Multicenter prospective randomized controlled clinical trial comparing the pocket-creation method with and without single-clip traction of colonic endoscopic submucosal dissection.

BACKGROUND: The pocket-creation method (PCM) was developed to overcome the technical difficulties of endoscopic submucosal dissection (ESD), although opening the pocket remains challenging. We developed a novel technique of PCM with single-clip traction (PCM-CT), which uses a reopenable clip as a traction device to maintain stability during the procedure. No prospective study has compared the efficacy of PCM-CT and PCM. This study aimed to investigate the effectiveness of PCM-CT vs. PCM in a randomized controlled trial. METHODS: This randomized controlled clinical trial was conducted at four Japanese institutions. Patients with superficial colorectal neoplastic lesions were included following Japanese guidelines for colorectal cancer. Seven moderately experienced endoscopists performed the ESD procedures using either PCM-CT or PCM. RESULTS: 100 patients were enrolled in the study. Compared with PCM, PCM-CT achieved significantly faster mean (SD) dissection speed (21.4 [10.8] vs. 27.0 [14.5] mm2/min [95%CI 0.5 to 10.7], P = 0.03), and reduced the mean procedure time (81.8 [57.9] vs. 64.8 [47.6] minutes [95%CI -38.2 to 4.3], P = 0.12) and pocket-opening time (37.8 [33.0] vs. 30.0 [28.9] minutes [95%CI -20.2 to 4.6], P = 0.22). En bloc and R0 resection rates were not significantly different between the two groups (100% vs. 100%, P >0.99; 100% vs. 96%, P = 0.50, respectively). No significant differences were observed in adverse events between the two groups. CONCLUSION: ESD facilitated by the novel PCM-CT method appeared to be significantly faster than PCM. Both methods achieved high R0 resection rates.

Comparison between CT volumetry, technetium99m galactosyl-serum-albumin scintigraphy, and gadoxetic-acid-enhanced MRI to estimate the liver fibrosis stage in preoperative patients.

OBJECTIVES: To compare the efficacy of computed tomography volumetry (CTV), technetium99m galactosyl-serum-albumin (99mTc-GSA) scintigraphy, and gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic-acid-enhanced MRI (EOB-MRI) in estimating the liver fibrosis (LF) stage in patients undergoing liver resection. METHODS: This retrospective study included 91 consecutive patients who had undergone preoperative dynamic CT and 99mTc-GSA scintigraphy. EOB-MRI was performed in 76 patients. CTV was used to measure the total liver volume (TLV), spleen volume (SV), normalised to the body surface area (BSA), and liver-to-spleen volume ratio (TLV/SV). 99mTc-GSA scintigraphy provided LHL15, HH15, and GSA indices. The liver-to-spleen ratio (LSR) was calculated in the hepatobiliary phase of EOB-MRI. Hyaluronic acid and type 4 collagen levels were measured in 65 patients. Logistic regression and receiver operating characteristic (ROC) analyses were performed to identify useful parameters for estimating the LF stage and laboratory data. RESULTS: According to the multivariable logistic regression analysis, SV/BSA (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.003-1.02; p = 0.011), LSR (OR, 0.06; 95%CI, 0.004-0.70; p = 0.026), and hyaluronic acid (OR, 1.01; 95%CI, 1.001-1.02; p = 0.024) were independent variables for severe LF (F3-4). Combined SV/BSA, LSR, and hyaluronic acid correctly estimated severe LF, with an AUC of 0.91, which was significantly larger than the AUCs of the GSA index (AUC = 0.84), SV/BSA (AUC = 0.83), or LSR (AUC = 0.75) alone. CONCLUSIONS: Combined CTV, EOB-MRI, and hyaluronic acid analyses improved the estimation accuracy of severe LF compared to CTV, EOB-MRI, or 99mTc-GSA scintigraphy individually. CLINICAL RELEVANCE STATEMENT: The combined analysis of spleen volume on CT volumetry, liver-to-spleen ratio on gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic-acid-enhanced MRI, and hyaluronic acid can identify severe liver fibrosis associated with a high risk of liver failure after hepatectomy and recurrence in patients with hepatocellular carcinoma. KEY POINTS: • Spleen volume of CT volumetry normalised to the body surface area, liver-to-spleen ratio of EOB-MRI, and hyaluronic acid were independent variables for liver fibrosis. • CT volumetry and EOB-MRI enable the detection of severe liver fibrosis, which may correlate with post-hepatectomy liver failure and complications. • Combined CT volumetry, gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic-acid-enhanced MRI (EOB-MRI), and hyaluronic acid analyses improved the estimation of severe liver fibrosis compared to technetium99m galactosyl-serum-albumin scintigraphy.

