Stage at diagnosis of colorectal cancer through diagnostic route: Who should be screened?

BACKGROUND: Colorectal cancer (CRC) is a global health concern, with advanced-stage diagnoses contributing to poor prognoses. The efficacy of CRC screening has been well-established; nevertheless, a significant proportion of patients remain unscreened, with > 70% of cases diagnosed outside screening. Although identifying specific subgroups for whom CRC screening should be particularly recommended is crucial owing to limited resources, the association between the diagnostic routes and identification of these subgroups has been less appreciated. In the Japanese cancer registry, the diagnostic routes for groups discovered outside of screening are primarily categorized into those with comorbidities found during hospital visits and those with CRC-related symptoms. AIM: To clarify the stage at CRC diagnosis based on diagnostic routes. METHODS: We conducted a retrospective observational study using a cancer registry of patients with CRC between January 2016 and December 2019 at two hospitals. The diagnostic routes were primarily classified into three groups: Cancer screening, follow-up, and symptomatic. The early-stage was defined as Stages 0 or I. Multivariate and univariate logistic regressions were exploited to determine the odds of early-stage diagnosis in the symptomatic and cancer screening groups, referencing the follow-up group. The adjusted covariates were age, sex, and tumor location. RESULTS: Of the 2083 patients, 715 (34.4%), 1064 (51.1%), and 304 (14.6%) belonged to the follow-up, symptomatic, and cancer screening groups, respectively. Among the 2083 patients, CRCs diagnosed at an early stage were 57.3% (410 of 715), 23.9% (254 of 1064), and 59.5% (181 of 304) in the follow-up, symptomatic, and cancer screening groups, respectively. The symptomatic group exhibited a lower likelihood of early-stage diagnosis than the follow-up group [P < 0.001, adjusted odds ratio (aOR), 0.23; 95% confidence interval (95%CI): 0.19-0.29]. The likelihood of diagnosis at an early stage was similar between the follow-up and cancer screening groups (P = 0.493, aOR for early-stage diagnosis in the cancer screening group vs follow-up group = 1.11; 95%CI = 0.82-1.49). CONCLUSION: CRCs detected during hospital visits for comorbidities were diagnosed earlier, similar to cancer screening. CRC screening should be recommended, particularly for patients without periodical hospital visits for comorbidities.

Pharmacokinetic and Pharmacodynamic Analysis of the 3CL Protease Inhibitor Ensitrelvir in a SARS-CoV-2 Infection Mouse Model.

The small-molecule antiviral drug ensitrelvir targets the 3C-like protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study evaluated its inhibitory effect on viral replication in a delayed-treatment mouse model and investigated the relationship between pharmacokinetic (PK) parameters and pharmacodynamic (PD) effects. SARS-CoV-2 gamma-strain-infected BALB/c mice were orally treated with various doses of ensitrelvir starting 24 h post-infection. Effectiveness was determined 48 h after first administration based on lung viral titers. Ensitrelvir PK parameters were estimated from previously reported plasma concentration data and PK/PD analyses were performed. Ensitrelvir doses ≥ 16 mg/kg once daily, ≥8 mg/kg twice daily, or ≥8 mg/kg thrice daily for two days significantly reduced lung viral titers compared to that of the vehicle. PK/PD analyses revealed that mean AUC0-48h post-first administration, plasma concentration 48 h post-first administration (C48h), and total time above the target plasma concentration (TimeHigh) were PK parameters predictive of viral titer reduction. In conclusion, ensitrelvir dose-dependently reduced lung SARS-CoV-2 titers in mice, suggesting it inhibited viral replication. PK parameters C48h and TimeHigh were associated with sustained ensitrelvir plasma concentrations and correlated with the reduced viral titers. The findings suggest that maintaining ensitrelvir plasma concentration is effective for exerting antiviral activity against SARS-CoV-2.

A protease activity-based machine-learning approach as a complementary tool for conventional diagnosis of diarrhea-predominant irritable bowel syndrome.

Irritable bowel syndrome (IBS) has no clinically accepted biomarkers even though it affects a large number of individuals worldwide. To address this lack of understanding, we evaluated peptidase activity in fecal samples from 35 patients with diarrheal IBS without symptom exacerbation (IBS-n) and 35 healthy subjects using a library of 384 fluorescent enzymatic substrate probes. IBS-n patients had high trypsin-like peptidase activity for cleavage of C-terminal lysine and arginine residues and low elastase-like activity for cleavage of C-terminal serine and glycine residues. These fluorescent probe library data, together with diagnostic machine-learning techniques, were able to accurately predict IBS-n. This approach can be used to diagnose diseases where no clinically accepted biomarkers exist, in which fecal enzyme activity is altered and also suggests that the development of new therapies targeting enzyme activities is possible.

