Pathogenicity of Highly Pathogenic Avian Influenza A(H5N1) Viruses Isolated from Cats in Mice and Ferrets, South Korea, 2023.

The prevalence of highly pathogenic avian influenza (HPAI) A(H5N1) viruses has increased in wild birds and poultry worldwide, and concomitant outbreaks in mammals have occurred. During 2023, outbreaks of HPAI H5N1 virus infections were reported in cats in South Korea. The H5N1 clade 2.3.4.4b viruses isolated from 2 cats harbored mutations in the polymerase basic protein 2 gene encoding single amino acid substitutions E627K or D701N, which are associated with virus adaptation in mammals. Hence, we analyzed the pathogenicity and transmission of the cat-derived H5N1 viruses in other mammals. Both isolates caused fatal infections in mice and ferrets. We observed contact infections between ferrets, confirming the viruses had high pathogenicity and transmission in mammals. Most HPAI H5N1 virus infections in humans have occurred through direct contact with poultry or a contaminated environment. Therefore, One Health surveillance of mammals, wild birds, and poultry is needed to prevent potential zoonotic threats.

Validation of Adult Sepsis Event and Epidemiologic Analysis of Sepsis Prevalence and Mortality Using Adult Sepsis Event's Electronic Health Records-Based Sequential Organ Failure Assessment Criteria: A Single-Center Study in South Korea.

OBJECTIVES: In 2018, the Centers for Disease Control and Prevention introduced the Adult Sepsis Event (ASE) definition, using electronic health records (EHRs) data for surveillance and sepsis quality improvement. However, data regarding ASE outside the United States remain limited. We therefore aimed to validate the diagnostic accuracy of the ASE and to assess the prevalence and mortality of sepsis using ASE. DESIGN: Retrospective cohort study. SETTING: A single center in South Korea, with 2732 beds including 221 ICU beds. PATIENTS: During the validation phase, adult patients who were hospitalized or visiting the emergency department between November 5 and November 11, 2019, were included. In the subsequent phase of epidemiologic analysis, we included adult patients who were admitted from January to December 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: ASE had a sensitivity of 91.6%, a specificity of 98.3%, a positive predictive value (PPV) of 57.4%, and a negative predictive value of 99.8% when compared with the Sepsis-3 definition. Of 126,998 adult patient hospitalizations in 2020, 6,872 cases were diagnosed with sepsis based on the ASE (5.4% per year), and 893 patients were identified as having sepsis according to the International Classification of Diseases , 10th Edition (ICD-10) (0.7% per year). Hospital mortality rates were 16.6% (ASE) and 23.5% (ICD-10-coded sepsis). Monthly sepsis prevalence and hospital mortality exhibited less variation when diagnosed using ASE compared with ICD-10 coding (coefficient of variation [CV] for sepsis prevalence: 0.051 vs. 0.163, Miller test p < 0.001; CV for hospital mortality: 0.087 vs. 0.261, p = 0.001). CONCLUSIONS: ASE demonstrated high sensitivity and a moderate PPV compared with the Sepsis-3 criteria in a Korean population. The prevalence of sepsis, as defined by ASE, was 5.4% per year and was similar to U.S. estimates. The prevalence of sepsis by ASE was eight times higher and exhibited less monthly variability compared with that based on the ICD-10 code.

Associations of combined polygenic risk score and glycemic status with atrial fibrillation, coronary artery disease and ischemic stroke.

