA). The aim of this study was to develop a machine learning algorithm to predict post-operative subsidence with high accuracy. METHODS: The acoustic parameters of the hammering sounds during a broaching procedure for 62 hips in 55 patients who underwent THAs with cementless taper-wedged stem were analysed. The patient's basic background such as age, sex, height, weight and body mass index, the femoral morphological parameters and the hammering sound characteristics of 24 features of normalised sound pressure (nSP) in 24 frequency ranges were applied to binary classification using a support vector machine using the following models with different features: model A, nSP only; model B, nSP + patients' basic background features; model C, nSP + patients' basic background features + femoral morphological parameters. RESULTS: In 62 hips with 310 hammering sounds, 12 hips (19.4%) showed ≥ 3 mm of post-operative subsidence; hence, 60 hammering sounds were set as positive examples and 250 hammering sounds were set as negative examples. The AUC was very high in all models. The accuracy (AUC/sensitivity/specificity/positive predictive value/negative predictive value/accuracy rate) of each model was as follows: model A, 0.963/0.656/0.996/0.980/0.925/0.934; model B, 0.9866/0.675/1.000/1.000/0.928/0.937 and model C, 0.998/0.750/1.000/1.000/0.950/0.957. CONCLUSION: In this study, we developed a high-accuracy machine learning algorithm for post-operative subsidence using acoustic parameters and additional pre-operative features. Our results represent a step toward the realisation of acoustic monitoring to avoid the complication in cementless THA.

We Should Pay More Attention to Sex Differences to Predict the Risk of Severe COVID-19: Men Have the Same Risk of Worse Prognosis as Women More Than 10 Years Older.

BACKGROUND: Prioritization for novel coronavirus disease 2019 (COVID-19)-related health policies usually considers age and certain other characteristics, but sex is rarely included, despite the higher risk of severe disease in men. The aim of this study was to compare the impact of sex and age on the severity of COVID-19 by estimating the age difference in years for which the risk for men versus women is the same. METHODS: We analyzed 23,414 Japanese COVID-19 inpatients aged 20-89 years (13,360 men and 10,054 women). We graded the severity of COVID-19 (0 to 5) according to the most intensive treatment required during hospitalization. The risk of grade 2/3/4/5 (non-invasive positive pressure ventilation/invasive mechanical ventilation/extracorporeal membrane oxygenation/death), grade 3/4/5, and separately grade 5 was analyzed using a multiple logistic regression model. RESULTS: The odds ratio (OR) of grades 2/3/4/5, 3/4/5 (primary outcome), and 5 for men relative to women was 2.76 (95% CI, 2.44-3.12), 2.78 (95% CI, 2.42-3.19), and 2.60 (95% CI, 2.23-3.03), respectively, after adjustment for age and date of admission. These risks for men were equivalent to those for women 14.1 (95% CI, 12.3-15.8), 11.2 (95% CI, 9.7-12.8), and 7.5 (95% CI, 6.3-8.7) years older, respectively. CONCLUSION: The risks of worse COVID-19 prognosis (grades 3/4/5) in men were equivalent to those of women 11.2 years older. Reanalyzing data extracted from four previous studies also revealed a large impact of sex difference on the severity of COVID-19. We should pay more attention to sex differences to predict the risk of COVID-19 severity and to formulate public health policy accordingly.

Number of Children and Risk of Cardiovascular Disease in Japanese Women: Findings from the Tohoku Medical Megabank.

AIM: Cardiovascular disease (CVD) is the second largest cause of death in Japanese women. Pregnancy and childbirth are events that put a strain on the cardiovascular system. When postpartum weight retention is insufficient, weight gain due to fat deposition during pregnancy might lead to obesity. Thus, we examined the effects of body mass index (BMI) in middle and older ages and the number of children on CVD and metabolic disorders. METHODS: From the Tohoku Medical Megabank database, we used data from 32,000 women aged ≥ 50 years. This database contains obstetrical history, medical history, and laboratory data obtained once from 2013 to 2015. RESULTS: The mean age of participants was 64.2 years, and 47.7% of women had two children. Compared with nulliparous women, those who had a higher number of children had higher BMI and systolic blood pressure. The prevalence of CVD was highest in obese class I (30 kg/m2 ≤ BMI) women with three or more children and the prevalence of hypertension was high in pre-obese (25 kg/m2 ≤ BMI ＜30 kg/m2) and obese class I women with children. Conversely, the prevalence of diabetes and proportion of women whose HbA1c values were ＞6.5% was highest in obese class I women with no children. CONCLUSION: In this study, we found that not only BMI but also the number of children influenced the health status of middle- and older-aged women, suggesting the importance of childbirth history in the health management of women.

