Artemisia argyi extracts overcome lapatinib resistance via enhancing TMPRSS2 activation in HER2-positive breast cancer.

Breast cancer stands as the predominant malignancy and primary cause of cancer-related mortality among females globally. Approximately 25% of breast cancers exhibit HER2 overexpression, imparting a more aggressive tumor phenotype and correlating with poor prognoses. Patients with metastatic breast cancer receiving HER2 tyrosine kinase inhibitors (HER2 TKIs), such as Lapatinib, develop acquired resistance within a year, posing a critical challenge in managing this disease. Here, we explore the potential of Artemisia argyi, a Chinese herbal medicine known for its anti-cancer properties, in mitigating HER2 TKI resistance in breast cancer. Analysis of the Cancer Genome Atlas (TCGA) revealed diminished expression of transmembrane serine protease 2 (TMPRSS2), a subfamily of membrane proteolytic enzymes, in breast cancer patients, correlating with unfavorable outcomes. Intriguingly, lapatinib-responsive patients exhibited higher TMPRSS2 expression. Our study unveiled that the compounds from Artemisia argyi, eriodictyol, and umbelliferone could inhibit the growth of lapatinib-resistant HER2-positive breast cancer cells. Mechanistically, they suppressed HER2 kinase activation by enhancing TMPRSS2 activity. Our findings propose TMPRSS2 as a critical determinant in lapatinib sensitivity, and Artemisia argyi emerges as a potential agent to overcome lapatinib via activating TMPRSS2 in HER2-positive breast cancer. This study not only unravels the molecular mechanisms driving cell death in HER2-positive breast cancer cells induced by Artemisia argyi but also lays the groundwork for developing novel inhibitors to enhance therapy outcomes.

Real-world epidemiology, treatment patterns and disease burden of patients diagnosed with chronic hepatitis B in Taiwan.

BACKGROUND AND AIMS: This study aimed to update the epidemiology, clinical, and economic outcomes of patients diagnosed with chronic hepatitis B (CHB) infection in Taiwan. METHODS: This is a retrospective observational study using claims data from the National Health Insurance Research Database. Cases were identified between 2010 and 2019 using CHB diagnosis codes and claims for alanine aminotransferase laboratory tests or CHB treatment within one year of the first CHB diagnosis. Patient characteristics, epidemiology, clinical, and economic outcomes were described. RESULTS: A total of 730 154 CHB-diagnosed cases were identified. The prevalence of diagnosed CHB increased from 1.13% in 2010 to 2.43% in 2019, with the highest occurring among those aged 55-64 years (4.76%) and 45-54 years (4.37%) and being higher in men (2.98%) than in women (2.21%). The majority of newly diagnosed CHB patients were 35 years of age or older (86.6%), with a median age of 49 years. After a median follow-up period of 6.42 years, 12.5%, 7.9%, 2.8%, and 0.35% were diagnosed with cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and liver transplantation respectively. Among 456 706 incident CHB-diagnosed patients, 17.4% had received at least one CHB medication, with the majority taking entecavir (67.9%). Patients with increasing disease severity had higher healthcare resource utilization, and inpatient costs accounted for 48.9%-65.5% of the overall medical cost in different health states. CONCLUSION: Despite the decreasing incidence of newly diagnosed CHB, the prevalence of diagnosed CHB remains high and poses a significant healthcare challenge owing to the high economic burden associated with the complications of CHB.

Changes in cervical elastography, cervical length and endocervical canal width after cerclage for cervical insufficiency: an observational ultrasound study.

