Viral Pneumonia during the COVID-19 Pandemic, 2019-2021 Evoking Needs for SARS-CoV-2 and Additional Vaccinations.

Coronaviruses can cause pneumonia, with clinical symptoms that may be similar to the symptoms of other viral pneumonias. To our knowledge, there have been no reports regarding cases of pneumonia caused by coronaviruses and other viruses among hospitalized patients in the past 3 years before and during coronavirus disease 2019 (COVID-19). Here, we analysed the causes of viral pneumonia among hospitalized patients during the coronavirus disease 2019 (COVID-19) pandemic (2019-2021). Between September 2019 and April 2021, patients hospitalized at Shuang Ho Hospital in north Taiwan with a diagnosis of pneumonia were enrolled in this study. Age, sex, onset date, and season of occurrence were recorded. Respiratory tract pathogens were identified with molecular detection using the FilmArray® platform from nasopharyngeal swabs. In total, 1147 patients (128 patients aged <18 years and 1019 patients aged ≥18 years) with pneumonia and identified respiratory tract pathogens were assessed. Among the 128 children with pneumonia, the dominant viral respiratory pathogen was rhinovirus (24.2%), followed by respiratory syncytial virus (RSV; 22.7%), parainfluenza virus (1 + 2 + 3 + 4) (17.2%), adenovirus (12.5%), metapneumovirus (9.4%), coronavirus (1.6%), and influenza virus (A + B) (1.6%). Among the 1019 adults with pneumonia, the dominant viral respiratory pathogen was rhinovirus (5.0%), followed by RSV (2.0%), coronavirus (2.0%), metapneumovirus (1.5%), parainfluenza virus (1 + 2 + 3 + 4) (1.1%), adenovirus (0.7%), and influenza virus (A + B) (0%). From 2019-2021, older patients (aged >65 years) with pneumonia tested positive for coronavirus most commonly in autumn. Coronavirus was not detected during summer in children or adults. Among children aged 0-6 years, RSV was the most common viral pathogen, and RSV infection occurred most often in autumn. Metapneumovirus infection occurred most often in spring in both children and adults. In contrast, influenza virus was not detected in patients with pneumonia in any season among children or adults from January 2020 to April 2021. Among all patients with pneumonia, the most common viral pathogens were rhinovirus in spring, adenovirus and rhinovirus in summer, RSV and rhinovirus in autumn, and parainfluenza virus in winter. Among children aged 0-6 years, RSV, rhinovirus, and adenovirus were detected in all seasons during the study period. In conclusion, the proportion of pneumonia cases caused by a viral pathogen was higher in children than the proportion in adults. The COVID-19 pandemic period evoked a need for SARS-CoV-2 (severe acute respiratory disease coronavirus 2) vaccination to prevent the severe complications of COVID-19. However, other viruses were also found. Vaccines for influenza were clinically applied. Active vaccines for other viral pathogens such as RSV, rhinovirus, metapneuomoccus, parainfluenza, and adenovirus may need to be developed for special groups in the future.

Factors affecting the patency and complications of peripheral intravenous catheters in newborns.