De Novo Discovery of Pseudo-Natural Prenylated Macrocyclic Peptide Ligands.

Prenylation of peptides is widely observed in the secondary metabolites of diverse organisms, granting peptides unique chemical properties distinct from proteinogenic amino acids. Discovery of prenylated peptide agents has largely relied on isolation or genome mining of naturally occurring molecules. To devise a platform technology for de novo discovery of artificial prenylated peptides targeting a protein of choice, here we have integrated the thioether-macrocyclic peptide (teMP) library construction/selection technology, so-called RaPID (Random nonstandard Peptides Integrated Discovery) system, with a Trp-C3-prenyltransferase KgpF involved in the biosynthesis of a prenylated natural product. This unique enzyme exhibited remarkably broad substrate tolerance, capable of modifying various Trp-containing teMPs to install a prenylated residue with tricyclic constrained structure. We constructed a vast library of prenylated teMPs and subjected it to in vitro selection against a phosphoglycerate mutase. This selection platform has led to the identification of a pseudo-natural prenylated teMP inhibiting the target enzyme with an IC50 of 30 nM. Importantly, the prenylation was essential for the inhibitory activity, enhanced serum stability, and cellular uptake of the peptide, highlighting the benefits of peptide prenylation. This work showcases the de novo discovery platform for pseudo-natural prenylated peptides, which is readily applicable to other drug targets.

Impact of patient characteristic factors on the dynamics of liver glucose metabolism: Evaluation of multiparametric imaging with dynamic whole-body 18 F-fluorodeoxyglucose-positron emission tomography.

AIMS: To assess the impact of various patient characteristics on the dynamics of liver glucose metabolism using automated multiparametric imaging with whole-body dynamic 18 F-fluorodeoxyglucose (FDG)-positron emission tomography (PET). MATERIALS AND METHODS: We retrospectively enrolled 540 patients who underwent whole-body dynamic FDG-PET. Three quantitative indices representing hepatic glucose metabolism [mean standardized uptake value normalized by lean body mass (SULmean), metabolic glucose rate (kinetic index) and distribution volume (DV)] were measured from multiparametric PET images produced automatically based on the Patlak plot model. Patient characteristics including age, sex, body mass index, fasting time, blood glucose level, and the presence of diabetes mellitus (DM) or hepatic steatosis (HS) were collected. We examined the correlations between the characteristic factors and three quantitative indices using multiple regression analysis. RESULTS: The success rate of kinetic analysis using multiparametric PET imaging was 93.3% (504/540). Hepatic SULmean was significantly correlated with age (p < .001), sex (p < .001) and blood glucose level (p = .002). DV was significantly correlated with age (p = .033), sex (p < .001), body mass index (p = .002), fasting time (p = .043) and the presence of HS (p = .002). The kinetic index was significantly correlated with age (p < .001) and sex (p = .004). In the comparison of the healthy, DM and HS groups, patients with DM had a significantly increased SULmean, whereas patients with HS had a significantly decreased DV. CONCLUSIONS: Our results showed that liver glucose metabolism was influenced by various patient characteristic factors. Multiparametric FDG-PET imaging can be used to analyse the kinetics of liver glucose metabolism in routine clinical practice.

Pulmonary interstitial glycogenosis in Birt-Hogg-Dubé syndrome-associated lung cysts: A new insight into the pathogenesis?