BACKGROUND: We previously demonstrated that pregnant women with a history of cervical insufficiency had a softer anterior cervical lip, shorter cervical length and wider endocervical canal in the first trimester. The aim of this study was to investigate changes in cervical elastography, cervical length, and endocervical canal width in the second trimester after cerclage, and further discuss whether these ultrasound parameters are predictive of preterm delivery. METHODS: This was a secondary analysis of cervical changes in singleton pregnancies after cerclage from January 2016 to June 2018. Cervical elastography, cervical length, and endocervical canal width were measured during the second trimester in the cervical insufficiency group and control group without cervical insufficiency. Strain elastography under transvaginal ultrasound was used to assess cervical stiffness and presented as percentage (strain rate). RESULTS: Among the 339 pregnant women enrolled, 24 had a history of cervical insufficiency and underwent cerclage. Both anterior and posterior cervical lips were significantly softer in the cervical insufficiency group even though they received cerclage (anterior strain rate: 0.18 ± 0.06% vs. 0.13 ± 0.04%; P = 0.001; posterior strain rate: 0.11 ± 0.03% vs. 0.09 ± 0.04%; P = 0.017). Cervical length was also shorter in the cervical insufficiency group (36.3 ± 3.6 mm vs. 38.3 ± 4.6 mm; P = 0.047). However, there was no significant difference in endocervical canal width between the two groups (5.4 ± 0.7 mm vs. 5.6 ± 0.7 mm; P = 0.159). Multivariate logistic regression analysis also revealed significant differences in anterior cervical lip strain rate (adjusted odds ratio [OR], 7.32, 95% confidence interval [CI], 1.70-31.41; P = 0.007), posterior cervical lip strain rate (adjusted OR, 5.22, 95% CI, 1.42-19.18; P = 0.013), and cervical length (adjusted OR, 3.17, 95% CI,1.08-9.29; P = 0.035). Among the four ultrasound parameters, softer anterior cervical lip (P = 0.024) and shorter cervical length (P < 0.001) were significantly related to preterm delivery. CONCLUSIONS: Cervical cerclage can prevent widening of the endocervical canal, but not improve cervical elasticity or cervical length. Measuring anterior cervical elastography and cervical length may be valuable to predict preterm delivery.

Prescribing patterns for attention deficit hyperactivity disorder among children and adolescents in Taiwan from 2004 to 2017.

This study documented the prescribing patterns of methylphenidate and atomoxetine among patients aged 3 to 18 in Taiwan diagnosed with attention deficit hyperactivity disorder (ADHD) between 2004 and 2017. Initial treatment for ADHD, the time between the first diagnosis and the first prescription, and medication-switching patterns were investigated. The final cohort consisted of 256,882 patients, and 147,210 (57.3%) of them received medication treatment. Most of the patients (98.2%) received methylphenidate. Atomoxetine use increased from 0.1% in 2007 to 5.5% in 2017. The median time between the ADHD diagnosis and the first prescription was 21 days (IQR: 0-212 days). In patients who initiated methylphenidate, 12,406 (8.4%) patients switched to atomoxetine; 850 (31.3%) of the children began with atomoxetine and switched to methylphenidate. In conclusion, methylphenidate was the predominant treatment for ADHD in 2004-2017. However, the prevalence of pharmacotherapy for ADHD was relatively low. Further investigation on the reasons behind this pattern is recommended.

Cardiovascular Event Recurrence and Costs after First Myocardial Infarction, Ischemic Stroke, or Intracerebral Hemorrhage in Taiwan.

