Diagnostic Performance of a Novel Ultra-Thin Endoscopy under Narrow-Band Imaging for Superficial Squamous Cell Carcinoma of the Pharynx and Esophagus.

This study aimed to evaluate the diagnostic utility of the ultra-thin endoscope (UTE) for superficial squamous cell carcinoma (SSCC) compared to magnifying endoscopy (ME) under narrow-band imaging. Participants underwent endoscopic examination, and images of pharyngeal and esophageal SCCs, as along with suspicious SSCC lesions, were collected using UTE and ME on the same day. Three image catalogs (UTE, ME-1, and ME-2) were created and reviewed by three expert endoscopists. ME-1 and ME-2 contained the same endoscopic images. The primary endpoint was the intra-observer agreement for diagnosing SCC. Eighty-six lesions (SCC = thirty-nine, non-SCC = forty-seven) in 43 participants were identified. The kappa values for the intra-observer agreement between UTE and ME-1 vs. the control (ME-1 vs. ME-2) were 0.74 vs. 0.84, 0.63 vs. 0.76, and 0.79 vs. 0.88, respectively. The accuracies for diagnosing SCC by UTE and ME-1 were 87.2% vs. 86.0%, 78.0% vs. 73,2%, and 75.6 vs. 82.6%, respectively, with no significant differences (p > 0.05). The rates of lesions that were diagnosed with confidence by UTE and ME-1 were 30.2% vs. 27.9%, 55.8% vs. 62.8%, and 58.1% vs. 55.8%, respectively. UTE demonstrates substantial diagnostic performance for SSCC in the pharynx and esophagus.

Texture and color enhancement imaging improves the visibility of gastric neoplasms: clinical trial with image catalogue assessment using conventional and newly developed endoscopes.

BACKGROUND: Texture and color enhancement imaging (TXI) enhances the changes in endoscopic features caused by gastric neoplasms, such as redness/whiteness and elevation/depression. This study aimed to demonstrate the effectiveness of TXI in improving the visibility of gastric neoplasms compared with white light imaging (WLI) using conventional (CE) and newly developed endoscopes (NE). METHODS: We recruited patients who were histologically diagnosed with gastric neoplasms; endoscopy was performed, and gastric neoplasms photographed using three imaging modalities, including WLI, TXI mode 1 (TXI-1) and TXI mode 2 (TXI-2). Two different endoscopes (CE and NE) were used for the same patients. Six endoscopists provided the visibility scale scores ranging from 1 (poor) to 4 (excellent) for gastric neoplasms. The primary outcome was the visibility scale scores based on each modality and endoscope. The secondary outcome was the identification of factors including H. pylori infection, atrophy, location, size, morphology, histological diagnosis and intestinal metaplasia that affect the differences in visibility scale scores between TXI-1/TXI-2 and WLI. RESULTS: Fifty-two gastric neoplasms were analyzed. The mean visibility scale scores with the NE were 2.79 ± 1.07, 3.23 ± 0.96 and 3.14 ± 0.92 for WLI, TXI-1 and TXI-2, respectively. The mean visibility scales with the CE were 2.53 ± 1.10, 3.04 ± 1.05 and 2.96 ± 1.92 for WLI, TXI-1 and TXI-2, respectively. For both endoscopes, significant differences were observed in visibility scale scores between WLI and TXI-1 (p < 0.001) and between WLI and TXI-2 (p < 0.001). The visibility scale scores of NE were superior to those of CE in all modalities. In the secondary outcome, there was no factor affected the differences of visibility scale scores between TXI-1/TXI-2 and WLI. CONCLUSIONS: This study demonstrated that TXI-1 and TXI-2 enhanced the visibility scale scores of gastric neoplasms compared with that of WLI. Moreover, newly developed endoscope has the potential to improve visibility compared to conventional endoscope. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network (UMIN000042429, 16/11/2020).

Stability and Relevance of Marriage Desires: Importance of Age Norms and Partnering Opportunities.

