Performance Evaluation of Interim Analysis in Bioequivalence Studies.

Under current bioequivalence guidelines in Japan, it is mandatory to establish bioequivalence using a single pivotal study. Clinical trials with limited resources usually have a pre-defined maximum permissible number of participants. In this manuscript, we considered a trial design that would allow for bioequivalence evaluation at an interim analysis in which the total number of participants takes into account the resource constraints. Then, available options at the interim analysis are group sequential designs and adaptive designs, A comparison of the performance of the two methods under same maximum participant number has not been conducted thus far. So we examined which method should be used by conducting a simulation study. Since bioequivalence is expected to be achieved at the interim analysis, a study design using a Pocock-type alpha spending function is preferrable. Simulation results using a Pocock-type alpha spending function showed similar performance between group sequential and adaptive designs. Consequently, due to statistical and operational complexity, it is preferable to choose group sequential designs for bioequivalence study in Japan.

Preoperative predictive factors for positive peritoneal cytology results in patients with pancreatic ductal adenocarcinomas: a retrospective study.

BACKGROUND: The clinical importance of positive peritoneal cytology results in patients with pancreatic ductal adenocarcinomas remains controversial. We evaluated the prognosis of these patients and the predictive preoperative risk factors for positive peritoneal cytology results. METHODS: We retrospectively reviewed patients who underwent curative-intent surgery at our institution between May 2010 and June 2020. Preoperative risk factors for positive peritoneal cytology results were identified using logistic regression analysis. A scoring model was constructed using the total number of significant independent predictors for positive peritoneal cytology results. RESULTS: Of 233 patients, 18 (7.7%) had positive peritoneal cytology results. The recurrence-free survival and cancer-specific survival were markedly worse in patients with positive peritoneal cytology results than in those with negative peritoneal cytology results (recurrence-free survival: 6.0 months vs. 16.6 months, p = 0.050; cancer-specific survival: 19.4 months vs. 47.5 months, p = 0.034). Tumor location (odds ratio: 3.760, 95% confidence interval: 1.099-11.818, p = 0.023), tumor size > 25 mm (odds ratio: 3.410, 95% confidence interval: 1.031-11.277, p = 0.046), preoperative serosal invasion (odds ratio: 5.193, 95% confidence interval: 1.099-24.531, p = 0.038), and preoperative carcinoembryonic antigen level > 5.6 ng/mL (odds ratio: 3.816, 95% confidence interval: 1.248-10.667, p = 0.019) were identified as significant independent predictive factors. Our predictive model's optimal cutoff and positive predictive values for positive peritoneal cytology results were 3 and 27.9%, respectively. CONCLUSIONS: The indications for curative-intent surgery should be considered carefully in patients with high-risk factors for positive peritoneal cytology results.

Gut microbiota of one-and-a-half-year-old food-allergic and healthy children.

BACKGROUND: Intestinal bacteria may play a role in the development of food allergies. This study aimed to analyze and compare the gut microbiota of food-allergic children with that of healthy children of the same age. METHODS: Stool samples were collected from one-and-a-half-year-old food-allergic (FA group, n = 29) and healthy controls (HC group, n = 19). A questionnaire was provided to examine the children's birth, dietary, medical, and social histories. The gut microbiota was profiled by 16S rRNA sequencing. Differences in taxonomic composition were assessed using linear discriminant analysis effect size (LEfSe), and microbial functional profiles were predicted with Tax4Fun2. RESULTS: No significant difference in the alpha diversity index between the two groups; however, a negative correlation was observed between the Shannon diversity index and the relative abundance of Bacteroides. A significant difference was observed in beta diversity (permutational multivariate analysis of variance) in the bacterial composition between the FA and HC groups (P < 0.05). The FA group had a higher abundance of Escherichia and Anaeromassilibacillus and a lower abundance of Bacteroides, Oscillibacter, Ruminococcus, Hungateiclostridium and Anaerotaenia than the HC group (LEfSe: linear discriminant analysis score >2). The FA group showed a predicted increase in the expression levels of genes associated with intestinal pathogenicity compared with that in the HC group. CONCLUSIONS: The gut microbiota of food-allergic children has a higher abundance of bacteria involved in intestinal inflammation and a lower abundance of bacteria involved in immune tolerance than that of healthy children. This dysbiosis may also be associated with food allergies.