Physical oral care prevents ventilator-associated pneumonia in Vietnam: A prospective interventional study.

BACKGROUND: Ventilator-associated pneumonia (VAP) has emerged as a critical issue in the intensive care unit (ICU) because of its high burden on patients and medical staff. Here, we examined the potential for reducing VAP incidence through physical oral care interventions without any medication. METHODS: This prospective interventional study compared VAP incidence during an 8-month baseline period (usual oral care) and a 9-month intervention period (physical oral care with sponge brush) among patients who received mechanical ventilation for >48 h in a tertiary care hospital in Vietnam from 2017 to 2019. Physical oral care was provided by general ICU nurses who had been trained by dentists and infection control nurses. VAP was diagnosed using the Clinical Pulmonary Infection Score. RESULTS: In total, 423 patients were enrolled in the baseline group and 454 patients were enrolled in the intervention group; 303 and 300 patients, respectively, were included in the analysis. Two hundred thirty-eight VAP episodes were identified: 135 (44.6%) during the baseline period and 103 (34.3%) during the intervention period. Univariate analysis revealed significant reduction of VAP occurrence in the intervention period (odds ratio = 0.65; 95% confidence interval = 0.47-0.90; P = 0.010). The incidences of VAP per 1000 ventilator-days were 63.4 (135/2128) during the baseline period and 48.4 (103/2128) during the intervention period (P = 0.038). CONCLUSIONS: Physical oral care without any medication (e.g., chlorhexidine) reduced VAP incidence in the ICU. This method could be used to reduce VAP incidence, particularly in countries with limited medical resources.

Cardiotoxicity of adjuvant chemotherapy with trastuzumab: a Japanese claim-based data analysis.

OBJECTIVE: Adjuvant chemotherapy with trastuzumab improves the postoperative life expectancy of women with early-stage breast cancer. Although trastuzumab is reportedly cardiotoxic, quantification based on real-world evidence is lacking. Therefore, in this study, we aimed to analyse trastuzumab cardiotoxicity using a nationwide claim-based database. METHODS: In this retrospective study, we used data from a nationwide claims database (Japan Medical Data Center, Tokyo, Japan) under the universal healthcare system. Women with breast cancer who underwent initial surgery were included. Patients with recurrent or advanced-stage breast cancer, with a history of heart failure, receiving neoadjuvant chemotherapy or a preoperative history of less than 6 months were excluded. Propensity score (PS) was calculated using logistic regression based on age, cardiovascular risk factors, radiotherapy and concomitant anthracyclines (AC). RESULTS: We identified 12 060 eligible patients (mean age 50.8±8.56 years) between January 2010 and December 2019. After 1:2 PS matching (trastuzumab users, TZ, n=1005; non-users, NT, n=2010), Cox proportional hazards model analysis showed that the rate of heart failure development within 18 months postoperative was significantly higher in the TZ group than in the NT group (adjusted HR 2.28, 95% CI 1.38 to 3.77). Baseline cardiac evaluation in the combined AC/TZ cases was 27.2% preoperative, 66.0% pre-AC and 86.6% pre-TZ, respectively. CONCLUSION: Trastuzumab cardiotoxicity remained relevant in the claim-based analysis adjusted for AC effects. Further collaborative studies in cardio-oncology with real-world data are warranted to improve the rate of baseline cardiovascular risk assessment in patients with cancer scheduled for cardiotoxic cancer treatment.

