The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D.

The initiation of cell division integrates a large number of intra- and extracellular inputs. D-type cyclins (hereafter, cyclin D) couple these inputs to the initiation of DNA replication1. Increased levels of cyclin D promote cell division by activating cyclin-dependent kinases 4 and 6 (hereafter, CDK4/6), which in turn phosphorylate and inactivate the retinoblastoma tumour suppressor. Accordingly, increased levels and activity of cyclin D-CDK4/6 complexes are strongly linked to unchecked cell proliferation and cancer2,3. However, the mechanisms that regulate levels of cyclin D are incompletely understood4,5. Here we show that autophagy and beclin 1 regulator 1 (AMBRA1) is the main regulator of the degradation of cyclin D. We identified AMBRA1 in a genome-wide screen to investigate the genetic basis of  the response to CDK4/6 inhibition. Loss of AMBRA1 results in high levels of cyclin D in cells and in mice, which promotes proliferation and decreases sensitivity to CDK4/6 inhibition. Mechanistically, AMBRA1 mediates ubiquitylation and proteasomal degradation of cyclin D as a substrate receptor for the cullin 4 E3 ligase complex. Loss of AMBRA1 enhances the growth of lung adenocarcinoma in a mouse model, and low levels of AMBRA1 correlate with worse survival in patients with lung adenocarcinoma. Thus, AMBRA1 regulates cellular levels of cyclin D, and contributes to cancer development and the response of cancer cells to CDK4/6 inhibitors.

True diagnostic ability of EUS-guided fine-needle aspiration/biopsy sampling for small pancreatic lesions ≤10 mm and salvage diagnosis by pancreatic juice cytology: a multicenter study.

BACKGROUND AND AIMS: The diagnostic performance of EUS-guided fine-needle aspiration/biopsy sampling (EUS-FNAB) for pancreatic ductal adenocarcinoma (PDAC) ≤10 mm in diameter is relatively low. Pancreatic juice cytology (PJC) has gained attention because of its high sensitivity for small PDACs. We aimed to clarify the diagnostic ability of EUS-FNAB and the salvage ability of PJC for PDAC ≤10 mm. METHODS: Data obtained from attempted EUS-FNAB for patients with EUS-confirmed pancreatic tumors ≤10 mm (excluding pancreatic metastases/malignant lymphomas) were retrospectively analyzed. Patients who experienced technical failure or had a negative EUS-FNAB result and had a strong likelihood of PDAC based on imaging characteristics underwent PJC. PDAC was diagnosed using resected histologic specimens, EUS-FNAB-positive tumor growth on the imaging examination, or additional EUS-FNAB-positive results after increase in tumor size. The primary endpoint was the diagnostic ability of EUS-FNAB for PDAC ≤10 mm. The salvage ability of PJC was also assessed. RESULTS: Overall, 86 of 271 patients with pancreatic tumors ≤10 mm who underwent attempted EUS-FNAB were diagnosed with PDAC. The technical success rate, sensitivity, specificity, and accuracy of EUS-FNAB for PDAC ≤10 mm were 80.8%, 82.3%, 94.9%, and 91.3%, respectively. Among the 35 PDAC patients who experienced technical failure or false-negative results of EUS-FNAB, 26 (74.3%) were correctly diagnosed using salvage PJC. CONCLUSIONS: The true success rate and sensitivity of EUS-FNAB for PDAC ≤10 mm were relatively low. When EUS-FNAB for a pancreatic lesion ≤10 mm strongly suspected to be PDAC is unsuccessful or yields a negative result, PJC is recommended. (Clinical trial registration number: UMIN000049965.).

ERCP using balloon-assisted endoscopes versus EUS-guided treatment for common bile duct stones in Roux-en-Y gastrectomy.

