Safety and immunogenicity of the Euvichol-S oral cholera vaccine for prevention of Vibrio cholerae O1 infection in Nepal: an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial.

BACKGROUND: In October, 2017, WHO launched a strategy to eliminate cholera by 2030. A primary challenge in meeting this goal is the limited global supply capacity of oral cholera vaccine and the worsening of cholera outbreaks since 2021. To help address the current shortage of oral cholera vaccine, a WHO prequalified oral cholera vaccine, Euvichol-Plus was reformulated by reducing the number of components and inactivation methods. We aimed to evaluate the immunogenicity and safety of Euvichol-S (EuBiologics, Seoul, South Korea) compared with an active control vaccine, Shanchol (Sanofi Healthcare India, Telangana, India) in participants of various ages in Nepal. METHODS: We did an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial at four hospitals in Nepal. Eligible participants were healthy individuals aged 1-40 years without a history of cholera vaccination. Individuals with a history of hypersensitivity reactions to other preventive vaccines, severe chronic disease, previous cholera vaccination, receipt of blood or blood-derived products in the past 3 months or other vaccine within 4 weeks before enrolment, and pregnant or lactating women were excluded. Participants were randomly assigned (1:1:1:1) by block randomisation (block sizes of two, four, six, or eight) to one of four groups (groups A-D); groups C and D were stratified by age (1-5, 6-17, and 18-40 years). Participants in groups A-C were assigned to receive two 1·5 mL doses of Euvichol-S (three different lots) and participants in group D were assigned to receive the active control vaccine, Shanchol. All participants and site staff (with the exception of those who prepared and administered the study vaccines) were masked to group assignment. The primary immunogenicity endpoint was non-inferiority of immunogenicity of Euvichol-S (group C) versus Shanchol (group D) at 2 weeks after the second vaccine dose, measured by the seroconversion rate, defined as the proportion of participants who had achieved seroconversion (defined as ≥four-fold increase in V cholerae O1 Inaba and Ogawa titres compared with baseline). The primary immunogenicity endpoint was assessed in the per-protocol analysis set, which included all participants who received all their planned vaccine administrations, had no important protocol deviations, and who provided blood samples for all immunogenicity assessments. The primary safety endpoint was the number of solicited adverse events, unsolicited adverse events, and serious adverse events after each vaccine dose in all ages and each age stratum, assessed in all participants who received at least one dose of the Euvichol-S or Shanchol. Non-inferiority of Euvichol-S compared with Shanchol was shown if the lower limit of the 95% CI for the difference between the seroconversion rates in Euvichol-S group C versus Shanchol group D was above the predefined non-inferiority margin of -10%. The trial was registered at ClinicalTrials.gov, NCT04760236. FINDINGS: Between Oct 6, 2021, and Jan 19, 2022, 2529 healthy participants (1261 [49·9%] males; 1268 [50·1%] females), were randomly assigned to group A (n=330; Euvichol-S lot number ES-2002), group B (n=331; Euvichol-S ES-2003), group C (n=934; Euvichol-S ES-2004]), or group D (n=934; Shanchol). Non-inferiority of Euvichol-S versus Shanchol in seroconversion rate for both serotypes at 2 weeks after the second dose was confirmed in all ages (difference in seroconversion rate for V cholerae O1 Inaba -0·00 [95% CI -1·86 to 1·86]; for V cholerae O1 Ogawa -1·62 [-4·80 to 1·56]). Treatment-emergent adverse events were reported in 244 (9·7%) of 2529 participants in the safety analysis set, with a total of 403 events; 247 events were reported among 151 (9·5%) of 1595 Euvichol-S recipients and 156 events among 93 (10·0%) of 934 Shanchol recipients. Pyrexia was the most common adverse event in both groups (57 events among 56 [3·5%] of 1595 Euvichol-S recipients and 37 events among 35 [3·7%] of 934 Shanchol recipients). No serious adverse events were deemed to be vaccine-related. INTERPRETATION: A two-dose regimen of Euvichol-S vaccine was non-inferior to the active control vaccine, Shanchol, in terms of seroconversion rates 2 weeks after the second dose. The simplified formulation and production requirements of the Euvichol-S vaccine have the potential to increase the supply of oral cholera vaccine and reduce the gap between the current oral cholera vaccine supply and demand. FUNDING: The Bill & Melinda Gates Foundation. TRANSLATION: For the Nepali translation of the abstract see Supplementary Materials section.