Objective: This study investigates shifts in marriage desires during singlehood and the potential consequences associated with these shifts in Japan, a country epitomizing later and less marriage without substantial increases in nonmarital childbearing. Background: Despite researchers' long-standing interest in values potentially motivating demographic changes, few have systematically examined marriage desires among unmarried adults. Even fewer have considered how marriage desires may change during adulthood and how relevant such changes are to marriage and family behavior. Method: The analysis uses 11 waves of the Japan Life Course Panel Survey, which tracks singles' marriage desires yearly. Fixed effects models are estimated to demonstrate factors associated with within-person changes and account for unobserved heterogeneity. Results: Japanese singles' marriage desires decline with age but are stronger when they perceive greater opportunities to form romantic relationships or marriage. Singles experiencing an increase in the desire to marry are more likely to take actions to seek partners and to enter a romantic relationship or marriage subsequently. The associations between marriage desires and the various behavioral changes strengthen with age and feasibility of marriage. Increases in marriage desires also correspond to increases in single men's parenthood desires and ideal numbers of children, and the link between marriage desires and fertility preferences is stronger as they age. Conclusion: Marriage desires are not always stable or equally relevant throughout singlehood. Our study suggests that age norms and partnering opportunities both contribute to the fluctuation of marriage desires and affect when such desires would have behavioral implications.

Clinical course and management of adverse events after endoscopic resection of superficial duodenal epithelial tumors: Multicenter retrospective study.

OBJECTIVES: This study aimed to elucidate the clinical course and management of adverse events (AEs) after endoscopic resection (ER) for superficial duodenal epithelial tumors (SDETs). METHODS: Consecutive patients who underwent ER of SDETs between January 2008 and July 2018 at 18 Japanese institutions were retrospectively enrolled. The study outcomes included the clinical course, management, and risk of surgical conversion with perioperative AEs after ER for SDETs. RESULTS: Of the 226 patients with AEs, the surgical conversion rate was 8.0% (18/226), including 3.7% (4/108), 1.0% (1/99), and 50.0% (12/24) of patients with intraoperative perforation, delayed bleeding, or delayed perforation, respectively. In the multivariate logistic analysis, involvement of the major papilla (odds ratio [OR] 12.788; 95% confidence interval [CI] 2.098-77.961, P = 0.006) and delayed perforation (OR 37.054; 95% CI 10.219-134.366, P < 0.001) were significant risk factors for surgical conversion after AEs. Delayed bleeding occurred from postoperative days 1-14 or more, whereas delayed perforation occurred within 3 days in all cases. CONCLUSIONS: The surgical conversion rate was higher for delayed perforation than those for other AEs after ER of SDETs. Involvement of the major papilla and delayed perforation were significant risk factors for surgical conversion following AEs. In addition, reliable prevention of delayed perforation is required for 3 days after duodenal ER to prevent the need for surgical interventions.

Characteristics of synchronous and metachronous duodenal tumors and association with colorectal cancer: a supplementary analysis.

BACKGROUND: We previously reported outcomes of endoscopic resection for duodenal tumors in a large cohort. This study investigated the frequency and characteristics of synchronous and metachronous lesions, and their association with colorectal advanced adenoma (CAA) and colorectal cancer (CRC). METHODS: Patients underwent duodenal endoscopic resection during January 2008 to December 2018. Background and characteristics, incidence of synchronous and metachronous lesions, and incidence of CAA and CRC were investigated. Patients without synchronous lesions were classified as the single group, and those with synchronous lesions as the synchronous group. Patients were also classified as the metachronous and non-metachronous groups. The characteristics among the groups were compared. RESULTS: We included 2658 patients with 2881 duodenal tumors: 2472 (93.0%) patients had single, 186 (7.0%) had synchronous, and 54 (2.0%) had metachronous lesions. The 5-year cumulative incidence of metachronous lesions was 4.1%. In total, 208 (7.8%) had CAA and 127 (4.8%) patients had CRC, and colonoscopy was performed in 936 (35.2%) patients. The incidence of CAA in the synchronous groups tended to be higher compared with that in the single groups (11.8% vs 7.5%, adjusted risk ratio 1.56), and the incidence of CRC in the metachronous groups tended to be higher compared with that in the non-metachronous groups (13.0% vs 4.6%, adjusted risk ratio 2.75), but there was no difference after adjusting for colonoscopy. CONCLUSIONS: This study showed the incidence of synchronous and metachronous duodenal lesions. There was no significant difference in incidence of CAA and CRC among each group, but further studies are warranted.