BACKGROUND AND AIMS: We compared ERCP using a balloon-assisted endoscope (BE-ERCP) with EUS-guided antegrade treatment (EUS-AG) for removal of common bile duct (CBD) stones in patients with Roux-en-Y (R-Y) gastrectomy. METHODS: Consecutive patients who had previous R-Y gastrectomy undergoing BE-ERCP or EUS-AG for CBD stones in 16 centers were retrospectively analyzed. RESULTS: BE-ERCP and EUS-AG were performed in 588 and 59 patients, respectively. Baseline characteristics were similar, except for CBD diameter and angle. The technical success rate was 83.7% versus 83.1% (P = .956), complete stone removal rate was 78.1% versus 67.8% (P = .102), and early adverse event rate was 10.2% versus 18.6% (P = .076) in BE-ERCP and EUS-AG, respectively. The mean number of endoscopic sessions was smaller in BE-ERCP (1.5 ± .8 vs 1.9 ± 1.0 sessions, P = .01), whereas the median total treatment time was longer (90 vs 61.5 minutes, P = .001). Among patients with biliary access, the complete stone removal rate was significantly higher in BE-ERCP (93.3% vs 81.6%, P = .009). Negative predictive factors were CBD diameter ≥15 mm (odds ratio [OR], .41) and an angle of CBD <90 degrees (OR, .39) in BE-ERCP and a stone size ≥10 mm (OR, .07) and an angle of CBD <90 degrees (OR, .07) in EUS-AG. The 1-year recurrence rate was 8.3% in both groups. CONCLUSIONS: Effectiveness and safety of BE-ERCP and EUS-AG were comparable in CBD stone removal for patients after R-Y gastrectomy, but complete stone removal after technical success was superior in BE-ERCP.

Difference in reaction mechanism between ZnZrOx and InZrOx for CO2 hydrogenation.

Oxide solid-solution catalysts, such as Zn-doped ZrO2 (ZnZrOx) and In-doped ZrO2 (InZrOx), exhibit distinctive catalytic capabilities for CH3OH synthesis via CO2 hydrogenation. We investigated the active site structures of these catalysts and their associated reaction mechanisms using both experimental and computational approaches. Electron microscopy and X-ray absorption spectroscopy reveal that the primary active sites are isolated cations, such as Zn2+ and In3+, dissolved in tetragonal ZrO2. Notably, for Zn2+, decomposition of the methoxy group, which is an essential intermediate in CH4 synthesis, is partially suppressed because of the relatively high stability of the methoxy group. Conversely, the methyl group strongly adsorbs on In3+, facilitating the conversion of the methoxy species into methyl groups. The decomposition of CH3OH is also suggested to contribute to CH4 synthesis. These results highlight the generation of CH4 as a byproduct of the InZrOx catalyst. Understanding the active site structure and elucidating the reaction mechanism at the atomic level are anticipated to contribute significantly to the future development of oxide solid-solution catalysts.

Utility of Contrast-Enhanced Harmonic Endoscopic Ultrasonography to Diagnose Pancreaticobiliary Maljunction.

BACKGROUND: Detection of a common channel outside the duodenal wall is important in diagnosing pancreaticobiliary maljunction (PBM). The present study evaluated the utility of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) in diagnosing PBM. METHODS: This single-center retrospective study enrolled 45 patients who were diagnosed with PBM or high confluence of pancreatobiliary ducts (HCPBD) between January 2007 and December 2021. The diagnostic sensitivities of contrast-enhanced computed tomography (CE-CT), magnetic resonance imaging (MRI), and CH-EUS for diagnosing PBM were analyzed. Imaging findings were evaluated by two reviewers blinded to the clinicopathological results. RESULTS: Based on diagnostic criteria, 33 patients were diagnosed with PBM and 12 with HCPBD. Compared with the patients with HCPBD, those with PBM had significantly longer common channel (12.5 mm vs. 8.1 mm, P = 0.018) and common bile duct (13.0 mm vs. 8.6 mm, P = 0.049) lengths. The κ-coefficients for differentiating PBM and HCPBD were 0.871 between CE-CT and MRI, 0.330 between CE-CT and CH-EUS, and 0.611 between MRI and CH-EUS. The diagnostic sensitivity of CH-EUS (95.2%) was higher than that of CE-CT (83.3%) and MRI (82.8%), although the differences were not statistically significant. CONCLUSION: CH-EUS may be useful for the diagnosis of PBM.

Highly soluble bisurea derivatives for anion recognition.