Association of maternal obesity with growth of fetal fractional limb volume.

BACKGROUND: Maternal obesity influences birth weight and newborn adiposity. Fetal fractional limb volume has recently been introduced as a useful parameter for the proxy of fetal adiposity. However, the association between maternal adiposity and the growth of fetal fractional limb volume has not been examined. AIMS: To investigate the association of maternal pre-pregnancy BMI with the growth of fetal fractional limb volume. STUDY DESIGN: Prospective cohort study. SUBJECTS: Women with singleton uncomplicated pregnancies enrolled between July 2017 and June 2020. OUTCOME MEASURES: Fetal fractional limb volume was assessed between 20 and 40 weeks' gestation, measured as cylindrical limb volume based on 50 % of the total diaphysis length. The measured fractional limb volume at each gestational week were converted to z-scores based on a previous report. The association between pre-pregnancy BMI and fetal fractional limb volume was examined. Maternal age, parity, gestational weight gain and fetal sex were considered as potential confounding variables. RESULTS: Ultrasound scans of 455 fractional arm volume and thigh volume were obtained. Fractional limb volume increased linearly until the second trimester of gestation, then increased exponentially in the third trimester. Maternal pre-pregnancy BMI was significantly correlated with z-scores of fractional arm volume and thigh volume across gestation. The post-hoc analysis showed the association between pre-pregnancy BMI and fractional arm volume was significant especially between 34 and 40 weeks. CONCLUSIONS: Maternal obesity influences the growth pattern of fetal fractional limb volume. Fractional arm volume may potentially provide a useful surrogate marker of fetal nutritional status in late gestation.

Effect of maturation at birth on the clinical features of neonatal cow's milk protein allergy: A retrospective study.

Neonatal immune regulation transitions from fetal immunity and varies with maturation status, but its role in neonatal cow's milk protein allergy (CMPA) remains unknown. We studied the association between maturation status at birth and neonatal CMPA. Clinical and laboratory data of neonates presenting with CMPA symptoms were retrospectively collected from two tertiary hospitals. Patients were assessed according to gestational age at birth: preterm, late-preterm, and full-term. Fifty-five infants (26 females, 14 preterm, 15 late-preterm, and 26 full-term) were included; 44 were negative for milk-specific IgE. Neonatal CMPA was common during moderately premature periods. Preterm infants exhibited longer latency from initial CM exposure to disease onset, lower incidence of bloody stool, and absence of elevated monocyte counts. However, immunoreactivity to CM antigens was retained in all infants. Neonatal CMPA features varied with infant maturation status at birth. Our results improve the understanding of intestinal immunity development, fetal/neonatal immune regulation, and CMPA pathogenesis.

Retrospective study on the effect of adipose stem cell transplantation on jaw bone regeneration.

PURPOSE: In patients with jaw bone atrophy, dental implant therapy requires bone augmentation on the alveolar ridge. Common methods are autologous bone transplantation or bone substitutes. The latter technique is less surgically invasive because it does not require bone harvesting; however, blood supply from the surrounding tissues and local differentiation of osteoblasts are not guaranteed, so adequate bone regeneration for dental implant therapy is often not achieved. Therefore, at our hospital we introduced a bone regenerative medicine technique that uses adipose stem cells (ASCs) from adipose tissue. The new approach is less surgically invasive and appears to have a better effect on bone regeneration. The current retrospective study aimed to demonstrate the efficacy of ASC transplantation in patients who underwent alveolar ridge bone augmentation at our hospital. METHODS: We compared medical records, postoperative radiographic findings, and histological results from patients treated between January 2018 and March 2022 by augmentation of the jaw bone with bone substitutes (carbonate apatite) mixed with ASCs (ASCs+ group) and those treated with bone substitutes (carbonate apatite) alone (ASCs- group). RESULTS: After 6 months, the survival rate of augmented bone and the gray scale value in dental cone beam computed tomography (a bone density index) were significantly higher in the ASCs+ group than in the ASCs- group. Histological analysis at 6 months showed more adequate bone tissue regeneration in the ASCs+ group. CONCLUSIONS: The findings suggest the effectiveness of using ASCs in bone augmentation on the alveolar ridge in patients with jaw bone atrophy.