Spatiotemporal Study of Galactolipid Biosynthesis in Duckweedwith Mass Spectrometry Imaging and in vivo Isotope Labeling.

Isotope labeling coupled with mass spectrometry imaging (MSI) presents a potent strategy for elucidating the dynamics of metabolism in cellular resolution, yet its application to plant systems is scarce. It has the potential to reveal the spatiotemporal dynamics in lipid biosynthesis during plant development. In this study, we explore its application to galactolipid biosynthesis of an aquatic plant, Lemna minor, with D2O labeling. Specifically, matrix-assisted laser desorption/ionization (MALDI) MSI data of two major galactolipids in L. minor, monogalactosyldiacylglycerol and digalactosyldiacylglycerol, were studied after growing in 50% D2O media over fifteen-day time period. When they were partially labeled after five days, three distinct binomial isotopologue distributions were observed corresponding to the labeling of partial structural moieties: galactose only, galactose and a fatty acyl chain, and the entire molecule. The temporal change of the relative abundance of these distributions follows the expected linear pathway of galactolipid biosynthesis. Notably, their MS images revealed the localization of each isotopologue group to the old parent frond, the intermediate tissues, and the newly grown daughter fronds. Besides, two additional labeling experiments, 1) 13CO2 labeling and 2) backward labeling of completely 50% D2O labeled L. minor in H2O media, confirm the observations in forward labeling. Further, these experiments unveiled hidden isotopologue distributions indicative of membrane lipid restructuring. This study suggests the potential of isotope labeling with MSI to provide spatiotemporal details in lipid biosynthesis in plant development.

ß-Ga2O3 Air-Channel Field-Emission Nanodiode with Ultrahigh Current Density and Low Turn-On Voltage.

Field-emission nanodiodes with air-gap channels based on single ß-Ga2O3 nanowires have been investigated in this work. With a gap of ∼50 nm and an asymmetric device structure, the proposed nanodiode achieves good diode characteristics through field emission in air at room temperature. Measurement results show that the nanodiode exhibits an ultrahigh emission current density, a high enhancement factor of >2300, and a low turn-on voltage of 0.46 V. More impressively, the emission current almost keeps constant over a wide range (8 orders of magnitude) of air pressures below 1 atm. Meanwhile, the fluctuation in field-emission current is below 8.7% during long-time monitoring, which is better than the best reported field-emission device based on ß-Ga2O3 nanostructures. All of these results indicate that ß-Ga2O3 air-gapped nanodiodes are promising candidates for vacuum electronics that can also operate in air.

Pregnancy After Breast Cancer in Young BRCA Carriers: An International Hospital-Based Cohort Study.

Importance: Young women with breast cancer who have germline pathogenic variants in BRCA1 or BRCA2 face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regarding BRCA carriers. Objective: To investigate cumulative incidence of pregnancy and disease-free survival in young women who are BRCA carriers. Design, Setting, and Participants: International, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants in BRCA1 and/or BRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023. Exposure: Pregnancy after breast cancer. Main Outcomes and Measures: Primary end points were cumulative incidence of pregnancy after breast cancer and disease-free survival. Secondary end points were breast cancer-specific survival, overall survival, pregnancy, and fetal and obstetric outcomes. Results: Of 4732 BRCA carriers included, 659 had at least 1 pregnancy after breast cancer and 4073 did not. Median age at diagnosis in the overall cohort was 35 years (IQR, 31-38 years). Cumulative incidence of pregnancy at 10 years was 22% (95% CI, 21%-24%), with a median time from breast cancer diagnosis to conception of 3.5 years (IQR, 2.2-5.3 years). Among the 659 patients who had a pregnancy, 45 (6.9%) and 63 (9.7%) had an induced abortion or a miscarriage, respectively. Of the 517 patients (79.7%) with a completed pregnancy, 406 (91.0%) delivered at term (≥37 weeks) and 54 (10.4%) had twins. Among the 470 infants born with known information on pregnancy complications, 4 (0.9%) had documented congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in disease-free survival was observed between patients with or without a pregnancy after breast cancer (adjusted hazard ratio, 0.99; 95% CI, 0.81-1.20). Patients who had a pregnancy had significantly better breast cancer-specific survival and overall survival. Conclusions and Relevance: In this global study, 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03673306.