Endovascular versus open repair in patients with abdominal aortic aneurysm: a claims-based data analysis in Japan.

Objectives: Endovascular aortic repair (EVAR) evolved through competition with open aortic repair (OAR) as a safe and effective treatment option for appropriately selected patients with abdominal aortic aneurysm (AAA). Although endoleaks are the most common reason for post-EVAR reintervention, compliance with lifelong regular follow-up imaging remains a challenge. Design: Retrospective data analysis. Setting: The Japan Medical Data Center (JMDC), a claims database with anonymous data linkage across hospitals, consists of corporate employees and their families of ≤75 years of age. Participants: The analysis included participants in the JMDC who underwent EVAR or OAR for intact (iAAA) or ruptured (rAAA) AAA. Patients with less than 6 months of records before the aortic repair were excluded. Main outcome measures: Overall survival and reintervention rates. Results: We identified 986 cases (837 iAAA and 149 rAAA) from JMDC with first aortic repairs between January 2015 and December 2020. The number of patients, median age (years (IQR)), follow-up (months) and post-procedure CT scan (times per year) were as follows: iAAA (OAR: n=593, 62.0 (57.0-67.0), 26.0, 1.6, EVAR: n=244, 65.0 (31.0-69.0), 17.0, 2.2), rAAA (OAR: n=110, 59.0 (53.0-59.0), 16.0, 2.1, EVAR: n=39, 62.0 (31.0-67.0), 18.0, 2.4). Reintervention rate was significantly higher among EVAR than OAR in rAAA (15.4% vs 8.2%, p=0.04). In iAAA, there were no group difference after 5 years (7.8% vs 11.0%, p=0.28), even though EVAR had initial advantage. There were no differences in mortality rate between EVAR and OAR for either rAAA or iAAA. Conclusions: Claims-based analysis in Japan showed no statistically significant difference in 5-year survival rates of the OAR and EVAR groups. However, the reintervention rate of EVAR in rAAA was significantly higher, suggesting the need for regular post-EVAR follow-up with imaging. Therefore, international collaborations for long-term outcome studies with real-world data are warranted.

Incidence of venous thromboembolism in advanced lung cancer and efficacy and safety of direct oral anticoagulants: a multicenter, prospective, observational study (Rising-VTE/NEJ037 study).

Background: Venous thromboembolism (VTE) is a well-known type of cancer-associated thrombosis and a common complication of malignancy. However, the incidence of VTE associated with lung cancer and the effectiveness of direct oral anticoagulants remain unclear. This study aimed to identify the incidence of VTE associated with lung cancer at the time of diagnosis or during treatment, the efficacy and safety of edoxaban, and associated risk factors. Methods: The Rising-VTE/NEJ037 study was a multicenter prospective observational study. Altogether, 1021 patients with lung cancer who were unsuitable for radical resection or radiation were enrolled and followed up for 2 years. Patients with VTE at the time of lung cancer diagnosis started treatment with edoxaban. The primary endpoint of this trial was the rate of newly diagnosed VTE after enrollment or recurrence rate 6 months after treatment initiation. Results: Data were available for 1008 patients. The median age was 70 years (range: 30-94 years), and 70.8% were men. Sixty-two patients had VTE at the time of lung cancer diagnosis, and 38 (9.9%) developed VTE at follow-up. No cases of VTE recurrence were recorded 6 months after treatment initiation with edoxaban. Major and clinically relevant non-major bleeding events occurred in 4.9% of patients and increased to 22.7% in the edoxaban treatment group. Conclusions: VTE occurrence should be monitored during lung cancer treatment. Although treatment with edoxaban was highly effective in preventing VTE recurrence, its administration should be cautiously considered because of the high bleeding rate. Trial registration: jRCTs061180025.

A phase I/II study of triple-mutated oncolytic herpes virus G47∆ in patients with progressive glioblastoma.