BACKGROUND: Peripheral intravenous catheters (PICs) are necessary for medication, nutrient, and fluid administration in pediatric patients. However, PICs are uneasy to access and maintain in young infants. This study identified risk factors affecting the complications and patency of PICs. METHODS: This retrospective cohort study included neonates and infants aged <4 months. All PICs inserted in the neonatal intensive care unit and intermediate care nursery were analyzed more than 5 months. The variables included gestational age, age and body weight at PIC insertion, insertion site, methods to maintain PIC patency (continuous intravenous drip [CIVD] versus intermittent flushing), fluid infusion rate and osmolarity, and ampicillin and cefotaxime concentrations. The effects of these variables on PIC complications and lifespan were assessed using binary logistic regression analysis and a general linear model, respectively. RESULTS: In total, 315 PICs were analyzed. The mean indwelling time was 33.8 ± 21.5 h and complication rate was 82.2%. The most frequent complications were infiltration (55.9%) and leakage (22.2%). The infusion rate and method to maintain PICs significantly impacted PIC patency. A negative correlation was noted between the infusion rate and PIC patency, with the patency decreasing by 0.9 h (p = 0.047) on increasing the infusion rate by 1 mL/h. Notably, compared with intermittent flushing, CIVD using a hypertonic solution significantly decreased PIC patency by 14 h (p = 0.006). As the patients' age increased by a month, the complication risk decreased by 35% (p = 0.027). However, as the infusion rate increased by 1 mL/h, the complication risk increased by 17% (p = 0.018). CONCLUSIONS: Intermittent flushing may be preferred over CIVD to preserve PIC patency. An increased infusion rate is correlated with decreased PIC patency and increased complications. For the peripheral administration of ampicillin, we recommended preparing final concentrations below 50 mg/dL to prevent PIC complications.

Classic Ehlers-Dalnos syndrome presenting as atypical chronic haematoma: a case report with novel frameshift mutation in COL5A1.

BACKGROUND: Ehlers-Danlos syndrome (EDS) is a group of inherited connective tissue disorders characterized by skin hyperextensibility, joint hypermobility and soft tissue vulnerable to blunt injury. Early recognition and diagnosis are crucial to patients to provide appropriate treatment, as well as to screen for life-threatening conditions such as aortic dissection and hollow organ perforation. The diagnosis of EDS is made based on clinical presentations, skin biopsy, and electron microscopy findings. To date, mutations in at least 20 genes have been found to cause the Ehlers-Danlos syndromes. However, EDS is still underestimated due to lack of awareness of its variable clinical presentations. Here we reported an EDS case with atypical initial presentation and a novel genetic mutation. CASE PRESENTATION: This 4-year-old Taiwanese male patient presented with easy bruising, multiple ecchymoses, joint hypermobility, hyperextensible skin, and prolonged pretibial haematoma. He was initially suspected of a bleeding tendency due to coagulation disorders. The coagulation test results were normal. DNA sequencing was performed for molecular diagnosis. Subsequently, the diagnosis of classical EDS was made by identifying a novel frameshift mutation in COL5A1 [NM_000093.4:c.4211_4212delAG, p.Gln1404Arg]. This mutation in the type V collagen gene COL5A1 contributes to the phenotype of classical EDS. This novel frameshift mutation may disturb the structural stability of collagen V and interfere with its heparin binding capacity, explaining the chronic haematoma. CONCLUSION: The reported case showed the unusual features of chronic haematoma. This novel frameshift mutation and its phenotype correlation can provide useful information for practitioners about early recognition in Ehlers-Danlos syndrome.

Therapeutic effects of children with refractory epilepsy after vagus nerve stimulation in Taiwan.

BACKGROUND: Vagus nerve stimulation (VNS) is used as an add-on treatment for epilepsy. This study aimed to use Taiwanese nationwide registry data to analyze the therapeutic effects of VNS in children with refractory epilepsy (RE) and try to explore predictive factors of VNS treatment effectiveness. METHODS: This retrospective study collected data from December 2007 to December 2014. Patient variables included gender, age, VNS implantation date, epilepsy duration, seizure frequency, seizure type, etiology, and antiepileptic drug (AED) history. We divided patients into three groups: Group I as seizure frequency >80 times per month, Group II as seizure frequency 24-80 times per month, and Group III as seizure frequency <24 times per month. Multivariate regression analysis was performed to determine predictors of seizure frequency reduction after VNS treatment. RESULTS: A total of 80 patients were included in this study. Three or more AED types were prescribed for 61 (77.1%) patients. Seizure frequency decreased significantly at 12 and 24 months after VNS treatment. The mean seizure reduction rates were 44.6% and 50.1% at 12 and 24 months after VNS treatment, with the difference between them reaching statistical significance (p = 0.001). In multivariate linear regression, high seizure frequency (Group I) was a positive predictor of seizure frequency reduction (p < 0.001). The most common complication was coughing (eight patients, 10%) and no patient had early withdrawal or premature termination of VNS use due to complications. CONCLUSION: VNS is an effective palliative treatment for children with RE for different seizure types. Seizure reduction rate at 24 months after VNS was better than at 12 months after VNS. High seizure frequency can be regarded as a positive predictor for seizure frequency reduction in children with RE treated with VNS.

Far-infrared radiation prevents decline in ß-cell mass and function in diabetic mice via the mitochondria-mediated Sirtuin1 pathway.

Insulin deficiency in type 2 diabetes mellitus (DM) involves a decline in both pancreatic ß-cell mass and function. Enhancing ß-cell preservation represents an important therapeutic strategy to treat type 2 DM. Far-infrared (FIR) radiation has been found to induce promyelocytic leukemia zinc finger protein (PLZF) activation to protect the vascular endothelium in diabetic mice. The influence of FIR on ß-cell preservation is unknown. Our previous study reveals that the biologically effective wavelength of FIR is 8-10 µm. In the present study, we investigated the biological effects of FIR (8-10 µm) on both survival and insulin secretion function of ß-cells. FIR reduced pancreatic islets loss and increased insulin secretion in nicotinamide-streptozotocin-induced DM mice, but only promoted insulin secretion in DM PLZF-/- mice. FIR-upregulated PLZF to induce an anti-apoptotic effect in a ß cell line RIN-m5f. FIR also upregulated mitochondrial function and the ratio of NAD+/NADH, and then induced Sirtuin1 (Sirt1) expression. The mitochondria Complex I inhibitor rotenone blocked FIR-induced PLZF and Sirt1. The Sirt1 inhibitor EX527 and Sirt1 siRNA inhibited FIR-induced PLZF and insulin respectively. Sirt1 upregulation also increased CaV1.2 expression and calcium influx that promotes insulin secretion in ß-cells. In summary, FIR-enhanced mitochondrial function prevents ß-cell apoptosis and enhances insulin secretion in DM mice through the Sirt1 pathway.

Iron Status of Infants in the First Year of Life in Northern Taiwan.

Iron deficiency (ID) and iron deficiency anemia (IDA) typically occur in developing countries. Notably, ID and IDA can affect an infant's emotion, cognition, and development. Breast milk is considered the best food for infants. However, recent studies have indicated that breastfeeding for more than six months increases the risk of ID. This study investigated the prevalence of ID and IDA, as well as the association between feeding type and iron nutritional status in northern Taiwan. A cross-sectional study was conducted on infants who returned to the well-baby clinic for routine examination from October 2012 to January 2014. Overall, 509 infants aged 1-12 months completed the iron nutritional status analysis, anthropometric measurement, and dietary intake assessment, including milk and complementary foods. The results revealed that 49 (10%) and 21 (4%) infants in their first year of life had ID and IDA, respectively, based on the World Health Organization criteria. Breastfed infants had a higher prevalence rate of ID and IDA than mixed-fed and formula-fed infants (p < 0.001). Regarding biomarkers of iron status, plasma hemoglobin (Hb), ferritin, and transferrin saturation (%) levels were significantly lower in ID and IDA groups. The prevalence of ID and IDA were 3.7% and 2.7%, respectively, in infants under six months of age, but increased to 20.4% and 6.6%, respectively, in infants above six months of age. The healthy group had a higher total iron intake than ID and IDA groups, mainly derived from infant formula. The total dietary iron intake was positively correlated with infants' Hb levels. Compared with formula-fed infants, the logistic regression revealed that the odds ratio for ID was 2.157 (95% confidence interval [CI]: 1.369-3.399) and that for IDA was 4.196 (95% CI: 1.780-9.887) among breastfed infants (p < 0.001) after adjusted for all confounding factors (including gestational week, birthweight, sex, body weight percentile, body length percentile, age of infants, mothers' BMI, gestational weight gain, education level, and hemoglobin level before delivery). In conclusion, our results determined that breastfeeding was associated with an increased the prevalence of ID and/or IDA, especially in infants above six months. This suggests that mothers who prolonged breastfeed after six months could provide high-quality iron-rich foods to reduce the prevalence of ID and IDA.

Camptothecin activates SIRT1 to promote lipid catabolism through AMPK/FoxO1/ATGL pathway in C2C12 myogenic cells.

Caloric restriction activates sirtuin 1 (SIRT1) and induces a variety of metabolic effects that are beneficial for preventing age-related disease. The present study screened a commercially available used drug library to develop small molecule activators of SIRT1 as therapeutics for treatment of metabolic disorders. Using an in vitro fluorescence assay, the cancer therapeutic camptothecin increased SIRT1 enzymatic activity by 5.5-fold, indicating it to be a potent SIRT1 activator. Camptothecin also elevated the nicotinamide adenine dinucleotide (NAD)+/NADH ratio and increased SIRT1 protein levels in differentiated C2C12 myogenic cells. Treatment of C2C12 myotubes with camptothecin increased phosphorylation of AMP-dependent kinase (AMPK) and acetyl-coenzyme A carboxylase, caused nuclear translocation and deacetylation of forkhead box O1 (FoxO1), increased transcription and protein expression of adipose triglyceride lipase (ATGL), decreased the amount of intracellular oil droplets, and significantly increased ß-oxidation of fatty acids. These in vitro data were confirmed in vivo as camptothecin treatment of C57BL/6J mice reduced fat and plasma triglyceride levels. All of the above camptothecin-induced alterations were attenuated by the SIRT1-specific inhibitor nicotinamide and/or 6-[4-(2-piperidin-1-ylethoxy) phenyl]-3-pyridin-4-ylpyrazolo [1,5-a]pyrimidin (compound C). Thus, camptothecin activation of SIRT1 promotes lipid catabolism through AMPK/FoxO1/ATGL signaling.

ETF-QO Mutants Uncoupled Fatty Acid ß-Oxidation and Mitochondrial Bioenergetics Leading to Lipid Pathology.

The electron-transfer flavoprotein dehydrogenase gene (ETFDH) that encodes the ETF-ubiquinone oxidoreductase (ETF-QO) has been reported to be the major cause of multiple acyl-CoA dehydrogenase deficiency (MADD). ETF-QO is an electron carrier that mainly functions in mitochondrial fatty acid ß-oxidation and the delivery of electrons to the ubiquinone pool in the mitochondrial respiratory chain. A high frequency of c.250G>A has been found in Taiwanese patients with late-onset MADD. We postulated that the ETFDH c.250G>A mutation may concomitantly impair fatty acid ß-oxidation and mitochondrial function. Using MADD patient-derived lymphoblastoid cells and specifically overexpressed ETFDH c.92C>T, c.250G>A, or coexisted c.92C>T and c.250G>A (c.92C>T + c.250G>A) mutated lymphoblastoid cells, we addressed the genotype-phenotype relationship of ETFDH variation in the pathogenesis of MADD. The decreased adenosine triphosphate synthesis, dissipated mitochondrial membrane potentials, reduced mitochondrial bioenergetics, and increased neutral lipid droplets and lipid peroxides were found in the MADD patient-derived lymphoblastoid cells. Riboflavin and/or coenzyme Q10 supplementation rescued cells from lipid droplet accumulation. All three mutant types, c.92C>T, c.250G>A, or c.92C>T + c.250G>A, had increased lipid droplet accumulation after treatment with palmitic acid. These results help to clarify the molecular pathogenesis of MADD as a result of the high frequency of the ETFDH c.250G>A and c.92C>T mutations.