Background/Objectives: We aimed to assess the incidence of recurrent cardiovascular (CV) events after the first myocardial infarction (MI), ischemic stroke (IS), or intracerebral hemorrhage (ICH) and to estimate acute and follow-up medical costs. Methods: Using Taiwan's National Health Insurance Research Database, we identified patients with their first MI, IS, or ICH between 2011 and 2017. The cumulative incidence rates of second CV events (including events of the same type [recurrent] or of the other two types) were estimated. The costs for hospitalization and all-cause follow-up were calculated for the first and recurrent CV events and are presented as median (Q1~Q3) in 2017 US dollars. Results: We identified 70,428 patients with a first MI, 123,857 with a first IS, and 41,347 with a first ICH. The cumulative incidence rates of recurrence during the first year and after six years were 3.9% and 10.1% for MI, 5.3% and 13.8% for IS, and 3.9% and 8.9% for ICH, respectively. For first and recurrent nonfatal events, acute hospitalization costs were $4,729 (3,737~5,985) and $4,459 (2,887~6,026) for MI; $1,136 (756~2,183) and $1,224 (774~2,412) for IS; and $2,985 (1,264~8,831) and $2,170 (1,183~4,675) for ICH, respectively. Total annual costs for nonfatal first events in the first year and second year of follow-up were $2413 (1,393~6,120) and $1,293 (654~2,868) for MI, $2,174 (1,040~5,472) and $1,394 (602~3,265) for IS, and $2,963 (995~8,352) and $1,185 (405~3,937) for ICH, respectively. Conclusions: In patients with a first MI, IS, and ICH, recurrent CV events continue to substantially impact public health and escalate the economic burden.

Pulse Wave Analysis Predicts Invasive Hemodynamics in Pre-Capillary Pulmonary Hypertension.

Background: We tested the hypothesis that non-invasive pulse wave analysis (PWA)-derived systemic circulation variables can predict invasive hemodynamics of pulmonary circulation and the indicator of right heart function, N-terminal pro-brain natriuretic peptide (NT-proBNP), in patients with precapillary pulmonary hypertension (PH). Methods: This prospective study enrolled patients with group 1 and 4 PH who had complete PWA, NT-proBNP, and hemodynamics data. Risk assessment-based "hemodynamic score (HS)" and principal component analysis-based PWA variable grouping were determined/performed. Models of hierarchical multiple linear regression (HMLR) and receiver operating characteristic (ROC) curves were used to determine the relationships of PWA variables with HS and NT-proBNP and to predict the latter parameters. Results: Fifty-three PWAs were included. PWA variables were classified into 4 eigenvalue principal components (representing 90% configuration). Univariate analysis showed that left ventricular ejection time (LVET) was significantly negatively associated with HS and NT-proBNP levels. HMLR analysis showed that LVET was still significantly, negatively, and independently associated with HS (B = -0.006 [-0.010~-0.001]) and NT-proBNP (B = -13.47 [-21.20~-5.73]). ROC curve analysis showed that LVET > 306.9 msec and > 313.2 msec predicted the low-risk group of HS (AUC: 0.802; p = 0.001; sensitivity: 100%; and specificity: 59%) and low-to-intermediate risk levels of NT-proBNP (AUC: 0.831; p < 0.001; sensitivity: 100%; and specificity: 59%). Conclusions: The non-invasive PWA parameter, LVET, is an independent predictor of invasive right heart HS and NT-proBNP levels; it may serve as a novel biomarker of right ventricular function in patients with pre-capillary PH.

Machine Learning Models for ASCVD Risk Prediction in an Asian Population - How to Validate the Model is Important.

Introduction: Atherosclerotic cardiovascular disease (ASCVD) is prevalent worldwide including Taiwan, however widely accepted tools to assess the risk of ASCVD are lacking in Taiwan. Machine learning models are potentially useful for risk evaluation. In this study we used two cohorts to test the feasibility of machine learning with transfer learning for developing an ASCVD risk prediction model in Taiwan. Methods: Two multi-center observational registry cohorts, T-SPARCLE and T-PPARCLE were used in this study. The variables selected were based on European, U.S. and Asian guidelines. Both registries recorded the ASCVD outcomes of the patients. Ten-fold validation and temporal validation methods were used to evaluate the performance of the binary classification analysis [prediction of major adverse cardiovascular (CV) events in one year]. Time-to-event analyses were also performed. Results: In the binary classification analysis, eXtreme Gradient Boosting (XGBoost) and random forest had the best performance, with areas under the receiver operating characteristic curve (AUC-ROC) of 0.72 (0.68-0.76) and 0.73 (0.69-0.77), respectively, although it was not significantly better than other models. Temporal validation was also performed, and the data showed significant differences in the distribution of various features and event rate. The AUC-ROC of XGBoost dropped to 0.66 (0.59-0.73), while that of random forest dropped to 0.69 (0.62-0.76) in the temporal validation method, and the performance also became numerically worse than that of the logistic regression model. In the time-to-event analysis, most models had a concordance index of around 0.70. Conclusions: Machine learning models with appropriate transfer learning may be a useful tool for the development of CV risk prediction models and may help improve patient care in the future.