Here, we report the results of a phase I/II, single-arm study (UMIN-CTR Clinical Trial Registry UMIN000002661) assessing the safety (primary endpoint) of G47∆, a triple-mutated oncolytic herpes simplex virus type 1, in Japanese adults with recurrent/progressive glioblastoma despite radiation and temozolomide therapies. G47Δ was administered intratumorally at 3 × 108 pfu (low dose) or 1 × 109 pfu (set dose), twice to identical coordinates within 5-14 days. Thirteen patients completed treatment (low dose, n = 3; set dose, n = 10). Adverse events occurred in 12/13 patients. The most common G47Δ-related adverse events were fever, headache and vomiting. Secondary endpoint was the efficacy. Median overall survival was 7.3 (95%CI 6.2-15.2) months and the 1-year survival rate was 38.5%, both from the last G47∆ administration. Median progression-free survival was 8 (95%CI 7-34) days from the last G47∆ administration, mainly due to immediate enlargement of the contrast-enhanced area of the target lesion on MRI. Three patients survived >46 months. One complete response (low dose) and one partial response (set dose) were seen at 2 years. Based on biopsies, post-administration MRI features (injection site contrast-enhancement clearing and entire tumor enlargement) likely reflected tumor cell destruction via viral replication and lymphocyte infiltration towards tumor cells, the latter suggesting the mechanism for "immunoprogression" characteristic to this therapy. This study shows that G47Δ is safe for treating recurrent/progressive glioblastoma and warrants further clinical development.

Intratumoral oncolytic herpes virus G47∆ for residual or recurrent glioblastoma: a phase 2 trial.

This investigator-initiated, phase 2, single-arm trial primarily assessed the efficacy of G47∆, a triple-mutated, third-generation oncolytic herpes simplex virus type 1, in 19 adult patients with residual or recurrent, supratentorial glioblastoma after radiation therapy and temozolomide (UMIN-CTR Clinical Trial Registry UMIN000015995). G47Δ was administered intratumorally and repeatedly for up to six doses. The primary endpoint of 1-yr survival rate after G47∆ initiation was 84.2% (95% confidence interval, 60.4-96.6; 16 of 19). The prespecified endpoint was met and the trial was terminated early. Regarding secondary endpoints, the median overall survival was 20.2 (16.8-23.6) months after G47∆ initiation and 28.8 (20.1-37.5) months from the initial surgery. The most common G47∆-related adverse event was fever (17 of 19) followed by vomiting, nausea, lymphocytopenia and leukopenia. On magnetic resonance imaging, enlargement of and contrast-enhancement clearing within the target lesion repeatedly occurred after each G47∆ administration, which was characteristic to this therapy. Thus, the best overall response in 2 yr was partial response in one patient and stable disease in 18 patients. Biopsies revealed increasing numbers of tumor-infiltrating CD4+/CD8+ lymphocytes and persistent low numbers of Foxp3+ cells. This study showed a survival benefit and good safety profile, which led to the approval of G47∆ as the first oncolytic virus product in Japan.

Association between prenatal exposure to antidepressants and neonatal morbidity: An analysis of real-world data from a nationwide claims database in Japan.

BACKGROUND: Depression during pregnancy is relatively undertreated; however, the relationship between prenatal exposure to antidepressants and neonatal outcomes remains controversial. METHODS: This retrospective cohort study used a Japanese nationwide claims database. Data of 114,359 singletons born between January 2005 and November 2019 were used to evaluate the relationship between prenatal exposure to antidepressants and neonatal morbidity. RESULTS: Of 2892 mothers with a history of depression before delivery, 352 (12.1%) received prescriptions within three months before delivery (MP3), and 2540 did not (non-MP3). The participants were propensity score matched (PSM) in a ratio of 1:3 using logistic regression (MP3_PSM [n = 351] vs non-MP3_PSM [n = 1052]), and maternal prescriptions of antidepressants within three months before delivery were associated with neonatal morbidity indicators, including admission to the neonatal intensive care unit (NICU) (15.7 vs. 9.1%, odds ratio (OR) 1.9 [95% confidence interval (CI): 1.3-2.6]), poor neonatal adaptation syndrome (6.0 vs 1.0%, OR 6.6 [95% CI: 3.1-14.2]), transient tachycardia (15.7 vs. 6.7%, OR 2.6 [95% CI: 1.8-3.8]), and meconium aspiration syndrome (3.1 vs 0.7%, OR 4.8 [95% CI, 1.9-12.5]). There were no significant differences in the long-term duration of stay at the NICU (>15 days). LIMITATIONS: Confounding factors may remain even after the propensity matching. CONCLUSION: Maternal prescription of antidepressants within three months before delivery was associated with increased admission to the NICU. However, the absolute risk of severe neonatal morbidity was low. Therefore, collaborative care for prenatal depression and the neonatal intensive care is warranted.