Ferrous glycinate regulates cell energy metabolism by restrictinghypoxia-induced factor-1α expression in human A549 cells.

Iron or oxygen regulates the stability of hypoxia inducible factor-1α (HIF-1α). We investigated whether ferrous glycinate would affect HIF-1α accumulation, aerobic glycolysis and mitochondrial energy metabolism in human A549 lung cancer cells. Incubation of A549 cells with ferrous glycinate decreased the protein levels of HIF-1α, which was abrogated by proteosome inhibitor, or prolyl hydroxylase inhibitor. The addition of ferrous glycinate decreased protein levels of glucose transporter-1, hexokinase-2, and lactate dehydrogenase A, and decreased pyruvate dehydrogenase kinase-1 (PDK-1) and pyruvate dehydrogenase (PDH) phosphorylation in A549 cells. Ferrous glycinate also increased the expression of the mitochondrial transcription factor A (TFAM), and the mitochondrial protein, cytochrome c oxidase (COX-IV). Silencing of HIF-1α expression mimicked the effects of ferrous glycinate on PDK-1, PDH, TFAM and COX-IV in A549 cells. Ferrous glycinate increased mitochondrial membrane potential and ATP production in A549 cells. These results suggest that ferrous glycinate may reverse Warburg effect through down regulating HIF-1α in A549 cells.

JARID1B Expression Plays a Critical Role in Chemoresistance and Stem Cell-Like Phenotype of Neuroblastoma Cells.

Neuroblastoma (NB) is a common neural crest-derived extracranial solid cancer in children. Among all childhood cancers, NB causes devastating loss of young lives as it accounts for 15% of childhood cancer mortality. Neuroblastoma, especially high-risk stage 4 NB with MYCN amplification has limited treatment options and associated with poor prognosis. This necessitates the need for novel effective therapeutic strategy. JARID1B, also known as KDM5B, is a histone lysine demethylase, identified as an oncogene in many cancer types. Clinical data obtained from freely-accessible databases show a negative correlation between JARID1B expression and survival rates. Here, we demonstrated for the first time the role of JARID1B in the enhancement of stem cell-like activities and drug resistance in NB cells. We showed that JARID1B may be overexpressed in either MYCN amplification (SK-N-BE(2)) or MYCN-non-amplified (SK-N-SH and SK-N-FI) cell lines. JARID1B expression was found enriched in tumor spheres of SK-N-BE(2) and SK-N-DZ. Moreover, SK-N-BE(2) spheroids were more resistant to chemotherapeutics as compared to parental cells. In addition, we demonstrated that JARID1B-silenced cells acquired a decreased propensity for tumor invasion and tumorsphere formation, but increased sensitivity to cisplatin treatment. Mechanistically, reduced JARID1B expression led to the downregulation of Notch/Jagged signaling. Collectively, we provided evidence that JARID1B via modulation of stemness-related signaling is a putative novel therapeutic target for treating malignant NB.

Alpha-lipoic acid induces adipose triglyceride lipase expression and decreases intracellular lipid accumulation in HepG2 cells.

Non-alcoholic fatty liver disease can be attributed to the imbalance between lipogenesis and lipolysis in the liver. Alpha-lipoic acid has been shown to activate the 5'-AMP-activated protein kinase (AMPK) signalling pathway and to effectively inhibit the lipogenesis pathway in liver. However, whether alpha-lipoic acid stimulates lipolysis remains unclear. Recently, adipose triglyceride lipase (ATGL) was shown to be responsible for triacylglycerol hydrolase activity in cells. In the present study, we established a fatty liver cell model by incubating HepG2 cells in a high glucose (30mM glucose) and high fat (0.1mM palmitate) medium. We found that the activation of the AMPK signalling pathway induced ATGL protein expression and enhanced lipid hydrolysis. Similarly, treatment of the fatty liver cell model with alpha-lipoic acid reduced intracellular lipid accumulation in HepG2 cells, increased AMPK phosphorylation, and induced ATGL expression. We showed that insulin phosphorylates the transcription factor forkhead box O1 (FOXO1), which regulates ATGL expression and inhibits FOXO1 translocation into the nucleus. In contrast, alpha-lipoic acid dephosphorylated FOXO1 and reversed the nuclear exclusion of FOXO1. These data suggest that alpha-lipoic acid can effectively ameliorate intracellular lipid accumulation and induce ATGL expression through the FOXO1/ATGL pathway in liver cells. Thus, alpha-lipoic acid may be a potential therapeutic agent for treating fatty liver disease.

Utility of laboratory tests for children in the emergency department with a first seizure.

OBJECTIVE: The objective of the study was to evaluate the factors associated with abnormal laboratory findings in patients visiting the emergency department (ED) after having their first seizure. METHODS: We included ED patients with first seizures and divided them into groups based on normal and abnormal laboratory results for serum levels of sodium, potassium, calcium, and glucose. We evaluated the differences in age, sex, the presence of fever, the presence of gastrointestinal symptoms, the duration and pattern of the seizure, and whether the seizure was still present at the ED. RESULTS: We evaluated 240 patients. Among them, abnormalities were found in 83 (34.8%) of 238 for serum sodium, 16 (6.7%) of 238 for potassium, 11 (6.2%) of 177 for calcium, and 121 (52.3%) of 231 for glucose. In the serum sodium and calcium group, no differences in associated factors between patients with and without abnormal laboratory results were found. However, results revealed differences in seizure duration between patients with and without abnormal laboratory glucose results (P = 0.005) and in age between patients with normal and abnormal potassium results (P = 0.002). CONCLUSIONS: There was no significant association among the factors of sex, fever, gastrointestinal symptoms, seizure duration, and seizures in patients who came to the ED with electrolyte abnormalities after a first seizure. However, glucose level abnormalities may have an association with increased seizure duration. We still do not have any suggestions as to which associated factors should be considered when doing common blood examinations in these patients.

Rapid progressive course of later-onset Pompe disease in Chinese patients.

BACKGROUND: Pompe disease presents with a wide variety of phenotypes ranging from a fatal disease in infancy (the infantile-onset form) to other milder later-onset forms. Currently, the clinical manifestations in Chinese patients with later-onset Pompe disease are still not well understood. METHODS: Fifteen Chinese patients who were clinically diagnosed with Pompe disease at later than one year of age at the National Taiwan University Hospital from 1993 to 2009 were included in this study. Confirmatory diagnosis included both biochemical and molecular tests. Patient outcomes after recombinant human acid α-glucosidase (GAA) therapy were also evaluated by assessing the percentage of predicted forced vital capacity in the upright position, hours of daily ventilator use, and the functional status change using Walton Gardner Medwin Scale. RESULTS: The median age at symptom onset was 15 (12-35)years, and the median age at diagnosis was 21 (10-38)years. At the time of diagnosis or shortly after, 8 patients (53%) required mechanical ventilation. A quadriceps muscle biopsy from a 13-year-old boy already showed extensive glycogen storage and muscle fiber destruction. Mutation analysis revealed that the two dual mutations in the GAA gene c.[1935C>A; 1726G>A] (p.[D645E; G576S]) and c.[2238G>C; 1726G>A] (p.[W746C; G576S]) represented 66.5% of the mutated chromosomes. Using mutagenesis, we showed that the p.G576S pseudodeficiency mutation significantly decreased the residual enzyme activity of p.W746C. Most patients responded poorly to recombinant human GAA. CONCLUSIONS: Chinese patients with later-onset Pompe disease often showed onset of symptoms in their second decade of life with rapid disease progression, which is probably due to a specific pattern of GAA gene mutation. Therefore, early diagnosis and early treatment would be necessary to improve the prognosis of these patients.