BACKGROUND: It is unknown whether high hemoglobin A1c (HbA1c) is associated with increases in the risk of cardiovascular disease among individuals with elevated genetic susceptibility. We aimed to investigate the association between HbA1c and atrial fibrillation (AF), coronary artery disease (CAD), and ischemic stroke according to the polygenic risk score (PRS). METHODS: The UK Biobank cohort included 502,442 participants aged 40-70 years who were recruited from 22 assessment centers across the United Kingdom from 2006 to 2010. This study included 305,605 unrelated individuals with available PRS and assessed new-onset AF, CAD, and ischemic stroke. The participants were divided into tertiles based on the validated PRS for each outcome. Within each PRS tertiles, the risks of incident events associated with HbA1c levels were investigated and compared with HbA1c < 5.7% and low PRS. Data were analyzed from November 2022 to May 2023. RESULTS: Of 305,605 individuals, 161,605 (52.9%) were female, and the mean (SD) age was 56.6 (8.1) years. During a median follow-up of 11.9 (interquartile range 11.1-12.6) years, the incidences of AF, CAD, and ischemic stroke were 4.6, 2.9 and 1.1 per 100 person-years, respectively. Compared to individuals with HbA1c < 5.7% and low PRS, individuals with HbA1c ≥ 6.5% and high PRS had a 2.67-times higher risk for AF (hazard ratio [HR], 2.67; 95% confidence interval (CI), 2.43-2.94), 5.71-times higher risk for CAD (HR, 5.71; 95% CI, 5.14-6.33) and 2.94-times higher risk for ischemic stroke (HR, 2.94; 95% CI, 2.47-3.50). In the restricted cubic spline models, while a U-shaped trend was observed between HbA1c and the risk of AF, dose-dependent increases were observed between HbA1c and the risk of CAD and ischemic stroke regardless PRS tertile. CONCLUSIONS: Our results suggest that the nature of the dose-dependent relationship between HbA1c levels and cardiovascular disease in individuals with different PRS is outcome-specific. This adds to the evidence that PRS may play a role together with glycemic status in the development of cardiovascular disease.

Prognosis of mechanically ventilated patients with COVID-19 after failure of high-flow nasal cannula: a retrospective cohort study.

BACKGROUND: There is an argument whether the delayed intubation aggravate the respiratory failure in Acute respiratory distress syndrome (ARDS) patients with coronavirus disease 2019 (COVID-19). We aimed to investigate the effect of high-flow nasal cannula (HFNC) failure before mechanical ventilation on clinical outcomes in mechanically ventilated patients with COVID-19. METHODS: This retrospective cohort study included mechanically ventilated patients who were diagnosed with COVID-19 and admitted to the intensive care unit (ICU) between February 2020 and December 2021 at Asan Medical Center. The patients were divided into HFNC failure (HFNC-F) and mechanical ventilation (MV) groups according to the use of HFNC before MV. The primary outcome of this study was to compare the worst values of ventilator parameters from day 1 to day 3 after mechanical ventilation between the two groups. RESULTS: Overall, 158 mechanically ventilated patients with COVID-19 were included in this study: 107 patients (67.7%) in the HFNC-F group and 51 (32.3%) in the MV group. The two groups had similar profiles of ventilator parameter from day 1 to day 3 after mechanical ventilation, except of dynamic compliance on day 3 (28.38 mL/cmH2O in MV vs. 30.67 mL/H2O in HFNC-F, p = 0.032). In addition, the HFNC-F group (5.6%) had a lower rate of ECMO at 28 days than the MV group (17.6%), even after adjustment (adjusted hazard ratio, 0.30; 95% confidence interval, 0.11-0.83; p = 0.045). CONCLUSIONS: Among mechanically ventilated COVID-19 patients, HFNC failure before mechanical ventilation was not associated with deterioration of respiratory failure.

Pleionea litopenaei sp. nov., isolated from the gastric tract of juvenile Pacific white shrimp Litopenaeus vannamei.