Clinical Trial of Autologous Cultivated Limbal Epithelial Cell Sheet Transplantation for Patients with Limbal Stem Cell Deficiency.

PURPOSE: To confirm the efficacy and safety of Good Manufacturing Practice (GMP)-compliant autologous cultivated limbal epithelial cell sheets in government-controlled clinical trials that adhered to Good Clinical Practice stipulations for patients with unilateral limbal stem cell deficiency (LSCD). DESIGN: A prospective, multicenter, open-label, uncontrolled, single-arm clinical trial. PARTICIPANTS: Ten consecutive eyes of 10 patients with unilateral LSCD were followed for 2 years after surgery. Preoperative LSCD stage was IIB in 4 eyes and III in 6 eyes. METHODS: A limbal tissue biopsy was obtained from the healthy eye, after which limbal stem cells were dissociated and cultivated on temperature-responsive culture surfaces. All cell sheets were fabricated in a GMP-grade facility under established standard operating procedures. Cell sheets were evaluated using defined shipment criteria before transplantation, and only those that met the criteria were used. The cell sheet was transplanted onto each of the patients' diseased eye after removing the conjunctival scar tissue that covered the corneal surface. The severity of LSCD was determined according to a staging method agreed on by global consensus, with eyes evaluated as being in stages IA-C representing successful corneal epithelial reconstruction. Diagnosis and staging of LSCD were determined by the trial's Eligibility Judgment Committee and Effect Assessment Committee using slit-lamp photographs including fluorescein staining. Both committees comprised 2 or 3 third-party cornea specialists, who were provided with information anonymously and randomly. MAIN OUTCOME MEASURE: Corneal epithelial reconstruction rate was the primary end point. RESULTS: Corneal epithelial reconstruction was successful in 6 of 10 eyes (60%) 1 year postoperatively and was significantly higher than the 15% clinically significant efficacy rate achieved by allogeneic limbal transplantation. The reconstruction rate was 70% of eyes 2 years postoperatively. Additionally, improvements in visual acuity were noted in 50% and 60% of eyes at 1 and 2 years, respectively. No clinically significant transplantation-related adverse events were observed. CONCLUSIONS: The efficacy and safety of cultivated limbal epithelial cell sheet transplantation were thus confirmed, and the cell sheet, named "Nepic," is now approved as a cellular and tissue-based product in Japan. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

The Advantage of Immunohistochemical Staining for Evaluating Lymphovascular Invasion Is Limited for Patients with Esophageal Squamous Cell Carcinoma Invading the Muscularis Mucosa.

The cumulative metastasis rate of esophageal squamous cell carcinoma (ESCC) pathologically invading the muscularis mucosae (pT1a-MM), based on lymphovascular invasion (LVI) evaluated by immunohistochemical (IHC) staining is unknown. This retrospective study included patients with endoscopically resected pT1a-MM ESCC. The primary endpoint was the metastasis rate of pT1a-MM based on LVI, evaluated using IHC and additional prophylactic therapy. The secondary endpoint was the identification of independent factors for metastasis based on lesion characteristics. The prognosis was also analyzed considering the impact of head and neck cancer. A total of 104 patients were analyzed, with a median follow-up of 74 months. The positive rate for LVI was 43.3% (45/104). In 33 patients, IHC was not performed at the time of clinical evaluation, 8 of whom exhibited LVI. However, these patients did not exhibit metastasis. The metastasis rates of patients without LVI, those with LVI and additional therapy, and those with LVI without additional therapy were 5.1%, 20.8%, and 0%, respectively. Lesion size ≥ 25 mm was the only independent factor for metastasis in multivariate analysis. The advantage of IHC for determining additional prophylactic therapy is limited for patients with pT1a-MM ESCC.