Multivariate generalized mixed-effects models for screening multiple adverse drug reactions in spontaneous reporting systems.

Introduction: For assessing drug safety using spontaneous reporting system databases, quantitative measurements, such as proportional reporting rate (PRR) and reporting odds ratio (ROR), are widely employed to assess the relationship between a drug and a suspected adverse drug reaction (ADR). The databases contain numerous ADRs, and the quantitative measurements need to be calculated by performing the analysis multiple times for each ADR. We proposed a novel, simple, and easy-to-implement method to estimate the PRR and ROR of multiple ADRs in a single analysis using a generalized mixed-effects model for signal detection. Methods: The proposed method simultaneously analyzed the association between any drug and numerous ADRs, as well as estimated the PRR and ROR for a specific combination of drugs and suspected ADRs. Furthermore, the proposed method was applied to detect drug-drug interactions associated with the concurrent use of two or more drugs. Results and discussion: In our simulation studies, the false-positive rate and sensitivity of the proposed method were similar to those of the traditional PRR and ROR. The proposed method detected known ADRs when applied to the Food and Drug Administration Adverse Event Reporting System database. As an important advantage, the proposed method allowed the simultaneous evaluation of several ADRs using multiple drugs.

Biparametric versus Multiparametric Magnetic Resonance Imaging for Assessing Muscle Invasion in Bladder Urothelial Carcinoma with Variant Histology Using the Vesical Imaging-Reporting and Data System.

BACKGROUND: The diagnostic performance of contrast medium-free biparametric magnetic resonance imaging (bpMRI; combining T2-weighted imaging [T2WI] and diffusion-weighted imaging [DWI]) for evaluating variant-histology urothelial carcinoma (VUC) remains unknown. OBJECTIVE: To compare the diagnostic performance of bpMRI and multiparametric MRI (mpMRI; combining T2WI, DWI, and dynamic contrast-enhanced MRI]) for assessing muscle invasion of VUC. DESIGN, SETTING, AND PARTICIPANTS: This multi-institution retrospective analysis included 118 patients with pathologically verified VUC who underwent bladder mpMRI before transurethral bladder tumor resection between 2010 and 2019. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Three board-certified radiologists separately evaluated two sets of images, set 1 (bpMRI) and set 2 (mpMRI), in accordance with the Vesical Imaging Reporting and Data System (VI-RADS). The histopathology results were utilized as a reference standard. Receiver operating characteristic curve analysis, Z test, and Wald test were used to assess diagnostic abilities. RESULTS AND LIMITATIONS: Sixty-six (55.9%) and 52 (44.1%) of the 118 patients with VUC included in the analysis (mean age, 71 ± 10 yr; 88 men) had muscle-invasive bladder cancer (MIBC) and non-MIBC, respectively. For the diagnosis of MIBC, the areas under the curve for bpMRI were significantly smaller than those for mpMRI (0.870-0.884 vs 0.902-0.923, p < 0.05). The sensitivity of bpMRI was significantly lower than that of mpMRI for all readers with a VI-RADS cutoff score of 4 (65.2-66.7% vs 77.3-80.3%, p < 0.05). The specificity of bpMRI and mpMRI did not differ significantly for all readers (88.5-90.4 vs 88.5-92.3, p > 0.05). A limitation of the study is the limited sample size because of the rarity of VUC. CONCLUSIONS: In patients with VUC, on applying VI-RADS, the diagnostic results of bpMRI were inferior to those of mpMRI for evaluating muscle invasion. Therefore, mpMRI-based methods are recommended for evaluating muscle invasiveness of VUC. PATIENT SUMMARY: Contrast medium-free biparametric magnetic resonance imaging (bpMRI)-based Vesical Imaging Reporting and Data System (VI-RADS) can accurately diagnose pure urothelial carcinomas, similar to conventional multiparametric magnetic resonance imaging-based VI-RADS. However, bpMRI-based VI-RADS may misdiagnose muscle invasiveness of urothelial carcinoma with variant histology, particularly when its cutoff score is 4.