Highly soluble bisurea derivatives having 1,2-phenoxyethane (receptors 2) and 1,2-ethoxyethane (3) moieties as spacer groups were designed and prepared based on previously reported receptors with the 2,2'-binaphthyl group as a spacer (1). The receptors can be prepared in fewer steps from commercially available starting materials. The solubilities and anion recognition abilities were evaluated by UV-vis and NMR spectral methods. Receptors 2 and 3 bearing a flexible linker showed good solubilities in common organic solvents such as CHCl3, MeCN, 2-butanone, toluene, and THF. Although the anion recognition abilities of receptors 2 and 3 were lower than those of receptors 1, the greatly improved solubilities of receptors 2 and 3 allow the association of anions under more concentrated conditions for the solubilisation of salts such as lithium chloride in organic solvents.

Comparison of the oxidative profiles before and after revascularization in peripheral arterial disease: a pilot study.

Reactive and highly reactive oxygen species (ROS and hROS) produced by white blood cells are essential for innate immunity; however, they may cause oxidative stress in the host. We developed systems for simultaneously monitoring ROS and hROS, i.e., superoxide radicals (O2•-) and hypochlorite ions (OCl-) secreted from stimulated white blood cells in a few microliters of whole blood. We previously reported on the evaluation of healthy volunteers' blood using the developed system; however, whether patients' blood can be assessed remains unclear. Here, we report a pilot study of 30 cases (28 patients) with peripheral arterial disease, in whom we measured the ROS and hROS levels before and approximately one month after endovascular treatment (EVT) using the system (CFL-H2200) that we developed. At approximately the same time points, physiological indices of blood vessels, oxidative stress markers, and standard clinical parameters in the blood were also monitored. The ankle-brachial index, a diagnostic tool for peripheral arterial disease, was significantly improved after EVT (p<0.001). The ROS-hROS ratio, low-density lipoprotein cholesterol, and hematocrit levels were decreased after EVT (p<0.05), while triglyceride and lymphocyte levels were increased after EVT (p<0.05). The correlations between the study parameters were also analyzed.

Clinical implication of immune checkpoint inhibitor on the chronic hepatitis B virus infection.

AIM: The risk of hepatitis B virus (HBV) reactivation with immune checkpoint inhibitors (ICIs) is an important issue that has not yet been fully investigated. ICI is also expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect. We herein investigated the risk of HBV reactivation and the antiviral effect of ICI administration. METHODS: This study included 892 patients on ICIs between September 2014 and May 2021 at our hospital. The frequency of HBV reactivation and antiviral effects were investigated. RESULTS: Among the 892 patients who underwent ICI, 27 were hepatitis B surface antigen (HBsAg) positive. HBV reactivation was evaluated in 24 cases, among which 4.1% (1/24) had HBV reactivation. Nucleic acid analog prophylaxis was not administered to patients with reactivation. In a study of 15 cases, the amount of HBsAg decreased from baseline; 2.18 ± 0.77 log to 48 weeks later; 1.61 ± 1.38 log (p = 0.17). Forty-eight weeks after the start of ICI, disappearance of HBsAg was observed in two out of 15 cases (13.3%), and one case each with and without nucleic acid analog. CONCLUSION: In rare cases, HBsAg-positive patients may be reactivated by ICI administration. On the other hand, when ICI is administered, it is expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect, and future drug development is expected.

Progression from early to advanced stage of immune-related cholangitis.

AIM: We report a rare case of immune-related cholangitis in which the natural course could be demonstrated. CASE PRESENTATION: Eight courses of pembrolizumab maintenance therapy were given as first-line treatment for squamous cell lung cancer; however, the patient was subsequently hospitalized due to a rapid increase in hepatobiliary enzymes. On endoscopic ultrasound, the common bile duct was dilated to 11 mm, and the wall, throughout its length from the papilla, was thickened. Endoscopic retrograde cholangiopancreatography showed no obvious stenosis in the lower bile duct; however, a parapapillary diverticulum was found, and papillary incision and bile duct plastic stent insertion were carried out. However, the liver disorder did not improve and overt jaundice appeared subsequently; therefore, an immune-related cholangitis was suspected, and prednisolone (PSL) 35 mg/day was introduced from day 59 of admission. Following PSL initiation, a decrease in serum bilirubin level was observed; however, significant decrease was not observed in alkaline phosphatase. Given the history of recurrent infectious cholangitis, magnetic resonance cholangiopancreatography was carried out on day 70 of admission. The intrahepatic bile duct showed stenosis and dilated findings, which was considered to be a factor for repeated infectious cholangitis. CONCLUSION: No previous case reports have described the changes and progression in bile duct images in immune-related adverse events. Therefore, this case is noteworthy for considering the progression of immune-related cholangitis.

Value of artificial intelligence with novel tumor tracking technology in the diagnosis of gastric submucosal tumors by contrast-enhanced harmonic endoscopic ultrasonography.

BACKGROUND AND AIM: Contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) is useful for the diagnosis of lesions inside and outside the digestive tract. This study evaluated the value of artificial intelligence (AI) in the diagnosis of gastric submucosal tumors by CH-EUS. METHODS: This retrospective study included 53 patients with gastrointestinal stromal tumors (GISTs) and leiomyomas, all of whom underwent CH-EUS between June 2015 and February 2020. A novel technology, SiamMask, was used to track and trim the lesions in CH-EUS videos. CH-EUS was evaluated by AI using deep learning involving a residual neural network and leave-one-out cross-validation. The diagnostic accuracy of AI in discriminating between GISTs and leiomyomas was assessed and compared with that of blind reading by two expert endosonographers. RESULTS: Of the 53 patients, 42 had GISTs and 11 had leiomyomas. Mean tumor size was 26.4 mm. The consistency rate of the segment range of the tumor image extracted by SiamMask and marked by the endosonographer was 96% with a Dice coefficient. The sensitivity, specificity, and accuracy of AI in diagnosing GIST were 90.5%, 90.9%, and 90.6%, respectively, whereas those of blind reading were 90.5%, 81.8%, and 88.7%, respectively (P = 0.683). The κ coefficient between the two reviewers was 0.713. CONCLUSIONS: The diagnostic ability of CH-EUS results evaluated by AI to distinguish between GISTs and leiomyomas was comparable with that of blind reading by expert endosonographers.

Development of 60 MHz integrated backscatter intravascular ultrasound and tissue characterization of attenuated signal coronary plaques that cause myocardial injury after percutaneous coronary intervention.

The purpose of the present study was to develop a 60 MHz integrated backscatter intravascular ultrasound (IB-IVUS) and to evaluate its usefulness for the detection of lipid area with backward attenuation of ultrasound signal (AT) that for the prediction of post-procedural myocardial injury (PMI) after percutaneous coronary intervention (PCI). In a pathological study, images were acquired from 221 cross-sections of 18 coronary arteries from 13 cadavers obtained at autopsy. In the clinical training study, we compared non-targeted plaques in 38 patients by a previous IB-IVUS system (38 MHz) and a new IB-IVUS system (60 MHz). In the clinical testing study, we included 70 consecutive patients who underwent PCI. Serum troponin-I was measured just before and 24 h after PCI to evaluate PMI. As the % microcalcification + % cholesterol cleft area increased, the attenuation of IB values increased (r = 0.56, p < 0.001). The slopes of regression lines of the area of each tissue component between 38 and 60 MHz IB-IVUS were excellent. The lipid pool area with AT tended to be more useful than that of the conventional lipid pool area for the prediction of PMI (p = 0.11). We developed a 60 MHz IB-IVUS imaging system for tissue characterization of coronary plaques. Cutoff value of purple color was the most reliable value for the prediction of PMI.

Serological Screening of Immunoglobulin G against SARS-CoV-2 Nucleocapsid and Spike Protein before and after Two Vaccine Doses among Healthcare Workers in Japan.

This study sought to evaluate the effects of two vaccine doses and the extent of SARS-CoV-2 infection among healthcare workers. We measured immunoglobulin G antibody titers against SARS-CoV-2 nucleocapsid and spike protein among healthcare workers at Gunma University Hospital. In March 2021, prior to BNT-162b2 vaccination, two of 771 participants were seropositive for nucleocapsid and spike protein, whereas 768 were seronegative. The remaining one participant was seropositive for nucleocapsid protein but seronegative for spike protein. A total of 769 participants were seropositive for spike protein after two vaccination doses. The two seropositive participants prior to vaccination showed the highest antibody titers after the second vaccination. They were probably infected with SARS-CoV-2 without clinical symptoms before March 2021. Four weeks after the second vaccination, a younger age was associated with higher antibody titers against SARS-CoV-2 spike protein. Thirty-two weeks after the second vaccination, blood samples were collected from 342 of 769 participants. Antibody titers at 32 weeks after the second vaccination significantly decreased compared with those at 4 weeks after the second vaccination among all age groups. The rate of decrease in antibody titers between 4 and 32 weeks after the second vaccination was greater in the female participants. No sex differences were observed in the antibody titers within each age group. BNT-162b2 vaccination thus induced seroconversion in an age-dependent manner. Serological screening could further establish the likelihood of subclinical SARS-CoV-2 infection.