Multiple lung cysts are one of the major features of Birt-Hogg-Dubé syndrome (BHD), but little is known about their nature and pathogenesis. We report a case of a woman diagnosed with BHD lung cysts who exhibited pulmonary interstitial glycogenosis (PIG), a mesenchymal abnormality hitherto undescribed in this disease, in specimens resected at 14 and 29 years of age. Histopathologically, oval to spindle clear cells were seen in the subepithelial interstitial tissue of septal structures and the walls of the cysts. They had abundant periodic acid-Schiff-positive cytoplasmic glycogen. Immunohistochemically, these cells were positive for a few markers of mesenchymal stem cell-like lineage, including vimentin, CD44, and CD10, and negative for markers of epithelial or specific mesenchymal differentiation; these results were consistent with the reported immunophenotype of PIG cells. These PIG cells were more abundant in her specimen at age 14 years than in the second specimen from adulthood. The present case suggests that BHD lung cysts belong to a group of pulmonary developmental disorders characterized by combined PIG and alveolar simplification/cystic change. Disorders with PIG may persist until adulthood and may be of clinical and pathological significance.

Comparison between CT volumetry and extracellular volume fraction using liver dynamic CT for the predictive ability of liver fibrosis in patients with hepatocellular carcinoma.

OBJECTIVES: To compare the predictive ability of liver fibrosis (LF) by CT-volumetry (CTV) for liver and spleen and extracellular volume fraction (ECV) for liver in patients undergoing liver resection. METHODS: We retrospectively analysed 90 consecutive patients who underwent CTV and ECV. Manually placed region-of-interest ECV (manual-ECV), rigid-registration ECV (rigid-ECV), and nonrigid-registration ECV (nonrigid-ECV) were calculated as ECV(%) = (1-haematocrit) × (ΔHUliver/ΔHUaorta), where ΔHU = subtraction of unenhanced phase from equilibrium phase (240 s). Manual-ECV was compared with CTV for the estimation of LF. The total liver volume to body surface area (TLV/BSA), splenic volume to BSA (SV/BSA), ratio of TLV to SV (TLV/SV), ratio of right liver volume to SV (RV/SV), and liver segmental volume ratio (LSVR) were measured. ROC analyses were performed for ECV and CTV. RESULTS: After excluding 10 patients, seventy-eight (97.5%) out of 80 patients had a Child-Pugh score of 5 points, and two (2.5%) patients had a Child-Pugh score of 6 points. AUC of ECV showed no significant difference among manual-ECV, rigid-ECV, and nonrigid-ECV. TLV/BSA, SV/BSA, TLV/SV, and RV/SV had a higher correlation with LF grades than manual-ECV. AUC of SV/BSA was significantly higher than that of manual-ECV in F0-1 vs F2-4 and F0-2 vs F3-4. AUC of SV/BSA (0.76-0.83) was higher than that of manual-ECV (0.61-0.75) for all LF grades, although manual-ECV could differentiate between F0-3 and F4 at high AUC (0.75). CONCLUSIONS: In patients undergoing liver resection, SV/BSA is a better method for estimating severe LF grades, although manual-ECV has the ability to estimate cirrhosis (≥ F4). KEY POINTS: The splenic volume is a better method for estimating liver fibrosis grades. The extracellular volume fraction is also a candidate for the estimation of severe liver fibrosis.

Images of laser and light-emitting diode colonoscopy for comparing large colorectal lesion visibility with linked color imaging and white-light imaging.