l-lactic acidosis confers insensitivity to PKC inhibitors by competing for uptake via monocarboxylate transporters.

Targeting protein kinase C (PKC) family was found to repress the migration and resistance of non-small cell lung cancer cells to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, none of the PKC inhibitors has been approved for anticancer therapy yet due to the limited efficacy in clinical trials, and the underlying mechanisms remain unclear. l-lactic acidosis, a common condition comprising high l-lactate concentration and acidic pH in the tumor microenvironment, has been known to induce tumor metastasis and drug resistance. In this study, l-lactic acid was found to reverse the inhibitory effects of pan-PKC inhibitors GO6983 on PKC activity, cell migration, and EGFR-TKI resistance, but these effects were not affected by the modulators of lactate receptor GPR81. Interestingly, blockade of lactate transporters, monocarboxylate transporter-1 and -4 (MCT1 and MCT4), attenuated the intracellular level of GO6983, and its inhibitory effect on PKC activity, suggesting that lactic acid promotes the resistance to PKC inhibitors by competing for the uptake through these transporters rather than by activating its receptor, GPR81. Our findings explain the underlying mechanisms of the limited response of PKC inhibitors in clinical trials.

Unveiling the transcriptomic landscape and the potential antagonist feedback mechanisms of TGF-ß superfamily signaling module in bone and osteoporosis.

BACKGROUND: TGF-ß superfamily signaling is indispensable for bone homeostasis. However, the global expression profiles of all the genes that make up this signaling module in bone and bone-related diseases have not yet been well characterized. METHODS: Transcriptomic datasets from human bone marrows, bone marrow-derived mesenchymal stem cells (MSCs) and MSCs of primary osteoporotic patients were used for expression profile analyses. Protein treatments, gene quantification, reporter assay and signaling dissection in MSC lines were used to clarify the interactive regulations and feedback mechanisms between TGF-ß superfamily ligands and antagonists. Ingenuity Pathway Analysis was used for network construction. RESULTS: We identified TGFB1 in the ligand group that carries out SMAD2/3 signaling and BMP8A, BMP8B and BMP2 in the ligand group that conducts SMAD1/5/8 signaling have relatively high expression levels in normal bone marrows and MSCs. Among 16 antagonist genes, the dominantly expressed TGF-ß superfamily ligands induced only NOG, GREM1 and GREM2 via different SMAD pathways in MSCs. These induced antagonist proteins further showed distinct antagonisms to the treated ligands and thus would make up complicated negative feedback networks in bone. We further identified TGF-ß superfamily signaling is enriched in MSCs of primary osteoporosis. Enhanced expression of the genes mediating TGF-ß-mediated SMAD3 signaling and the genes encoding TGF-ß superfamily antagonists served as significant features to osteoporosis. CONCLUSION: Our data for the first time unveiled the transcription landscape of all the genes that make up TGF-ß superfamily signaling module in bone. The feedback mechanisms and regulatory network prediction of antagonists provided novel hints to treat osteoporosis. Video Abstract.

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.

Prognostic Factors for Clinical Outcomes in Patients with Newly Diagnosed Advanced-stage Hodgkin Lymphoma: A Nationwide Retrospective Study.