Decreased SMP30 Expression Is Related With EMT in the Kidneys of Two Siberian Tigers With CKD.

BACKGROUND/AIM: Chronic kidney disease (CKD) is one of the most common causes of mortality in wild non-domestic felidae. The molecular mechanism regulating renal fibrosis in nephropathy is not fully understood especially in the felidae. This study aimed to elucidate senescence marker protein 30 (SMP30) expression patterns and its relationship with epithelial-mesenchymal transition (EMT) by immunostaining in two necropsied Siberian tigers (Panthera tigris altaica) with CKD. MATERIALS AND METHODS: Two kidney samples from male Siberian tigers were fixed and tissue sections were stained for histopathological assay. RESULTS: In CKD, renal tubular epithelial cells lost their tubular structures surrounded by severe interstitial fibrosis and were detached from the basement membrane. These damaged cells resembled the morphology of mesenchymal cells and showed much lower SMP30 expression compared with intact tubular epithelial cells. These cells also expressed vimentin, which is specifically expressed by mesenchymal cells, and through double staining, it was observed that vimentin was expressed in the tubular epithelial cells where SMP30 was not expressed. In addition, double-positive expression of pan-cytokeratin (pan-CK) and vimentin was found in damaged epithelial cells with mesenchymal features. CONCLUSION: We demonstrated possible evidence to understand the role of SMP30 as a new pivotal factor and the possibility of decreased SMP30 as a potential indicator of EMT at the end stage of CKD.

Mobilized Electrospray Device for On-Tissue Chemical Derivatization in MALDI-MS Imaging.

Applying solutions of a matrix or derivatization agent via microdroplets is a common sample preparation technique for matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) experiments. Mobilized nebulizer sprayers are commonly used to create a homogeneous matrix or reagent layer across large surfaces. Electrospray devices have also been used to produce microdroplets for the same purpose but are rarely used for large tissues due to their immobility. Herein, we present a movable electrospray device that can be used for large tissue sample preparation through a simple modification to an automatic commercial nebulizer device. As demonstrated for on-tissue chemical derivatization (OTCD) with Girard's reagent T using a mimetic tissue model, the sprayer has the additional benefit of being able to investigate reaction acceleration in OTCD when comparing electrostatically charged spray to electrostatically neutral spray. Finally, MALDI-MSI of fatty aldehydes is successfully demonstrated in rat brain tissues using this device for both OTCD and matrix application.

Rapid detection of antimicrobial resistance in methicillin-resistant Staphylococcus aureus using MALDI-TOF mass spectrometry.

Antimicrobial resistance is a growing problem in modern healthcare. Most antimicrobial susceptibility tests (AST) require long culture times which delay diagnosis and effective treatment. Our group has previously reported a proof-of-concept demonstration of a rapid AST in Escherichia coli using deuterium labeling and MALDI mass spectrometry. Culturing bacteria in D2O containing media incorporates deuterium in newly synthesized lipids, resulting in a mass shift that can be easily detected by mass spectrometry. The extent of new growth is measured by the average mass of synthesized lipids that can be correlated with resistance in the presence of antimicrobials. In this work, we adapt this procedure to methicillin-resistant Staphylococcus aureus using the Bruker MALDI-TOF Biotyper, a low-cost instrument commonly available in diagnostic laboratories. The susceptible strain showed a significant decrease in average mass in on-target microdroplet cultures after 3 hours of incubation with 10 µg/mL methicillin, while the resistant strain showed consistent labeling regardless of methicillin concentration. This assay allows us to confidently detect methicillin resistance in S. aureus after only 3 hours of culture time and minimal sample processing, reducing the turn-around-time significantly over conventional assays. The success of this work suggests its potential as a rapid AST widely applicable in many clinical microbiology labs with minimal additional costs.

Age-Related Incidence and Peak Occurrence of Contralateral Breast Cancer.

