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BackgroundThe Japanese Network of Cardiovascular Departments for Adult Congenital Heart Disease (JNCVD-ACHD) was founded in 2011 for the lifelong care of adult patients with congenital heart disease (ACHD patients). This network maintains the first Japanese ACHD registry.Methods and resultsFrom 2011 to 2019, the JNCVD-ACHD registered 54 institutions providing specialized care for ACHD patients in 32 of the 47 prefectures in Japan. The registry collected data on the disease profile for 24,048 patients from 50 institutions and the patient characteristics for 9743 patients from 24 institutions. The most common ACHDs were atrial septal defect (20.5 %), ventricular septal defect (20.5 %), tetralogy of Fallot (12.9 %), and univentricular heart (UVH)/single ventricle (SV; 6.6 %). ACHD patients without biventricular repair accounted for 37.0 % of the population. Also examined were the serious anatomical and/or pathophysiological disorders such as pulmonary arterial hypertension (3.0 %) including Eisenmenger syndrome (1.2 %), systemic right ventricle under biventricular circulation (sRV-2VC; 2.8 %), and Fontan physiology (6.0 %). The sRV-2VC cases comprised congenitally corrected transposition of the great arteries without anatomical repair (61.9 %) and transposition of the great arteries with atrial switching surgery (38.1 %). The primary etiology (86.4 %) for Fontan physiology was UVH/SV. In addition, developmental/chromosomal/genetic disorders were heterotaxy syndromes (asplenia, 0.9 %; polysplenia, 0.7 %), trisomy 21 (4.0 %), 22q11.2 deletion (0.9 %), Turner syndrome (0.2 %), and Marfan syndrome (1.1 %).ConclusionsAlthough the specific management of ACHD has systematically progressed in Japan, this approach is still evolving. For ideal ACHD care, the prospective goals for the JNCVD-ACHD are to create local networks and provide a resource for multicenter clinical trials to support evidence-based practice.

Decisions concerning approval of human papillomavirus (HPV) vaccines and their use are based on expert evaluation of the vaccines. However, the quantitative differences between vaccine benefits and risks are difficult for non-experts to understand. In this study, we developed a new method to calculate the benefits and risks of the HPV vaccines using disability-adjusted life year (DALY) as the mono-scaled weight for various benefits and risks relevant to the vaccines. We evaluated benefits as a gain of DALY values for cervical cancer and risks as the loss of DALY values for various adverse events by the vaccination. To calculate the loss of DALY values, we integrated all adverse events in the International Classification of Diseases chapters. The novel method reflected the men-women ratio of this epidemiological disease to a certain extent. Among the vaccinated women, 111372 and 477190 received a bivalent and quadrivalent vaccine, respectively. The DALY rate of cervical cancer was 148.7. The calculated benefit for the bivalent and quadrivalent vaccines was 149.1 and 638.8, respectively, and set as the theoretical maximum. The risk was calculated as 129.3 and 49.6 in the bivalent and quadrivalent vaccines, respectively. Since HPV vaccines prevent several other cancers, the benefit of the vaccination extends beyond the risk according to this new method.

In open-label trials, the details of the adjudicators are essential to evaluate the risk of detection bias. We aimed to describe how the adjudicators of progression-free survival (PFS) and objective response rate (ORR) have been reported in open-label trials of anticancer drugs.A literature search was conducted using MEDLINE via PubMed. We included open-label, parallel-group superiority randomized trials that investigated the PFS and ORR of anticancer drugs for solid tumors. After screening based on the titles and abstracts, 200 articles were randomly selected from 2017 to 2021. The researchers independently checked the eligibility and collected the adjudicators' information in the protocol, registry, and original article.One hundred fifty five studies reported the PFS and ORR. Approximately half of the studies did not report adjudicators (47.7% in PFS and 47.6% in ORR) in the published articles. The inconsistency between the protocol/registry and the published article was 31.0% for PFS and 33.5% for ORR. The prespecified outcomes were not reported in 5.2% of the studies evaluating PFS and 4.5% evaluating ORR.This methodological review found that adjudicators were poorly and inconsistently reported between the protocol/registry and the final publication in open-label trials of anticancer drugs.

Background Combined resection of the right hepatic artery (RHA) is sometimes required to achieve complete resection of hilar cholangiocarcinoma. The present study aimed to evaluate the feasibility of combined resection and subsequent reconstruction by continuous suture of the RHA during left hepatectomy for cholangiocarcinoma. Materials and methods We retrospectively compared the outcomes after left hepatectomy with biliary reconstruction for cholangiocarcinoma between patients with and without RHA resection and reconstruction. Results Of the 25 patients who underwent left hepatectomy combined with biliary reconstruction, eight patients (32%) underwent combined resection and reconstruction of the RHA (AR group). The demographic characteristics were not different between the AR and non-AR groups. The amount of intraoperative bleeding was significantly greater in patients with AR (2350 mL vs. 900 mL, p = 0.017). The prevalence of early complications above grade III in Clavien–Dindo classification and late complications were not significantly different between the AR and non-AR groups. In the AR group, complications directly associated with AR, such as thrombosis or reanastomosis, were not observed. On Kaplan–Meier analysis, recurrence-free survival (p = 0.618) and overall survival (p = 0.803) were comparable between the two groups despite the advanced T stages in the AR group. Conclusions Combined resection and subsequent reconstruction of the RHA during left-sided hepatectomy is a feasible treatment alternative for cholangiocarcinoma.

Neglected tropical diseases (NTDs) are communicable diseases that are uncommon in developed countries but epidemic in developing countries of the tropical and subtropical regions around the world. One of the important contributions expected of pharmaceutical companies is the development and provision of drugs effective against NTDs. Firstly, Eisai has distributed at price zero to endemic countries worldwide diethylcarbamazine (DEC) tablets for patients suffering with lymphatic filariasis (LF). Eisai's efforts toward improving global health have resulted in a rich portfolio of assets addressing six infectious diseases: malaria, tuberculosis, Chagas disease, LF, leishmaniasis, and mycetoma. As the most advanced project, Eisai has developed E1224, which is available in both intravenous and oral formulations, and delivers ravuconazole, the active form of fosravuconazole, with a long plasma half-life. The first clinical trials of E1224 for Chagas disease have already been completed, led by the Drugs for Neglected Diseases initiative (DNDi). As a result, parasite clearance was observed with E1224 during the treatment phase, but parasite regrowth was observed after the end of drug administration. On the other hand, a clinical trial for eumycetoma in collaboration with DNDi is ongoing supported by the Global Health Innovative Technology (GHIT) Fund. In this manner, Eisai will continue its Medicine Creation research projects in collaboration with various Product Development Partnerships (PDPs) and academia.

