Recurrent infections drive persistent bladder dysfunction and pain via sensory nerve sprouting and mast cell activity.

Urinary tract infections (UTIs) account for almost 25% of infections in women. Many are recurrent (rUTI), with patients frequently experiencing chronic pelvic pain and urinary frequency despite clearance of bacteriuria after antibiotics. To elucidate the basis for these bacteria-independent bladder symptoms, we examined the bladders of patients with rUTI. We noticed a notable increase in neuropeptide content in the lamina propria and indications of enhanced nociceptive activity. In mice subjected to rUTI, we observed sensory nerve sprouting that was associated with nerve growth factor (NGF) produced by recruited monocytes and tissue-resident mast cells. Treatment of rUTI mice with an NGF-neutralizing antibody prevented sprouting and alleviated pelvic sensitivity, whereas instillation of native NGF into naïve mice bladders mimicked nerve sprouting and pain behavior. Nerve activation, pain, and urinary frequency were each linked to the presence of proximal mast cells, because mast cell deficiency or treatment with antagonists against receptors of several direct or indirect mast cell products was each effective therapeutically. Thus, our findings suggest that NGF-driven sensory sprouting in the bladder coupled with chronic mast cell activation represents an underlying mechanism driving bacteria-independent pain and voiding defects experienced by patients with rUTI.

Analysis of Plasma Circulating Tumor DNA in Borderline Resectable Pancreatic Cancer Treated with Neoadjuvant Modified FOLFIRINOX: Clinical Relevance of DNA Damage Repair Gene Alteration Detection.

PURPOSE: There are no reliable biomarkers to guide treatment for patients with borderline resectable pancreatic cancer (BRPC) in the neoadjuvant setting. We used plasma circulating tumor DNA (ctDNA) sequencing to search biomarkers for patients with BRPC receiving neoadjuvant mFOLFIRINOX in our phase 2 clinical trial (NCT02749136). MATERIALS AND METHODS: Among the 44 patients enrolled in the trial, patients with plasma ctDNA sequencing at baseline or post-operation were included in this analysis. Plasma cell-free DNA isolation and sequencing were performed using the Guardant 360 assay. Detection of genomic alterations, including DNA damage repair (DDR) genes, were examined for correlations with survival. RESULTS: Among the 44 patients, 28 patients had ctDNA sequencing data qualified for the analysis and were included in this study. Among the 25 patients with baseline plasma ctDNA data, 10 patients (40%) had alterations of DDR genes detected at baseline, inclu-ding ATM, BRCA1, BRCA2 and MLH1, and showed significantly better progression-free survival than those without such DDR gene alterations detected (median, 26.6 vs. 13.5 months; log-rank p=0.004). Patients with somatic KRAS mutations detected at baseline (n=6) had significantly worse overall survival (median, 8.5 months vs. not applicable; log-rank p=0.003) than those without. Among 13 patients with post-operative plasma ctDNA data, eight patients (61.5%) had detectable somatic alterations. CONCLUSION: Detection of DDR gene mutations from plasma ctDNA at baseline was associated with better survival outcomes of pati-ents with borderline resectable pancreatic ductal adenocarcinoma treated with neoadjuvant mFOLFIRINOX and may be a prognostic biomarker.

Quadruple nanoelectrode assembly for simultaneous analysis of multiple redox species and its application to multi-channel scanning electrochemical microscopy.

Development of ultramicroelectrodes and nanoelectrodes opened interesting possibilities in the investigation electron transfer phenomena, including their application as probe electrodes in scanning electrochemical microscopy (SECM). Analytical prowess of SECM was often shadowed by long operation times required for analysis of a wide sample area. In this report, we developed a multi-channel nanoelectrode bundle for simultaneous electroanalysis of multiple orthogonal redox reactions in one bath. Four nanoelectrodes of diameters 100-400 nm were shown to be bundled in a 2 µm disk area. The nanoelectrode assembly was implemented as a tip electrode for multi-channel SECM, dramatically improving the time efficiency of SECM operations. The nanoelectrode bundle was also demonstrated as a stand-alone microprobe for electroanalytical investigations in small volumes such as ceramic confinements and biologically important compartments. The development reported in this work should benefit electrochemical analyses of various systems, especially those involving SECM and fine spatial control.

Prognostic implication of serum AFP in patients with hepatocellular carcinoma treated with regorafenib.

Background: This multicenter study investigated the predictive value of baseline AFP and on-treatment AFP response for survival in hepatocellular carcinoma (HCC) patients with regorafenib. Materials & methods: A total of 578 patients with HCC treated with regorafenib from 12 institutions in South Korea and Italy were included. Baseline AFP (cutoff, 400 ng/ml) and AFP response (20% reduction from baseline) were analyzed for overall survival (OS) and progression-free survival (PFS). Results: Baseline AFP below 400 ng/ml was a significant factor that was independently associated with longer OS and PFS. AFP response was also a significant factor independently associated with longer OS and PFS. Conclusion: Baseline AFP and AFP response may be used as prognostic factors for survival in HCC treated with regorafenib.

Regorafenib is standard second-line therapy for patients with hepatocellular carcinoma (HCC) who show failure to sorafenib treatment, but there is no reliable factor to predict survival. In this multicenter, retrospective study with patients from South Korea and Italy, we have found that both baseline AFP level and on-treatment AFP response have independent predictive value for survival in patients with HCC under regorafenib treatment. We observed similar results when the patients were divided according to their nationality (South Korea vs Italy), despite the fact that the baseline characteristics of the patients from the two cohorts were significantly different.

Factors affecting successful esophageal foreign body removal using a Foley catheter in pediatric patients.

OBJECTIVE: This study aimed to determine the factors that affect successful esophageal foreign body (FB) removal using a Foley catheter and to identify methods to increase the success rate. METHODS: In this retrospective, cross-sectional study, we included pediatric patients who presented with esophageal FB impaction that was removed using a Foley catheter in the emergency departments of tertiary care and academic hospitals. We analyzed the effect of the patients' age, sex, and symptoms; FB type, size, and location; Foley catheter size; complications during FB removal; duration between FB ingestion and removal; operator's years of training; sedation; success rate of FB removal; endoscopy; and patient's posture during FB removal on the success of Foley catheter-based FB removal. RESULTS: Of the 43 patients we enrolled, Foley catheter-based FB removal was successful in 81.4% (35/43) but failed in 18.6% (8/43) of patients; no FB-removal-related complications were reported. There was no significant association between the success rate of Foley catheter-based FB removal and any study variable. A higher number of years in training tended to increase the success rate of Foley catheter-based FB removal, although statistical significance was not achieved. CONCLUSION: Children's esophageal FB removal is a practical challenge in the emergency rooms, and using a Foley catheter is associated with a high success rate of the removal and low occurrence of complications. In this study, no single variable was found correlated with the success rate of Foley catheter-based esophageal FB removal in pediatric patients, which may indicate multiple variables interacting with one another to affect the success rate.

Highly efficient oxygen evolution reaction via facile bubble transport realized by three-dimensionally stack-printed catalysts.

Despite highly promising characteristics of three-dimensionally (3D) nanostructured catalysts for the oxygen evolution reaction (OER) in polymer electrolyte membrane water electrolyzers (PEMWEs), universal design rules for maximizing their performance have not been explored. Here we show that woodpile (WP)-structured Ir, consisting of 3D-printed, highly-ordered Ir nanowire building blocks, improve OER mass activity markedly. The WP structure secures the electrochemically active surface area (ECSA) through enhanced utilization efficiency of the extended surface area of 3D WP catalysts. Moreover, systematic control of the 3D geometry combined with theoretical calculations and various electrochemical analyses reveals that facile transport of evolved O2 gas bubbles is an important contributor to the improved ECSA-specific activity. The 3D nanostructuring-based improvement of ECSA and ECSA-specific activity enables our well-controlled geometry to afford a 30-fold higher mass activity of the OER catalyst when used in a single-cell PEMWE than conventional nanoparticle-based catalysts.

Case Report: Polymerase Chain Reaction Testing of Tick Bite Site Samples for the Diagnosis of Human Granulocytic Anaplasmosis.