Importance: Young patients with breast cancer have higher risk for developing contralateral breast cancer (CBC) and have epidemiologic characteristics different from those of older patients. Objective: To examine the incidence and peak occurrence of CBC according to age at primary breast cancer (PBC) surgery. Design, Setting, and Participants: This cohort study included patients who were diagnosed with and underwent surgery for unilateral nonmetastatic breast cancer at Asan Medical Center, Korea, between January 1, 1999, and December 31, 2013, with follow-up through December 31, 2018. Data were analyzed from December 1, 2021, through April 30, 2023. Patients were divided into 2 groups according to their age at surgery for PBC: younger (≤35 years) vs older (>35 years). Main Outcomes and Measures: The main outcomes were cumulative incidence and hazard rate of CBC in the entire study population and in subgroups divided by cancer subtype, categorized according to hormone receptor (HR) and ERBB2 status. Results: A total of 16 251 female patients with stage 0 to III breast cancer were analyzed; all patients were Korean. The mean (SD) age was 48.61 (10.06) years; 1318 patients (8.11%) were in the younger group, and 14 933 (91.89%) were in the older group. Median follow-up was 107 months (IQR, 79-145 months). Compared with the older group, the younger group had significantly higher incidence of CBC (10-year cumulative incidence, 7.1% vs 2.9%; P < .001) and higher risk (hazard ratio, 2.10; 95% CI, 1.62-2.74) of developing CBC. The hazard rate, which indicates risk for developing CBC at a certain time frame, differed according to the subtype of primary cancer. In patients with the HR+/ERBB2- subtype, the risk increased continuously in both age groups. In patients with the triple negative subtype, the risk increased until approximately 10 years and then decreased in both age groups. Meanwhile, in the HR-/ERBB2+ subtype, risk peaked earlier, especially in the younger group (1.7 years since first surgery in the younger group and 4.8 years in the older group). Conclusions and Relevance: In this cohort study, patients aged 35 years or younger with breast cancer had a higher risk of developing CBC than older patients. Moreover, young patients with the HR-/ERBB2+ subtype tended to have a shorter interval for developing CBC. These findings might be useful in guiding treatment decisions, such as contralateral prophylactic mastectomy.

Case report: Fatal neonatal sepsis associated with Escherichia fergusonii infection in a common bottlenose dolphin (Tursiops truncatus).

A 25-day-old male common bottlenose dolphin (Tursiops truncatus) died suddenly while swimming at a dolphinarium. The gross examination revealed ulceration on the dorsal and pectoral fins and rostrum. Severe congestion, hemorrhage, and edema were observed in the gastrointestinal tract, liver, mesenteric lymph nodes, lungs, and kidneys. Fibrinosuppurative arthritis of the atlantooccipital joint and extension of fibrin into the spinal canal caused compression of the spinal cord. Histopathological examination revealed tracheitis, fibrinosuppurative bronchopneumonia and enteritis. In the central nervous system, meningeal vessel congestion in the brain, and intraparenchymal hemorrhages with neurodegeneration were observed in the spinal cord. Based on the histopathological findings, representative samples, including lung, liver, mesenteric lymph node, blood obtained from the jugular vein, and fluid sample of the ascites, were inoculated on tryptic soy agar and blood agar for routine bacterial isolation. Each isolated bacterial colony was streaked aseptically onto tryptic soy agar and blood agar for pure culture. After then, polymerase chain reaction (PCR) was performed for further identification of pathogenic microorganisms. PCR identified Escherichia fergusonii, Shewanella haliotis, Enterococcus faecalis, and Staphylococcus schleiferi. E. fergusonii was considered the primary etiologic agent in this case since it was the only species identified in all representative samples. The cause of death in this animal was E. fergusonii sepsis. To the best of our knowledge, this is the first case of neonatal sepsis associated with E. fergusonii infection in a dolphin, and suggests E. fergusonii as an opportunistic pathogen associated with sepsis in dolphins.

Moderating Role of Communication Competence in the Association between Professionalism and Job Satisfaction in Korean Millennial and Generation Z Nurses: A Cross-Sectional Study.

Millennial and Generation Z (MZ generation) nurses, the core of the Republic of Korean nursing workforce, are leaving hospitals. We, therefore, aimed to determine the mediating role of communication competence between nursing professionalism and job satisfaction of MZ generation nurses in Republic of Korea. A total of 188 nurses aged 20-39 years belonging to the MZ generation, who had been working in a general hospital for over six months, participated in an online survey from 27 October 2022 to 11 January 2023. Data analysis was conducted using the bootstrapping method with the SPSS PROCESS macro program to confirm the mediating role of communication competence. Job satisfaction, professionalism, and communication skills were significantly positively correlated (r = 0.36-0.72, p < 0.001). Communication competence was found to be a mediating factor in the relationship between professionalism and job satisfaction. The results showed that when professionalism related to job satisfaction, good communication further enhanced job satisfaction. In order to enhance MZ generation nurses' job satisfaction, it is necessary to improve nursing professionalism and implement training programs to improve communication skills considering generation-specific characteristics.

Disrupted intestinal mucosal barrier mediated by alcohol consumption aggravates systemic microplastic accumulation.

Waste plastics are degraded into microplastics (MPs), which are easily accumulated in the human body through digestive tracts, via the food chain. Alcohol is a widely consumed chemical throughout the world with the ability to alter the intestinal barrier. For this reason, this study was aimed to investigate exact relevance between alcohol consumption and organ distributions of MPs in an ethanol feeding animal model characterized by disrupted intestinal mucosal barriers. In this study, C57BL/6 mice were separated into control, control + MP, ethanol (EtOH), and EtOH + MP groups. Mice in the EtOH group ingested a Lieber-DeCarli diet containing EtOH. Mice in the MP groups ingested 0.1 mg/kg fluorophore polymerized polystyrene microplastics via oral gavage polystyrene MPs via oral gavage. The EtOH + MP group showed higher MP accumulation in the liver than the control + MP group. The same pattern was observed in the intestines, spleen, and brain. This pattern was more prominent in the intestines, with the EtOH + MP group showing the most severe damage due to EtOH ingestion. This result suggests that the intestinal mucosa disruption caused by EtOH ingestion exacerbates MP accumulation in the organs. Moreover, hepatic steatosis was more severe in the EtOH + MP group than in the EtOH group, suggesting the secondary manifestation mediated by MP accumulation. This study reports a novel MP accumulation pattern in the body by providing novel insights into alcohol-induced gut permeability and microplastics toxicity from the perspective of gut-liver axis.

Predicting Fingerprint Age Based on Ozonolysis Kinetics of Unsaturated Triacylglycerol Degradation.

Answering the question, "How old is a fingerprint?", is a highly sought-after aim in forensic science. Despite several decades of studies to find an empirical correlation in fingerprint aging, there has been no reliable method so far. In this study, we attempt to determine the time since deposition (TSD) of aged fingerprints from the chemical profile captured within a matrix-assisted laser desorption/ionization mass spectrometry data set. Our approach is based on the chemical kinetics associated with the ambient ozonolysis of unsaturated triacylglycerols (TGs), a major component in fingerprint lipids. First, ozone concentration and ambient temperature were determined to be the major factors in the degradation of unsaturated TGs. A simple kinetics model is then developed to describe the decay of unsaturated TGs, dictated only by the temperature and ozone concentration. This model is then applied to the degradation of TGs in a mixture of TG standards and multiple individuals' fingerprints. The overall decay of unsaturated TGs follows the pseudo-first-order reaction kinetics, validating our hypothesis; however, there are significant person-to-person variations in the initial abundance of unsaturated TGs and the decay rate, hampering the accurate prediction of TSD unless they are corrected for each individual. Nevertheless, the model's applicability for ambient fingerprint aging data was successfully demonstrated.

Survey of clinicians on the use of adjuvant therapy for premenopausal women with breast cancer.