Changes in Cranial Shape and Developmental Quotient at 6 Months of Age in Preterm Infants.

The purpose of this study was to investigate changes in cranial shape among preterm neonates aged 1-6 months and the relationship between developmental quotient (DQ) and cranial shape at 6 months of age. Preterm infants who were hospitalized in our hospital were prospectively followed for 6 months. The cephalic index (CI) and cranial vault asymmetry index (CVAI) were evaluated at 1 (T1), 3 (T2), and 6 months (T3) of age and compared with those of the full-term infants. The relationship between CI or CVAI and DQ at T3 was analyzed using the Enjoji Scale of Infant Analytical Development. A total of 26 participants born at 34.7 ± 1.9 weeks of gestation were included. The CI increased with age (T1: 77.2%, T2: 82.9%, T3: 85.4%, p < 0.01). The prevalence of dolichocephaly at T3 did not significantly differ from that in full-term infants (15.4% vs. 4.5%, p = 0.08). CVAI did not significantly differ between preterm and full-term infants. The DQ showed no significant correlation with either the CI or CVAI (correlation coefficients: 0.23 for CI, -0.01; CVAI). Dolichocephaly improved over time in preterm infants and no relationship between cranial shape and development was observed in preterm infants at 6 months of age.

Cranial Shape Measurements Obtained Using a Caliper and Elastic Bands Are Useful for Brachycephaly and Deformational Plagiocephaly Screening.

We assessed a method for screening the cranial shape of 1-month-old infants using a simple measuring instrument instead of a three-dimensional scanner. The Mimos craniometer was used to measure cranial length, cranial width, and two diagonal lengths to calculate the cranial index (CI) and cranial asymmetry (CA). We defined a CI > 90% as brachycephaly and CA > 5 mm as deformational plagiocephaly (DP). Intra- and inter-examiner accuracy analyses were performed on a dummy doll and 1-month-old infants. The measurements of healthy 1-month-old infants were compared with previously reported three-dimensional scanner measurements. Intra- and inter-rater measurements showed good accuracy; diagnostic accuracy comparisons of brachycephaly and DP using a three-dimensional scanner showed kappa values of 1.0 and 0.8, respectively. Comparisons were made among 113 infants matched for day-age at the date of measurement; there were no significant differences in the CI (85.0% vs. 85.2%, p = 0.98) and CA (5.9 mm vs. 6.0 mm, p = 0.48) between the scanner and caliper measurements, nor in the prevalence of brachycephaly (12.4% vs. 17.7%, p = 0.35) or DP (58.4% vs. 56.6%, p = 0.89). This simple measurement method using calipers and bands was useful in screening for brachycephaly and DP in 1-month-old infants.

Efficacy comparison of 3CL protease inhibitors ensitrelvir and nirmatrelvir against SARS-CoV-2 in vitro and in vivo.

OBJECTIVES: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become established in the human population, making the need to develop safe and effective treatments critical. We have developed the small-molecule antiviral ensitrelvir, which targets the 3C-like (3CL) protease of SARS-CoV-2. This study evaluated the in vitro and in vivo efficacy of ensitrelvir compared with that of another SARS-CoV-2 3CL PI, nirmatrelvir. METHODS: Cultured cells, BALB/cAJcl mice and Syrian hamsters were infected with various SARS-CoV-2 strains, including the ancestral strain WK-521, mouse-adapted SARS-CoV-2 (MA-P10) strain, Delta strain and Omicron strain. Ensitrelvir efficacy was compared with that of nirmatrelvir. Effective concentrations were determined in vitro based on virus-induced cytopathic effects, viral titres and RNA levels. Lung viral titres, nasal turbinate titres, body-weight changes, and animal survival were also monitored. RESULTS: Ensitrelvir and nirmatrelvir showed comparable antiviral activity in multiple cell lines. Both ensitrelvir and nirmatrelvir reduced virus levels in the lungs of mice and the nasal turbinates and lungs of hamsters. However, ensitrelvir demonstrated comparable or better in vivo efficacy than that of nirmatrelvir when present at similar or slightly lower unbound-drug plasma concentrations. CONCLUSIONS: Direct in vitro and in vivo efficacy comparisons of 3CL PIs revealed that ensitrelvir demonstrated comparable in vitro efficacy to that of nirmatrelvir in cell culture and exhibited equal to or greater in vivo efficacy in terms of unbound-drug plasma concentration in both animal models evaluated. The results suggest that ensitrelvir may become an important resource for treating individuals infected with SARS-CoV-2.