OBJECTIVES: In light-emitting diode (LED) and laser colonoscopy, linked color imaging (LCI) superiority to white-light imaging (WLI) for polyp detection is shown separately. We analyzed the noninferiority of LCI between LED and laser colonoscopy and that of WLI (LECOL study). METHODS: We prospectively collected nonpolypoid lesions with WLI and LCI using LED and laser colonoscopy from January 2021 to August 2021. All images were evaluated randomly by 12 endoscopists (six nonexperts and six experts in three institutions) using the polyp visibility score: 4, excellent; 3, good; 2, fair; and 1, poor. The comparison score (LED better/similar/laser better) for redness and brightness was evaluated for WLI and LCI pictures of each lesion. RESULTS: Finally, 63 nonpolypoid lesions were evaluated, and the mean polyp size was 24.5 ± 13.4 mm. Histopathology revealed 13 serrated lesions and 50 adenomatous/cancerous lesions. The mean polyp visibility scores of LCI pictures were significantly higher than those of WLI in the LED (3.35 ± 0.85 vs. 3.08 ± 0.91, P < 0.001) and the laser (3.40 ± 1.71 vs. 3.05 ± 0.97, P < 0.001) group, and the noninferiority of LCI pictures between LED and laser was significant (P < 0.001). The comparison scores revealed that the evaluation of redness and brightness (LED better/similar/laser better) were 26.8%/40.1%/33.1% and 43.5%/43.5%/13.0% for LCI pictures (P < 0.001) and 20.6%/44.3%/35.1% and 60.3%/31.7%/8.0% for WLI pictures (P < 0.001), respectively. CONCLUSION: The noninferiority of polyp visibility with WLI and LCI in LED and laser colonoscopy was shown. WLI and LCI of LED tended to be brighter and less reddish than those of laser.

Identification of Neoantigens in Cancer Cells as Targets for Immunotherapy.

The clinical benefits of immune checkpoint blockage (ICB) therapy have been widely reported. In patients with cancer, researchers have demonstrated the clinical potential of antitumor cytotoxic T cells that can be reinvigorated or enhanced by ICB. Compared to self-antigens, neoantigens derived from tumor somatic mutations are believed to be ideal immune targets in tumors. Candidate tumor neoantigens can be identified through immunogenomic or immunopeptidomic approaches. Identification of neoantigens has revealed several points of the clinical relevance. For instance, tumor mutation burden (TMB) may be an indicator of immunotherapy. In various cancers, mutation rates accompanying neoantigen loads may be indicative of immunotherapy. Furthermore, mismatch repair-deficient tumors can be eradicated by T cells in ICB treatment. Hence, immunotherapies using vaccines or adoptive T-cell transfer targeting neoantigens are potential innovative strategies. However, significant efforts are required to identify the optimal epitopes. In this review, we summarize the recent progress in the identification of neoantigens and discussed preclinical and clinical studies based on neoantigens. We also discuss the issues remaining to be addressed before clinical applications of these new therapeutic strategies can be materialized.

Guest Recognition Control Accompanied by Stepwise Gate Closing and Opening of a Macrocyclic Metallohost.

Host-guest binding behavior of macrocyclic hosts is significantly influenced by the shapes and sizes of the hosts. In particular, closing/opening the apertures of the hosts controls the guest uptake/release. A post-metalation modification method was used to achieve the open/close conversions. The starting open complex, [LCo2 (pip)4 ](OTf)2 , was efficiently converted to the closed complex, [LCo2 (hda)2 ](OTf)2 , which has a doubly bridged structure. The conversion of this closed complex to the open complex [LCo2 (hda)2 (OAc)]+ was too slow to be completed, but this gate-opening was dramatically accelerated by the addition of Na+ . The Na+ binding was also significantly enhanced by the gate-opening, that is, conversion of [LCo2 (hda)2 ]2+ to [LCo2 (hda)2 (OAc)]+ .

Treatment effect prediction using CT after balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension.