PURPOSE: Considering prognostic and anatomic stages in early-stage premenopausal patients with breast cancer, clinicians decide on performing the multigene assay, adjuvant chemotherapy, or ovarian function suppression (OFS). This decision is also based on genetic information related to hormone receptor-positive and human epidermal growth factor receptor 2 negative results. We aimed to determine the tendency to use adjuvant therapy in clinical practice. METHODS: From April to May 2022, clinicians of the Korean Breast Cancer Society responded to a web-based survey. The survey included 62 multiple-choice questions mainly on decision-making under different pathologic conditions. RESULTS: Among 92 responding clinicians, 91.3% were breast surgeons. For 35-year-old patients (pT2N0 and Ki-67 50% profile), 96.8% of clinicians selected chemotherapy, whereas 50.7% selected chemotherapy for patients with pT1N0, Ki-67 10%, and without Oncotype Dx (ODX). Only 35.6% selected chemotherapy for 47-year-old patients with the same profiles, while 84.3% and 49.1% chose chemotherapy with ODX recurrence score 21 and 16, respectively. More clinicians selected tamoxifen (TMX) plus OFS than aromatase inhibitor (AI) plus OFS for 5 years of endocrine therapy in patients with adjuvant chemotherapy regardless of genomic and clinical risks. However, for the same patients without adjuvant chemotherapy, more clinicians selected AI plus OFS. A longer duration of additional OFS and TMX was selected in patients with high clinical and genomic risks, and the duration of OFS was relatively shorter in older patients. CONCLUSION: The decision regarding adjuvant therapy should be made considering clinical and genomic risks and age, and clinicians should consult with patients about adverse effects and compliance.

Ki-67, 21-Gene Recurrence Score, Endocrine Resistance, and Survival in Patients With Breast Cancer.

Importance: Both high 21-gene recurrence score (RS) and high Ki-67 level are poor prognostic factors in patients with estrogen receptor (ER)-positive ERBB2-negative (ER+/ERBB-) breast cancer; however, a discrepancy between the 2 has been noted. Survival differences according to these 2 biomarkers are not well known. Objective: To assess the associations between RS and Ki-67 expression and between Ki-67 expression and recurrence-free survival in patients with ER+/ERBB- breast cancer with low RS. Design, Setting, and Participants: This cohort study included women treated for ER+/ERBB2- breast cancer who underwent the 21-gene RS test from March 2010 to December 2020 in 2 hospitals in Korea. Exposures: Recurrence score and Ki-67 level. Main Outcomes and Measures: A Cox proportional hazards regression model was used to examine the association of Ki-67 with recurrence-free survival (RFS), while a binary logistic regression model was used to examine the association between Ki-67 and secondary endocrine resistance. High Ki-67 expression was defined as 20% or greater, and low genomic risk as an RS of 25 or less. Secondary endocrine resistance was defined as breast cancer recurrence that occurred after at least 2 years of endocrine therapy and during or within the first year after completing 5 years of adjuvant endocrine therapy. Results: A total of 2295 female patients were included (mean [SD] age, 49.8 [9.3] years), of whom 1948 (84.9%) were in the low genomic risk group and 1425 (62.1%) had low Ki-67 level. The median follow-up period was 40 months (range, 0-140 months). The RS and Ki-67 level had a moderate correlation (R = 0.455; P < .001). Of the patients with low Ki-67 level, 1341 (94.1%) had low RS, whereas 607 of 870 patients with high Ki-67 level (69.8%) had low RS. In patients with low RS, the RFS differed significantly according to Ki-67 level (low Ki-67, 98.5% vs high Ki-67, 96.5%; P = .002). Among the 1807 patients with low genomic risk who did not receive chemotherapy, high Ki-67 level was independently associated with recurrence (hazard ratio, 2.51; 95% CI, 1.27-4.96; P = .008). Recurrence after 3 years differed significantly according to Ki-67 level (low Ki-67, 98.7% vs high Ki-67, 95.7%; P = .003), whereas recurrence within 3 years did not differ (low Ki-67, 99.3% vs high Ki-67, 99.3%; P = .90). In addition, Ki-67 was associated with secondary endocrine resistance in patients with low RS who did not receive chemotherapy (odds ratio, 2.49; 95% CI, 1.13-5.50; P = .02). Conclusions and Relevance: In this cohort study of patients with ER+/ERBB2- breast cancer, a moderate correlation was observed between Ki-67 and RS, and high Ki-67 level in patients with low genomic risk was associated with increased risk of secondary endocrine resistance.

Waiting Time for Breast Cancer Treatment in Korea: A Nationwide Cohort Study.

PURPOSE: This study aimed to analyze the waiting time for initial treatment after breast cancer diagnosis and determine the factors influencing treatment delay in South Korea. METHODS: This nationwide retrospective cohort study was conducted using the Health Insurance Review and Assessment data. The participants were classified according to the regions where their biopsy and treatment were performed (Seoul-Seoul, Metro-Metro, Other-Other, Metro-Seoul, Other-Seoul). Waiting time was analyzed according to regional subgroup, year of diagnosis, and type of treatment. Multivariable logistic regression models were constructed to identify the factors associated with treatment delay (after 30 days of diagnosis). RESULTS: A total of 133,514 participants newly diagnosed between January 2010 and December 2017 were included in the study. The median waiting time for initial treatment in the total population increased from 8 days, in 2010, to 14 days, in 2017. In the Seoul-Seoul group, the waiting time increased from 10 days, in 2010, to 16 days, in 2017. Although the median waiting time was approximately 10 days in the Metro-Metro and Other-Other groups, it was 27 and 24 days, in the Metro-Seoul and Other-Seoul group, respectively, in 2017. The proportion of delayed upfront surgery by more than 30 days was higher in the Metro-Seoul (odds ratio [OR], 8.088; 95% confidence interval [CI], 7.357-8.893; p < 0.001) and Other-Seoul (OR, 6.210; 95% CI, 5.717-6.750; p < 0.001) groups than in the Metro-Metro (OR, 1.468; 95% CI, 1.352-1.594; p < 0.001) and Other-Other (reference) groups. Previous medical history and treatment at tertiary hospital were observed as factors related to delayed surgery. CONCLUSION: Waiting times for breast cancer surgery have increased across all regions of Korea, with those traveling to Seoul experiencing particularly long wait times.

Draft genome sequence and probiotic functional property analysis of Lactobacillus gasseri LM1065 for food industry applications.

Probiotics are defined as live organisms in the host that contribute to health benefits. Lactobacillus gasseri LM1065, isolated from human breast milk, was investigated for its probiotic properties based on its genome. Draft genome map and de novo assembly were performed using the PacBio RS II system and hierarchical genome assembly process (HGAP). Probiotic properties were determined by the resistance to gastric conditions, adherence ability, enzyme production, safety assessment and mobile genetic elements. The fungistatic effect and inhibition of hyphae transition were studied using the cell-free supernatant (CFS). L. gasseri LM1065 showed high gastric pepsin tolerance and mild tolerance to bile salts. Auto-aggregation and hydrophobicity were measured to be 61.21% and 61.55%, respectively. The adherence to the human intestinal epithelial cells was measured to be 2.02%. Antibiotic-resistance genes and putative virulence genes were not predicted in the genomic analysis, and antibiotic susceptibility was satisfied by the criteria of the European Food Safety Authority. CFS showed a fungistatic effect and suppressed the tricarboxylic acid cycle in Candida albicans (29.02%). CFS also inhibited the transition to true hyphae and damaged the blastoconidia. This study demonstrates the essential properties of this novel probiotic, L. gasseri LM1065, and potential to inhibit vaginal C. albicans infection.

Survival outcomes of breast cancer patients with recurrence after surgery according to period and subtype.

PURPOSE: To analyze and compare the survival rates of recurrent breast cancer patients in Korea between two periods (period I: 2000-2007; period II: 2008-2013) and to identify the factors associated with outcomes and changes over time in the duration of survival after recurrence. METHODS: We retrospectively analyzed 2,407 patients who had recurrent breast cancer with treated between January 2000 and December 2013 and divided them into two periods according to the year of recurrence. We reviewed the age at diagnosis, clinical manifestations, pathology report, surgical methods, types of adjuvant treatment, type of recurrence, and follow-up period. RESULTS: The median follow-up was 30.6 months (range, 0-223.4) from the time of relapse, and the median survival time was 42.3 months. Survival after recurrence (SAR) significantly improved from 38.0 months in period I to 49.7 months in period II (p < 0.001). In the analysis performed according to the hormone receptor and HER2 status subtypes, all subtypes except the triple-negative subtype showed higher SAR in period II than period I. Age at diagnosis, tumor stage, and treatment after recurrence were significantly correlated with survival outcomes. CONCLUSION: The survival outcomes of Korean patients with breast cancer after the first recurrence have improved in Korea. Such improvements may be attributed to advances in treatment.