Human granulocytic anaplasmosis (HGA) is a tick-borne infectious disease caused by Anaplasma phagocytophilum, an obligate intracellular bacterium. Until now, the utility of tick-bite site samples for HGA diagnosis has not been reported. Using a patient's buffy coat and tick-bite site crust samples, we performed polymerase chain reaction (PCR) testing using Ehrlichia- or Anaplasma-specific primers. PCR with buffy coat and crust samples obtained before doxycycline administration was positive. Six days after doxycycline administration, PCR with the buffy coat sample was negative but PCR with a crust tissue sample from the tick-bite site remained positive. This is the first case to suggest that crust tissue at the tick-bite site may be useful for early HGA diagnosis in patients who have already been treated with antibiotics such as doxycycline.

Accuracy of Conventional PCR Targeting the 16S rRNA Gene with the Ot-16sRF1 and Ot-16sRR1 Primers for Diagnosis of Scrub Typhus: a Case-Control Study.

We retrospectively evaluated the accuracy of conventional PCR targeting the 16S rRNA gene (16S C-PCR) using the Ot-16sRF1/Ot-16sRR1 primers for diagnosing scrub typhus. The diagnosis of Orientia tsutsugamushi infection by 16S C-PCR presented an increased sensitivity of 87.0% and specificity of 100% compared with those obtained with other targets and is thus a simple and clinically useful method with good diagnostic accuracy.

Upgrading and upstaging of low-risk prostate cancer among Korean patients: a multicenter study.

Only 54% of prostate cancer cases in Korea are localized compared with 82% of cases in the US. Furthermore, half of Korean patients are upgraded after radical prostatectomy (41.6%-50.6%). We investigated the risk factors for upgrading and/or upstaging of low-risk prostate cancer after radical prostatectomy. We retrospectively reviewed the medical records of 1159 patients who underwent radical prostatectomy at five hospitals in Honam Province. Preoperative data on standard clinicopathological parameters were collected. The radical prostatectomy specimens were graded and staged and we defined a "worsening prognosis" as a Gleason score ≥ 7 or upstaging to ≥ pT3. Multivariate logistic regression models were used to assess factors associated with postoperative pathological upstaging. Among the 1159 patients, 324 were classified into the clinically low-risk group, and 154 (47.5%) patients were either upgraded or upstaged. The multivariable analysis revealed that the preoperative serum prostate-specific antigen level (odds ratio [OR], 1.131; 95% confidence interval [CI], 1.007-1.271; P= 0.037), percent positive biopsy core (OR: 1.018; 95% CI: 1.002-1.035; P= 0.032), and small prostate volume (≤30 ml) (OR: 2.280; 95% CI: 1.351-3.848; P= 0.002) were predictive of a worsening prognosis. Overall, 47.5% of patients with low-risk disease were upstaged postoperatively. The current risk stratification criteria may be too relaxed for our study cohort.

Clinical Efficacy of Ertapenem for Recurrent Cystitis Caused by Multidrug-Resistant Extended-Spectrum ß-Lactamase-Producing Escherichia coli in Female Outpatients.

PURPOSE: To evaluate the clinical outcomes of ertapenem administered as an outpatient parenteral antibiotic therapy for intractable cystitis caused by extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli. MATERIALS AND METHODS: We retrospectively reviewed a case series of 3 years of therapeutic experience with ertapenem for intractable recurrent cystitis caused by ESBL-producing E. coli. Ertapenem 1 g/d was parenterally administered to the patients on an outpatient basis until the acquisition of symptomatic improvement and negative conversion of urine culture. Demographic and clinical characteristics of patients, antimicrobial resistance, and clinical response data were analyzed from the patients' medical records. RESULTS: During the course of this study, a total of 383 patients were diagnosed with cystitis, and 24 of them showed ESBL-producing E. coli (6.26%). The mean treatment duration of all patients was 8.5 days. The early clinical and microbiological cure rates 0 to 7 days after the end of treatment were 91.7% (22/24) and 90.9% (20/22), respectively. The late clinical and microbiological cure rates 4 to 6 weeks after the end of treatment were 72.2% (13/18) at both time points. CONCLUSIONS: Parenteral ertapenem treatment can be an effective and well-tolerated treatment option for intractable recurrent cystitis by multidrug-resistant ESBL-producing E. coli.