Renin-angiotensin system blocker and the COVID-19 aggravation in patients with hypertension, diabetes, renal failure, Cerebro-cardiovascular disease, or pulmonary disease: Report by the COVID-19 Registry Japan.

BACKGROUND: The role of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) in the pandemic context of coronavirus disease 2019 (COVID-19) continues to be debated. Patients with hypertension, diabetes mellitus, chronic renal failure, cerebro-cardiovascular disease, or chronic obstructive pulmonary disease (COPD), who often use ACEi/ARB, may be at risk of severe COVID-19. However, there are no data available on the association of ACEi/ARB use with COVID-19 severity in this population. METHODS: This study is an observational study of patients with a positive severe acute respiratory syndrome coronavirus 2 test and inpatient treatment at a healthcare facility, using the registry information of COVIREGI-JP. Our primary outcomes were in-hospital death, ventilator support, extracorporeal membrane oxygenation support, and intensive care unit admission. Out of the 6055 patients, 1921 patients with preexisting hypertension, diabetes mellitus, chronic renal failure, cerebro-cardiovascular disease, or COPD were enrolled. RESULTS: Factors associated with an increased risk of the primary outcomes were aging, male sex, COPD, severe renal impairment, and diabetes mellitus. No correlations were observed with ACEi/ARB, cerebro-cardiovascular diseases, or hypertension. Associated factors in male patients were aging, renal impairment, hypertension, and diabetes. In female patients, factors associated with an increased risk were aging, ACEi/ARB, renal impairment, and diabetes, whereas hypertension was associated with a lower risk of the primary outcomes. CONCLUSIONS: Independent factors for the primary outcomes were aging, male sex, COPD, severe renal impairment, and diabetes, but not ACEi/ARB. Based on this registry data analysis, more detailed data collection and analysis is needed with the cooperation of multiple healthcare facilities.

Clinical characteristics of the first three waves of hospitalised patients with COVID-19 in Japan prior to the widespread use of vaccination: a nationwide observational study.

Background: Before widespread coronavirus disease (COVID-19) vaccinations, Japan experienced three COVID-19 epidemic waves. This study aimed to evaluate the characteristics of hospitalised COVID-19 patients and reveal temporal changes. Methods: This study included 33,554 hospitalised patients with COVID-19 from 553 healthcare facilities. Data were analysed by age group and epidemic wave (first wave, 01/01/2020-05/31/2020; second wave, 06/01/2020-10/31/2020; and third wave, 11/01/2020-03/31/2021). Findings: By age group, 3% (under 18), 22% (young), 34% (middle-aged), and 41% (older patients) were aged 0-17, 18-39, 40-64, and >65 years; while 16%, 35%, and 49% were in the first, second, and third wave, respectively. The patients' overall median age (58 years; interquartile range, 39-74) was lowest and highest during the second and third waves, respectively. The frequency of any comorbidity was lowest and highest during the second (44·5%) and third (63·6%) waves, respectively. The symptoms at admission and exposure history differed considerably with age. The overall case fatality rate (5%) was highest among older patients (11·4%). Case fatality rate was highest and lowest during the first (7·3%) and second (2·8%) waves, respectively. Medication use changed over time. Interpretation: Although the overall case fatality rate remained relatively low, it was more than twice as high among older patients. After adjusting for age and comorbidities, the risk of death was highest in the first wave. Funding: This work was supported by the Ministry of Health, Labour and Welfare "Research on Emerging and Re-emerging Infectious Diseases and Immunization" 19HA1003].