INTRODUCTION: While Hodgkin lymphoma (HL) is mostly curable, outcomes for advanced-stage HL remain unsatisfactory. The International Prognostic Score and its modifications were developed to predict HL prognosis; however, more straightforward prognostic factors are needed. This study aimed to identify simpler prognostic factors for advanced-stage newly diagnosed HL (NDHL). METHODS: This retrospective study used the Taiwan National Health Insurance Research Database and the Taiwan Cancer Registry. Patients with advanced-stage NDHL receiving ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or ABVD-like regimens between 2009 and 2016 were enrolled. Cox proportional hazards models were used to identify prognostic factors for the time to next treatment (TTNT) and overall survival (OS). We used the time-dependent area under the receiver operating characteristic curve (AUROC) to evaluate model performance. RESULTS: The study included 459 patients with advanced-stage NDHL. A bimodal age distribution (peaks 20-44 and >65 years) was observed. Over a median follow-up of 4.7 years, the complete remission and OS rates were 52% and 76%, respectively. Age ≥60 years (adjusted hazard ratio [aHR]: 1.73, 95% confidence interval [CI]: 1.23-2.43), extranodal involvement (1.40, 1.05-1.87), B symptoms (1.53, 1.13-2.06), and Charlson Comorbidity Index (CCI) ≥1 (1.49, 1.08-2.06) were significantly associated with a shorter TTNT. The time-dependent AUROC was .65. With a time-dependent AUROC of .81, age ≥60 years (4.55, 2.90-7.15) and CCI ≥1 (1.86, 1.18-2.91) were risk factors for worse OS. CONCLUSION: Older age and more comorbidities were risk factors for an inferior OS in advanced-stage NDHL, while older age, extranodal involvement, B-symptoms, and higher CCI were significantly associated with disease relapse.

Amantadine treatment and delayed onset of levodopa-induced dyskinesia in patients with early Parkinson's disease.

BACKGROUND AND PURPOSE: Levodopa-induced dyskinesia (LID) is a common motor complication in patients with Parkinson's disease (PD). Although amantadine is indicated for LID treatment, it is uncertain whether early treatment with amantadine reduces the risk of LID in patients with PD. We aimed to evaluate the association between amantadine treatment and LID onset in patients with early-stage PD. METHODS: This was a hospital-based retrospective cohort study that used electronic medical records from January 1, 2009 to October 31, 2016. The effect of amantadine on LID onset was compared with those of anticholinergics and monoamine oxidase type B inhibitors in patients with PD. Propensity-score weighting and landmark analysis were used to reduce potential confounding. The time to LID onset was analyzed using Cox models. Sensitivity analyses were performed to determine the robustness of the results. RESULTS: The analyses included 807, 661, and 518 patients at 6-, 12-, and 18-month landmark points, respectively. Amantadine use was associated with delayed LID onset in the 6- and 12-month landmark analyses, with adjusted hazard ratios of 0.65 (95% confidence interval [CI] = 0.49-0.86) and 0.64 (95% CI = 0.47-0.88), respectively. Sensitivity analysis findings were comparable to those of the main analysis. CONCLUSIONS: Early treatment with amantadine may delay LID onset more than treatment with other symptomatic agents. Further studies are needed to elucidate the mechanism of amantadine in LID onset delay and to validate our findings.

Hyper-expression and hypomethylation of TM4SF1 are associated with lymph node metastases in papillary thyroid carcinoma patients.