Association of estimated plasma volume and weight loss after long-term administration and subsequent discontinuation of the sodium-glucose cotransporter-2 inhibitor tofogliflozin.

Sodium-glucose cotransporter-2 inhibitors (SGLT2) are drugs that have been reported to have several effects through the regulation of plasma volume, for example, antihypertensive effects. This study aimed to clarify the impact of long-term administration and subsequent discontinuation of the SGLT2 inhibitor tofogliflozin on estimated plasma volume (ePV), brain natriuretic peptide (BNP) and the relationship between changes in ePV, BNP and body weight (BW). Data from 157 participants with type 2 diabetes receiving tofogliflozin monotherapy in a phase 3 study were analysed. Changes in variables or correlations among them during a 52-week administration and a 2-week post-treatment period were investigated. Percent change in ePV was calculated using the Strauss formula. Significant decreases in BW, ePV and ln-transformed BNP (ln-BNP) were noted by week 52. %ΔBW was not significantly correlated with %ΔePV and Δln-BNP, while %ΔePV was significantly correlated with Δln-BNP. Two weeks after discontinuation of tofogliflozin, BW, ePV and ln-BNP were significantly increased. %ΔBW was significantly correlated with %ΔePV and Δln-BNP. Furthermore, ePV and BNP were significantly higher than baseline levels.

Transverse colonic volvulus due to mesenteric fibromatosis: a case report.

BACKGROUND: Colonic volvulus, a condition in which a colonic segment partially twists around its base, is the third leading cause of large bowel obstruction after colonic neoplasms and diverticular disease. However, volvulus of the transverse colon is the rarest type of large intestinal volvulus. Moreover, the occurrence of transverse colonic volvulus secondary to a benign tumor originating from outside the intestine has never been reported. We hereby report a case of transverse colonic volvulus caused by mesenteric fibromatosis. CASE PRESENTATION: A 53-year-old female with a history of rheumatoid arthritis and thyroid tumor presented with abdominal pain for 1 day. Abdominal computed tomography revealed intestinal torsion at the hepatic flexure. Twisted and obstructed mucosa of the transverse colon was observed during colonoscopy, but no tumor invasion of the mucosal surface was detected. A solid mass of a mesenteric origin with involvement of the transverse colon was observed during surgery. The mass was diagnosed surgically as transverse colonic volvulus induced by a mesenteric tumor. Hence, the patient underwent a right hemicolectomy. Histopathological results indicated mesenteric desmoid-type fibromatosis. The postoperative recovery was uneventful, and the patient was discharged 8 days after surgery. CONCLUSIONS: Although mesenteric fibromatosis is rare, this disease should be considered when managing transverse colonic volvulus resulting from nonmucosal tumors.

ß-Glycyrrhetinic acid inhibits the bacterial growth and biofilm formation by supragingival plaque commensals.

ß-Glycyrrhetinic acid (BGA) is a natural antibacterial agent. Previous studies reported that BGA has antibacterial effects against several bacteria. This study evaluated the effects of BGA on the regulation of supragingival plaque bacteria. First, the minimum inhibitory concentrations (MICs) of BGA against oral bacteria were measured. Next, the minimum concentrations for inhibition of biofilm formation were evaluated against Streptococcus mutans and Streptococcus sobrinus, possessing insoluble glucan synthesis abilities. The MICs of biofilm formation by these bacteria ranged from 1/8 to 2× MIC. Furthermore, the inhibition effects of BGA against the coaggregation of Porphyromonas gingivalis and Streptococcus gordonii were evaluated. BGA at 32 or 64 µg/mL inhibited the coaggregation of these bacteria after a 30 min incubation. Lastly, the inhibition effects of BGA against human supragingival plaque bacteria were evaluated. Human supragingival plaque samples were obtained from 12 healthy donors. The inhibition effects of BGA against biofilm formation by these plaque bacteria were evaluated. Of 12 samples, the biofilm formation by 11 was significantly attenuated by 128-256 µg/mL of BGA. The number of colony forming units in these biofilms was also significantly attenuated. In conclusion, it was revealed that BGA inhibits the growth and biofilm formation of bacteria, furthermore, the same effect was confirmed with supragingival plaque bacteria. BGA is a good candidate for a natural agent that prevents the outbreak and progression of periodontal disease because it suppresses not only the growth and biofilm formation of bacteria, but also the coaggregation of P. gingivalis with plaque bacteria.