FIVE-YEAR VISUAL OUTCOME OF TREATMENT FOR RETINOPATHY OF PREMATURITY IN INFANTS WEIGHING <500 G AT BIRTH: A Multicenter Cohort Study From J-CREST.

PURPOSE: To investigate the 5-year treatment outcomes of retinopathy of prematurity in infants <500 g birth weight and compare laser and anti-vascular endothelial growth factor therapies. METHODS: A multicenter retrospective study comprised 24 eyes of 13 patients treated for Type 1 retinopathy of prematurity, followed for 5 years. Initial treatment was laser and anti-vascular endothelial growth factor in 13 and 11 eyes, respectively. Data collected included sex, birth characteristics, retinopathy of prematurity characteristics at the time of treatment, best-corrected visual acuity (BCVA), spherical equivalent, and astigmatism at 5 years posttreatment. RESULTS: Median BCVA was 0.15 logarithm of the minimum angle of resolution (interquartile range, 0.0-0.5). Snellen BCVA was ≥20/40 in 73% and ≥20/20 in 27% of eyes. Median spherical equivalent was -2.37 (interquartile range, -6.1 to -0.1); 75% had myopia (≤-0.5 D), and 25% had high myopia (≤-6.0 D). Median astigmatism was 1.25 (interquartile range, 0.9-3.0); 46% had ≥1.5 D. Anti-vascular endothelial growth factor-treated eyes showed less myopia ( P < 0.009), with no BCVA or astigmatism difference ( P = 0.997, P = 0.271) compared with laser-treated eyes. CONCLUSION: One-quarter of the eyes exhibited good visual acuity (Snellen BCVA of ≥20/20) 5 years after retinopathy of prematurity treatment. Refractive errors were common. Anti-vascular endothelial growth factor therapy may be superior to laser therapy in myopic refractive error.

Effect of intranasal insulin administration on postoperative delirium prevention in elderly cardiac surgery patients: study protocol for a multicenter, double-blind, randomized, controlled trial.

BACKGROUND: Postoperative delirium (POD) is a complication after surgery which leads to worse outcomes. The frequency of this syndrome is increasing as more elderly patients undergo major surgery. The frequency is around 10-25% but reaches as high as 50% for cardiac surgery. Although intranasal insulin (INI) administration of up to 160 units in patients with cognitive dysfunction and delirium has been shown to improve memory function and brain metabolism without complications such as hypoglycemia, it remains unknown whether INI prevents POD after cardiac surgery METHODS: A multicenter, double-blind, randomized, controlled trial will be conducted at University of Tsukuba Hospital and Tsukuba Medical Center Hospital, Japan, from July 1, 2023, to December 31, 2025. A total of 110 elderly patients (65 years old or older) undergoing cardiac surgery requiring cardiopulmonary bypass will be enrolled and randomly allocated to intranasal insulin or intranasal saline groups. The primary outcome is the incidence of POD within 7 days after surgery. Secondary outcomes include days and times of delirium, screening tests of cognitive function, pain scores, duration of postoperative tracheal intubation, and length of ICU stay. DISCUSSION: The present objective is to assess whether 80 IU INI administration during surgery prevents POD after cardiac surgery. The results may provide strategic choices to prevent POD in patients with cardiac surgery requiring cardiopulmonary bypass. TRIAL REGISTRATION: The trial was registered with the Japan Registry for Clinical Trials with identifier jRCTs031230047  on April 21, 2023.

Risk Factors for Post-Stroke Pneumonia in a Patient Population with Subacute Stroke: A Retrospective Cohort Study.

The risk of pneumonia and death is higher in acute stroke patients with signs of pulmonary infection on chest computed tomography (CT) at admission. However, few reports have examined the incidence of pneumonia and its predictors in subacute stroke patients. The aim of this study was to examine factors related to post-stroke pneumonia in subacute stroke patients. A total of 340 subacute stroke patients were included. Univariable logistic regression analysis was performed using variables that may contribute to pneumonia, with the development of pneumonia as the dependent variable. Multivariable logistic regression analysis using the three independent variables with the lowest p-values on the univariable logistic regression analysis was also performed to calculate adjusted odds ratios. Twenty-two patients developed pneumonia during hospitalization. The univariable logistic regression analysis showed that the top three items were serum albumin (Alb), functional Oral Intake Scale (FOIS) score, and signs of pulmonary infection on chest CT at admission. Multivariable logistic regression analysis adjusted for these three items showed that the presence of signs of pulmonary infection on chest CT at admission was the independent variable (OR: 4.45; 95% CI: 1.54-12.9). When signs of pulmonary infection are seen on admission chest CT, careful follow-up is necessary because pneumonia is significantly more likely to occur during hospitalization.

p62 Is a Potential Biomarker for Risk of Malignant Transformation of Oral Potentially Malignant Disorders (OPMDs).

To determine the intracellular behavior of p62, a marker of selective autophagy, in oral potentially malignant disorders (OPMDs). This retrospective study includes 70 patients who underwent biopsy or surgical resection and were definitively diagnosed with OPMDs. Immunohistochemical staining for p62, XPO1, p53, and ki67 was performed on all samples and positive cell occupancy was calculated. We statistically investigated the correlation between protein expression in OPMDs and the association between malignant transformation, clinicopathological characteristics, and occupancy. ki67 expression was negatively correlated with p62 expression in the nucleus (p < 0.01) and positively correlated with p62 expression in the cytoplasm (p < 0.01). For malignant transformation, the expression of p62 in the nucleus (p = 0.03) was significantly lower in malignant transformation cases, whereas the expression of p62 in the cytoplasm (p = 0.03) and the aggregation expression (p < 0.01) were significantly higher. Our results suggest that the function of p62 is altered by its subcellular localization. In addition, defects in selective autophagy occur in cases of malignant transformation, suggesting that p62 is a potential biomarker of the risk of malignant transformation of OPMDs.

Continuous glucose monitoring-derived time in range and CV are associated with altered tissue characteristics of the carotid artery wall in people with type 2 diabetes.

AIMS/HYPOTHESIS: Previous studies have suggested that glucose variability may accelerate atherosclerosis progression in people with type 2 diabetes. Current guidelines recommend assessing glycaemic control using continuous glucose monitoring (CGM), which provides a comprehensive glycaemic profile to supplement HbA1c measurement. However, the association between CGM-derived metrics and atherosclerosis progression is not entirely clear. METHODS: This exploratory study used baseline data and data obtained after 104 weeks from an ongoing prospective, multicentre, observational study. Six hundred study participants with type 2 diabetes and no apparent history of symptomatic cardiovascular disease underwent CGM and ultrasonographic atherosclerosis measurements of the carotid arteries, including the intima-media thickness (IMT) and grey-scale median (GSM), at baseline and 104 weeks. Non-invasive ultrasonic tissue characterisation of the carotid artery wall or plaque using the GSM reflects vascular composition. Multivariate regression models were used to analyse the association between CGM-derived indices, mainly time in range (TIR) and CV, and changes in carotid atherosclerosis index values. RESULTS: Over the 104-week study period, there were modest increases in mean IMT (from 0.759±0.153 to 0.773±0.152 mm, p<0.001) and thickened-lesion GSM (from 43.5±19.5 to 53.9±23.5 units, p<0.001), but no significant changes in common carotid artery maximum-IMT (from 1.109±0.442 to 1.116±0.469 mm, p=0.453) or mean GSM (from 48.7±19.3 to 49.8±20.8 units, p=0.092). In a linear regression model with adjustment for possible atherosclerotic risk factors, including HbA1c, TIR and CV at baseline were significantly associated with the annual change in mean GSM (regression coefficient per 10% increase in TIR 0.52; 95% CI 0.06, 0.98; Hochberg-adjusted p value 0.038; regression coefficient per 1% increase in CV -0.12; 95% CI -0.22, -0.02; Hochberg-adjusted p value 0.038). TIR and CV at baseline were also significantly associated with the annual change in thickened-lesion GSM (regression coefficient per 10% increase in TIR 0.95; 95% CI 0.12, 1.79; Hochberg-adjusted p value 0.038; regression coefficient per 1% increase in CV -0.19; 95% CI -0.36, -0.01; Hochberg-adjusted p value 0.038). Participants who achieved target CGM-derived metrics at baseline, as proposed by an international consensus, showed significant annual changes in mean GSM compared with those who did not (0.94±6.88 vs -0.21±6.19 units/year, p=0.007). CONCLUSIONS/INTERPRETATION: TIR and CV were significantly associated with changes in the tissue characteristics of the carotid artery wall. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry, number UMIN000032325.

MEF2C/p300-mediated epigenetic remodeling promotes the maturation of induced cardiomyocytes.

Cardiac transcription factors (TFs) directly reprogram fibroblasts into induced cardiomyocytes (iCMs), where MEF2C acts as a pioneer factor with GATA4 and TBX5 (GT). However, the generation of functional and mature iCMs is inefficient, and the molecular mechanisms underlying this process remain largely unknown. Here, we found that the overexpression of transcriptionally activated MEF2C via fusion of the powerful MYOD transactivation domain combined with GT increased the generation of beating iCMs by 30-fold. Activated MEF2C with GT generated iCMs that were transcriptionally, structurally, and functionally more mature than those generated by native MEF2C with GT. Mechanistically, activated MEF2C recruited p300 and multiple cardiogenic TFs to cardiac loci to induce chromatin remodeling. In contrast, p300 inhibition suppressed cardiac gene expression, inhibited iCM maturation, and decreased the beating iCM numbers. Splicing isoforms of MEF2C with similar transcriptional activities did not promote functional iCM generation. Thus, MEF2C/p300-mediated epigenetic remodeling promotes iCM maturation.

Comparison of long-term treatment outcomes of laser and anti-VEGF therapy in retinopathy of prematurity: a multicentre study from J-CREST group.

OBJECTIVES: To compare real-world, long-term outcomes of laser and anti-vascular endothelial growth factor (VEGF) therapies in patients with retinopathy of prematurity (ROP). METHODS: This was a multicentre retrospective study. We included 264 eyes of 139 patients treated for type 1 ROP or aggressive ROP (AROP) who were followed for at least 4 years. Laser treatment was initially performed in 187 eyes (the laser group), and anti-VEGF therapy was initially performed in 77 eyes (the anti-VEGF group). We collected data on sex, birth characteristics, zone, stage, and the presence of plus disease at the time of treatment and best-corrected visual acuity (BCVA), spherical equivalent (SE), and ocular complications (amblyopia and strabismus) in patients aged 4-6 years. We investigated the associations between treatment outcomes (BCVA, SE and the presence of amblyopia and strabismus) and influencing factors, including treatment procedure (anti-VEGF or laser therapy), sex, birth characteristics, zone, stage, and the presence of plus disease, using multivariable analysis and logistic regression analyses. RESULTS: The initial treatment procedure was not associated with any specific treatment outcome. Subgroup analysis of patients with zone I ROP revealed that the anti-VEGF-treated eyes had significantly better BCVA and higher SE than laser-treated eyes (p = 0.004, p = 0.009, respectively). Female patients presented significantly better BCVA, less amblyopia and less strabismus than male patients (p < 0.001, p = 0.029, p = 0.008, respectively). CONCLUSIONS: In zone I ROP, anti-VEGF therapy led to better visual acuity and less myopic refractive error than laser treatment.