Lymph node metastases (LNM) are an indicator for recurrence in papillary thyroid carcinoma (PTC) patients. However, prophylactic neck dissection (ND) cannot improve survival or recurrence rate because of increased surgical complications and occult LNM. Biomarkers are needed for the prediction of high-risk of LNM to avoid unnecessary operation and reduce the missed malignant lymph nodules. GEO database was searched for the differentially expressed genes (DEGs) between PTC patients with LNM (N1) and those without LNM (N0), transcriptional and methylation data of DEGs in THCA were examined from databases. The expression and methylation of TM4SF1 in fresh and paraffin tissues of PTC patients were examined by qRT-PCR, IHC, and MSP. TM4SF1 was the only one significantly associated with LNM. UALCAN revealed that TM4SF1 was overexpressed and hypomethylated in LNM patients. MEXPRESS presented a negative correlation between gene expression and promoter methylation of TM4SF1. DEGs were enriched in multiple pathways and the Extracellular Matrix (ECM)-receptor interaction pathway showed the greatest correlation with LNM. IHC and qRT-PCR of tissues demonstrated that the expression of TM4SF1 in the N1 group was 4.5-fold higher than that in the N0 group (p<0.05). MSP exhibited that the positive rate of aberrant promoter methylation of TM4SF1 was 8.38% in N1 and 66.7% in N0 group (p<0.05). Hyper-expression and hypomethylation of TM4SF1 are associated with lymph node metastases in PTC patients.

Neurodevelopmental outcomes at 6, 12, and 24 months of age in preterm infants with very low birth weights in Taiwan.

OBJECTIVE/PURPOSE: To identify perinatal antecedents associated with neurodevelopmental impairment for very low birth weight (VLBW) preterm infants at ages 6, 12, and 24 months and the stability of neurodevelopmental assessments. METHODS: A multicenter-based VLBW cohort was recruited, and the mental development index (MDI) and psychomotor development index (PDI) were used to evaluate children's neurodevelopment stages at ages 6, 12, and 24 months. Perinatal risk factors were determined through univariate and multivariate hierarchical linear analyses. Differences and predictability in MDI or PDI scores between ages 6 and 24 months were assessed. RESULTS: Covariates including father's education level; teenage pregnancy, multiple pregnancies; infant's gestational age, gender, and birth weight <999 gm, duration of neonatal intensive care unit stay; and presence of various diseases were adversely associated with poor MDI or PDI scores in 8517 eligible VLBW infants during the study period. Polyhydramnios, emergency cesarean delivery, birth weight of <1250 gm, and periventricular/intraventricular hemorrhage stage I-II were additional risk factors of VLBW infants with an adverse PDI score. An increased number of infants with a MDI or PDI score of <55 at age 24 months was observed. Six-month MDI or PDI assessments had a low ability to predict outcomes at 24 months, with sensitivity and positive predictive values under 60% and specificity and negative predictive values over 85%. CONCLUSION: Multiple perinatal risk factors are associated with poor MDI and PDI scores among VLBW preterm infants. Six-month developmental assessments exhibited low sensitivity and positive predictive values for outcomes at 24 months.

Predictors of repeated adolescent self-harm: The display of multiple variables and mediators in a 2-year study.

BACKGROUND: Data on self-harm (SH) repetition in non-Western adolescents are limited; this study is to survey the predictors. METHODS: A total of 5879 adolescents (mean age 16.02 years) in Northern Taiwan were recruited. The participants filled in online questionnaires about their sociodemographic data, suicidality, depressive symptoms, self-esteem, social support, family discord, impulsivity, and alcohol and tobacco use at baseline (T1) and at the 1 year follow-up (T2). We used logistic regression analysis to examine the predictors of SH continuation. Generalized structural equation modeling (GSEM) was then estimated to analyze the treatable variables for both years and to investigate their relationships and mediating effects. RESULTS: A total of 125 students were identified as being in the SH continuation group; while 470 students were identified as being in the SH stop group. The SH continuation rate was 21%; no significant gender difference was found. Logistic regression analysis showed that the predictors of SH continuation were low school ranking, poor quality of listening from relatives, use of the cutting method for SH, and a suicide plan in the past year at T1, and more depressed mood, use of the cutting method for SH, more suicide ideation and plans at T2. Similar predictors were found by GSEM; self-esteem at T1 and depressed mood at T2 were found to be mediators in the pathways. CONCLUSION: The continuation rate of SH was similar to that reported in Western countries. These predictors should be included in the treatment plan to prevent SH continuation.

Comparison of risk of acute kidney injury between patients receiving the combination of teicoplanin and piperacillin/tazobactam versus vancomycin and piperacillin/tazobactam.