OBJECTIVE: To evaluate whether the change in computed tomography pulmonary angiography (CTPA) metrics after balloon pulmonary angioplasty (BPA) can predict treatment effect in chronic thromboembolic pulmonary hypertension (CTEPH) patients. METHODS: This study included 82 CTEPH patients who underwent both CTPA and right heart catheterization (RHC) before and at the scheduled time of 6 months after BPA. The diameters of the main pulmonary artery (dPA), ascending aorta (dAA), right atrium (dRA), right ventricular free wall thickness (dRVW), and right and left ventricles (dRV, dLV) were measured on CTPA. The correlation of the New York Heart Association functional class (NYHA FC), 6-minute walking distance (6MWD), brain natriuretic peptide (BNP) level, and calculated CT metrics with a decrease in mean pulmonary artery pressure (ΔmPAP) using RHC (used as the reference for BPA effect) was investigated. Using multiple regression analysis, independent variables were also identified. RESULTS: In univariate analysis, clinical indicators (NYHA FC, 6MWD, and BNP level) improved significantly after BPA and were significantly correlated with ΔmPAP (p < 0.01). In the univariate analysis of CTPA parameters, dPA, dRA, dPA/dAA ratio, dRVW, and dRV/dLV ratio decreased significantly and were significantly correlated with ΔmPAP (p < 0.01). Multivariate analysis demonstrated that decreased dPA (p = 0.001) and decreased dRA (p = 0.039) on CTPA were independent predictive factors of ΔmPAP. CONCLUSIONS: Decreased dPA and dRA on CTPA could predict a decrease in mPAP after BPA, thus potentially eliminating unnecessary invasive catheterization. KEY POINTS: • The reduction in mean pulmonary artery pressure after balloon pulmonary angioplasty in CTEPH patients was significantly correlated with the clinical indices improvement and CTPA parameter decrease. • The decreased diameter of the main pulmonary artery and the decreased diameter of the right atrium on CTPA were independent predictors of mean pulmonary artery pressure reduction.

Swallowing Dynamics and Breathing-Swallowing Coordination Are Altered in Patients with Mild Cognitive Impairment.

INTRODUCTION: Postinspiratory activity, which is essential for laryngeal closure during swallowing to prevent aspiration of food into the airways, is reduced in a mouse model of tauopathy. Therefore, we hypothesized that patients at the stage of mild cognitive impairment (MCI) exhibit alterations in swallowing dynamics and coordination between swallowing and breathing. METHODS: We examined breathing-swallowing coordination in patients with MCI. Patients who scored ≥24 on the Mini-Mental State Examination and <26 on the Japanese version of the Montreal Cognitive Assessment were recruited at Sumoto Itsuki Hospital. Parameters associated with breathing-swallowing coordination were assessed using a combination of two sensors: a respiratory flow sensor and a piezoelectric sensor attached to the skin surface of the anterior neck. RESULTS: Nineteen patients met the criteria for MCI; 16 of these patients (79.5 ± 9.1 years old) scored <3 on the 10-item Eating Assessment Tool and were enrolled in the study. Their data were compared with those of an age-matched elderly cohort (79.9 ± 2.9 years old). The frequencies of swallowing during inspiration and swallowing immediately followed by inspiration in patients with MCI were 6.9% and 9.6%, respectively; these frequencies were not significantly different from those of the age-matched elderly cohort. However, the timing of swallowing in the respiratory cycle was significantly delayed in the MCI patients, and both time from the onset to the peak of laryngeal elevation and the duration between the onset of rapid laryngeal elevation and the time when the larynx returned to the resting position were significantly lengthened in this group. CONCLUSION: At the stage of MCI, breathing-swallowing coordination has already started to decline.

Case report of portal hepatic schwannoma: presentation of multimodality images.

BACKGROUND: Portal hepatic schwannoma is a rare benign tumor and difficult to diagnose preoperatively because of its rarity and imaging manifestations that mimic malignancy. We present a case of portal hepatic schwannoma that showed moderate contrast enhancement on computed tomography (CT), extension along the bile duct on T2-weighted imaging and magnetic resonance cholangiopancreatography (MRCP), and uptake of 18F-fluorodeoxyglucose (FDG) on positron emission tomography. CASE PRESENTATION: Ultrasonography at an annual health checkup identified a hepatic mass in a 38-year-old woman. CT showed a well-defined portal hepatic tumor with mild contrast enhancement. T2-weighted imaging and MRCP showed a clavate tumor extending along the intrahepatic bile ducts but no dilatation of the ducts. The tumor exhibited increased FDG uptake, such as maximum standardized uptake values of 5.0 and 6.5 in the early and late phases, respectively. Neither dilatation of intrahepatic bile ducts nor lymphadenopathy was identified, and the multimodality imaging suggested hepatic portal lymphoma, gastrointestinal tumor, or IgG4-related disease rather than cholangiocarcinoma. A needle biopsy via endoscopic ultrasonography was performed, and immunohistology confirmed the tumor as a schwannoma. CONCLUSIONS: The diagnosis of a portal hepatic schwannoma requires immunohistological examinations in addition to multimodality imaging studies to reflect fully the pathohistological characteristics of the tumor.