Clinical characteristics of lacrimal drainage pathway disease-associated keratopathy.

PURPOSE: To report the clinical characteristics of 13 cases of noninfectious corneal ulceration related to lacrimal drainage pathway disease. METHODS: Medical records of 13 patients with lacrimal drainage pathway disease-associated keratopathy who were examined at Ehime University Hospital between April 2007 and December 2021 were analyzed. RESULTS: The predisposing lacrimal drainage pathway diseases for corneal ulceration were chronic dacryocystitis in seven patients and lacrimal canaliculitis in six patients. The corneal ulcers were located at the peripheral cornea in 10 patients and the paracentral cornea in three patients. All patients indicated few cellular infiltrations of the ulcerated area at the slit-lamp examination. Corneal perforation was found in seven patients. The primary identified organisms were Streptococcus spp. in chronic dacryocystitis and Actinomycetes spp. in lacrimal canaliculitis. All patients showed rapid healing of the epithelial defects after treatment of the lacrimal drainage pathway disease. The mean time elapsed between treatment of the lacrimal drainage pathway disease and re-epithelialization of corneal ulcer was 14.5 ± 4.8 days. CONCLUSION: Lacrimal drainage pathway disease-associated keratopathy may be characterized by peripheral corneal ulcer with few cellular infiltrations, occasionally leading to corneal perforation. Treatment of the lacrimal drainage pathway disease could be the most effective treatment for lacrimal drainage pathway disease-associated keratopathy.

Effect of storage temperature and flash-freezing on salivary microbiota profiles based on 16S rRNA-targeted sequencing.

The sample storage environment affects gut microbial profiles as assessed using 16S rRNA sequencing. However, the influence of storage condition on human salivary microbial profiles has not been well characterized. Here, we performed an observational study to assess the robustness of microbiota profiles in three different storage environments (-80°C after flash-freezing, -80°C, and -15°C; all for 14 days) compared to immediate DNA extraction using the MiSeq Illumina platform. Notably, the 16S rRNA V1-V2 region amplicon sequencing revealed no difference in microbiota profiles between the immediate extraction and each of three storage conditions. An almost perfect correlation was shown between the immediate extraction and the -15°C storage group for relative abundance at the genus and operational taxonomic unit levels. The intraindividual UniFrac distances among storage methods were significantly shorter than those of interindividual distances. None of the amount of extracted DNA, the α-diversity indices, or the relative abundance at the phylum/genus/operational taxonomic unit level differed among storage methods. These findings indicate that a storage temperature of -15°C without flash-freezing may be optimal in terms of cost advantage and simplicity in 16S rRNA sequencing-based salivary microbial research.

Outcomes of endoscopic resection for superficial duodenal tumors: 10 years' experience in 18 Japanese high volume centers.