BACKGROUND/PURPOSE: To compare the risk of acute kidney injury (AKI) among patients receiving teicoplanin (TA) plus piperacillin/tazobactam (TZP) versus vancomycin (VAN) plus TZP. METHODS: This was a retrospective cohort study using electronic health records. Patients were included if a combination of glycopeptide and TZP or other selected ß-lactams were used during hospitalization. In the main analysis, two study groups were identified: TA + TZP and VAN + TZP. We used 1:1 propensity score matching to control for potential confounders, and hazard ratio (HR) of AKI between study groups was calculated. We further compared the risk of AKI between patients receiving VAN + TZP and VAN + ß-lactams as an auxiliary analysis to verify the validity of the study design. RESULTS: The final sample contained 211 pairs of patients receiving either TA + TZP or VAN + TZP. The median dosage of TA and VAN were 10.3 and 26.7 mg/kg/day, respectively. The median trough level of VAN was 12.3 mg/L. The AKI risk in the TA + TZP group was similar to that in the VAN + TZP group (12.3% vs. 11.4%; HR = 1.25 [0.72-2.18], p = 0.44). The auxiliary analysis showed a higher risk of AKI in the VAN + TZP group than in the VAN + ß-lactam group (13.2% vs. 9.6%; HR = 1.63 [1.04-2.55], p = 0.03). CONCLUSION: Our study results showed that the risk of AKI were similar for patients receiving TA + TZP and VAN + TZP. However, low VAN and high TA dose may play a role in this finding. Further investigation on the association between AKI and TA + TZP is required.

Clinical and epidemiological features in hospitalized young children with acute gastroenteritis in Taiwan: A multicentered surveillance through 2014-2017.

BACKGROUND/PURPOSE: Acute gastroenteritis (AGE) remains a significant health issue in children. The worldwide evolution of pediatric AGE pathogens had been recorded since the introduction of rotavirus vaccine. Ten years after the rotavirus vaccine was introduced to the private sectors in Taiwan, a nationwide study was conducted to elucidate the epidemiological changes among major AGE pathogens. METHODS: From January 2014 to December 2017, children younger than 5 years old, hospitalized with AGE at 10 hospitals across Taiwan were enrolled. Stool specimens were tested for Salmonella spp., Campylobacter spp., Clostridiodes difficile, norovirus, and rotavirus by polymerase chain reaction (PCR). The epidemiological and clinical information was collected. RESULTS: Enteric pathogen were detected in 1983 (42.2%) of 4700 subjects, with Salmonella spp. (12.5%) being the leading cause of AGE, followed by norovirus (11.2%), rotavirus (8.7%), C. difficile (4.2%), Campylobacter spp. (1.0%), and a mixture of at least 2 of 5 above-mentioned pathogens (4.6%). The case distributions varied across different regions. In eastern Taiwan, rotavirus (21/131, 16.0%) remained the most common pathogen detected. The rotavirus vaccine uptake rate is significantly lower in patients with rotavirus AGE. Besides, rotavirus AGE frequently occurred in children with foreign parent(s), Taiwanese indigenous people, and those with the household monthly income < NT$ 60,000. CONCLUSION: Salmonella spp. and norovirus were two major pathogens of pediatric AGE in Taiwan during 2014-17. Providing low-to middle-income households with free rotavirus vaccine nationwide and an industry-led act to reduce salmonellosis should be considered by the authorities.

Nephrotoxicity of teicoplanin-based combination therapy: focus on piperacillin/tazobactam and other anti-pseudomonal ß-lactams.