Late recurrence of renal cell carcinoma (RCC) is observed in some postoperative patients. In addition, some of these patients are lost to long-term postoperative follow-up. We reviewed the treatment results and prognosis of postoperative patients with RCC at Chiba University Hospital, with the aim of clarifying the proportion and background of patients lost to follow-up.This retrospective study included 1176 RCC patients who underwent radical or/and partial nephrectomy. Overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and lost follow-up free survival (LFFS) were evaluated and the risk factors for LFFS identified.The median RFS for stage II and II cases was 188.3 and 104.0 months, respectively. Even in stage I, recurrence was observed in about 20% of patients 20 years after surgery. The Kaplan-Meier curve for LFFS showed a linear descent over time, with 50% of patients lost to follow-up within 25 years. Older age (≥ 62 years), histological type (clear cell RCC), and no recurrence were significant risk factors for lost follow-up.Long-term follow-up is necessary after RCC surgery because late recurrence cases are not uncommon. We believe that lifelong follow-up with imaging studies is recommended for postoperative RCC patients. Early detection of recurrence in postoperative patients is a very important issue, and it may be worthwhile for improving the prognosis of postoperative patients to focus on patients lost to follow-up who may have been overlooked.

Compassionate use is a system that provides patients with exceptional access to investigational new drugs to treat life-threatening diseases that have no effective conventional treatments. The purpose of this study was to characterize and assess the current status of the compassionate use program's application in Japan by evaluating expanded access clinical trials (EACTs) conducted between 2016 and 2021. In this study, a data set containing all EACTs, and pivotal clinical trials (PCTs) conducted in Japan between February 2016 and April 2021 was obtained from the Pharmaceutical and Medical Devices Agency, systemically reviewed, and analyzed. During the 5 years since EACTs began in Japan, out of 2,031 PCTs, 31 EACTs were conducted in Japan. Twenty-four trials (77.4%) of the 31 EACTs used anticancer drugs and 5 of those trials (16.1%) were conducted in children. Furthermore, we conducted an EACT survey for drugs with a high degree of social and patient demands as recommended in the EACT notification. Among the 2,031 PCTs, we found 152 trials with high degree of social and patient demands. Of these, EACT was implemented in 17 trials (11.2%). Days from the start of the EACT to the submission of new drug applications and the approval were 9.0 (67.0-56.5) and 208.0 (172.8-308.8) days, respectively. Of the 31 EACTs conducted, 24 (77.4%) drugs have been approved as of August 2021. This first comprehensive study on EACTs clarified the current status and issues of Japan's compassionate use system and the 5 years since the program initiated.

A cancer diagnosis is devastating for both patients and their caregivers. With high morbidity and mortality, cancer is a serious disease area with unmet medical needs. Thus, innovative anticancer drugs are in high demand worldwide but are unequally available. Our study focused on first-in-class (FIC) anticancer drugs and investigated their actual development situation in the United States (US), European Union (EU), and Japan over the last two decades to obtain fundamental information for understanding how the aforementioned demands are met, especially to eliminate drug lags among regions. We identified FIC anticancer drugs using pharmacological classes for the Japanese drug pricing system. Most FIC anticancer drugs were first approved in the US. The median approval time for anticancer drugs in new pharmacological classes during the last two decades in Japan (5072 days) was significantly different (p=0.043) from that in the US (4253 days), though it was not significantly different from that in the EU (4655 days). Submission and approval lags between the US and Japan were more than 2.1 years, and those between the EU and Japan were more than 1.2 years. However, those between the US and the EU were less than 0.8 years. The development rate of FIC anticancer drugs in Japan is slower than in other regions. Even among developed countries, FIC anticancer drug lags exist. Considering the high impact of FIC anticancer drugs on society worldwide, we should work together to reduce drug lag among regions using an improved international cooperative framework.

Regulatory authorities in several regions have introduced a number of expedited programs (EPs) to promote the development of innovative drugs for patients in their own countries. The EPs in the United States (US), alone or in combination, have been successful in shortening the clinical development time in the US. We examined whether US-EPs, as well as other related factors, have an impact on the clinical development time in Japan to obtain new insights for more efficient drug development.In total, 168 drugs approved as new molecular entities (NMEs) in Japan and approved in the US between 2012 and 2019 were surveyed. We compared the clinical development time in Japan for those drugs with or without US-EPs. We also examined the impact of overlapping designations of US-EPs on clinical development time in Japan. Multiple regression analysis was performed to identify associated factors related to clinical development time in Japan, including US-EPs.The clinical development time in Japan was significantly shorter at 37.4 [Interquartile range, IQR, 28.7-48.9] months for Accelerated Approval (AA), 42.2 [30.0-53.6] months for Breakthrough Therapy (BT), 42.3 [29.3-56.4] months for Fast Track (FT), 44.5 [30.7-60.0] months for US Priority Review, and 45.2 [31.3-61.8] months for US Orphan Designation. Multiple regression analysis revealed that AA (p = 0.008), FT (p = 0.013), Japan Priority Review, and the difference in development initiation dates between the US and Japan were significant factors related to a decrease in the clinical development time in Japan, whereas Japan Orphan Designation and the development of anticancer drugs were significant factors linked to an increase in the clinical development time.US-EPs were associated with a decrease in the clinical development time in Japan for the drugs that were approved as NMEs in Japan and approved in the US. This association was not restricted to particular therapeutic areas or development strategies. Stakeholders involved in drug development, including the drug developers and regulatory authorities in Japan, should realize these effects for efficient drug development.

A 51-year-old woman was admitted because of hypercalcemia. Neck ultrasonography and computed tomography revealed the presence of parathyroid cysts on both sides. After primary hyperparathyroidism was diagnosed by technetium-99m-methoxyisobutylisonitrile scintigraphy, the patient was successfully treated with total parathyroidectomy and autotransplantation. She also had a non-functioning pancreatic neuroendocrine tumor, prolactinoma, and adrenal tumors with subclinical Cushing's syndrome. Given these clinical features and her family history, multiple endocrine neoplasia type 1 (MEN1) was suspected, and germline DNA sequencing revealed a missense mutation (c.1013TC, [corrected] p.Leu338Pro) in exon 7 of MEN1. This case demonstrates the phenotypic and genetic diversity of MEN1.

Transabdominal amnioinfusion is beneficial in oligohydramnios, which has high fetal mortality and does not improve with observation alone. However, there are few reports on the maternal adverse events of transabdominal amnioinfusion. This study aimed to evaluate the adverse events of amniocentesis with transabdominal amnioinfusion.This study is a retrospective cohort study at a single tertiary perinatal center in Japan. A total of 313 procedures in 126 patients who underwent amniocentesis for transabdominal amnioinfusion at our tertiary perinatal institution were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE). Adverse events were retrospectively examined using a 5-grade evaluation based on the CTCAE. Procedurally, a 21-23-G percutaneous transhepatic cholangiography drainage (PTCD) needle was advanced under ultrasound guidance into the amniotic fluid cavity with a gravity-fed infusion of warm saline solution.No maternal deaths were recorded. Only two maternal/fetal adverse events occurred, and grade 4 fetal adverse events requiring pregnancy termination were observed in seven cases. Fetal death occurred in five cases, all with severe oligohydramnios and premature rupture of the membranes. No placental abruption or bleeding occurred before or after delivery.Adverse events during transabdominal amnioinfusion were successfully analyzed using CTCAE. We also provided new terminology for evaluating adverse events during amnioinfusion. Our results may encourage obstetricians to perform amnioinfusion in difficult situations, with less concern for severe maternal or fetal adverse events.

