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Emerging evidence suggests that the presence of tertiary lymphoid structures (TLS) and neutrophil–lymphocyte ratio (NLR) in peripheral blood is associated with the treatment response to checkpoint inhibitors (CPIs), whereas there is limited knowledge regarding whether these factors reciprocally impact the treatment outcomes of CPIs in metastatic urothelial carcinoma (mUC). Herein, we investigated treatment outcomes of platinum‐refractory mUC patients (50 cases with whole‐exome and transcriptome sequencing) treated with pembrolizumab. The pathological review identified 24% of cases of TLS in the specimens. There was no significant difference in the NLR between the TLS− and TLS+ groups (p = 0.153). In the lower NLR group, both overall survival and progression‐free survival were significantly longer in patients with TLS than in those without TLS, whereas the favorable outcomes associated with TLS were not observed in patients in the higher NLR group. We explored transcriptomic differences in UC with TLS. The TLS was comparably observed between luminal (20%) and basal (25%) tumor subtypes (p = 0.736). Exploring putative immune‐checkpoint genes revealed that ICOSLG (B7‐H2) was significantly increased in tumors with lower NLR. KRT expression levels exhibited higher basal cell markers (KRT5 and KRT17) in the higher NLR group and lower differentiated cell markers (KRT8 and KRT18) in patients with TLS. In conclusion, the improved outcomes of pembrolizumab treatment in mUC are restricted to patients with lower NLR. Our findings begin to elucidate a distinct molecular pattern for the presence of TLS according to the NLR in peripheral blood. [ABSTRACT FROM AUTHOR]

Objective: We aimed to elucidate the ossification process of the otic capsule in postnatal C57BL/6 mice and depict the three‐dimensional (3D) process of otoconial mineralization in vivo. Methods: The otic capsules of C57BL/6 mice were stained with alizarin red and imaged/compared using micro‐computed tomography on postnatal day (P) between P0 and P8, P10, P15, and P30 and 3–4 months old (P3–4Mo). We reconstructed 3D images of the otic capsule and otoconia and measured the bone mineral density using x‐ray absorptiometry on each age. Results: The 3D reconstructed otic capsule images revealed two ossification centers of the otic capsule at P0. One was observed around the ampulla of the superior semicircular canal and utricle, and the other was observed around the ampulla of the posterior semicircular canal. The cross‐sectional views demonstrated that modiolar ossification developed from the base to the apex from P4 to P8. The inter‐scalar septum ossified bidirectionally from the modiolus and bony otic capsule from P8 to P15. The mineralized otoconia were first detected in the utricle at P3 and saccular otoconia at P6. The density of the utricle and saccular otoconia showed different growth trends. Conclusion: To the best of our knowledge, this is the first study to demonstrate the 3D appearance of the otic capsule and otoconia in different developmental stages of mice. We also revealed that modiolar and inter‐scalar septal calcification is the final event in the cochlea and that it can be susceptible to pathological conditions (cochlear congenital malformations and hereditary vestibular diseases). The unique features of the ossification process and duration may explain these pathological conditions observed in humans. Level of Evidence: 3 [ABSTRACT FROM AUTHOR]

Objective: To compare the microbiota between cholesteatoma and chronic suppurative otitis media (COM) and to identify potential pathogens that explain the relevant phenotypes of cholesteatoma. Study Design: Prospective cohort study. Methods: Surgical specimens collected from 20 cholesteatomas and nine COMs were treated to dissolve biofilms and subjected to 16S ribosomal RNA (rRNA) gene sequencing and amplicon sequence variant‐level analysis for microbiota profiling and quantitative comparison. Correlations between the relative abundance of potential pathogens and the volume of the primary resected cholesteatomas were examined. Results: Differences in bacterial composition (beta diversity) were observed between cholesteatomas and COM (p =.002), with a higher abundance of Staphylococcus in cholesteatomas than in COM (p =.005). Common genera in the external auditory canal (EAC) flora, such as Staphylococcus, Corynebacterium, and Cutibacterium, were predominant in both cholesteatoma and COM; Staphylococcus aureus and Pseudomonas aeruginosa were increased in both diseases compared with the EAC flora. Furthermore, coagulase‐negative staphylococci (CoNS) were more abundant in cholesteatomas than in COM (p = 0.002). Linear discriminant analysis coupled with effect size measurements (LEfSe) identified four CoNS as potential biomarkers for cholesteatoma. The relative abundance of S. aureus, a potential pathogen, was positively correlated with cholesteatoma volume (r =.60, p =.02). Conclusion: The microbiota of cholesteatoma and COM originated from EAC flora, but the bacterial composition was largely altered. Our results suggested that S. aureus infection is involved in cholesteatoma progression. Level of Evidence: 3b [ABSTRACT FROM AUTHOR]