Predictive biological factors for late survival in patients with HER2-positive breast cancer.

The human epidermal growth factor receptor-2 (HER2) enriched subtype of breast cancer is associated with early recurrence, mostly within 5 years. However, anti-HER2 therapies have improved outcomes and their benefits persist in the long term. This study aimed to determine predictive factors for late survival in patients with HER2-positive breast cancer. We analyzed 20,672 patients with HER2-positive stage I-III breast cancer. The patients were divided into two groups based on a follow-up period of 60 months. The multivariate analysis of factors associated with poor overall survival included old age, advanced pathologic tumor size stage (pT), advanced pathologic regional lymph node stage (pN), high histological grade, presence of lymphatic and vascular invasion, and HR-negative status within 60 months. In the breast cancer-specific survival (BCSS) of the > 60 months follow-up group, the hazard ratios (HRa) based on pN-negative were 3.038, 3.722, and 4.877 in pN1 (p = 0.001), pN2 (p < 0.001), and pN3 (p < 0.001), respectively. Only pT4 level was statistically significant in the pT group (HRa, 4.528; p = 0.007). Age (HRa, 1.045, p < 0.001) and hormone receptor-positive status (HRa, 1.705, p = 0.022) were also associated to worse BCSS. Although lymphatic invasion was not significantly associated with BCSS, there was a tendency toward a relationship (p = 0.079) with worse BCSS. In HER2-positive breast cancer patients, node status had a more significant relationship with long-term prognosis than T stage. Patients with HER2-positive breast cancer who have T4 or node-positive should be considered for clinical observation and education beyond 5 years.

Ginsenoside Rg3-enriched Korean Red Ginseng extract attenuates Non-Alcoholic Fatty Liver Disease by way of suppressed VCAM-1 expression in liver sinusoidal endothelium.

Background: The incidence and clinical importance of nonalcoholic fatty liver disease (NAFLD) has emerged. However, effective therapeutic strategies for NAFLD have yet to be found. Panax ginseng (P. ginseng) is a traditional herb in Eastern Asia with therapeutic effects in many chronic disorders. However, the precise effects of ginseng extract on NAFLD are currently unknown. In present study, the therapeutic effects of Rg3-enriched red ginseng extract (Rg3-RGE) on the progression of NAFLD were explored. Methods: Twelve-week-old C57BL/6 male mice were fed a chow or western diet supplemented with high sugar water solution with or without Rg3-RGE. Histopathology, immunohistochemistry, immunofluorescence, serum biochemistry, western blot analysis, and quantitative RT-PCR were used for in vivo experiment. Conditionally immortalized human glomerular endothelial cell (CiGEnC) and primary liver sinusoidal endothelial cells (LSECs) were used for in vitro experiments. Results: Eight weeks of Rg3-RGE treatment significantly attenuated the inflammatory lesions of NAFLD. Furthermore, Rg3-RGE inhibited the inflammatory infiltrate in liver parenchyma and the expression of adhesive molecules to LSECs. Moreover, the Rg3-RGE exhibited similar patterns on the in vitro assays. Conclusion: The results demonstrate that Rg3-RGE treatment ameliorates NAFLD progression by inhibiting chemotaxis activities in LSECs.

Effect of Reduction Sequence during Rolling on Deformed Texture and Anisotropy of Ferritic Stainless Steel.

This investigation studied the effect of reduction sequence during rolling of ferritic stainless steel on texture and anisotropy. A series of thermomechanical processes were performed on the present samples utilizing rolling deformation, with a total height reduction of 83% but with different reduction sequences, 67% + 50% (route A) and 50% + 67% (route B). Microstructural analysis showed that no significant difference was found in terms of the grain morphology between route A and route B. In terms of the texture, as compared to route A, route B developed a sharper texture on all components along the γ-fiber and a considerably higher fraction of boundaries that displayed 38°111 misorientations with respect to the surrounding deformed grains. In consequence, optimal deep drawing properties were achieved, where rm was maximized and Δr was minimized. Moreover, despite the similar morphology between the two processes, the resistance toward ridging was improved in the case of route B. This was explained in relation to the selective growth-controlled recrystallization, which favors the formation of microstructure with homogeneous distribution of the <111>//ND orientation.