Development of the Paternal Brain in Humans throughout Pregnancy.

Previous studies have demonstrated that paternal caregiving behaviors are reliant on neural pathways similar to those supporting maternal care. Interestingly, a greater variability exists in parental phenotypes in men than in women among individuals and mammalian species. However, less is known about when or how such variability emerges in men. We investigated the longitudinal changes in the neural, hormonal, and psychological bases of expression of paternal caregiving in humans throughout pregnancy and the first 4 months of the postnatal period. We measured oxytocin and testosterone, paternity-related psychological traits, and neural response to infant-interaction videos using fMRI in first-time fathers and childless men at three time points (early to mid-pregnancy, late pregnancy, and postnatal). We found that paternal-specific brain activity in prefrontal areas distinctly develops during middle-to-late pregnancy and is enhanced in the postnatal period. In addition, among fathers, the timing of the development of prefrontal brain activity was associated with specific parenting phenotypes.

Colitis with Hypereosinophilia following the Second Dose of the BNT162b2 mRNA COVID-19 Vaccine: A Case Report with a Literature Review.

A 61-year-old man presented with a 7-day history of watery diarrhea and loss of appetite after receiving the second dose of the Pfizer-BioNTech COVID-19 vaccine. Laboratory studies showed significant eosinophilia and an elevated IgE level (white cell count, 18.4×109/L; eosinophil count, 9.5×109/L; and IgE level, 540 IU/L). Symptoms resolved 10 days after vaccination without any steroids or antiallergic medications, and the eosinophil count had also returned to within normal limits 2 months later. Several cases of eosinophilic disorders following receipt of any type of injectable COVID-19 vaccine have been reported, so the etiology should be examined.

Impact of COVID-19 on the endoscopy department since the early phase of the pandemic in 2020: A questionnaire study among patients with canceled examinations at a single Japanese institution.

INTRODUCTION: In early 2020, the Japanese government declared a nationwide state of emergency for the COVID-19 pandemic. We investigated the impact of the emergency declaration on endoscopy adherence and conducted a follow-up study of patients with canceled examinations at a tertiary endoscopy facility in Japan in 2020. METHODS: We compared the number of endoscopies performed, and cancelations at the endoscopy unit between 2019 and 2020 and used the Bayesian structural time series (BSTS) model to estimate the decrease in the number of endoscopies in 2020. We administered a questionnaire to those who had not undergone a scheduled endoscopy. RESULTS: Of 14 146 and 13 338 scheduled examinations, 1233 (8.7%) and 1403 (10.5%) were canceled in 2019 and 2020, respectively. During both years, age < 50 years, age > 80 years, upper endoscopy, and experience of endoscopy in the past 5 years were significantly associated with cancelations. In 2020, cancelations in the 14th-26th week of the year, including the period of state of emergency, increased significantly, and more women canceled. Of the 409 questionnaire-respondents, 174 (42.5%) indicated that COVID-19 had influenced their cancelation, and 315 (77.0%) had not undergone similar endoscopic examinations since then. The BSTS model predicted a decrease of 957 (95% CI -1213 to -708, P = .003) examinations. CONCLUSION: In 2020, despite low numbers of COVID-19 cases in the study site, the number of endoscopies decreased, and cancelation increased. Further research is needed on the future impact of a decrease in the number of endoscopies during a COVID-19 pandemic.

Assigning a different endoscopist for each annual follow-up may contribute to improved gastric cancer detection rates.

Background and study aims Esophagogastroduodenoscopy (EGD) is an effective and important diagnostic tool to detect gastric cancer (GC). Although previous studies show that examiner, patient, and instrumental factors influence the detection of GC, we analyzed whether assigning a different examiner to surveillance EGD would improve the detection of GC compared to assigning the same examiner as in the previous endoscopy. Patients and methods We retrospectively reviewed patients who underwent two or more consecutive surveillance EGDs at a single center between 2017 and 2019. We identified factors associated with GC detection using multivariable regression analysis and propensity-score matching. Results Among 7794 patients, 99 GC lesions in 93 patients were detected by surveillance EGD (detection rate; 1.2 %), with a mean surveillance interval of 11.2 months. Among the detected 99 lesions, 87 (87.9 %) were curatively treated with endoscopy. There were no differences in the clinicopathologic characteristics of GC detected by the same or different endoscopists. GC detection in the group examined by different endoscopists was more statistically significant than in the group examined by the same endoscopist, even after propensity-score matching (1.6 % and 0.7 %; P  < 0.05). Endoscopic experience and other factors were not statistically significant between the two groups. Conclusions In surveillance EGD, having a different endoscopist for each exam may improve GC detection rates, regardless of the endoscopist's experience.

Omics profiles of fecal and oral microbiota change in irritable bowel syndrome patients with diarrhea and symptom exacerbation.

BACKGROUND: Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction, including dysregulation of the hypothalamic-pituitary-adrenal axis with salivary cortisol changes. However, the role of gastrointestinal microbiota during IBS symptom exacerbation remains unclear. We tested the hypothesis that the microbial species, gene transcripts, and chemical composition of fecal and oral samples are altered during the exacerbation of IBS symptoms. METHODS: Fecal, salivary, and dental plaque samples were collected at baseline from 43 men with IBS with diarrhea (IBS-D) and 40 healthy control (HC) men. Samples in the IBS-D patients were also collected during symptom exacerbation. The composition of the fecal microbiota was determined by analyzing the 16S rRNA gene, RNA-based metatranscriptome, and metabolites in samples from HC and IBS patients with and without symptom exacerbation. Oral samples were also analyzed using omics approaches. RESULTS: The fecal microbiota during IBS symptom exacerbation exhibited significant differences in the phylogenic pattern and short-chain fatty acid compared with fecal samples during defecation when symptoms were not exacerbated. Although there were no significant differences in the phylogenic pattern of fecal microbiota abundance between HCs and IBS-D patients, significant differences were detected in the expression patterns of bacterial transcriptomes related to butyrate production and neuroendocrine hormones, including tryptophan-serotonin-melatonin synthesis and glutamine/GABA. The composition of plaque microbiota was different between HC and IBS-D patients during normal defecation. CONCLUSIONS: Our findings suggest that colonic host-microbial interactions are altered in IBS-D patients during exacerbation of symptoms. There were no overlaps between feces and oral microbiomes.

Imaging Mass Spectrometry (IMS) for drug discovery and development survey: Results on methods, applications and regulatory compliance.

Imaging mass spectrometry (IMS) is increasingly used for drug discovery and development to understand target enagement, tissue distribution, drug toxicity, and disease mechanisms, etc. However, this is still a relatively new technique that requires further development validation before it will be an acceptable technique to support regulated development of new drugs. Thus, best practices will need to be established to build more confidence and gain wider acceptance by the scientific community, pharmaceutical industry, and regulatory authorities. The Imaging Mass Spectrometry Society (IMSS) and the Japan Association for Imaging Mass Spectrometry (JAIMS) have conducted a thorough survey to gather information on the current state of IMS and to identify key issues. The survey was sent to researchers or managers in the position who are currently using IMS techniques in support of their drug discovery and development efforts and/or who plan to use such tools as best practices are established. The survey probes questions related to details regarding technical aspects of IMS, which includes data acquisition, data analysis and quantitation, data integrity, reporting, applications, and regulatory concerns. This international survey was conducted online through the Survey Monkey (https://www.surveymonkey.com) in both English and Japanese from September 14 through September 30, 2020.

Concordant pattern of the HPA axis response to visceral stimulation and CRH administration.

The physiological and psychological mechanisms explaining the individual variability in the stress response are poorly understood. We tested the hypothesis that hypothalamic-pituitary- adrenal (HPA) axis responses to colorectal stimulation affect HPA axis reactivity to corticotropin-releasing hormone (CRH), the visceral pain threshold, and perceived stress. We examined 31 healthy volunteers and 27 individuals with irritable bowel syndrome. According to the ACTH response to colorectal stimulation, the participants were classified into three groups: flattened, decreased, and increased. We found significant differences in the abdominal pain threshold, discomfort threshold, and sensitivity to anxiety among the groups. There were significant differences in the ACTH change and peak level after CRH administration among the groups. The area under the curve of the cortisol response to CRH was significantly different among the groups. The increased group showed a higher basal ACTH level, earlier peak level in the CRH administration test, and higher stress rating during the experiment. The increased group had an exaggerated psychological and physiological stress response, whereas the decreased group had a higher anticipatory endocrine response, stress, and sensitivity to anxiety. Further studies are needed to determine factors including gut microbiota on the individual difference in HPA response.

Development of the paternal brain in expectant fathers during early pregnancy.

The human parenting brain network mediates caregiving behaviors. When exposed to the stimuli of their infants, compared with non-parents, both fathers and mothers exhibit distinct patterns of neural activation. As human males, relative to females, do not undergo robust physiological changes during pregnancy, when and how the paternal brain networks begin to form remains unclear. Thus, using functional MRI, we examined brain activation in response to infant-interaction videos in two groups, childless males and first-time expectant fathers during their partners' early pregnancy before remarkable changes in their partners' appearances commenced. Multivoxel pattern analysis revealed that expectant fathers' left anterior insula and inferior frontal gyrus showed incipient changes in response to parenthood during early pregnancy. Furthermore, these changes were associated with several paternal traits, such as a negative image toward parenting. Such external factors might influence the paternal brain's development during early pregnancy.

Simple methodology for ensuring the precision of measuring radioactivity at low concentrations in very small tissues using quantitative whole-body autoradiography.

Quantitative whole-body autoradiography (QWBA) is largely used to evaluate tissue distribution of small molecule drugs. In QWBA, radioactivity is measured as the intensity obtained from the autoradiogram. It is known that lower intensity per a region of interest (ROI) or smaller size of ROI increases the variability of intensity. In fact, as some tissues are very small (e.g., the choroidea), ensuring reliability on the intensity for measuring radioactivity in these tissues is difficult in case of under- or over-estimation of radioactivity concentration owing to their variation of low radioactivity intensity of ROI. We thus analyzed the relationships between the size, intensity, and precision of ROI to determine the statistically significant lower limit of quantification (LLOQ) in very small tissues. To investigate the difference in correlation between the radiation source (commercial planar radiation standard [com-ST] and self-made radiation standard [self-ST] consisting of radioactive compounds and matrices), apparatus, or setting environment of the apparatus, correlation analysis was conducted under various conditions. Our results revealed that LLOQ can be calculated by simply using the correlation equation because a common relationship was observed between self-ST, which is used in QWBA, and com-ST. This methodology was thus considered valuable for ensuring LLOQ determination in QWBA.

The risks and characteristics of the delayed bleeding after endoscopic submucosal dissection for early gastric carcinoma in cases with anticoagulants.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a minimally invasive treatment for early gastric carcinoma. Vitamin K antagonists and direct oral anticoagulants (DOAC) were reported to increase the risk of delayed bleeding after ESD. However, the evaluation of ESD cases taking anticoagulants is scarce. We analyzed the risk and characteristics of delayed bleeding after gastric ESD in patients on anticoagulants. METHODS: We performed a retrospective observational study at a single center. Consecutive patients who underwent ESD for early gastric carcinoma and took anticoagulants, including warfarin, rivaroxaban, dabigatran, apixaban, and edoxaban, between January 2012 and December 2018, were analyzed. We also calculated delayed bleeding rates for those without anticoagulants. RESULTS: Of 1855 eligible patients who underwent gastric ESDs, 143 took anticoagulants. Delayed bleeding occurred in 30 (21.0%) cases taking anticoagulants, with 15 (19.5%) cases in the DOAC group [rivaroxaban, seven cases (21.2%); dabigatran, four cases (20.0%); apixaban, four cases (23.5%); and edoxaban, zero cases (0%)] and 15 cases (22.7%) in the warfarin group. Furthermore, 43/344 (12.5%) patients taking antiplatelets and 76/1368 (5.6%) patients without antithrombic drugs experienced delayed bleeding. Multivariable logistic analysis revealed post-heart valve replacement (OR, 6.56; 95% CI, 1.75-24.7; p < .05) as a risk for delayed bleeding in warfarin-taking patients, while no statistically significant factor was found in DOAC-taking patients. CONCLUSIONS: Anticoagulants were associated with a high incidence of severe delayed bleeding. Careful attention should be paid to patients on anticoagulants after gastric ESD, especially those on warfarin after heart valve replacement.

Video-call based newborn triage system for local birth centres can be established without major instalment costs using commercially available smartphones.

Neonates often develop transition problems after low-risk birth, precise assessment of which is difficult at primary birth centres. The aim of this study was to assess whether a video triage system can be established without a specially designed communication system between local birth centres and a tertiary neonatal intensive care unit in a region with a population of 700,000. 761 neonates who were referred to a tertiary neonatal intensive care unit were examined. During period 1 (April 2011-August 2015), only a voice call was available for consultations, whereas, during period 2 (September 2015-December 2017), a video call was additionally available. The respiratory condition was assessed based on an established visual assessment tool. A video consultation system was established by connecting personal smartphones at local birth centres with a host computer at a tertiary neonatal intensive care centre. During period 2, video-based triage was performed for 42.4% of 236 consultations at 30 birth centres. Sensitivity and specificity for predicting newborns with critical respiratory dysfunction changed from 0.758 to 0.898 and 0.684 to 0.661, respectively. A video consultation system for ill neonates was established without major instalment costs. Our strategy might improve the transportation system in both high- and low-resource settings.