Idiopathic Sudden Sensorineural Hearing Loss: Speech Intelligibility Deficits Following Threshold Recovery.

OBJECTIVES: This retrospective study tests the hypothesis that patients who have recovered from idiopathic sudden sensorineural hearing loss (SSNHL) show deficits in word recognition tasks that cannot be entirely explained by a loss in audibility. DESIGN: We reviewed the audiologic profile of 166 patients presenting with a unilateral SSNHL. Hearing loss severity, degree of threshold recovery, residual hearing loss, and word recognition performance were considered as outcome variables. Age, route of treatment, delay between SSNHL onset and treatment, and audiogram configuration were considered as predictor variables. RESULTS: Severity, residual hearing loss, and recovery were highly variable across patients. While age and onset-treatment delay could not account for the severity, residual hearing loss and recovery in thresholds, configuration of the SSNHL and overall inner ear status as measured by thresholds on the contralateral ear were predictive of threshold recovery. Speech recognition performance was significantly poorer than predicted by the speech intelligibility curve derived from the patient's audiogram. CONCLUSIONS: SSNHL is associated with (1) changes in thresholds that are consistent with ischemia and (2) speech intelligibility deficits that cannot be entirely explained by a change in hearing sensitivity.

Post-Metalation Modification of a Macrocyclic Dicobalt(III) Metallohost by Site-Selective Ligand Exchange for Guest Recognition Control.

We propose post-metalation modification as a useful strategy to control the guest recognition behavior of a metal-containing macrocyclic host. This is based on the ligand exchange of the axial ligands of a cobalt(III) dinuclear macrocyclic host, [LCo2 X4 ]2+ (X=axial amine ligand). Four piperidine ligands in [LCo2 (pip)4 ]2+ (pip=piperidine) were site-selectively replaced with primary amines. The competitive experiments revealed that the order of the affinity toward the cobalt centers in [LCo2 X4 ]2+ is primary amine > secondary amine > tertiary amine and that the piperidine-coordinating complex, [LCo2 (pip)4 ]2+ , was reasonably reactive among the isolable complexes. Indeed, two piperidine ligands at the diagonal positions in [LCo2 (pip)4 ]2+ were site-selectively replaced with pyridine or acetate ion. The replacement of piperidine with acetate ion significantly enhanced the recognition ability towards Na+ .

Prospective randomized trial comparing the pocket-creation method and conventional method of colorectal endoscopic submucosal dissection.

BACKGROUND AND AIMS: Colorectal endoscopic submucosal dissection (ESD) is recognized as a challenging procedure. Previously, we reported that a new ESD strategy using the pocket-creation method (PCM) is useful for colorectal ESD, but no prospective randomized study has evaluated the efficacy of the PCM. The aim of this study was to evaluate the efficacy and safety of PCM for colorectal ESD compared with the conventional method (CM). METHODS: This was a prospective randomized controlled trial at 3 institutions in Japan. Patients with superficial colorectal neoplastic lesions >20 mm predicted to be intramucosal were randomly assigned to undergo ESD using the PCM or CM. Primary outcome was the ESD completion rate defined as completion of colorectal ESD with an en bloc resection using the assigned ESD method without changing to other methods or assisted by other devices. RESULTS: We analyzed 59 patients with 59 colorectal tumors in the PCM group and 55 in the CM group. The ESD completion rate was significantly higher in the PCM group compared with the CM group (93% [55/59] vs 73% [40/55]; P  = .01). En bloc resection rates, R0 resection rates, procedure time, and dissection speed were not significantly different between the 2 groups. The incidence of adverse events was similar in the 2 groups. CONCLUSIONS: Use of the PCM allows the endoscopist to complete the procedure with the intended method more often than the CM with similar clinical outcomes. (Clinical trial registration number: UMIN 000024394.).