Cancer cachexia and the associated skeletal muscle wasting are considered poor prognostic factors, although effective treatment has not yet been established. Recent studies have indicated that the pathogenesis of skeletal muscle loss may involve dysbiosis of the gut microbiota and the accompanying chronic inflammation or altered metabolism. In this study, we evaluated the possible effects of modifying the gut microenvironment with partially hydrolyzed guar gum (PHGG), a soluble dietary fiber, on cancer-related muscle wasting and its mechanism using a colon-26 murine cachexia model. Compared with a fiber-free (FF) diet, PHGG contained fiber-rich (FR) diet-attenuated skeletal muscle loss in cachectic mice by suppressing the elevation of the major muscle-specific ubiquitin ligases Atrogin-1 and MuRF1, as well as the autophagy markers LC3 and Bnip3. Although tight-junction markers were partially reduced in both FR and FF diet-fed cachectic mice, the abundance of Bifidobacterium, Akkermansia, and unclassified S24-7 family increased by FR diet, contributing to the retention of the colonic mucus layer. The reinforcement of the gut barrier function resulted in the controlled entry of pathogens into the host system and reduced circulating levels of lipopolysaccharide-binding protein (LBP) and IL-6, which in turn led to the suppression of proteolysis by downregulating the ubiquitin-proteasome system and autophagy pathway. These results suggest that dietary fiber may have the potential to alleviate skeletal muscle loss in cancer cachexia, providing new insights for developing effective strategies in the future.

Complete endoscopic mucosal healing is defined as a Mayo endoscopic subscore of 0. Some patients diagnosed with a Mayo endoscopic subscore 0 may present with subsequent clinical relapse. Here, we aimed to demonstrate mucosal cytokine profile as a predictor of clinical relapse in ulcerative colitis patients with a Mayo endoscopic subscore of 0 as a marker of mucosal healing.We conducted prospective observational pilot study to examine the relationship between mucosal cytokine expression and subsequent relapse of UC patients diagnosed with a Mayo endoscopic subscore of 0. We enrolled 55 patients, and expression of cytokines tumor necrosis factor-α, interferon γ, interleukin-1β, interleukin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-7, interleukin-8, interleukin-9, interleukin-10, interleukin-12, interleukin-13, interleukin-15, interleukin-17A, interleukin-17F, interleukin-18, interleukin-21, interleukin-22, interleukin-23, interleukin-27, and interleukin-33 was measured by quantitative real-time PCR using rectal mucosa biopsy materials. Cytokine expression levels were compared between patients who relapsed between March 1, 2016, and March 30, 2020, of the study period and those who remained in remission.Ten cytokines, including interleukin-2, interleukin-4, interleukin-8, interleukin-10, interleukin-12, interleukin-15, interleukin-17A, interleukin-21, interleukin-23, and interleukin-33, were significantly elevated in patients with subsequent relapse compared with those who remained in remission. Interleukin-8 expression was the most useful predictor.In the rectal mucosa of ulcerative colitis patients with Mayo endoscopic subscore 0, levels of several cytokines were elevated in cases of subsequent relapse. Among these, interleukin-8 expression was the most useful for predicting relapse.

Breast cancer is the most common global malignancy and the leading cause of cancer deaths. Despite this, undergraduate and postgraduate exposure to breast cancer is limited, impacting on the ability of clinicians to accurately recognise, assess and refer appropriate patients. This article provides a comprehensive review of the pathology, epidemiology, clinical presentation, referral pathways and management of breast cancer in the UK. It also describes how to conduct a thorough clinical breast examination.

Background Redundant publication of systematic reviews and meta-analyses (SRs/MAs) on the same topic presents an increasing burden for clinicians. The aim of this study was to describe variabilities in effect size and methodological quality of overlapping surgery-related SRs/MAs and to investigate factors associated with their postpublication citations. Methods PubMed/MEDLINE was searched to identify SRs/MAs of RCTs on thoracoabdominal surgeries published in 2015. Previous SRs/MAs on the same topics published within the preceding 5 years (2011–2015) were identified and 5-year citation counts (through to 2020) were evaluated. Discrepancies in pooled effect sizes and their methodological quality using A Measurement Tool to Assess Systematic Reviews (AMSTAR) among overlapping SRs/MAs were assessed. The SR/MA-level factors associated with 5-year citation counts were explored, using a mixed-effects regression model with a random intercept for surgical topics. Results A total of 57 surgery-related SRs/MAs (48 topics) published in 2015 were identified, and 146 SRs/MAs had overlapping publications on 29 topics (60.4 per cent of all topics) in the preceding 5 years. There was considerable variability in methodological quality of SRs/MAs and coverage probability for relevant RCTs, resulting in discrepant effect size estimates for the same topic. High quality (AMSTAR score 8–11) was independently associated with higher 5-year citation counts (coefficient = 32.82; 95 per cent c.i. 15.63 to 50.02; P Conclusion Overlapping SRs/MAs with high variability in results and methodological quality were common in surgery. A high-quality SR/MA score was an independent predictor of more frequent citations. Researchers and journal editors should concentrate their efforts on limiting publications to higher-quality reviews.

Background Severe adhesions and fibrosis between the posterior wall of the gallbladder and liver bed often render total cholecystectomy after percutaneous transhepatic gallbladder drainage (PTGBD) difficult, leading to high open conversion rates. Since the publication of Tokyo Guidelines 2018 (TG18), our policy has shifted from open conversion to subtotal cholecystectomy (SC) when total laparoscopic cholecystectomy for difficult cases of cholecystitis is not feasible. Recently, SC has been frequently applied as bailout surgery for complicated cholecystitis. Nonetheless, the efficacy and validity of laparoscopic SC after PTGBD remain unclear. This study aimed to evaluate the safety and feasibility of laparoscopic SC after PTGBD for grade II or III acute cholecystitis (AC) by comparing two periods of altered surgical strategies. Methods This retrospective cohort study was conducted between January 2013 and December 2020. A total of 44 eligible patients with grade II or III AC were divided according to the time of cholecystitis onset into the pre-TG18 group (2013–2017, n = 17) and post-TG18 group (2018–2020, n = 27). Patients’ background demographics, surgical method, surgical results, and postoperative complications were compared. Results The interval between PTGBD and surgery was significantly longer in the post-TG18 group than in the pre-TG18 group (15 [interquartile range: 9–42] days vs. 8 [4–11] days; P = 0.010). The frequency of laparoscopic cholecystectomy significantly increased from 52.9% in the pre-TG18 group to 88.9% in the post-TG18 group (P = 0.007), whereas the frequency of SC was 23.5% and 40.7%, respectively, which showed no statistically significant difference (P = 0.241). However, the rate of laparoscopic SC significantly increased from 0 to 90.9% among 15 SC cases, whereas the rate of open SC significantly plummeted from 100 to 9.1% (P = 0.001). Significant differences in the operative time, amount of intraoperative bleeding, and incidence of postoperative complications (wound infection and subhepatic abscess) were not observed. Mortality, bile leakage, and bile duct injury did not occur in either group. Conclusions For grade II or III AC after PTGBD, aggressive adoption of SC increased the completion rate of laparoscopic surgery. Laparoscopic SC is a safe and feasible treatment option.