BACKGROUND: The concurrent use of vancomycin and piperacillin/tazobactam increases the risk of acute kidney injury (AKI) compared with vancomycin use with other anti-pseudomonal ß-lactams (OAPBs). Teicoplanin is a glycopeptide antibiotic with lower nephrotoxicity than that of vancomycin. Whether the concomitant use of teicoplanin and piperacillin/tazobactam also increases the risk of AKI remains unknown. OBJECTIVES: To evaluate the AKI risk between teicoplanin-piperacillin/tazobactam and teicoplanin-OAPBs. METHODS: This was a retrospective, propensity score-matched cohort study. Adult patients receiving teicoplanin-based combination therapy were included. OAPBs included cefepime, cefoperazone/sulbactam, ceftazidime, doripenem, imipenem/cilastatin and meropenem. Propensity score matching was performed to balance demographic and confounding factors. The primary endpoint was AKI during combination therapy. RESULTS: After propensity score matching, 954 patients (teicoplanin-piperacillin/tazobactam: teicoplanin-OAPBs, 1:3 matched, 243 pairs in total) were included for analysis. The mean age was 66.3 years in the matched cohort and 17.1% of patients had shock. Use of nephrotoxic medications (45.7% versus 48.7%) and baseline renal function (78.88 ± 31.26 versus 81.05 ± 31.53 mL/min/1.73 m2) were similar in the two groups. The median teicoplanin dose was 10.7 mg/kg in both groups. The groups did not differ significantly in terms of AKI risk (14.8% versus 14.2%, P = 0.815). However, the time to AKI appeared shorter in the teicoplanin-piperacillin/tazobactam group (4.64 ± 2.33 versus 6.29 ± 4.72 days, P = 0.039). CONCLUSIONS: The combination of teicoplanin and piperacillin/tazobactam was not associated with an increased risk of AKI compared with teicoplanin and OAPBs.

Renoprotective effect of SGLT-2 inhibitors among type 2 diabetes patients with different baseline kidney function: a multi-center study.

BACKGROUND: To assess the effect of sodium glucose cotransporter-2 inhibitors (SGLT-2is) for type 2 diabetes on kidney outcomes stratified by patient baseline estimated glomerular filtration rate (eGFR) levels (i.e., eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 mL/min/1.73 m2). METHODS: Patients from three large healthcare delivery systems in Taiwan who had initiated SGLT-2is or other glucose-lowering drugs (oGLDs) between May 2016 and December 2017 were included. Main outcomes were the times to 30%, 40%, and 50% eGFR reduction after treatment initiation. One-to-one propensity score matching in the overall study cohort and in each eGFR subgroup between SGLT-2i and oGLD users was applied to ensure between-group comparability in baseline characteristics. RESULTS: There were 13,666 matched pairs of SGLT-2is and oGLD users in the overall cohort. While a sustained eGFR decline was revealed in oGLD-treated patients (mean values [standard errors] from 85.61 [0.43] to 82.49 [0.44] mL/min/1.73 m2 during the 12 months after treatment initiation), the mean eGFR values of SGLT-2i users decreased in the first 3 months (85.68 [0.37] to 79.71 [0.41] mL/min/1.73 m2) but then improved and sustained until the end of follow-up. There were 2300, 5705, and 5509 matched SGLT-2i and oGLD users in the eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 subgroups, respectively. Using SGLT-2is versus oGLDs was significantly associated with slower eGFR declines; hazard ratios (HRs) were 0.51 (95% CI 0.37-0.69), 0.51 (0.37-0.70), and 0.47 (0.31-0.71) for 40% eGFR reduction in the eGFR ≤ 60, 60 < eGFR ≤ 90, and eGFR > 90 subgroups, respectively. The renoprotective effect of SGLT-2is versus oGLDs was confirmed in the outcomes of 30% and 50% eGFR reduction across the three eGFR subgroups. CONCLUSIONS: This study supports the renoprotective benefit of real-world SGLT-2i use irrespective of patient baseline kidney function.

Prenatal antidepressant use and the implication of hypertensive disorders during pregnancy.

BACKGROUND: Evidence for the association between prenatal antidepressant use and the development of hypertensive disorders of pregnancy is inconsistent. