Profiling Humoral Immunity After Mixing and Matching COVID-19 Vaccines Using SARS-CoV-2 Variant Protein Microarrays.

In November 2022, 68% of the population received at least one dose of COVID-19 vaccines. Owing to the ongoing mutations, especially for the variants of concern (VOCs), it is important to monitor the humoral immune responses after different vaccination strategies. In this study, we developed a SARS-CoV-2 variant protein microarray that contained the spike proteins from the VOCs, e.g., alpha, beta, gamma, delta, and omicron, to quantify the binding antibody and surrogate neutralizing antibody. Plasmas were collected after two doses of matching AZD1222 (AZx2), two doses of matching mRNA-1273 (Mx2), or mixing AZD1222 and mRNA-1273 (AZ+M). The results showed a significant decrease of surrogate neutralizing antibodies against the receptor-binding domain in all VOCs in AZx2 and Mx2 but not AZ+M. A similar but minor reduction pattern of surrogate neutralizing antibodies against the extracellular domain was observed. While Mx2 exhibited a higher surrogate neutralizing level against all VOCs compared with AZx2, AZ+M showed an even higher surrogate neutralizing level in gamma and omicron compared with Mx2. It is worth noting that the binding antibody displayed a low correlation to the surrogate neutralizing antibody (R-square 0.130-0.382). This study delivers insights into humoral immunities, SARS-CoV-2 mutations, and mixing and matching vaccine strategies, which may provide a more effective vaccine strategy especially in preventing omicron.

Involvement of IL-17 A/IL-17 Receptor A with Neutrophil Recruitment and the Severity of Coronary Arteritis in Kawasaki Disease.

PURPOSE: To assess the role of the interleukin (IL)-17 A/IL-17 receptor A (IL-17RA) in Kawasaki disease (KD)-related coronary arteritis (CA). METHODS: In human study, the plasma levels of IL-17 A and coronary arteries were concurrently examined in acute KD patients. In vitro responses of human coronary endothelial cells to plasma stimulation were investigated with and without IL-17RA neutralization. A murine model of Lactobacillus casei cell-wall extract (LCWE)-induced CA using wild-type Balb/c and Il17ra-deficient mice were also inspected. RESULTS: The plasma levels of IL-17 A were significantly higher in KD patients before intravenous immunoglobulin therapy, especially in those with coronary artery lesion. The pre-IVIG IL-17 A levels positively correlated with maximal z scores of coronary diameters and plasma-induced endothelial mRNA levels of chemokine (C-X-C motif) ligand-1, IL-8, and IL-17RA. IL-17RA blockade significantly reduced such endothelial upregulations of aforementioned three genes and inducible nitric oxide synthase, and neutrophil transmigration. IL-17RA expression was enhanced on peripheral blood mononuclear cells in pre-IVIG KD patients, and in the aortic rings and spleens of the LCWE-stimulated mice. LCWE-induced CA composed of dual-positive Ly6G- and IL-17 A-stained infiltrates. Il17ra-deficient mice showed reduced CA severity with the fewer number of neutrophils and lower early inducible nitric oxide synthase and chemokine (C-X-C motif) ligand-1 mRNA expressions than Il17ra+/+ littermates, and absent IL-17RA upregulation at aortic roots. CONCLUSION: IL-17 A/IL-17RA axis may play a role in mediating aortic neutrophil chemoattraction, thus contributory to the severity of CA in both humans and mice. These findings may help to develop a new therapeutic strategy toward ameliorating KD-related CA.

Maternal risk factors associated with offspring biliary atresia: population-based study.

BACKGROUND: Biliary atresia (BA) is a progressive, idiopathic, fibro-obliterative disease of the intra and extrahepatic biliary tree. If untreated, it results in severe liver injury and death. The etiology and pathogenesis of BA remain unclear. Few studies have investigated the association between maternal illness/drug use and the occurrence of BA in offspring. METHODS: We used the data from the Birth Certificate Application of Taiwan and linked to National Health Insurance Research Database and Taiwan Maternal and Child Health Database for the years 2004 to 2017 (N = 1,647,231) on 2022/03, and identified BA cases according to diagnosis and procedure code. A total of 285 BA cases were identified. RESULTS: Mothers with type 2 diabetes mellitus and non-dependent drug abuse had higher rates having BA children than non-BA children, with an odds ratio of 2.17 (95% confidence interval [CI] = 1.04-4.53) and OR: 3.02 (95% CI = 1.34-6.78), respectively. CONCLUSION: These results support the notion that BA occurrence is related to maternal reasons. Further studies should be designed to identify additional maternal and pregnancy risk factors and to understand the underlying pathophysiology. IMPACT: 1. The occurrence of offspring biliary atresia may be related to maternal illness/drug use. 2. Maternal drug abuse and type 2 diabetes mellitus pose a high risk for offspring biliary atresia. 3. If maternal etiology is found, biliary atresia might be a preventable disease.

Profiling humoral responses to COVID-19 immunization in Kawasaki disease using SARS-CoV-2 variant protein microarrays.

Kawasaki disease (KD) is a form of acute systemic vasculitis syndrome that predominantly occurs in children under the age of 5 years. Its etiology has been postulated due to not only genetic factors but also the presence of foreign antigens or infectious agents. To evaluate possible associations between Kawasaki disease (KD) and COVID-19, we investigated humoral responses of KD patients against S-protein variants with SARS-CoV-2 variant protein microarrays. In this study, plasma from a cohort of KD (N = 90) and non-KD control (non-KD) (N = 69) subjects in categories of unvaccinated-uninfected (pre-pandemic), SARS-CoV-2 infected (10-100 days after infection), and 1-dose, 2-dose, and 3-dose BNT162b2 vaccinated (10-100 days after vaccination) was collected. The principal outcomes were non-KD-KD differences for each category in terms of anti-human/anti-His for binding antibodies and neutralizing percentage for surrogate neutralizing antibodies. Binding antibodies against spikes were lower in the KD subjects with 1-dose of BNT162b2, and mean differences were significant for the P.1 S-protein (non-KD-KD, 3401; 95% CI, 289.0 to 6512; P = 0.0252), B.1.617.2 S-protein (non-KD-KD, 4652; 95% CI, 215.8 to 9087; P = 0.0351) and B.1.617.3 S-protein (non-KD-KD, 4874; 95% CI, 31.41 to 9716; P = 0.0477). Neutralizing antibodies against spikes were higher in the KD subjects with 1-dose of BNT162b2, and mean percentage differences were significant for the 1-dose BNT162b2 B.1.617.3 S-protein (non-KD-KD, -22.89%; 95% CI, -45.08 to -0.6965; P = 0.0399), B.1.1.529 S-protein (non-KD-KD, -25.96%; 95% CI, -50.53 to -1.376; P = 0.0333), BA.2.12.1 S-protein (non-KD-KD, -27.83%; 95% CI, -52.55 to -3.115; P = 0.0195), BA.4 S-protein (non-KD-KD, -28.47%; 95% CI, -53.59 to -3.342; P = 0.0184), and BA.5 S-protein (non-KD-KD, -30.42%; 95% CI, -54.98 to -5.869; P = 0.0077). In conclusion, we have found that KD patients have a comparable immunization response to healthy individuals to SARS-CoV-2 infection and COVID-19 immunization.

Increased non-typhoidal Salmonella hospitalizations in transfusion-naïve thalassemia children: a nationwide population-based cohort study.

INTRODUCTION: Although non-typhoidal Salmonella (NTS) infection usually causes self-limited enterocolitis, several risk factors have been found to predispose individuals to more severe NTS infections. However, few studies have discussed the association between NTS infection and pediatric thalassemia populations. MATERIAL AND METHODS: A nationwide population-based retrospective cohort study was conducted using medical records of the selected children from the Taiwan National Health Insurance Research Database. Immunocompromised individuals or patients with a history of transfusion or splenectomy were excluded. One thalassemia patient was matched with four non-thalassemia patients based on their year of birth, sex, and urbanization level. RESULTS: In this cohort, 912 patients with thalassemia and 3648 comparison cohort were analyzed. The mean age of NTS hospitalization was 2.0 ± 1.4 in thalassemia cohort and 2.6 ± 2.4 in non-thalassemia cohort. Transfusion-naïve thalassemia children were proved to have a higher rate of NTS hospitalization (6.90 vs 4.11 per 1000 person-year; p = 0.0004) than the non-thalassemia cohort, with an adjusted hazard ratio (HR) of 1.68 (95% confidence interval [CI] = 1.26-2.24). CONCLUSION: Our research shows that transfusion-naïve thalassemia is associated with an increased risk of NTS hospitalization. Further prospective study comparing the incidence and severity of NTS infection among children with and without thalassemia is needed. IMPACT: Pediatric transfusion-naïve thalassemia patients have an 1.68-fold increased risk for hospitalization due to non-typhoidal Salmonella (NTS) infection. This is the first nationwide population-based cohort study based on an extremely large database that shows pediatric transfusion-naïve thalassemia patients have an increased risk for NTS hospitalizations. Besides the previously known risk factors such as extremes of age, sickle cell disease, or immunosuppressing conditions, clinicians must also take thalassemia as a possible risk factor for more severe NTS disease.

Clinical manifestations and microbiological features between indigenous and imported enteric fever in Taiwan, 2010-2020.

Previous studies had showed that indigenous clones of Salmonella Typhi and S. Paratyphi were originally imported from other countries in Taiwan. We presented the clinical manifestations and laboratory findings of indigenous and imported enteric fever cases in Taiwan in the current decade. We retrospectively reviewed typhoid and paratyphoid fever cases in two medical centers of Chang Gung Memorial Hospitals in 2010-2020. A total of 37 enteric fever cases including 24 typhoid fever and 13 paratyphoid fever were recorded. There were 20 indigenous cases, 16 imported cases, and one indetermined case. Splenomegaly and hepatitis were more frequent in typhoid fever than in paratyphoid fever (P < 0.05). Imported cases had more ciprofloxacin non-susceptibility rate (8/16, 50.0%) than indigenous cases (2/20, 10%). Indigenous ciprofloxacin non-susceptible S. Typhi isolates were found in 2018. One indigenous S. Paratyphi B isolate was multi-drug resistant (MDR) to chloramphenicol, ampicillin, and trimethoprim/sulfamethoxazole.

Enhanced H3K4 Trimethylation in TNF-α Promoter Gene Locus with Cell Apoptosis in the Ventral-Medial Striatum following Opioid Withdrawal of Neonatal Rat Offspring from Morphine-Addicted Mothers.

Prenatal opioid exposure might disturb epigenetic programming in the brain of neonatal offspring with various consequences for gene expressions and behaviors. This study determined whether altered trimethylation of histone 3 at lysine 4 (H3K4me3) in the promoter of the tumor necrosis factor-α (tnf-α) gene with neural cell apoptosis was involved in the ventral-medial striatum, an important brain region for withdrawal symptoms, of neonatal rat offspring from morphine-addicted mothers. Female adult rats were injected with morphine before gestation and until 14 days after giving birth. On postnatal day 14 (P14), rat offspring from morphine-addicted mothers were subjected to an opioid-withdrawal protocol and were analyzed 2 or 8 h after administration of that protocol. Expressions of the TNF-α protein, H3K4me3 in the tnf-α promoter gene, and neural cell apoptosis within the ventral-medial striatum of neonatal rat offspring were evaluated. In the absence of significant opioid withdrawal (2 h after initiation of the opioid-withdrawal protocol on P14), prenatal morphine exposure led to increased levels of H3K4me3 in the tnf-α promoter gene, of the TNF-α protein, and of neural cell apoptosis within the ventral-medial striatum of neonatal rat offspring. Following opioid withdrawal (8 h after initiation of the opioid-withdrawal protocol on P14), differential expression of H3K4me3 in the tnf-α promoter gene locus and upregulation of the level of TNF-α protein expression were further enhanced in these offspring. In addition, increased levels of caspase-3 and neural cell apoptosis were also observed. Taken together, this study revealed that prenatal opioid exposure can activate an epigenetic histone mechanism which regulates proinflammatory factor generation, which hence, led to cell apoptotic damage within the ventral-medial striatum of neonatal rat offspring from morphine-addicted mothers. More importantly, the opioid-withdrawal episode may provide augmented effects for the abovementioned alterations and could lead to deleterious effects in the neonatal brain of such offspring.

Dextromethorphan Suppresses Lipopolysaccharide-Induced Epigenetic Histone Regulation in the Tumor Necrosis Factor-α Expression in Primary Rat Microglia.

The activation of microglial cells plays an important role in the cascade of events leading to inflammation-mediated neurodegenerative disorders. Precision therapeutics require that adjunctively feasible drugs be found to prevent microglial cell activation and prevent inflammation-mediated neuronal injury. Dextromethorphan (DM) has been reported to possess neuroprotective effects in lipopolysaccharide- (LPS-) stimulated animals; however, it remains unclear whether epigenetic regulatory mechanisms in microglial cells are involved in such DM-mediated neuroprotective effects. In this study, DM simultaneously suppressed LPS-induced activation of tumor necrosis factor- (TNF-) α expression and subsequent caspase-3 signaling in primary microglial cells associated with notable morphological changes. Furthermore, therapeutic action sites of DM involved differential enhanced trimethylation of H3K4 modifications in the promoter region of tnf-α gene locus in primary microglial cells. In summary, DM may exert neuroprotective and anti-inflammatory effects through differential epigenetic histone modifications of TNF-α expression in microglial cells and might therefore raise the possibility of providing an adjunctively beneficial role for a tentative therapeutic strategy in neurodegenerative diseases resulting from inflammation.

Malassezia furfur Emergence and Candidemia Trends in a Neonatal Intensive Care Unit During 10 Years: The Experience of Fluconazole Prophylaxis in a Single Hospital.

BACKGROUND: Because Candida spp is a major cause of mortality and morbidity in preterm infants, fluconazole prophylaxis has been suggested by some experts and hospital policy. In our hospital, fluconazole prophylaxis was used in eligible preterm infants and set as the neonatal intensive care unit (NICU) practice in 2014. PURPOSE: This study focused on fungal bloodstream infections and aimed to evaluate the benefit and harm of fluconazole prophylaxis. METHODS/SEARCH STRATEGY: This retrospective, descriptive study involved medical record reviews in our hospital from April 2005 to October 2016. NICU patients were included if Candida species, yeast-like organisms, or Malassezia species were cultured from their venous catheter tips or blood cultures. FINDINGS/RESULTS: After fluconazole prophylaxis, cases of Candida spp decreased and those of Malassezia furfur emerged. We reviewed 19 cases of catheter-related M furfur colonization and 1 case of M furfur fungemia. The gestational age was 27.3 ± 2.0 weeks and birth weight was 959.2 ± 229.8 g. Hyperalimentation with lipid infusion was used in all cases. All of the neonates survived with antifungal agent use. IMPLICATIONS FOR PRACTICE: This study highlights that prophylactic fluconazole may be an associated factor of Malassezia colonization; M furfur remains a potential concern for fungemia in the care of premature infants and thus requires our attention. IMPLICATIONS FOR RESEARCH: Future studies should further investigate the incidence and impact of noncandidal fungal infections with fluconazole prophylaxis use in premature infants.

C-Reactive Protein Concentration Can Help to Identify Bacteremia in Children Visiting the Emergency Department: A Single Medical Center Experience.

BACKGROUND: For febrile children who are evaluated in a pediatric emergency department (PED), blood culture can be considered the laboratory criterion standard to detect bacteremia. However, high rates of negative, false-positive, or contaminated blood cultures in children often result in this testing being noncontributory. This study determined the factors associated with true-positive blood cultures in children. METHODS: This retrospective study was conducted at a tertiary medical center's PED. The blood culture use reports were prepared by an infectious disease specialist and were classified as bacteremia, nonbacteremia, and contamination. RESULTS: We registered a total of 239,459 PED visits during the 8-year period, and 21,841 blood culture samples were taken. Of the laboratory test studies, higher C-reactive protein (CRP) levels and lower hemoglobin levels were observed in the bacteremia group compared with other groups (all P < 0.001). The cut-off value calculated for each age group was adjusted for better clinical usage and significantly improved the blood culture clinical utility documented in the following age groups: 0 to 1 years (CRP level = 30 mg/L, odds ratio [OR] = 5.4, P < 0.001), 1 to 3 years (CRP level = 45 mg/L, OR = 3.7, P < 0.001), and 12 to 18 years (CRP level = 50 mg/L, OR = 6.3, P = 0.006). Using the CRP cut-off value established in this study, we could reduce the blood culture samples in the PED by 14,108 (64.6%). CONCLUSIONS: This study provides new evidence that CRP may be a useful indicator for blood culture sampling in certain age groups and may help improve the efficiency of blood culture in the PED.

Association between altered neurochemical metabolites and apathy in patients with Alzheimer's disease.

ABSTRACTBackground:Apathy is a condition characterized by a lack of motivation that manifests in emotional, behavioral, and cognitive domains. Although previous studies have indicated that apathy is associated with frontal lesions, few studies have focused on the different subdomains of apathy, and no in vivo human biochemical data have been obtained to examine the neurochemical changes related to apathy in patients with Alzheimer's disease (AD). Thus, we investigated the frontal neurochemical alterations related to apathy among patients with AD using proton magnetic resonance spectroscopy (1H MRS). METHODS: Apathy was assessed through the Apathy Evaluation Scale (AES). 1H MRS was performed to measure neurochemical metabolite levels in the anterior cingulate region and right orbitofrontal region. Associations between neurochemical metabolites and the total score and subscores of each domain of the AES were analyzed. RESULTS: Altogether, 36 patients completed the study. Patients with lower N-acetylaspartate/creatine ratios (NAA/Cr) in the anterior cingulate region demonstrated higher total apathy scores (ß = -0.56, p = 0.003) with adjustments for age, gender, educational level, dementia severity, and depression severity. In a further analysis, a lower NAA/Cr in the anterior cingulate region was associated with all subdomains of apathy, including cognition (ß = -0.43, p = 0.028), behavior (ß = -0.55, p = 0.002), and emotion (ß = -0.50, p = 0.005). No statistically significant associations were discovered in the right orbitofrontal region. CONCLUSIONS: Our results suggest that apathy, in each of its cognitive, behavioral, or emotional subdomains is associated with brain neurochemical alterations in the anterior cingulate region. Abnormal neuronal integrity over the anterior cingulate cortex may exhibit a central role in causing all aspects of apathy in patients with AD.

A male infant had subdural effusion and paroxysmal supraventricular tachycardia during the febrile episode of Kawasaki disease: a case report and literature review.

BACKGROUND: Kawasaki disease is an acute, febrile, self-limiting, inflammatory systemic vasculitis seen in early childhood, most commonly in those below 5 years of age. In Kawasaki disease, the coronary arteries are most commonly affected, which may lead to asymptomatic coronary artery ectasia or formation of an aneurysm. Paroxysmal supraventricular tachycardia(PSVT) is a severe and rare cardiovascular complication of Kawasaki disease. A case of Kawasaki disease presenting with unusual findings, including subdural effusion and PSVT is reported. CASE PRESENTATION: This is a 4-month-10-day-old boy presents with anterior fontanelle bulging and moderate bilateral subdural effusion at the acute stage of Kawasaki disease and PSVT at the subacute stage of Kawasaki disease. The subdural effusion was resolution after intravenous immunoglobulin(IVIG) administration. And the PSVT was subsided after administered 3 doses of adenosine, 1 dose of amiodarone loading and Propranolol twice per day use. At 1-year follow-up has made a complete recovery with no arrhythmia episodes, developmental effects or abnormal neurologic findings. CONCLUSION: Subdural effusion in the acute stage of Kawasaki disease may be an inflammatory response. It may resolves spontaneously after anti-inflammatory treatment such as IVIG infusion. PSVT is a severe cardiovascular complication of Kawasaki disease. In those who taking aspirin, we need to carefully observe the heart rhythm and PSVT side effects, especially in the first month.

Impact of Protein Binding Capacity and Daily Dosage of a Drug on Total Serum Bilirubin Levels in Susceptible Infants.

Hyperbilirubinemia is a common pathological condition in neonates. Free bilirubin can penetrate the blood-brain barrier (BBB), which can lead to bilirubin neurotoxicity. In the context of predicting the risk of bilirubin neurotoxicity, although the specificity and sensitivity of free bilirubin levels are higher than those of total serum bilirubin (TSB), free bilirubin is not widely monitored in clinical practice. The threshold TSB levels at which phototherapy must be administered have been established previously. However, TSB levels are not well correlated with neurodevelopmental outcomes. Currently, TSB levels are commonly used to guide phototherapy for neonatal hyperbilirubinemia. Some clinical drugs can displace bilirubin from its albumin-binding sites, and consequently upregulate plasma bilirubin. Daily dosages play a vital role in regulating bilirubin levels. A drug with both a high protein binding capacity and high daily dosage significantly increases bilirubin levels in infants. Premature or very low birth weight (VLBW) infants are vulnerable to the upregulation of bilirubin levels as they exhibit the lowest reserve albumin levels and consequently the highest bilirubin toxicity index. Because bilirubin is involved in maintaining the balance between pro-oxidant and antioxidant agents, the downregulation of bilirubin levels is not always desirable. This review provides insights into the impact of protein binding capacity and daily dosage of drugs on the bilirubin levels in susceptible infants.

Perception and Mental Health Status Regarding COVID-19 Vaccination Among Taiwanese Adolescents and Their Caregivers.

Background: Vaccinating adolescents is a vital strategy to enhance population protection without imposing overly restrictive measures on our daily lives during the COVID-19 pandemic. As teenagers gain more independence, their willingness to get vaccinated may depend on their own understanding of the pandemic, vaccines, and mental well-being, as well as that of their caregivers. Our study aimed to examine how Taiwanese adolescents and their caregivers perceive COVID-19 vaccination and assess their mental health status. Methods: We invited a total of 138 vaccinated adolescents and their caregivers to complete several questionnaires, including the Drivers of COVID-19 Vaccination Acceptance Scale (DrVac-COVID19S), Impact of Event Scale (IES), and Chinese Health Questionnaire (CHQ). Results: Among the adolescents, 76.8% considered the BNT162b2 vaccine (Pfizer-BioNTech) as the ideal option for COVID-19 vaccination, while 27.5% of caregivers expressed acceptance of any available vaccine. Adolescents scored higher than caregivers in terms of vaccine value (p<0.001) and autonomy (p<0.001), but lower in knowledge (p<0.001), as assessed by the DrVac-COVID19S subscales. The adolescents' intention to get vaccinated against COVID-19 (DrVac-COVID19S total score) showed a positive correlation with their perception of the pandemic's impact (IES scores, r=0.214, p=0.012) and their caregivers' vaccination intention (r=0.371, p<0.001). Furthermore, adolescents' mental health demonstrated a positive association with the mental health of their caregiver (CHQ total scores, r=0.481, p<0.001). Conclusion: During the COVID-19 outbreak, caregivers have encountered heightened levels of mental stress, and this stress has been found to be positively correlated with the mental stress experienced by adolescents and their intentions regarding vaccination. These findings can serve as crucial references for healthcare providers and governments when formulating vaccination policies for adolescents in the future.

The Clinical Implication of Serogroup Distribution and Drug Resistance of Non-Typhoidal Salmonella in Children: A Single Center Study in Southern Taiwan during 2004-2019.

Background: A regional antibiotic susceptibility database of certain pathogens is crucial for first-line physicians in terms of providing clinical judgement and appropriate selection of antimicrobial agents. The aim of this study is to update the epidemiological data of Salmonella serogroups and drug resistance in pediatric patients. Methods: This is a single-center retrospective study enrolling patients aged from 0 to 18 years who were hospitalized with cultured proven non-typhoidal Salmonella (NTS) infection from 2004 to 2019. The isolates were collected and the demographic data, serogroups of Salmonella and antimicrobial susceptibilities were further analyzed. Results: A total of 1583 isolates of NTS were collected. Serogroup C2 was prone to cause invasive non-typhoidal salmonellosis (iNTS), especially bacteremia. Patients aged < 2 years were associated with serogroups B and C2 infection, while those aged ≥ 2 years were associated with serogroups D and E infection. The prevalence of serogroup B declined with simultaneous increase in prevalence of serogroups D and E. Serogroups B and E were associated with ceftriaxone resistance, while Serogroup D was less drug-resistant than the others. The prevalence of ceftriaxone-resistant Salmonella had not increased, although more ciprofloxacin-resistant isolates were found in iNTS infection. Conclusions: Age < 2 years is a risk factor of iNTS for children, and the distribution of serogroup changes should be closely monitored. Ceftriaxone is still the drug of choice for treating pediatric iNTS infection, and although no increase was observed in the prevalence of ceftriaxone-resistant strains in this study, continuing surveillance of such cases is warranted.

Human Transcriptome Array Analysis Identifies CDR2 as a Novel Suppressed Gene for Kawasaki Disease.

Kawasaki disease (KD) is a febrile childhood vasculitis that involves the coronary arteries. Most previous studies have focused on the genes activated in the acute phase of KD. However, in this study, we focused on suppressed genes in the acute stage of KD and identified novel targets with clinical significance and potential prognostic value for KD patients. We enrolled 18 patients with KD, 18 healthy controls (HC), and 18 febrile controls (FC) for human transcriptome array analysis. Another 19 healthy controls, 20 febrile controls, and 31 patients with KD were recruited for RT-PCR validation of target mRNA expressions. The results of Human Transcriptome Array (HTA) 2.0 showed 461 genes that were significantly higher in KD and then normalized after IVIG, as well as 99 suppressed genes in KD. Furthermore, we identified the four genes in KD with the most downregulation, including BCL11B, DUSP2, DDX24, and CDR2, as well as the upregulation of their expression following IVIG administration. The mRNA expression of CDR2 by qRT-PCR was the most compatible with the pattern of the HTA2.0 results. Furthermore, we found higher DDX24 mRNA expression in KD patients with CAL when compared to those without CAL 3 weeks after IVIG administration. In summary, activated gene expression represented a majority in the immune response of KD. In this study, we identified CDR2 as a novel suppressed gene for Kawasaki disease via human transcriptome array analysis and DDX24 associated with CAL formation, which may contribute to further understanding of CAL pathogenesis in KD.

Increased Total Serum Bilirubin Level Post-Ibuprofen Use Is Inversely Correlated with Neonates' Body Weight.

Backgrounds: Drugs with the ability to displace bilirubin from albumin-binding sites subsequently leading to an increased bilirubin level may cause hyperbilirubinemia in neonates. Ibuprofen is commonly used to treat patent ductus arteriosus (PDA) in neonates, yet the use of ibuprofen has drawn mixed conclusions. We performed a retrospective study to determine how ibuprofen use influences the total serum bilirubin (TSB) level in neonates of differing birth weight (BW). Materials and methods: Neonates (including premature infants) born at Chang Gung Memorial Hospital, Taiwan during January 2004 to July 2020 were entered into this study. We recorded the phototherapy duration, including the initial day and end day, and determined the average influence of one-day phototherapy on TSB level. The highest monitored TSB level post-ibuprofen use minus the one measured prior to ibuprofen use was considered the TSB change following ibuprofen administration in this study, and the above-mentioned influence of daily phototherapy on the TSB level was used to correlate the results. Neonates with any of the following conditions were excluded: those who received ceftriaxone, those with intraventricular hemorrhage, and those infected with TORCH. Results: The average daily influence of phototherapy on the TSB level of neonates was −0.20 (−0.57~0.05) mg/dL, −0.28 (−0.84~0.13) mg/dL, −0.75 (−1.77~0.10) mg/dL, and −1.60 (−2.70~−0.50) mg/dL in neonates with BWs of <1 kg, 1−1.49 kg, 1.5−2.49 kg, and ≥2.5 kg, respectively, indicating that neonates with a BW ≥ 1.5 kg experienced a greater reduction in TSB level following phototherapy as compared with those with a BW < 1.5 kg. The average TSB increase following ibuprofen use in neonates was 3.38 ± 2.77 mg/dL, 2.04 ± 2.53 mg/dL, and 1.34 ± 2.24 mg/dL in neonates with BWs of <1 kg, 1−1.49 kg, and ≥1.5 kg, respectively, i.e., an elevated TSB change with a decreased neonate BW was noted post-ibuprofen use (p = 0.026, one-way analysis of variance (ANOVA)). Conclusions: As ibuprofen use is correlated with an apparent increase in TSB level in neonates with a lower BW, especially in those with a BW < 1 kg, iv acetaminophen can be an appropriate alternative to ibuprofen for ELBW neonates for the treatment of PDA if they are experiencing severe unconjugated hyperbilirubinemia.

Combination of Hemoglobin-for-Age Z-Score and Plasma Hepcidin Identified as a Novel Predictor for Kawasaki Disease.

Kawasaki disease (KD) is a febrile coronary vasculitis that affects younger children and includes complications such as coronary artery aneurysm. KD diagnoses are diagnosed based on clinical presentations, a process that still poses a challenge for front-line physicians. In the current study, we developed a novel predictor using the hemoglobin-for-age z-score (HbZ) and plasma hepcidin to differentiate Kawasaki disease (KD) from febrile children (FC). There were 104 FC and 115 KD subjects (89 typical KD; 26 incomplete KD) for this study, and data were collected on the biological parameters of hemoglobin and plasma hepcidin levels. A receiver operating characteristic curve (auROC), multiple logistics regression, and support vector machine analysis were all adopted to develop our prediction condition. We obtained both predictors, HbZ and plasma hepcidin, for distinguishing KD and FC. The auROC of the multivariate logistic regression of both parameters for FC and KD was 0.959 (95% confidence interval = 0.937-0.981), and the sensitivity and specificity were 85.2% and 95.9%, respectively. Furthermore, the auROC for FC and incomplete KD was 0.981, and the sensitivity and specificity were 92.3% and 95.2%, respectively. We further developed a model of support vector machine (SVM) classification with 83.3% sensitivity and 88.0% specificity in the training set, and the blind cohort performed well (78.4% sensitivity and 100% specificity). All data showed that sensitivity and specificity were 81.7% and 91.3%, respectively, by SVM. Overall, our findings demonstrate a novel predictor using a combination of HbZ and plasma hepcidin with a better discriminatory ability for differentiating from WBC and CRP between children with KD and other FC. Using this predictor can assist front-line physicians to recognize and then provide early treatment for KD.

Incidence rates, emerging serotypes and genotypes, and antimicrobial susceptibility of pneumococcal disease in Taiwan: A multi-center clinical microbiological study after PCV13 implementation.

Objectives The multi-center clinical microbiological study in Taiwan aimed to evaluate the impact of childhood PCV13 immunization on pneumococcal disease, and the magnitude of serotype replacement in invasive and non-invasive pneumococcal disease among all age groups. Methods The study of culture-confirmed pneumococcal disease (CCPD) was conducted at four hospitals across Taiwan in 2015-2018. Pneumococcal pneumonia was defined as clinical diagnosis with positive sputum or bronchoalveolar lavage culture. Serotyping, multi-locus sequence typing, and antimicrobial susceptibility testing for penicillin and ceftriaxone were performed. Results A total of 1413 CCPD cases were identified. Invasive pneumococcal disease (IPD) accounted for 13.4% (190/1413) of CCPD. PCV7-type CCPD incidence declined among all age groups between 2015 and 2018. In adults aged 50-64 years, PCV7-type pneumococcal pneumonia incidence in 2018 was 72% lower than that in 2015, and all pneumococcal pneumonia incidence was 35% lower than that in 2015. In children, CCPD incidence was higher in 2018 than in 2015 (IRR 1.75 for age < 5 years, IRR 1.56 for age 5-17 years). Incidence of CCPD caused by non-PCV13-types, mainly 15A and 23A, increased significantly in those younger than 50 years. Serotypes 19A and 19F constituted the largest clonal complex, CC236/320 (n = 280, 19.8%). The rates of penicillin and ceftriaxone non-susceptibility were higher in PCV13-type isolates. Conclusions Childhood PCV13 immunization exerted an indirect protection to vaccine serotype clinically defined non-bacteremic pneumococcal pneumonia among adults, especially those between 50 and 64 years of age. Emerging non-PCV13 serotypes mainly caused non-invasive mucosal disease among children.