Incidence and Characteristics of Coronary Artery Spasms Related to Atrial Fibrillation Ablation Procedures　- Large-Scale Multicenter Analysis.

BACKGROUND: Coronary artery spasms (CASs), which can cause angina attacks and sudden death, have been recently reported during catheter ablation. The aim of the present study was to report the incidence, characteristics, and prognosis of CASs related to atrial fibrillation (AF) ablation procedures.Methods and Results:The AF ablation records of 22,232 patients treated in 15 Japanese hospitals were reviewed. CASs associated with AF ablation occurred in 42 of 22,232 patients (0.19%). CASs occurred during ablation energy applications in 21 patients (50%). CASs also occurred before ablation in 9 patients (21%) and after ablation in 12 patients (29%). The initial change in the electrocardiogram was ST-segment elevation in the inferior leads in 33 patients (79%). Emergency coronary angiography revealed coronary artery stenosis and occlusions, which were relieved by nitrate administration. No air bubbles were observed. A comparison of the incidence of CASs during pulmonary vein isolation between the different ablation energy sources revealed a significantly higher incidence with cryoballoon ablation (11/3,288; 0.34%) than with radiofrequency catheter, hot balloon, or laser balloon ablation (8/18,596 [0.04%], 0/237 [0%], and 0/111 [0%], respectively; P<0.001). CASs most often occurred during ablation of the left superior pulmonary vein. All patients recovered without sequelae. CONCLUSIONS: CASs related to AF ablation are rare, but should be considered as a dangerous complication that can occur anytime during the periprocedural period.

Association between periodontitis and the Mediterranean diet in young Moroccan individuals.

BACKGROUND & OBJECTIVES: Adherence to the Mediterranean diet (MedDiet) has been reported to be associated with a lower risk of various chronic diseases. This cross-sectional study aimed to investigate the potential association between adherence to the MedDiet and periodontitis, which is highly prevalent in young Moroccan individuals. METHODS: We evaluated 1075 Moroccan individuals (72% women, mean [standard deviation] age = 20.2 [1.5] years). Adherence to the MedDiet was assessed using the MedDiet score (MDS) based on the frequency of intake of eight food groups (vegetables, legumes, fruits, cereals or potatoes, fish, red meat, dairy products, and olive oil). A value of 0 (unhealthy) or 1 (healthy) was assigned to each food group, and the MDS (range, 0-8 points) was generated by adding the individual scores, with a higher score indicating better adherence to the MedDiet. The logistic regression model was used to evaluate the MDS (high [5-8 points]/low [0-4 points]) and each component score (1/0) with the presence of periodontitis, which was determined through full-mouth periodontal examinations. Age, sex, and oral health behavior were considered as potential confounders. RESULTS: In total, 693 (64.5%) study participants showed high MDSs. Periodontitis was observed in 71 (6.6%) participants. No significant association between MDS and periodontitis was observed. Nonetheless, olive oil consumption, a component of the MDS, showed a significant inverse association with periodontitis (adjusted odds ratio = 0.55; 95% confidence interval, 0.32-0.96). CONCLUSIONS: The MedDiet was not significantly associated with periodontitis among young Moroccans. However, frequent consumption of olive oil may have a protective effect against periodontitis, although the temporal association needs to be clarified in further studies.

Comparison of efficacy and safety of entecavir and switching from entecavir to tenofovir alafenamide fumarate in chronic hepatitis B: Long-term effects from a prospective study.