A Gram-stain-negative, aerobic, rod-shaped and motile strain HL-JVS1T, was isolated from the gastric tract of a juvenile Pacific white shrimp. Molecular phylogenetic analysis based on 16S rRNA gene sequences of strain HL-JVS1T revealed its affiliation with the genus Pleionea, with close relatives including Pleionea mediterranea MOLA115T (97.5%) and Pleionea sediminis S1-5-21T (96.2%). The complete genome of strain HL-JVS1T consisted of a circular 4.4 Mb chromosome and two circular plasmids (6.6 and 35.0 kb) with a G + C content of 43.1%. The average nucleotide identity and digital DNA-DNA hybridization values between strain HL-JVS1T and the type strains of described Pleionea species were 69.7-70.4% and 18.3-18.6%, respectively. Strain HL-JVS1T grew at 10-40 °C (optimum, 30 °C) in the presence of 0.5 - 9.0% (w/v) sea salts (optimum, 2.0 - 2.5%), and at pH range of 5.5 - 10.0 (optimum, pH 6.5). The major fatty acids (> 10%) were summed feature 9 (iso-C17:1 ω9c and/or C16:0 10-methyl) (23.3%), iso-C16:0 (14.5%), iso-C11:0 3-OH (13.8%) and iso-C15:0 (11.0%). The polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, an unidentified aminophospholipid, two unidentified aminolipids, and two unidentified lipids. The respiratory quinone was ubiquinone-8. The comprehensive phylogenetic, phylogenomic, phenotypic and chemotaxonomic results showed that strain HL-JVS1T is distinct from other Pleionea species. Hence, we propose strain HL-JVS1T as a novel species belonging to the genus Pleionea, for which the name Pleionea litopenaei sp. nov. is proposed with HL-JVS1T (= KCCM 90514T = JCM 36490T) as the type strain.

Polymicrobial bloodstream infections per se do not increase mortality compared to monomicrobial bloodstream infections in sepsis patients: a Korean nationwide sepsis cohort study.

BACKGROUND: There is limited information about the outcomes of polymicrobial bloodstream infections in patients with sepsis. We aimed to investigate outcomes of polymicrobial bloodstream infections compared to monomicrobial bloodstream infections. METHODS: This study used data from the Korean Sepsis Alliance Registry, a nationwide database of prospective observational sepsis cohort. Adult sepsis patients with bloodstream infections from September 2019 to December 2021 at 20 tertiary or university-affiliated hospitals in South Korea were analyzed. RESULTS: Among the 3,823 patients with bloodstream infections, 429 of them (11.2%) had polymicrobial bloodstream infections. The crude hospital mortality of patients with sepsis with polymicrobial bloodstream infection and monomicrobial bloodstream infection was 35.7% and 30.1%, respectively (p = 0.021). However, polymicrobial bloodstream infections were not associated with hospital mortality in the proportional hazard analysis (HR 1.15 [0.97-1.36], p = 0.11). The inappropriate use of antibiotics was associated with increased mortality (HR 1.37 [1.19-1.57], p < 0.001), and source control was associated with decreased mortality (HR 0.51 [0.42-0.62], p < 0.001). CONCLUSIONS: Polymicrobial bloodstream infections per se were not associated with hospital mortality in patients with sepsis as compared to monomicrobial bloodstream infections. The appropriate use of antibiotics and source control were associated with decreased mortality in bloodstream infections regardless of the number of microbial pathogens.

Outcomes of Lung Transplantation in Patients With Right Ventricular Dysfunction: A Single-Center Retrospective Analysis Comparing ECMO Configurations in a Bridge-to-Transplant Setting.

This study aimed to assess the lung transplantation (LT) outcomes of patients with right ventricular dysfunction (RVD), focusing on the impact of various extracorporeal membrane oxygenation (ECMO) configurations. We included adult patients who underwent LT with ECMO as a bridge-to-transplant from 2011 to 2021 at a single center. Among patients with RVD (n = 67), veno-venous (V-V) ECMO was initially applied in 79% (53/67) and maintained until LT in 52% (35/67). Due to the worsening of RVD, the configuration was changed from V-V ECMO to veno-arterial (V-A) ECMO or a right ventricular assist device with an oxygenator (Oxy-RVAD) in 34% (18/67). They showed that lactic acid levels (2-6.1 mmol/L) and vasoactive inotropic score (6.6-22.6) increased. V-A ECMO or Oxy-RVAD was initiated and maintained until LT in 21% (14/67) of cases. There was no significant difference in the survival rates among the three configuration groups (V-V ECMO vs. configuration changed vs. V-A ECMO/Oxy-RVAD). Our findings suggest that the choice of ECMO configuration for LT candidates with RVD should be determined by the patient's current hemodynamic status. Vital sign stability supports the use of V-V ECMO, while increasing lactic acid levels and vasopressor needs may require a switch to V-A ECMO or Oxy-RVAD.

Impact of the timing of invasive mechanical ventilation in patients with sepsis: a multicenter cohort study.