Effect of Average Relative Humidity on Epistaxis.

Background Epistaxis is a very common symptom. The occurrence of epistaxis may be affected by dry environments, but there are some differences among previous reports and this view is controversial. Objective We investigated the relationship between the number of epistaxes and daily average relative humidity. Methods Data on patients with epistaxis between March 2011 and February 2021 were collected from two hospitals. The daily average relative humidity was examined, and the change in the number of patients with epistaxis due to humidity was investigated using a generalized linear mixed model. Results A total of 4184 cases of epistaxis were identified. The number of epistaxis cases per day was significantly associated with the daily average relative humidity (p < 0.001). One percent increment in average relative humidity decreases the number of epistaxis cases per day by 1.1%. Conclusion A negative correlation was found to exist between daily average relative humidity and occurrences of epistaxis.

A comparison of bias-adjusted generalized estimating equations for sparse binary data in small-sample longitudinal studies.

Using a generalized estimating equation (GEE) can lead to a bias in regression coefficients for a small sample or sparse data. The bias-corrected GEE (BCGEE) and penalized GEE (PGEE) were proposed to resolve the small-sample bias. Moreover, the standard sandwich covariance estimator leads to a bias of standard error for small samples; several modified covariance estimators have been proposed to address this issue. We review the modified GEEs and modified covariance estimators, and evaluate their performance in sparse binary data from small-sample longitudinal studies. The simulation results showed that GEE and BCGEE often failed to achieve convergence, whereas the convergence proportion for PGEE was quite high. The bias for the regression coefficients was generally in the ascending order of PGEE < $$ < $$ BCGEE < $$ < $$ GEE. However, PGEE and BCGEE did not sufficiently remove the bias involving 20-30 subjects with unequal exposure levels with a 5% response rate. The coverage probability (CP) of the confidence interval for BCGEE was relatively poor compared with GEE and PGEE. The CP with the sandwich covariance estimator deteriorated regardless of the GEE methods under the small sample size and low response rate, whereas the CP with the modified covariance estimators-such as Morel's method-was relatively acceptable. PGEE will be the reasonable way for analyzing sparse binary data in small-sample studies. Instead of using the standard sandwich covariance estimator, one should always apply the modified covariance estimators for analyzing these data.

Ultrasonographic Prediction of Placental Invasion in Placenta Previa by Placenta Accreta Index.

This study aimed to investigate the diagnostic accuracy of the placenta accreta index (PAI) for predicting placenta accreta spectrum (PAS) in women with placenta previa. We analyzed 33 pregnancies with placenta previa at Keio University Hospital. The PAI was assessed in the early third trimester, and PAS was diagnosed histologically or clinically defined as retained placenta after manual removal attempts. The PAI and incidence of PAS were analyzed. Ten women (30%) were diagnosed with PAS and had higher volumes of perioperative bleeding (p = 0.016), higher rate of requiring uterine artery embolization (p = 0.005), and peripartum hysterectomy (p = 0.0002) than women without PAS. A PAI > 2 was the most useful cut-off point for predicting PAS and was more sensitive than prediction values using traditional evaluation (history of cesarean section and placental location). Post-hoc analysis revealed a higher rate of previous history of cesarean delivery (30% vs. 4.4%, p = 0.038), severe placental lacunae (≥grade2) (70% vs. 8.7%, p = 0.0003), thin myometrial thickness (90% vs. 22%, p = 0.0003), anterior placenta (100% vs. 30%, p = 0.0002), and presence of bridging vessels (30% vs. 0%, p = 0.0059) in PAS women. PAI could help predict the outcomes of women with placenta previa with and without a history of cesarean delivery to reduce PAS-induced perinatal complications.