BACKGROUND: Data on endoscopic resection (ER) for superficial duodenal epithelial tumors (SDETs) are insufficient owing to their rarity. There are two main ER techniques for SDETs: endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD). In addition, modified EMR techniques, such as underwater EMR (UEMR) and cold polypectomy, are becoming popular. We conducted a large-scale retrospective multicenter study to clarify the detailed outcomes of duodenal ER. METHODS: Patients with SDETs who underwent ER at 18 institutions from January 2008 to December 2018 were included. The rates of en bloc resection and delayed adverse events (AEs; defined as delayed bleeding or perforation) were analyzed. Local recurrence was analyzed using the Kaplan-Meier method. RESULTS: In total, 3107 patients (including 1017 undergoing ESD) were included. En bloc resection rates were 79.1 %, 78.6 %, 86.8 %, and 94.8 %, and delayed AE rates were 0.5 %, 2.2 %, 2.8 %, and 6.8 % for cold polypectomy, UEMR, EMR and ESD, respectively. The delayed AE rate was significantly higher in the ESD group than in non-ESD groups for lesions < 19 mm (7.4 % vs. 1.9 %; P < 0.001), but not for lesions > 20 mm (6.1 % vs. 7.1 %; P = 0.64). The local recurrence rate was significantly lower in the ESD group than in the non-ESD groups (P < 0.001). Furthermore, for lesions > 30 mm, the cumulative local recurrence rate at 2 years was 22.6 % in the non-ESD groups compared with only 1.6 % in the ESD group (P < 0.001). CONCLUSIONS: ER outcomes for SDETs were generally acceptable. ESD by highly experienced endoscopists might be an option for very large SDETs.

Characteristics of superficial esophageal squamous cell carcinomas undetectable with narrow-band imaging endoscopy.

BACKGROUND: The detection rate of narrow-band imaging (NBI) for superficial esophageal squamous cell carcinoma (SESCC), including high-grade intraepithelial neoplasia, is significantly higher than that of white-light endoscopy. However, there are SESCCs that are undetectable by NBI but detectable by Lugol chromoendoscopy (LCE) and the characteristics of these SESCCs are still unknown. Thus, this study aimed to clarify the characteristics of SESCC that are undetectable using NBI. METHODS: Patients with current SCC or a history of SCC in the head and neck or in the esophagus were enrolled. The inspection of the esophagus was initiated by NBI, followed by LCE. Biopsies were taken of all suspected SESCC lesions during NBI observation and Lugol-voiding lesions (LVLs) that were irregularly shaped and >5 mm and/or pink in color during LCE observation. The characteristics of SESCC that were undetectable with NBI were statistically analysed. RESULTS: Overall, 147 lesions in 105 cases were histologically diagnosed as SESCC. Twenty in 15 cases were NBI-undetectable lesions, all of which were macroscopic flat type (0-IIb). The median sizes of the NBI-undetectable lesions and NBI-detectable lesions were both 15 mm (P = 0.47). Multivariate analysis revealed independent factors for NBI-undetectable lesions such as numerous irregularly shaped LVLs (odds ratio [OR]: 4.94, 95% confidence interval [CI]: 1.39-17.5, P < 0.05) and anterior wall position (OR: 4.99, 95% CI: 1.58-15.8, P < 0.05). CONCLUSIONS: The detection of SESCCs with NBI is challenging when lesions are morphologically completely flat, in cases with numerous irregularly shaped LVLs, and if located at the anterior wall.

Psychotic Features Among Patients in the Prodromal Stage of Dementia with Lewy Bodies During Longitudinal Observation.

BACKGROUND: Many cases of dementia with Lewy bodies (DLB) present with various psychotic features, including hallucinations, depression, catatonia, and delusions before the onset of cognitive impairment. However, the characteristic features of these psychotic symptoms in prodromal DLB have not been sufficiently described. OBJECTIVE: To clarify and describe the psychotic features of prodromal DLB before overt cognitive impairment. METHODS: The authors analyzed the characteristic psychotic features of prodromal DLB in 21 subjects who developed severe psychotic symptoms without dementia and were diagnosed as DLB after the longitudinal observation period. They were then confirmed to have DLB through indicative and supportive biomarkers of scintigraphy. RESULTS: The psychotic features included a wide variety of symptoms, but convergent to three principal categories: catatonia, delusions-hallucinations, and depression and/or mania. Catatonia was observed in nine cases, five were delusional-hallucinatory, and seven were manic and/or depressive. Seven of the 21 cases exhibited delirium during longitudinal observation. A psychotic state repeatedly appeared without any trigger in 20 of the 21 patients. All subjects developed cognitive impairment at 9.1±4.6 (mean±SD) years after the initial appearance of psychotic symptoms, and subsequently diagnosed with DLB at 71.3±6.1 (mean±SD) years. CONCLUSION: Elderly patients with psychotic symptoms, such as catatonia, delusion-hallucination, manic and/or depressive features, and delirium without dementia, could indicate symptomatic psychosis or a prodromal stage of any neurocognitive disorder such as DLB. Therefore, further extensive workout (e.g., radioisotope neuroimaging) is required to avoid misdiagnosis.

Metabolomic Alteration of Oral Keratinocytes and Fibroblasts in Hypoxia.

The oxygen concentration in normal human tissue under physiologic conditions is lower than the atmospheric oxygen concentration. The more hypoxic condition has been observed in the cells with wound healing and cancer. Somatic stem cells reside in a hypoxic microenvironment in vivo and prefer hypoxic culture conditions in vitro. Oral mucosa contains tissue-specific stem cells, which is an excellent tissue source for regenerative medicine. For clinical usage, maintaining the stem cell in cultured cells is important. We previously reported that hypoxic culture conditions maintained primary oral keratinocytes in an undifferentiated and quiescent state and enhanced their clonogenicity. However, the metabolic mechanism of these cells is unclear. Stem cell biological and pathological findings have shown that metabolic reprogramming is important in hypoxic culture conditions, but there has been no report on oral mucosal keratinocytes and fibroblasts. Herein, we conducted metabolomic analyses of oral mucosal keratinocytes and fibroblasts under hypoxic conditions. Hypoxic oral keratinocytes and fibroblasts showed a drastic change of metabolite concentrations in urea cycle metabolites and polyamine pathways. The changes of metabolic profiles in glycolysis and the pentose phosphate pathway under hypoxic conditions in the oral keratinocytes were consistent with those of other somatic stem cells. The metabolic profiles in oral fibroblasts showed only little changes in any pathway under hypoxia except for a significant increase in the antioxidant 2-oxoglutaric acid. This report firstly provides the holistic changes of various metabolic pathways of hypoxic cultured oral keratinocytes and fibroblasts.

Motherhood Penalties and Fatherhood Premiums: Effects of Parenthood on Earnings Growth Within and Across Firms.

Despite much interest in how parenthood contributes to the gender pay gap, prior research has rarely explored firms' roles in shaping the parenthood pay penalty or premium. The handful of studies that investigated parenthood's effects within and across firms generally compared parents and their childless peers at a given time and failed to account for unobserved heterogeneity between the two groups. Such comparisons also cannot inform how having children may alter individuals' earnings trajectories within and across firms. Using 26 rounds of the National Longitudinal Survey of Youth 1979 and fixed-effects models, we examine how being a mother or father is linked to earnings growth within and across firms. We find that women's pay decreases as they become mothers and that the across-employer motherhood penalty is larger than the within-employer penalty. By contrast, fatherhood is associated with a pay premium, and the within-employer fatherhood premium is considerably greater than the across-employer one. We argue that these results are consistent with the discrimination explanation of the motherhood penalty and fatherhood premium. Because employers are likely to trust women who become mothers while working for them more than new recruits who are mothers, their negative bias against mothers would be more salient when evaluating the latter, which could result in a larger between-organizational motherhood penalty. Conversely, employers' likely greater trust in existing workers who become fathers than fathers they hire from elsewhere may amplify their positive bias favoring fathers in assessing the former, which could explain the greater within-firm fatherhood premium.

Association between Endoscopic Milk-White Mucosa, Epithelial Intracellular Lipid Droplets, and Histological Grade of Superficial Non-Ampullary Duodenal Epithelial Tumors.