Objectives: To assess whether a new risk stratification system according to predictors for overall survival (OS) at the diagnosis of metastatic castration‐resistant prostate cancer (mCRPC) could determine treatment outcomes and assist in treatment decision‐making. Patients and Methods: Two independent clinical cohorts of patients, treated with androgen signalling inhibitors (ASIs: abiraterone and enzalutamide) or docetaxel as a first‐line treatment for mCRPC, were used in this study: a derivation cohort (196 patients with mCRPC) and an external validation cohort (211 patients with mCRPC). Results: Three independent predictors for OS, including duration of initial androgen deprivation therapy <12 months before mCRPC diagnosis, alkaline phosphatase level >350 U/dL and haemoglobin level <11 g/dL at the diagnosis of mCRPC, were defined as risk factors. Patients with zero, one and multiple risk factors were assigned to a favourable‐, intermediate‐ and poor‐risk group, respectively. The median OS values in each risk group were well separated in the derivation cohort (P < 0.001) as well as in the validation cohort (P < 0.001). Of a total of 407 patients with mCRPC, 84 were assigned to the poor‐risk group with the median OS of 12 months. In this group, a trend towards longer OS favouring docetaxel compared to ASIs as the first‐line treatment (medians of 17 and 12 months, respectively) was observed. Conclusion: The new risk group stratification system could predict patient survival at the diagnosis of mCRPC. Given the convenience of these risk definitions, physicians may be encouraged to consider these risk groups in daily practice. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to test the hypothesis that contrast‐enhanced 3D MRI with gradient‐echo sequences (CE‐3D‐GRE) can detect signs of vasculitis in the fallopian canal, which may cause otologic involvement, in four patients with antineutrophil cytoplasmic antibody‐associated vasculitis (AAV). Methods: CE‐3D‐GRE acquired at 3.0 Tesla was performed on four patients diagnosed with granulomatosis with polyangiitis or eosinophilic granulomatosis with polyangiitis, at onset or relapse of the disease, and in remission. Clinical correlations between otologic symptoms and radiological findings were examined for each patient. Furthermore, signal intensity of the mastoid segment of the fallopian canal was compared between the ears with active disease (n = 3) and those in remission or without vasculitis (n = 3). Results: Intense enhancement in the tympanic and mastoid segments of the fallopian canal was associated with development of external otitis, otitis media, and sensorineural hearing loss, and was unrelated to the presence of facial paresis. Maximal intensity projection images visualized the close relationship between the enhanced fallopian canal and middle ear inflammation. The findings were absent in remission. Signal intensity of the mastoid segment of the fallopian canal was higher in ears with active disease than in normal ears (P <.001) and decreased to normal levels during remission (P =.597). Conclusion: CE‐3D‐GRE can demonstrate vasculitis in the temporal bone, reflecting disease activity and the severity of otologic manifestations, including cochlear involvement, in AAV patients. Intense enhancement of the fallopian canal on CE‐3D‐GRE can be a potential marker for vasculitis of the temporal bone. Level of Evidence: 5. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the direct action of angiotensin II (Ang II) on myocardial conduction and transmembrane action potential immediately after reoxygenation. Method: After superfusion in a simulated ischemic solution, ventricular papillary muscle preparations of rat heart were washed with oxygenated Tyrode solution containing Ang II, Ang II plus CV-11974 (an AT1 receptor blocker), or Ang II plus 5-hydroxydecanoic acid (mito-KATP blocker), under rapid electrical stimulation (RES) for 60s. Results: In the control experiments, the incidence of conduction delay and block was the highest within the first 10s, and subsequently, 1:1 conduction was established after 40s. Ang II significantly enhanced the 2:1 conduction block during the later phase of RES (40–60s after reoxygenation). This effect of Ang II was abolished by either CV-11974 (P<0.001) or 5-HD (P<0.001). Conclusion: RES-induced conduction delay and block immediately after reoxygenation were accelerated by Ang II, which could be relevant to the maintenance of reperfusion arrhythmias. The mito-KATP channel may participate in the mechanism underlying this phenomenon. [Copyright &y& Elsevier]

ABSTRACT Aim Materials and Methods Results Conclusions Nocturia impairs the quality of life in patients with type 2 diabetes mellitus. Although sodium glucose co‐transporter 2 inhibitors (SGLT2i) such as tofogliflozin increase urine volume, their impact on nocturia, in conjunction with dietary salt restriction, is less clear.This multicenter, open‐label, randomized, parallel‐group trial included 80 subjects with type 2 diabetes and nocturia. The patients were divided into two groups: one receiving tofogliflozin, the shortest half‐life, without salt restriction, and the other receiving both tofogliflozin and dietary salt restriction. The primary endpoint was nocturia frequency at 12 weeks. The secondary outcomes included changes in daytime urination frequency, urine volume, and home blood pressure.At 12 weeks, there were no significant differences in nocturia changes between both groups. Nocturia frequency did not change in the tofogliflozin without salt restriction group from 1.5 ± 0.8 to 1.3 ± 1.1 times per night (P = 0.297), and significantly decreased from 1.6 ± 1.0 to 1.3 ± 0.7 times per night in the tofogliflozin and dietary salt restriction group (P = 0.049). There was a trend toward increased urine volume and frequency during the daytime in the group with salt restriction, indicating a time‐shift effect of the short half‐life tofogliflozin and salt restriction on urinary time.The frequency of nocturia after tofogliflozin did not increase. Tofogliflozin reduced nocturia when combined with salt restriction. Furthermore, daytime urine volume and frequency showed an increasing trend, suggesting a shift in urine production to daytime hours due to the short half‐life of tofogliflozin. Dietary modifications can enhance the therapeutic benefits of tofogliflozin in managing nocturia in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

We experienced a case of pacing failure with transient rise of the pacing threshold more than one year after implantation. Neither the generator nor lead system was found to be defective. During the antibiotics therapy to treat cholecystitis, which was found on admission, pacing failure was improved. The clinical course suggested that the infection was related to the improvement, although accurate mechanisms were unknown. [Copyright &y& Elsevier]

Two fragments of the C-terminal catalytic domain of human poly(ADP-ribose) polymerase (catPARP), Met-catPARP and Gly-Ser-catPARP, were purified and crystallized. Both catPARP crystals belong to space group C2, with almost the same unit-cell parameters. However, the shapes and harvest periods of both crystals were quite different owing to the slight mutation at the N-terminal position. Gly-Ser-catPARP was found to be more suitable for X-ray crystallography and crystals showed diffraction to at least 3.5 A resolution. [ABSTRACT FROM AUTHOR]