AIM: Both entecavir (ETV) and tenofovir alafenamide fumarate (TAF) are widely used to treat chronic hepatitis B (CHB) in Japan. However, it remains unclear whether the efficacy of TAF in decreasing the hepatitis B surface antigen (HBsAg) level, and its safety, are superior to those of ETV. This study aimed to report the long-term effects and safety of 96-week ETV and TAF treatment in patients with CHB. METHODS: A prospective comparative observational study was undertaken on the following two groups: patients with CHB who received continuous ETV (n = 32) and patients with CHB who were switched from ETV to TAF upon request (n = 48). The HBsAg, urinary ß2-microglobulin (ß2MG)/creatinine (Cr), urinary N-acetyl-ß-D-glucosaminidase (NAG)/Cr, and serum alanine aminotransferase (ALT) levels, estimated glomerular filtration rate (eGFR), and bone mineral density (lumbar spine and femur) at 96 weeks were compared. RESULTS: The two groups did not significantly differ with respect to mean age, male / female patient ratio, or rate of hepatitis B e antigen-positive status. The mean changes in serum HBsAg level and eGFR at 96 weeks were not significantly different between the two groups. The ß2MG/Cr and NAG/Cr levels at 96 weeks were similar between the two groups. Additionally, the bone mineral density of the lumbar spine and femur as well as the serum ALT did not significantly differ. CONCLUSIONS: When compared with patients who received continuous ETV, those who were introduced to TAF after ETV showed similar effects in terms of the decrease in HBsAg level and safety.

Programmed Scale Detachment in the Wing of the Pellucid Hawk Moth, Cephonodes hylas: Novel Scale Morphology, Scale Detachment Mechanism, and Wing Transparency.

No scales of most lepidopterans (butterflies and moths) detach from the wings through fluttering. However, in the pellucid hawk moth, Cephonodes hylas, numerous scales detach from a large region of the wing at initial take-off after eclosion; consequently, a large transparent region without scales appears in the wing. Even after this programmed detachment of scales (d-scales), small regions along the wing margin and vein still have scales attached (a-scales). To investigate the scale detachment mechanism, we analyzed the scale detachment process using video photography and examined the morphology of both d- and a-scales using optical and scanning electron microscopy. This study showed that d-scale detachment only occurs through fluttering and that d-scales are obviously morphologically different from a-scales. Although a-scales are morphologically common lepidopteran scales, d-scales have four distinctive features. First, d-scales are much larger than a-scales. Second, the d-scale pedicel, which is the slender base of the scale, is tapered; that of the a-scale is columnar. Third, the socket on the wing surface into which the pedicel is inserted is much smaller for d-scales than a-scales. Fourth, the d-scale socket density is much lower than the a-scale socket density. This novel scale morphology likely helps to facilitate scale detachment through fluttering and, furthermore, increases wing transparency.

Basal insulin secretion capacity predicts the initial response and maximum levels of beta-hydroxybutyrate during therapy with the sodium-glucose co-transporter-2 inhibitor tofogliflozin, in relation to weight loss.

AIMS: To investigate predictors of the initial response of beta-hydroxybutyrate (BHB) and maximum BHB (max-BHB) values during long-term therapy with the sodium-glucose co-transporter-2 inhibitor tofogliflozin (TOFO), and to explore the association of the initial elevation of BHB with subsequent clinical effects in people with type 2 diabetes mellitus. METHODS: We analysed 774 people receiving TOFO in phase 3 trials in two groups based on measurable BHB change at week 4 (initial response): the top quartile [n = 194] and the three lower quartiles [n = 579]. Multivariate analysis was used to determine baseline predictors of inclusion in the top quartile and the max-BHB values. To investigate the association of the initial response with subsequent clinical effects, adjusted changes in variables in the two groups were compared using an analysis of covariance model. RESULTS: Of the participants, 66% were men, and the mean age, glycated haemoglobin, body mass index and estimated glomerular filtration rate were 58.5 years, 8.1%, 25.6 kg/m2 and 83.9 mL/min/1.73 m2 , respectively. Median changes in BHB at week 4 in the top quartile and lower three quartiles were +246.4* and +30.8* µmol/L, respectively (*P < .001 vs baseline). Lower baseline insulin secretion capacity predicted the inclusion in the top quartile and greater max-BHB levels. The top quartile was associated with greater weight loss following greater increases in free fatty acids and greater reductions in fasting C-peptide levels compared with the lower three quartiles. CONCLUSIONS: Lower basal insulin secretion capacity might predict greater initial BHB elevations and max-BHB levels during long-term TOFO therapy. Greater weight loss through lipid use might be related to high initial BHB elevations.