BACKGROUND: The potential adverse effects associated with invasive mechanical ventilation (MV) can lead to delayed decisions on starting MV. We aimed to explore the association between the timing of MV and the clinical outcomes in patients with sepsis ventilated in intensive care unit (ICU). METHODS: We analyzed data of adult patients with sepsis between September 2019 and December 2021. Data was collected through the Korean Sepsis Alliance from 20 hospitals in Korea. Patients who were admitted to ICU and received MV were included in the study. Patients were divided into 'early MV' and 'delayed MV' groups based on whether they were on MV on the first day of ICU admission or later. Propensity score matching was applied, and patients in the two groups were compared on a 1:1 ratio to overcome bias between the groups. Outcomes including ICU mortality, hospital mortality, length of hospital and ICU stay, and organ failure at ICU discharge were compared. RESULTS: Out of 2440 patients on MV during ICU stay, 2119 'early MV' and 321 'delayed MV' cases were analyzed. The propensity score matching identified 295 patients in each group with similar baseline characteristics. ICU mortality was lower in 'early MV' group than 'delayed MV' group (36.3% vs. 46.4%; odds ratio, 0.66; 95% confidence interval, 0.47-0.93; p = 0.015). 'Early MV' group had lower in-hospital mortality, shorter ICU stay, and required tracheostomy less frequently than 'delayed MV' group. Multivariable logistic regression model identified 'early MV' as associated with lower ICU mortality (odds ratio, 0.38; 95% confidence interval, 0.29-0.50; p < 0.001). CONCLUSION: In patients with sepsis ventilated in ICU, earlier start (first day of ICU admission) of MV may be associated with lower mortality.

The association of arterial partial oxygen pressure with mortality in critically ill sepsis patients: a nationwide observational cohort study.

BACKGROUND: Although several trials were conducted to optimize the oxygenation range in intensive care unit (ICU) patients, no studies have yet reached a universal recommendation on the optimal a partial pressure of oxygen in arterial blood (PaO2) range in patients with sepsis. Our aim was to evaluate whether a relatively high arterial oxygen tension is associated with longer survival in sepsis patients compared with conservative arterial oxygen tension. METHODS: From the Korean Sepsis Alliance nationwide registry, patients treated with liberal PaO2 (PaO2 ≥ 80 mm Hg) were 1:1 matched with those treated with conservative PaO2 (PaO2 < 80 mm Hg) over the first three days after ICU admission according to the propensity score. The primary outcome was 28-day mortality. RESULTS: The median values of PaO2 over the first three ICU days in 1211 liberal and 1211 conservative PaO2 groups were, respectively, 107.2 (92.0-134.0) and 84.4 (71.2-112.0) in day 1110.0 (93.4-132.0) and 80.0 (71.0-100.0) in day 2, and 106.0 (91.9-127.4) and 78.0 (69.0-94.5) in day 3 (all p-values < 0.001). The liberal PaO2 group showed a lower likelihood of death at day 28 (14.9%; hazard ratio [HR], 0.79; 95% confidence interval [CI] 0.65-0.96; p-value = 0.017). ICU (HR, 0.80; 95% CI 0.67-0.96; p-value = 0.019) and hospital mortalities (HR, 0.84; 95% CI 0.73-0.97; p-value = 0.020) were lower in the liberal PaO2 group. On ICU days 2 (p-value = 0.007) and 3 (p-value < 0.001), but not ICU day 1, hyperoxia was associated with better prognosis compared with conservative oxygenation., with the lowest 28-day mortality, especially at PaO2 of around 100 mm Hg. CONCLUSIONS: In critically ill patients with sepsis, higher PaO2 (≥ 80 mm Hg) during the first three ICU days was associated with a lower 28-day mortality compared with conservative PaO2.

First Nationwide Mpox Vaccination Program in the Republic of Korea: Implications for an Enhanced Public Health Response.