Chronic Conductive Hearing Loss Is Associated With Speech Intelligibility Deficits in Patients With Normal Bone Conduction Thresholds.

OBJECTIVES: The main objective of this study is to determine whether chronic sound deprivation leads to poorer speech discrimination in humans. DESIGN: We reviewed the audiologic profile of 240 patients presenting normal and symmetrical bone conduction thresholds bilaterally, associated with either an acute or chronic unilateral conductive hearing loss of different etiologies. RESULTS: Patients with chronic conductive impairment and a moderate, to moderately severe, hearing loss had lower speech recognition scores on the side of the pathology when compared with the healthy side. The degree of impairment was significantly correlated with the speech recognition performance, particularly in patients with a congenital malformation. Speech recognition scores were not significantly altered when the conductive impairment was acute or mild. CONCLUSIONS: This retrospective study shows that chronic conductive hearing loss was associated with speech intelligibility deficits in patients with normal bone conduction thresholds. These results are as predicted by a recent animal study showing that prolonged, adult-onset conductive hearing loss causes cochlear synaptopathy.

Hearing Impairment and Prevalence of Mild Cognitive Impairment in Japan: Baseline Data From the Aidai Cohort Study in Yawatahama and Uchiko.

OBJECTIVES: Hearing impairment (HI) in midlife may increase the risk of dementia. However, epidemiological research on the association between HI and mild cognitive impairment (MCI) is very limited. DESIGN: The present cross-sectional study investigated the relationship between HI and MCI using baseline data from the Aidai Cohort Study. Study subjects were 995 Japanese adults aged 36 to 84 years. We used the audiometric definition of HI adopted by the World Health Organization, which identifies the speech-frequency pure-tone average hearing thresholds at 0.5, 1, 2, and 4 kHz tones. HI was defined as present when pure-tone average was >25 dB HL in the better hearing ear. MCI was defined as being present when a subject had a Japanese version of the Montreal Cognitive Assessment score of <26. Adjustment was made for age, sex, smoking status, alcohol consumption, leisure time physical activity, hypertension, dyslipidemia, diabetes mellitus, history of depression, body mass index, waist circumference, employment, education, and household income. RESULTS: Among the 995 study subjects, the prevalence values of HI and MCI were 24.3% and 44.5%, respectively. HI was independently positively associated with MCI: the multivariate-adjusted odds ratio (95% confidence interval) was 1.86 (1.32 to 2.62). HI was independently related to a higher prevalence of MCI in those aged 60 to 69 years and those aged 70 years or older: the multivariate-adjusted odds ratios (95% confidence intervals) were 1.64 (1.03 to 2.62) and 2.30 (1.04 to 5.27), respectively. CONCLUSIONS: HI may be associated with a higher prevalence of MCI.

Intraprocedurally EOB-MRI/US fusion imaging focusing on hepatobiliary phase findings can help to reduce the recurrence of hepatocellular carcinoma after radiofrequency ablation.

BACKGROUND & AIMS: To explore the ability of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid magnetic resonance imaging (EOB-MRI)/ultrasound (US) fusion imaging (FI) to improve the prognosis of radiofrequency ablation (RFA) by ablating the characteristic findings of hepatocellular carcinoma (HCC) in hepatobiliary phase (HBP) imaging. METHODS: We retrospectively recruited 115 solitary HCC lesions with size of (15.9 ± 4.6) mm. They were all treated by RFA and preoperative EOB-MRI. According to the modalities guiding RFA performance, the lesions were grouped into contrast enhanced US (CEUS)/US guidance group and EOB-MRI/US FI guidance group. For the latter group, the ablation scope was set to cover the HBP findings (peritumoral hypointensity and irregular protruding margin). The presence of HBP findings, the modalities guided RFA, the recurrence rate were observed. RESULTS: After an average follow-up of 377 days, local tumor progression (LTP) and intrahepatic distant recurrence (IDR) were 14.8% and 38.4%, respectively. The lesions having HBP findings exhibited a higher recurrence rate (73.7%) than the lesions without HBP findings (42.9%) (p = 0.002) and a low overall recurrence-free curve using the Kaplan-Meier method (p = 0.038). Using EOB-MRI/US FI as guidance, there was no difference in the recurrence rate between the groups with and without HBP findings (p = 0.799). In lesions with HBP findings, RFA guided by EOB-MRI/US FI (53.8%) produced a lower recurrence rate than CEUS/US (84.0%) (p = 0.045). CONCLUSIONS: The intraprocedurally application of EOB-MRI/US FI to determine ablation scope according to HBP findings is feasible and beneficial for prognosis of RFA.

Identification of critical residues for the catalytic activity of ComQ, a Bacillus prenylation enzyme for quorum sensing, by using a simple bioassay system.

Bacillus ComQ participates in the biosynthesis of a quorum-sensing signaling molecule (ComX pheromone) through catalyzing the prenylation at a Trp residue of the precursor peptide (pre-ComX) with geranyl diphosphate (C10 type) or farnesyl diphosphate (C15 type). We hypothesized that several residues specifically conserved among either type of ComQs are important for their substrate specificities. Using a simple bioassay, we revealed that Phe63, Asn186, and Gly190 in ComQRO-E-2 (C10 type) were nondisplaceable to Ser63, Gly186, and Val190, the corresponding residues in the C15-type ComQ, respectively. A three-dimensional model suggested that the 186th and 190th residues are involved in the pre-ComX binding. In vitro analysis showed that substitution of Phe63 with Ser in ComQRO-E-2 significantly reduced the geranylation activity but substantially enhanced the farnesylation activity, whereas substitution of Ser63 with Phe in ComQ168 (C15 type) reduced the farnesylation activity. Therefore, the 63rd residue was found to be significant for the prenyl-substrate preference.Abbreviations: GPP: geranyl diphosphate; FPP: farnesyl diphosphate; IPP: isopentenyl diphosphate; GGPP: geranylgeranyl diphosphate; FARM: first aspartate-rich motif; SARM: second aspartate-rich motif; ß-Gal: ß-galactosidase; TBABG: tryptose blood agar base supplemented with glucose; X-gal: 5-bromo-4-chloro-3-indolyl-ß-D-galactoside.

Cellular Fragments as Biomaterial for Rapid In Vitro Bone-Like Tissue Synthesis.

Current stem cell-based techniques for bone-like tissue synthesis require at least two to three weeks. Therefore, novel techniques to promote rapid 3D bone-like tissue synthesis in vitro are still required. In this study, we explored the concept of using cell nanofragments as a substrate material to promote rapid bone formation in vitro. The methods for cell nanofragment fabrication were ultrasonication (30 s and 3 min), non-ionic detergent (triton 0.1% and 1%), or freeze-dried powder. The results showed that ultrasonication for 3 min allowed the fabrication of homogeneous nanofragments of less than 150 nm in length, which mineralized surprisingly in just one day, faster than the fragments obtained from all other methods. Further optimization of culture conditions indicated that a concentration of 10 mM or 100 mM of ß-glycerophosphate enhanced, whereas fetal bovine serum (FBS) inhibited in a concentration-dependent manner, the mineralization of the cell nanofragments. Finally, a 3D collagen-cell nanofragment-mineral complex mimicking a bone-like structure was generated in just two days by combining the cell nanofragments in collagen gel. In conclusion, sonication for three min could be applied as a novel method to fabricate cell nanofragments of less than 150 nm in length, which can be used as a material for in vitro bone tissue engineering.