We previously reported that superficial non-ampullary duodenal tumors (SNADETs) commonly had a whitish mucosal surface, named milk-white mucosa (MWM). The aim of this study was to evaluate the association of MWM with epithelial intracellular lipid droplets (immunohistochemically stained by adipose differentiation-related protein (ADRP)) and histological tumor grades. We reviewed endoscopic images and the histopathology of SNADETs resected en bloc endoscopically. We analyzed the correlation between the positive rates of endoscopic MWM in preoperative endoscopy and resected specimens, and ADRP-positive rates in the resected specimens. Associations between the MWM-positive rates and tumor grades, high-grade intraepithelial neoplasia (HGIN)/intramucosal carcinoma (IC), and low-grade intraepithelial neoplasia (LGIN) were analyzed. All the 92 SNADETs analyzed were <20 mm and histologically classified into 39 HGIN/IC and 53 LGIN. Spearman's rank correlation coefficient showed a significant correlation between MWM-positive and ADRP-positive rates (p < 0.001). MWM-positive rates were significantly lower in the HGIN/IC than in the LGIN in preoperative endoscopy (p < 0.001) and resected specimens (p = 0.02). Our results suggest that endoscopic MWM is closely associated with epithelial intracellular lipid droplets and that the MWM-positive rate may be a predictor of histological grade in small SNADETs.

Value-Generating Exploratory Trials in Neurodegenerative Dementias.

Drug development for Alzheimer disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3 clinical trials that failed to show efficacy of investigational drugs. Despite differences in clinical and behavioral characteristics, these disorders have shared pathologies and face common challenges in designing early-phase trials that are predictive of late-stage success. Here, we discuss exploratory clinical trials in neurodegenerative dementias. These are generally phase 1b or phase 2a trials that are designed to assess pharmacologic effects and rely on biomarker outcomes, with shorter treatment durations and fewer patients than traditional phase 2 studies. Exploratory trials can establish go/no-go decision points, support proof of concept and dose selection, and terminate drugs that fail to show target engagement with suitable exposure and acceptable safety profiles. Early failure saves valuable resources including opportunity costs. This is especially important for programs in academia and small biotechnology companies but may be applied to high-risk projects in large pharmaceutical companies to achieve proof of concept more rapidly at lower costs than traditional approaches. Exploratory studies in a staged clinical development program may provide promising data to warrant the substantial resources needed to advance compounds through late-stage development. To optimize the design and application of exploratory trials, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration convened an advisory panel to provide recommendations on outcome measures and statistical considerations for these types of studies and study designs that can improve efficiency in clinical development.

Blood group O is a risk factor for delayed post-polypectomy bleeding.

BACKGROUND: Blood group O of ABO blood group system is considered as a risk factor for various bleeding events, but the relationship with endoscopic treatment-associated bleeding has yet to be investigated. This study aimed to evaluate whether blood group O is associated with delayed bleeding after colorectal endoscopic resection. METHODS: This was a retrospective observational study based on medical records at four university hospitals in Japan. We reviewed the records for consecutive patients who underwent colorectal endoscopic resection from January 2014 through December 2017. The primary outcome was the incidence of delayed bleeding, defined as hematochezia or melena, requiring endoscopy, transfusion, or any hemostatic intervention up to 28 days after endoscopic resection. Multivariate logistic regression analysis was performed to adjust the impact of blood group O on the delayed bleeding. RESULTS: Among 10,253 consecutive patients who underwent colorectal endoscopic resection during the study period, 8625 patients met the criteria. In total, delayed bleeding occurred in 255 patients (2.96%). The O group had significantly more bleeding events compared with the non-O group (A, B, and AB) (relative risk, 1.62 [95% confidence interval, 1.24-2.10]; P < 0.001). In multivariate logistic regression analysis, blood group O remained an independent risk factor for the bleeding (adjusted odds ratio, 1.60 [95% confidence interval, 1.18-2.17]; P = 0.002). CONCLUSIONS: Blood group O was associated with an increased risk of delayed bleeding in patients undergoing colorectal endoscopic resection. Preoperative screening for ABO blood group could improve risk assessments.