On May 1, 2024, the Republic of Korea lifted the infectious disease crisis alert for mpox, almost two years after the first case was reported. The Korea Disease Control and Prevention Agency (KDCA) has led the response, which included diagnosis, epidemiological investigations, treatment, and vaccination. This article particularly reviews the vaccination strategy implemented and proposes suggestions for enhancing future response efforts. Initially, the KDCA recommended pre-exposure prophylaxis for high-risk groups, later expanding to include broader demographics as domestic cases rose. By April 2024, a total of 6,863 individuals had received their first vaccine dose, with 3,875 completing the second dose of third-generation vaccines. Strategies to improve future responses include addressing stigma, securing nationally representative safety data, and conducting vaccine cost-benefit analyses. These measures will help ensure a robust and effective response to future outbreaks.

Pre-Sepsis Length of Hospital Stay and Mortality: A Nationwide Multicenter Cohort Study.

BACKGROUND: Prolonged length of hospital stay (LOS) is associated with an increased risk of hospital-acquired conditions and worse outcomes. We conducted a nationwide, multicenter, retrospective cohort study to determine whether prolonged hospitalization before developing sepsis has a negative impact on its prognosis. METHODS: We analyzed data from 19 tertiary referral or university-affiliated hospitals between September 2019 and December 2020. Adult patients with confirmed sepsis during hospitalization were included. In-hospital mortality was the primary outcome. The patients were divided into two groups according to their LOS before the diagnosis of sepsis: early- (< 5 days) and late-onset groups (≥ 5 days). Conditional multivariable logistic regression for propensity score matched-pair analysis was employed to assess the association between late-onset sepsis and the primary outcome. RESULTS: A total of 1,395 patients were included (median age, 68.0 years; women, 36.3%). The early- and late-onset sepsis groups comprised 668 (47.9%) and 727 (52.1%) patients. Propensity score-matched analysis showed an increased risk of in-hospital mortality in the late-onset group (adjusted odds ratio [aOR], 3.00; 95% confidence interval [CI], 1.69-5.34). The same trend was observed in the entire study population (aOR, 1.85; 95% CI, 1.37-2.50). When patients were divided into LOS quartile groups, an increasing trend of mortality risk was observed in the higher quartiles (P for trend < 0.001). CONCLUSION: Extended LOS before developing sepsis is associated with higher in-hospital mortality. More careful management is required when sepsis occurs in patients hospitalized for ≥ 5 days.

Clinical Features of Mpox Patients in Korea: A Multicenter Retrospective Study.

BACKGROUND: Mpox is a viral illness with a characteristic skin rash caused by the monkeypox virus. In 2022, Mpox spread throughout the world, and an epidemic through domestic transmission started in South Korea in early 2023. This study aimed to summarize the clinical features of Mpox patients in South Korea. METHODS: This is a multicenter retrospective study conducted at four hospitals in South Korea. All adult patients diagnosed with Mpox who were admitted to the study hospitals between June 1, 2022 and May 26, 2023 and were discharged by June 30, 2023 were reviewed. RESULTS: Sixty patients were included, accounting for 65.9% of Mpox cases reported in South Korea during the study period. Median age was 32 years and 97% (58/60) of patients were male. In total, 85% (51/60) of patients reported their sexual orientation as homosexual or bisexual. The most common route of transmission was sexual or close contact (55/60). Every patient had a skin rash and 88% (53/60) had constitutional symptoms. In total, 42% (25/60) of patients had human immunodeficiency virus and 25% (15/60) had concomitant sexually transmitted infections. Severe manifestations of Mpox were identified in only two patients. CONCLUSION: Mpox patients in South Korea were mainly young adult males and were infected through sexual contact. The clinical outcomes were favorable.

Early Prediction of Mortality for Septic Patients Visiting Emergency Room Based on Explainable Machine Learning: A Real-World Multicenter Study.

BACKGROUND: Worldwide, sepsis is the leading cause of death in hospitals. If mortality rates in patients with sepsis can be predicted early, medical resources can be allocated efficiently. We constructed machine learning (ML) models to predict the mortality of patients with sepsis in a hospital emergency department. METHODS: This study prospectively collected nationwide data from an ongoing multicenter cohort of patients with sepsis identified in the emergency department. Patients were enrolled from 19 hospitals between September 2019 and December 2020. For acquired data from 3,657 survivors and 1,455 deaths, six ML models (logistic regression, support vector machine, random forest, extreme gradient boosting [XGBoost], light gradient boosting machine, and categorical boosting [CatBoost]) were constructed using fivefold cross-validation to predict mortality. Through these models, 44 clinical variables measured on the day of admission were compared with six sequential organ failure assessment (SOFA) components (PaO2/FIO2 [PF], platelets (PLT), bilirubin, cardiovascular, Glasgow Coma Scale score, and creatinine). The confidence interval (CI) was obtained by performing 10,000 repeated measurements via random sampling of the test dataset. All results were explained and interpreted using Shapley's additive explanations (SHAP). RESULTS: Of the 5,112 participants, CatBoost exhibited the highest area under the curve (AUC) of 0.800 (95% CI, 0.756-0.840) using clinical variables. Using the SOFA components for the same patient, XGBoost exhibited the highest AUC of 0.678 (95% CI, 0.626-0.730). As interpreted by SHAP, albumin, lactate, blood urea nitrogen, and international normalization ratio were determined to significantly affect the results. Additionally, PF and PLTs in the SOFA component significantly influenced the prediction results. CONCLUSION: Newly established ML-based models achieved good prediction of mortality in patients with sepsis. Using several clinical variables acquired at the baseline can provide more accurate results for early predictions than using SOFA components. Additionally, the impact of each variable was identified.

The Immobilization of an FGF2-Derived Peptide on Culture Plates Improves the Production and Therapeutic Potential of Extracellular Vesicles from Wharton's Jelly Mesenchymal Stem Cells.

The skin is an essential organ that protects the body from external aggressions; therefore, damage from various wounds can significantly impair its function, and effective methods for regenerating and restoring its barrier function are crucial. This study aimed to mass-produce wound-healing exosomes using a fragment of the fibroblast growth factor 2 (FGF2)-derived peptide (FP2) to enhance cell proliferation and exosome production. Our experiments demonstrated increased cell proliferation when Wharton's jelly mesenchymal stem cells (WJ MSCs) were coated with FP2. Exosomes from FP2-coated WJ MSCs were analyzed using nanoparticle-tracking analysis, transmission electron microscopy, and Western blotting. Subsequently, fibroblasts were treated with these exosomes, and their viability and migration effects were compared. Anti-inflammatory effects were also evaluated by inducing pro-inflammatory factors in RAW264.7 cells. The treatment of fibroblasts with FP2-coated WJ MSC-derived exosomes (FP2-exo) increased the expression of FGF2, confirming their wound-healing effect in vivo. Overall, the results of this study highlight the significant impact of FP2 on the proliferation of WJ MSCs and the anti-inflammatory and wound-healing effects of exosomes, suggesting potential applications beyond wound healing.

Influence of gender on age-associated in-hospital mortality in patients with sepsis and septic shock: a prospective nationwide multicenter cohort study.

BACKGROUND: Numerous epidemiological studies investigating gender-dependent clinical outcomes in sepsis have shown conflicting evidence. This study aimed to investigate the effect of gender on in-hospital mortality due to sepsis according to age group. METHODS: This study used data from the Korean Sepsis Alliance, an ongoing nationwide prospective multicenter cohort from 19 participating hospitals in South Korea. All adult patients diagnosed with sepsis in the emergency departments of the participating hospitals between September 2019 and December 2021 were included in the analysis. Clinical characteristics and outcomes were compared between male and female. Eligible patients were stratified by age into 19-50 years, 50-80 years, and ≥ 80 years old individuals. RESULTS: During the study period, 6442 patients were included in the analysis, and 3650 (56.7%) were male. The adjusted odds ratio (OR) [95% confidence interval (CI)] for in-hospital mortality for male compared with female was 1.15 (95% CI = 1.02-1.29). Interestingly, in the age 19-50 group, the risk of in-hospital mortality for males was significantly lower than that of females [0.57 (95% CI = 0.35-0.93)]. For female, the risk of death remained relatively stable until around age 80 (P for linearity = 0.77), while in males, there was a linear increase in the risk of in-hospital death until around age 80 (P for linearity < 0.01). Respiratory infection (53.8% vs. 37.4%, p < 0.01) was more common in male, whereas urinary tract infection (14.7% vs. 29.8%, p < 0.01) was more common in female. For respiratory infection, male had significantly lower in-hospital mortality than female in the age 19-50 groups (adjusted OR = 0.29, 95% CI = 0.12-0.69). CONCLUSIONS: Gender may influence age-associated sepsis outcomes. Further studies are needed to replicate our findings and fully understand the interaction of gender and age on the outcomes of patients with sepsis.

Evolution and Variations of the Ovine Model of Spina Bifida.

Spina bifida is the most common congenital anomaly of the central nervous system and the first non-fatal fetal lesions to be addressed by fetal intervention. While research in spina bifida has been performed in rodent, nonhuman primate, and canine models, sheep have been a model organism for the disease. This review summarizes the history of development of the ovine model of spina bifida, previous applications, and translation into clinical studies. Initially used by Meuli et al. [Nat Med. 1995;1(4):342-7], fetal myelomeningocele defect creation and in utero repair demonstrated motor function preservation. The addition of myelotomy in this model can reproduce hindbrain herniation malformations, which is the leading cause of mortality and morbidity in humans. Since inception, the ovine models have been validated numerous times as the ideal large animal model for fetal repair, with both locomotive scoring and spina bifida defect scoring adding to the rigor of this model. The ovine model has been used to study different methods of myelomeningocele defect repair, the application of various tissue engineering techniques for neuroprotection and bowel and bladder function. The results of these large animal studies have been translated into human clinical trials including Management of Meningocele Study (MOMS) trial that established current standard of care for prenatal repair of spina bifida defects, and the ongoing trials including the Cellular Therapy for In Utero Repair of Myelomeningocele (CuRe) trial using a stem cell patch for repair. The advancement of these life savings and life-altering therapies began in sheep models, and this notable model continues to be used to further the field including current work with stem cell therapy.

Prenatal Rupture of Hydrocolpos in a Cloacal Malformation.

INTRODUCTION: Cloacal dysgenesis occurs from failure of embryological division of urogenital sinus and hindgut, leading to a single common perineal opening for genitourinary and gastrointestinal tracts. The prenatal diagnosis of cloacal malformation is imprecise, but the clinical correlation of postnatal findings to prenatal history can help reveal explanations for unusual pathological findings in patients with urogenital abnormalities. CASE PRESENTATION: A 21-year-old woman was referred after her 20-week ultrasound demonstrated anhydramnios and concern for dilated fetal bowel. Fetal MRI confirmed anhydramnios and a dilated fetal colon, in addition to hydronephrosis and a pelvic cyst. Repeat ultrasound at 27 weeks showed unexpected complete resolution of her anhydramnios but new fetal ascites. The newborn girl was postnatally diagnosed with a cloacal malformation and an unusual near-complete fusion of her labia. She underwent proximal sigmoid colostomy and a tube vaginostomy at birth followed by cloacal reconstruction at 1.5 years old. CONCLUSION: In female fetus with a pelvic cyst, one should have a high index of suspicion for cloacal anomaly and consider the possibility of urinary obstruction leading to alteration in amniotic fluid.

Inhibition of Melanogenesis by Essential Oils from the Citrus Cultivars Peels.

Citrus is one of the most popular and widely grown fruit crops in the world. However, the bioactivity of only certain species of citrus cultivars is studied. In this study, the effects of essential oils from 21 citrus cultivars on melanogenesis were investigated in an effort to identify active anti-melanogenesis constituents. The essential oils from the peels of 21 citrus cultivars obtained by hydro-distillation were analyzed using gas chromatography-mass spectrometry. Mouse melanoma B16BL6 cells were used in all assays conducted in this study. The tyrosinase activity and melanin content were determined using the lysate of α-Melanocyte-stimulated B16BL6 cells. In addition, the melanogenic gene expression was determined by quantitative reverse transcription-polymerase chain reaction. Overall, the essential oils of (Citrus unshiu X Citrus sinensis) X Citrus reticulata, Citrus reticulata, and ((Citrus unshiu X Citrus sinensis) X Citrus reticulata) X Citrus reticulata provided the best bioactivity and comprised five distinct constituents compared to other essential oils such as limonene, farnesene, ß-elemene, terpinen-4-ol, and sabinene. The anti-melanogenesis activities of the five individual compounds were evaluated. Among the five essential oils, ß-elemene, farnesene, and limonene showed dominating properties. The experimental results indicated that (Citrus unshiu X Citrus sinensis) X Citrus reticulata, Citrus reticulata, and ((Citrus unshiu X Citrus sinensis) X Citrus reticulata) X Citrus reticulara are potential candidates with anti-melanogenesis activity for use as cosmetics and pharmaceutical agents against skin hyperpigmentation.

Diplacone Isolated from Paulownia tomentosa Mature Fruit Induces Ferroptosis-Mediated Cell Death through Mitochondrial Ca2+ Influx and Mitochondrial Permeability Transition.

The recently defined type of cell death ferroptosis has garnered significant attention as a potential new approach to cancer treatment owing to its more immunogenic nature when compared with apoptosis. Ferroptosis is characterized by the depletion of glutathione (GSH)/glutathione peroxidase-4 (GPx4) and iron-dependent lipid peroxidation. Diplacone (DP), a geranylated flavonoid compound found in Paulownia tomentosa fruit, has been identified to have anti-inflammatory and anti-radical activity. In this study, the potential anticancer activity of DP was explored against A549 human lung cancer cells. It was found that DP induced a form of cytotoxicity distinct from apoptosis, which was accompanied by extensive mitochondrial-derived cytoplasmic vacuoles. DP was also shown to increase mitochondrial Ca2+ influx, reactive oxygen species (ROS) production, and mitochondrial permeability transition (MPT) pore-opening. These changes led to decreases in mitochondrial membrane potential and DP-induced cell death. DP also induced lipid peroxidation and ATF3 expression, which are hallmarks of ferroptosis. The ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 were effective in counteracting the DP-mediated ferroptosis-related features. Our results could contribute to the use of DP as a ferroptosis-inducing agent, enabling studies focusing on the relationship between ferroptosis and the immunogenic cell death of cancer cells.

The Utility of Discharge Antibiotics in Pediatric Perforated Appendicitis Without Leukocytosis.

INTRODUCTION: Optimal management of pediatric perforated appendicitis remains a topic of active investigation. Our institutional clinical practice guidelines (CPGs) were modified to discontinue antibiotics on discharge for patients with normal white blood cell count (WBC) without left shift. We hypothesized that patients would receive fewer antibiotics without increased complications. METHODS: Patients <18 y old with perforated appendicitis who underwent laparoscopic appendectomy between November 1, 2016 and May 31, 2021 at a tertiary care children's hospital were included. Primary outcome was adverse events: postdischarge surgical site infection (SSI), 30-day emergency department (ED) visits, or readmissions. Outcomes were compared before and after CPG modification. Multivariable regression was performed to identify factors associated with SSI. RESULTS: There were 113 patients pre- and 97 patients post-CPG modification. 23.1% of patients in the pre-cohort had an elevated discharge WBC or left shift compared to 18.9% of patients in the post-cohort (P = 0.48). Significantly fewer patients were prescribed antibiotics on discharge in the post-cohort (70.8% pre versus 14.4% post, P < 0.0001) and for fewer days (2 pre versus 0 post, P < 0.0001). Total antibiotic days decreased significantly (6.1 pre versus 4.6 post, P < 0.0001). There was an increase in postdischarge SSIs on univariate analysis (1.8% pre versus 9.3% post, P = 0.03), ED visits (9.7% pre versus 19.6% post, P = 0.04), and readmissions (5.3% pre versus 11.3% post, P = 0.13). On multivariable analysis, being in the post-cohort was not significantly associated with post-discharge SSIs after adjusting for sex, symptom duration, initial WBC, and discharge antibiotic duration (OR 0.25, 95% CI 0.04-1.4, P = 0.11). CONCLUSIONS: Modification of a pediatric perforated appendicitis clinical practice guideline to discontinue antibiotics on discharge with a normal WBC without left shift was effective in decreasing antibiotic duration. This was associated with an increase in SSIs on univariate analysis, which did not persist on multivariable analysis and requires further investigation.