Copper is one of the essential trace elements in humans, and its deficiency causes various diseases. Zinc acetate dihydrate is administered to treat hypozincemia in preterm infants; however, zinc inhibits the gastrointestinal absorption of copper, which may cause copper deficiency. To safely treat hypozincemia in preterm infants, we retrospectively analyzed the factors reducing serum copper concentrations when zinc is administered to preterm infants with hypozincemia. Seventy preterm infants were included in the present study. Serum zinc and copper concentrations, doses, and other clinical characteristics were retrieved from electronic medical records. The administration of zinc acetate dihydrate decreased serum copper concentrations in 21 out of 70 patients. In comparisons between the two groups with and without a decrease in serum copper concentrations, significant differences were observed in postmenstrual age (34.9 and 35.9 weeks, respectively) and serum zinc concentrations (62.0 and 58.0 μg/dL, respectively) at the start of the zinc acetate dihydrate treatment. A logistic regression analysis identified postmenstrual age as a significant factor decreasing serum copper concentrations. In the ROC curve, the cut-off value for postmenstrual age for a decrease in serum copper concentrations was 34.143 weeks. The present results suggest that when zinc acetate dihydrate is administered to preterm infants with a low postmenstrual age who are at higher risk of decreased serum copper concentrations, particularly to those with a postmenstrual age34 weeks, it is important to consider copper deficiency and periodically measure serum copper concentrations.

A 67-year-old woman underwent polypectomy for a tumor at the descending colon. Pathologically, the tumor was diagnosed as adenocarcinoma with an invasion of 2000 μm. Computed tomography showed a swollen paracolic lymph node and a mass lesion in the presacral space. Magnetic resonance imaging revealed a multio-cular cystic lesion. On diagnosis of descending colon cancer and tailgut cyst, she underwent synchronous lapa-roscopic resection. Histopathologically, the colon cancer was diagnosed as pT1bN1M0, pStage IIIa. The pre-sacral cystic lesion was diagnosed as a nonmalignant tailgut cyst with negative surgical margin. The patient is currently doing well without recurrence at 28 months.

Dysphagia can result from shock, trauma, aging, head and neck neoplasms, and some cerebrovascular diseases or neuromotor degenerative disorders. Swallowing rehabilitation therapy combined with postural control of the neck, head, and body can be effective for patients with dysphagia. Though the lateral decubitus posture has been a favorable option for swallowing rehabilitation therapy, available clinical data pertaining to it are scarce. Twenty-seven healthy volunteers were enrolled in this study. The subjects underwent a repetitive saliva swallowing test, food swallowing test, and water swallowing test. The trials were performed in four different positions: upright sitting position, lateral decubitus position with the head raised to 60°, lateral decubitus position with the head raised to 30°, and complete lateral decubitus position. After each trial, the subjects were asked to declare the swallowing difficulty utilizing a visual analogue scale. Swallowing time and swallowing sound level were recorded simultaneously, as objective evaluation in each trial. We analyzed the visual analogue scale scores, swallowing time, and swallowing sound levels for all the four positions. The results of the visual analogue scale of the water swallowing test in the sitting position were significantly lower than those of the complete lateral decubitus position (p

INTRODUCTION Local impedance (LI) drops during radiofrequency ablation can predict lesion formation. Some conduction gaps during pulmonary vein isolation (PVI) can be associated with nonendocardial connections. This study aimed to investigate the incidence, characteristics, and predictors of endocardial and nonendocardial conduction gaps during an LI-guided PVI. METHODS AND RESULTS We prospectively enrolled 157 consecutive patients undergoing an initial LI-guided extensive PVI of atrial fibrillation (AF). After the first-pass encirclement, the residual conduction gaps and reconnected gaps were mapped using Rhythmia (Boston Scientific) and a mini-basket catheter. Right and left PV (RPV/LPV) gaps were observed in 22.3% and 18.5% of the patients, respectively: 27 endocardial and 49 nonendocardial gaps. The carina regions were common sites for the gaps (51 carina-related vs. 25 noncarina-related). The carina-related gaps consisted of more nonendocardial gaps than endocardial gaps (RPVs: 90.0% vs. 10.0%, p = .001; LPVs: 76.2% vs. 23.8%, p

WHAT IS KNOWN AND OBJECTIVE Drug development is generally a long and expensive process. Regulatory authorities have established several expedited regulatory pathways, such as accelerated approval designation in the United States (1992) and conditional approval regulation in Japan (2017). In Japan, prior to 2017, the Pharmaceutical and Medical Device Agency (PMDA) granted marketing approval without requesting the results of confirmatory clinical trials case by case basis, and even after 2018, only three drugs have been approved via the conditional approval pathway, although many drugs without confirmatory clinical trials have been approved without this pathway; therefore, it is difficult to predict the circumstances under which confirmatory clinical trials may be waived. The aim of this study was to investigate the characteristics of drugs for which the requirement of confirmatory clinical trials for approval was waived in Japan. We also aimed to identify factors and formulae to predict a waiver of confirmatory clinical trials. METHODS Data on approved drugs and their characteristics were mainly extracted from the Japan Pharmaceuticals and Medical Device Agency database. The seriousness of the disease, existence of available treatments and number of patients were considered as candidate factors. The influence of each factor on receiving a waiver was determined using logistic regression analysis comparing drugs approved with and without confirmatory clinical trials as the binary response variable. The predictive formula was derived from the results of the logistic regression analysis. A receiver operating characteristic curve was used to evaluate the accuracy of the prediction. RESULTS AND DISCUSSION Categorization of drugs as antineoplastic agents, use of the cost accounting method in the drug pricing system, "orphan" designation and accelerated approval designation in the United States emerged as significant factors in the logistic regression analysis, predicting a waiver for confirmatory clinical trials (p ≤ 0.05). These factors were then used to establish a predictive model to ascertain whether confirmatory clinical trials would be necessary for a new drug, exhibiting good sensitivity (0.8) and specificity (0.8) and high accuracy for newly approved drugs. WHAT IS NEW AND CONCLUSION The identification of key factors that can predict waivers of confirmatory clinical trials may accelerate the development of clinically important drugs and improve patient access globally.

Background:There is no established treatment for fetal growth restriction during pregnancy. We report two cases that represent an example of an amnioinfusion-based management strategy for severe fetal growth restriction with umbilical cord complications., Case presentation:We encountered two cases of fetal growth restriction with abnormal fetal Doppler velocity. In one case, fetal ultrasound revealed a hypercoiled umbilical cord with a single umbilical artery and oligohydramnios, while fetal Doppler revealed a reversed end-diastolic flow in the umbilical artery and reversed a-waves of the ductus venosus. Umbilical cord compression was confirmed at 22 weeks and 2 days of gestation, and nine amnioinfusions were performed to relieve the umbilical cord compression. A cesarean section was performed at 31 weeks and 2 days of gestation because of severe preeclampsia. The Asian infant is now a normally developed 6-month-old. In another Asian case, fetal ultrasound revealed a hypercoiled cord, while fetal Doppler revealed a reversed end-diastolic flow in the umbilical artery and intermittent reversed a-waves of the ductus venosus. Umbilical cord compression was confirmed at 24 weeks and 5 days of gestation, and seven amnioinfusions were performed. A cesarean section was performed at 31 weeks and 1 day of gestation because of nonreassuring fetal status. At the age of 1 month, the Asian infant was stable on respiratory circulation. In both cases, fetal Doppler findings improved significantly following amnioinfusions., Conclusions:Amnioinfusion is a symptomatic treatment for umbilical cord compression. However, to determine the therapeutic effect of amnioinfusion, complete resolution of the umbilical cord compression should be ascertained by ultrasonography.

We recently identified a CD63-interacting protein to understand the role of CD63 in virion production of the human immunodeficiency virus type 1, and we have found that Rab3a forms a complex with CD63. In this study, we analysed the effect of Rab3a on virion production of the murine leukaemia virus (MLV), which is another member of the retrovirus family. We found that Rab3a silencing induced lysosomal degradation of the MLV Gag protein, and recovery of the Rab3a expression restored the level of the Gag protein through a complex formation of MLV Gag and Rab3a, indicating that Rab3a is required for MLV Gag protein expression. In contrast, CD63 silencing decreased the infectivity of released virions but had no effect on virion production, indicating that CD63 facilitates the infectivity of released MLV particles. Although Rab3a induced CD63 degradation in uninfected cells, the complex of MLV Gag and Rab3a suppressed the Rab3a-mediated CD63 degradation in MLV-infected cells. Finally, we found that the MLV Gag protein interacts with Rab3a to stabilize its own protein and CD63 that facilitates the infectivity of released MLV particles. Considering the involvement of Rab3a in lysosome trafficking to the plasma membrane, it may also induce cell surface transport of the MLV Gag protein., Small GTPases, 13(1), pp.162-182; 2022

This illustrated conversation between The Incredible, Edible, Akynos, Monica Jones, PJ Starr and Bambi Katsura unpacks how we use media to continue our sex worker activism during the multiple pandemics of COVID-19, police violence and environmental disasters. We each bring our histories and theoretical innovations to the table including the framework of the 'Whore Gaze' developed by PJ, Monica's approach to documentary that ensures trans people narrate their own lives, Akynos' scripted film series Chronicles of a Black Heaux that may re-imagine the 'melomentary form' for sex worker representation and Bambi's experience as a filmmaker and curator. In our conversation, we discuss how we use film, photography, film festivals, animation and other forms for our activism to promote social justice. We also describe how we are systematically unlearning the codes of representation of research and human rights documentation, so that we can create materials that are accessible to our communities, to people with disabilities and be freed from the dead-end of respectability politics.

BackgroundSleep habits are related to children's behavior, emotions, and cognitive functioning. A strong relationship exists between sleep habits and behavioral problems. However, precisely which sleep habits are associated with behavioral problems remains unclear. Therefore, the purpose of this study is to clarify the relationship between sleep habits and behavioral problems in early adolescence.MethodsThis study used data from a larger longitudinal research, specifically, data from the year 2021. First-year junior high school students (12–14 years) in Japan were surveyed; their parents (N = 1288) completed a parent-report questionnaire. The main survey items were subject attributes, the Pittsburgh Sleep Quality Index (PSQI), and the Strength and Difficulties Questionnaire (SDQ).ResultsOf the 652 valid responses received, 604 individuals who met the eligibility criteria (no developmental disability in the child and completion of all survey items) were included in the analysis. To examine the relationship between sleep habits and behavioral problems, logistic regression analysis using the inverse weighted method with propensity score was conducted with sleep habits (sleep quality, time to fall asleep, sleep duration, sleep efficiency, sleep difficulty, use of sleeping pills, difficulty waking during the day, and sleep disturbances) as explanatory variables and behavioral problems (overall difficulty in SDQ) as objective variables. The propensity score was calculated by employing the logistic regression using the inverse weighted method based on propensity scores. Propensity scores were calculated based on gender, family structure, household income, and parental educational background. The results showed that behavioral problems tended to be significantly higher in the group at risk for sleep quality, sleep difficulties, daytime arousal difficulties, and sleep disturbances than in the group with no risk.ConclusionThe results suggest that deterioration in sleep quality, sleep difficulties, daytime arousal difficulties, and sleep disturbances may increase the risk of behavioral problems in adolescents.

The long-term follow-up of lung function (LF) in extremely preterm (EP) infants with bronchopulmonary dysplasia (BPD) has shown a worldwide increase in small airway obstructions (SAO).We investigated the relationships between intrauterine Ureplasma infection in EP infants and bubbly/cystic lung, BPD, and SAO at school age.Placental pathology, placental Ureaplasma DNA (pU-DNA), and cord blood immunoglobulin M (IgM) (C-IgM) were investigated in 360 EP infants born from 1981 to 2004. Maternal amniotic inflammatory response (M-AIR) scores and hemosiderin deposition (HD) were estimated in the chorioamnion. The study subjects were divided into groups based on their M-AIR scores. Their LF at school age was compared with those of 33 healthy siblings.pU-DNA and C-IgM were significantly related to SAO at school age (p 0.012). M-AIR score 3 and pU-DNA1000 units had an odds ratio (OR) of 35 (95% confidence interval: 10-172) and 18 (5.6-67) for bubbly/cystic lung, and 11 (3.1 - 43) and 31 (4.5-349) for severe BPD, and 5.3 (2.1-11) and 12 (2.4-74) for SAO, respectively. The ORs of surfactant treatment, BPD grade III, OOur long-term cohort study of LF in EP infants revealed that intrauterine Ureaplasma was associated with bubbly/cystic lung, severe BPD, and SAO at school age.

X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disorder caused by the intronic insertion of a SINE-VNTR-Alu (SVA) retrotransposon carrying an (AGAGGG)subn/subrepeat expansion in the TAF1 gene. The molecular mechanisms by which this mutation causes neurodegeneration remain elusive.We investigated whether (AGAGGG)subn/subrepeats undergo repeat-associated non-AUG (RAN) translation, a pathogenic mechanism common among repeat expansion diseases.XDP-specific RAN translation reporter plasmids were generated, transfected in HEK293 cells, and putative dipeptide repeat proteins (DPRs) were detected by Western blotting. Immunocytochemistry was performed in COS-7 cells to determine the subcellular localization of one DPR.We detected putative DPRs from two reading frames, supporting the translation of poly-(Glu-Gly) and poly-(Arg-Glu) species. XDP RAN translation initiates within the (AGAGGG)subn/subsequence and poly-(Glu-Gly) DPRs formed nuclear inclusions in transfected cells.In summary, our work provides the first in-vitro proof of principle that the XDP-linked (AGAGGG)subn/subrepeat expansions can undergo RAN translation. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background Stratifying risk of postoperative pulmonary complications after major abdominal surgery allows clinicians to modify risk through targeted interventions and enhanced monitoring. In this study, we aimed to identify and validate prognostic models against a new consensus definition of postoperative pulmonary complications. Methods We did a systematic review and international external validation cohort study. The systematic review was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched MEDLINE and Embase on March 1, 2020, for articles published in English that reported on risk prediction models for postoperative pulmonary complications following abdominal surgery. External validation of existing models was done within a prospective international cohort study of adult patients (≥18 years) undergoing major abdominal surgery. Data were collected between Jan 1, 2019, and April 30, 2019, in the UK, Ireland, and Australia. Discriminative ability and prognostic accuracy summary statistics were compared between models for the 30-day postoperative pulmonary complication rate as defined by the Standardised Endpoints in Perioperative Medicine Core Outcome Measures in Perioperative and Anaesthetic Care (StEP-COMPAC). Model performance was compared using the area under the receiver operating characteristic curve (AUROCC). Findings In total, we identified 2903 records from our literature search; of which, 2514 (86·6%) unique records were screened, 121 (4·8%) of 2514 full texts were assessed for eligibility, and 29 unique prognostic models were identified. Nine (31·0%) of 29 models had score development reported only, 19 (65·5%) had undergone internal validation, and only four (13·8%) had been externally validated. Data to validate six eligible models were collected in the international external validation cohort study. Data from 11 591 patients were available, with an overall postoperative pulmonary complication rate of 7·8% (n=903). None of the six models showed good discrimination (defined as AUROCC ≥0·70) for identifying postoperative pulmonary complications, with the Assess Respiratory Risk in Surgical Patients in Catalonia score showing the best discrimination (AUROCC 0·700 [95% CI 0·683–0·717]). Interpretation In the pre-COVID-19 pandemic data, variability in the risk of pulmonary complications (StEP-COMPAC definition) following major abdominal surgery was poorly described by existing prognostication tools. To improve surgical safety during the COVID-19 pandemic recovery and beyond, novel risk stratification tools are required. Funding British Journal of Surgery Society.

The purpose of this study was to elucidate the imaging characteristics of the gubernaculum tracts in successional teeth related to fused deciduous teeth on computed tomography. The imaging findings of 15 gubernaculum tracts in successional teeth related to fused deciduous teeth were retrospectively analyzed using cone-beam computed tomography or multidetector computed tomography. In cases without a congenitally defected successor, the two gubernaculum tracts of two successional teeth related to fused deciduous teeth were fused into one. Gubernaculum tracts (GTs) in mesial successors were vertical, but in distal successors they were inclined to mesial. The major abnormalities of the successional teeth related to fused deciduous teeth were delayed eruption and delayed formation. No inclined mesial successors were found, whereas most of the distal successors were inclined to mesial along with the inclined GT. The gubernaculum tracts of successors with a congenital defect of the other successors were vertical, and such successors had no abnormalities. The present study showed the imaging characteristics of gubernaculum tracts in successional teeth related to fused deciduous teeth. The abnormal eruption of successional teeth related to fused deciduous teeth may be associated with the characteristics of their gubernaculum tracts.

Objective Cancer-associated fibroblasts (CAFs) play a significant role in tumor progression within the tumor microenvironment. Previously, we have used near-infrared photoimmunotherapy (NIR-PIT), a next-generation cancer cell-targeted phototherapy, to establish CAF-targeted NIR-PIT. In this study, we investigated whether dual-targeted NIR-PIT targeting cancer cells and CAFs could be a therapeutic strategy. Methods A total of 132 cases of esophageal cancer were analyzed for epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), and fibroblast activation protein (FAP) expression using immunohistochemistry. Human esophageal cancer cells and CAFs were co-cultured and treated with single- or dual-targeted NIR-PIT in vitro. These cells were co-inoculated into BALB/c-nu/nu mice and the tumors were treated with single-targeted NIR-PIT or dual-targeted NIR-PIT in vivo. Results Survival analysis showed FAP- or EGFR-high patients had worse survival than patients with low expression of FAP or EGFR (log-rank, p p = 0.074, respectively), while no difference was observed in HER2 status. In vitro, dual (EGFR/FAP)-targeted NIR-PIT induced specific therapeutic effects in cancer cells and CAFs along with suppressing tumor growth in vivo, whereas single-targeted NIR-PIT did not show any significance. Moreover, these experiments demonstrated that dual-targeted NIR-PIT could treat cancer cells and CAFs simultaneously with a single NIR light irradiation. Conclusion We demonstrated the relationship between EGFP/FAP expression and prognosis of patients with esophageal cancer and the stronger therapeutic effect of dual-targeted NIR-PIT than single-targeted NIR-PIT in experimental models. Thus, dual-target NIR-PIT might be a promising therapeutic strategy for cancer treatment.

Granulocyte-colony stimulating factor (G-CSF) stimulates bone marrow progenitor cell proliferation and enhances neutrophil production. Exogenous G-CSF administration is indicated for chemotherapy-induced neutropenia management. However, there is a paucity of basic research examining the effects of the concomitant use of G-CSF and chemotherapy on myeloid cells in vivo. Whether concomitant G-CSF and chemotherapy adversely affect myeloid cell proliferation have not been determined. Herein, we examined the effects of the concomitant use of pegfilgrastim and 5-fluorouracil on myeloid cells and peripheral blood cells in mouse models. Balb/c mice were treated intraperitoneally with 5-fluorouracil (20 μg/g b.w.) or a vehicle as a control for 5 days, and pegfilgrastim was administered subcutaneously at 1 μg/g b.w. on day 3. As a result, we demonstrated that the concomitant use of pegfilgrastim suppressed the 5-fluorouracil-induced decrease of granulocytic cells in both bone marrow and peripheral blood in mice. To assess the clinical efficacy of early administration of pegfilgrastim during docetaxel, cisplatin, and 5-fluorouracil therapy in patients with esophageal cancer, we retrospectively identified 42 consecutive patients treated with this regimen. The incidence of both febrile neutropenia and grade 4 neutropenia was significantly lower in patients who received pegfilgrastim than in those who did not receive it (P = 0.002 and P = 0.002, respectively). These results suggest that the concomitant use of pegfilgrastim and chemotherapy, consisting of continuous infusions of 5-fluorouracil, improved chemotherapy-induced neutropenia without detrimental effects on proliferating myeloid granulocytic cells.

Maternal perception of decreased fetal movement is associated with adverse perinatal outcomes. Although there have been several studies on interventions related to the fetal movements count, most focused on adverse perinatal outcomes, and little is known about the impact of the fetal movement count on maternal behavior after the perception of decreased fetal movement. We investigated the impact of the daily fetal movement count on maternal behavior after the perception of decreased fetal movement and on the stillbirth rate in this prospective population-based study. Pregnant women in Shiga prefecture of Japan were asked to count the time of 10 fetal movements from 34 weeks of gestation. We analyzed 101 stillbirths after the intervention compared to 121 stillbirths before the intervention. In multivariable analysis, maternal delayed visit to a health care provider after the perception of decreased fetal movement significantly reduced after the intervention (aOR 0.31, 95% CI 0.11–0.83). Our regional stillbirth rates in the pre-intervention and post-intervention periods were 3.06 and 2.70 per 1000 births, respectively. Informing pregnant women about the fetal movement count was associated with a reduction in delayed maternal reaction after the perception of decreased fetal movement, which might reduce stillbirths.

Objectives This study aimed to clarify the accuracy of intraoral ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI) in preoperative image depth of invasion (DOI) measurement of T1/T2 tongue cancer through comparison with histopathological measurements. Methods Imaging of the primary lesions was performed at our hospital; the lesions were classified into T1 and T2 based on the 8th edition of the AJCC/UICC, and surgery performed. There was histopathological confirmation of lesions as squamous cell carcinoma in 48 patients with tongue cancer. T3 and T4 cases, cases in which preoperative chemotherapy and radiation therapy were performed, and cases where biopsy was performed before imaging were excluded. The radiological DOI in US, CT, and MRI and the histopathological DOI as base were comparatively investigated and statistical analyses were performed by Bland–Altman analysis and Spearman's rank correlation coefficient. Results Bland–Altman analysis showed that the US radiological DOI was overestimated by an average of 0.2 mm compared to the histopathological DOI, while CT and MRI radiological DOI were overestimated by an average of 2–3 mm. The comparison of CT and MRI revealed that the difference between the MRI and histopathological DOI, as well as the 95% limit of agreement, were smaller than those of the CT radiological DOI. Conclusions US is the most accurate preoperative diagnostic tool for T1 and T2 squamous cell carcinoma; CT and MRI tend to have an overestimation of about 2–3 mm and so caution is required.

Esophageal cancer is a disease showing poor prognosis. Although combination chemotherapy using cisplatin (CDDP) and 5-fluorouracil is standard for unresectable esophageal cancer, the response rate is 35%. Cancer stem cells (CSCs) and inflammation are reportedly responsible for the poor prognosis of esophageal cancer. However, comprehensive analyses have not been conducted and proposals for progress remain lacking. Iron is known to be a key factor in the stemness of CSCs. Our study focused on the therapeutic potential of iron control using iron chelators for CSCs in esophageal cancer. Among 134 immunohistochemically analyzed cases, Nanog expression was high in 98 cases and low in 36 cases. High Nanog expression correlated with low overall and disease-free survivals. The iron chelators deferasirox (DFX) and SP10 suppressed the proliferation and expression of stemness markers in TE8 and OE33 cells. DFX and SP10 did not induce compensatory interleukin (IL)-6 secretion, although CDDP did result in high induction. Moreover, BBI608 and SSZ, as other CSC-targeting drugs, could not suppress the expression of stemness markers. Overall, Nanog expression appears related to poor prognosis in esophageal cancer patients, and inhibition of stemness and compensatory IL-6 secretion by iron chelators may offer a novel therapeutic strategy for esophageal cancer.

Background The role of IL-12/23 in the pathogenesis of ulcerative colitis (UC) is unclear. We analyzed mucosal IL-12/23 expression and its relationship with endoscopic severity, histological activity, and UC relapse. Methods Rectal biopsies were collected from 70 UC patients with clinical remission. IL-12, IL-23, IFN-γ, IL-17A, and IL-17F mRNA expression was measured by real-time PCR. Endoscopic severity and histological activity were evaluated using the Mayo endoscopic subscore (MES) and the Geboes score, respectively. Results The longest follow-up period was 51 months. Thirty-four patients relapsed during the study period. Samples from these subsequently relapsed patients formed the “relapse” group, while those from patients that did not relapse formed the “remission” group. IL-12 (P = 0.0003) and IL-23 (P = 0.014) mRNA expression was significantly higher in the relapse than the remission group. Expression of IL-23 (P = 0.015) but not IL-12 (P = 0.374) was correlated with MES. However, in patients with an MES of 0 and 1, IL-12 expression was statistically higher in the relapse than the remission group (P = 0.0015, P = 0.0342). IL-12 and IL-23 expression did not vary significantly between histologically active and inactive mucosa; both were higher in histologically inactive patients in the remission group (IL-12: P = 0.0002, IL-23: P = 0.046). Conclusions Rectal IL-12 and IL-23 expression was elevated in the relapse group, but IL-12 was more strongly associated with UC relapse, irrespective of endoscopic severity and histological activity. Mucosal IL-12 was elevated in patients with deep mucosal healing. Our results suggest an important role of IL-12 in UC pathogenesis and the molecular mechanism of UC relapse.

The aim of this study was to compare the estimated public medical care cost of measures to address metallic dental restorations (MDRs) for head and neck radiotherapy using high-energy mega-voltage X-rays. This was considered a first step to clarify which MDR measure was more cost-effective. We estimated the medical care cost of radiotherapy for two representative MDR measures: (i) with MDR removal or (ii) without MDR removal (non-MDR removal) using magnetic resonance imaging and a spacer. A total of 5520 patients received head and neck radiation therapy in 2018. The mean number of MDRs per person was 4.1 dental crowns and 1.3 dental bridges. The mean cost per person was estimated to be 121 720 yen for MDR removal and 54 940 yen for non-MDR removal. Therefore, the difference in total public medical care cost between MDR removal and non-MDR removal was estimated to be 303 268 800 yen. Our results suggested that non-MDR removal would be more cost-effective than MDR removal for head and neck radiotherapy. In the future, a national survey and cost-effectiveness analysis via a multicenter study are necessary; these investigations should include various outcomes such as the rate of local control, status of oral mucositis, frequency of hospital visits and efforts of the medical professionals.

A number of scholarly reports have shown the importance of mental health care during pregnancy, especially for women with mental disorders. Nevertheless, the postpartum mortality rate due to mental disorders has been a serious issue in Japan. Therefore, since January 2015, our hospital has implemented a liaison system in which one psychiatric nurse specialist contributes to perinatal care. The aim of this study is to explore the impacts of a psychiatric nurse specialist as a liaison for pregnant women with mental disorders. More specifically, the investigation was retrospectively performed from January 2011 to December 2019 using medical records from a single university medical hospital in Japan. Participants comprised pregnant women with mental disorders. Of the 4,066 total deliveries completed during the study period, 152 women were detected as being exposed to the liaison system (2015-2019), while 92 were recognized as controls (2011-2014). We then conducted a comparative analysis between those who were exposed to the liaison system and the control group. Except for Apgar scores taken five minutes after birth, there were no intergroup differences in the patient characteristics or perinatal psychiatric outcomes. We found that the liaison system was associated with an increased rate of referral to the local public health center (p = 0.003). The system also significantly delayed the time at which patients first visited a psychiatrist because a psychiatric nurse could determine the urgency through interviews with the patients. Overall, our results suggest that the liaison system is helpful for pregnant women with mental disorders.

Background: About twice as many boys as girls undergo growth hormone (GH) therapy in GH deficiency (GHD). However, this sex difference may not correctly reflect a real incidence. Objectives: We analyzed the evidence of a selection bias whereby more boys seek treatment at short stature clinics. Subjects and Methods: The present study included 3,902 children who visited 17 short stature clinics with a height SD score of −2 SD or less. The percentage of children who underwent the GH stimulation test was compared between boys and girls, as was the percentage of children ultimately diagnosed with GHD. Results: The children comprised 2,390 boys (61.3%) and 1,512 girls (38.7%), with a boy:girl ratio of 1.58:1. The percentage of children who underwent the GH stimulation test did not differ between boys (45.7%) and girls (49.8%). Among the children who underwent the GH stimulation test, the percentage diagnosed with GHD did not differ significantly between boys (22.0%) and girls (20.1%). The boy:girl ratio of children diagnosed with GHD was 1.59:1. Conclusions: The boy:girl ratio of children with short stature (1.58:1) did not differ significantly from that of children diagnosed with GHD (1.59:1). These results indicate that the predominance of boys in GHD does not reflect a real incidence, but rather a selection bias whereby a higher proportion of boys with short stature seek treatment at clinics. This difference arises because parents are more concerned about boys’ height, and because boys reach adult height at an older age.

Radiation therapy (RT) continues to play a central role as an effective therapeutic modality for a variety of tumors and vascular malformations in the central nervous system. Although the planning and delivery techniques of RT have evolved substantially during the past few decades, the structures surrounding the target lesion are inevitably exposed to radiation. A wide variety of radiation-induced changes may be observed at posttreatment imaging, which may be confusing when interpreting images. Histopathologically, radiation can have deleterious effects on the vascular endothelial cells as well as on neuroglial cells and their precursors. In addition, radiation induces oxidative stress and inflammation, leading to a cycle of further cellular toxic effects and tissue damage. On the basis of the time of expression, radiation-induced injury can be divided into three phases: acute, early delayed, and late delayed. Acute and early delayed injuries are usually transient and reversible, whereas late delayed injuries are generally irreversible. The authors provide a comprehensive review of the timeline and expected imaging appearances after RT, including the characteristic imaging features after RT with concomitant chemotherapy. Specific topics discussed are imaging features that help distinguish expected posttreatment changes from recurrent disease, followed by a discussion on the role of advanced imaging techniques. Knowledge of the RT plan, the amount of normal structures included, the location of the target lesion, and the amount of time elapsed since RT is highly important at follow-up imaging, and the reporting radiologist should be able to recognize the characteristic imaging features after RT and differentiate these findings from tumor recurrence. ©RSNA, 2020.

Ultrasonography and fetal heart rate monitoring are subjective assessments of fetal condition, which warrants the need for objective markers to predict fetal condition. Urinary L-type fatty acid-binding protein (L-FABP) levels correlate with hypoperfusion. Elevated amniotic fluid L-FABP levels may represent fetal tissue hypoperfusion since the amniotic fluid contains fetal urine. In this study, we aimed to analyze the effectiveness of amniotic fluid L-FABP as a predictor of fetal condition. We classified singleton pregnancies into groups based on fetal growth restriction (FGR) with and without fetal blood flow abnormalities (FGR and healthy-FGR groups, respectively) and the non-FGR group (control group). We collected amniotic fluid at the time of vaginal delivery, cesarean section and amniocentesis, and compared the patient characteristics, clinical outcomes and amniotic fluid levels of L-FABP between the groups. We analyzed 153 singleton pregnancies and 186 amniotic fluid samples (FGR group, 6 (3.9%) pregnancies and 23 (12.4%) samples; healthy-FGR group, 15 (9.8%) pregnancies and 20 (10.7%) samples; control group, 132 (86.3%) pregnancies and 143 (76.9%) samples). The amniotic fluid L-FABP level was significantly higher in the FGR group compared to that in the healthy-FGR and control groups. Multivariate analysis revealed that the amniotic fluid L-FABP level was not affected by fetal body weight. Additionally, the amniotic fluid L-FABP levels increased significantly in cases with fetal blood flow abnormalities or early gestational age. Therefore, amniotic fluid L-FABP level may be an objective and accurate predictive marker of fetal condition.

The growing prevalence of Alzheimer's disease (AD) worldwide has sparked the implementation of national policies to support the growing burden among caregivers of AD/dementia patients. This study aims to quantify and compare the burden of AD/dementia caregivers and evaluate how different living arrangements might impact health outcomes among caregivers in Japan, five European countries (5EU), and the United States (US).This is a cross-sectional study based on existing data from the 2018 National Health and Wellness Survey. Health outcome measures included health-related quality of life (HRQoL), health state utilities, work productivity and activity impairment (WPAI), and measurement of depression and anxiety amongst AD/dementia caregivers and non-caregivers. Pairwise comparisons between AD/dementia caregivers in Japan, 5EU, and the US were conducted. Multivariate analysis was used to compare across groups within each region, with adjustment for potential confounding effects.A higher proportion of caregivers of AD/dementia patients in Japan were 65 years or older as compared to 5EU and US. On the contrary, female caregivers were significantly higher in the US than Japan and 5EU. The HRQoL and health state utilities index scores amongst AD/dementia caregivers were highest in Japan and lowest in the US. Caregivers in Japan incurred the lowest WPAI among the three regions. The proportion of AD/dementia patients reportedly living in an institution was highest in Japan as compared to the US and EU. Notably, US caregivers whose patients lived in an institution experienced significantly less caregiving burden as compared to caregivers whose patients lived in the community.The caregiving burden among AD/dementia caregivers was substantial across the three regions, with similarities and differences between the West and Japan. The lower caregiving burden in Japan was potentially associated with national policies supporting long-term healthcare and institutionalized nursing care facilities for AD/dementia patients.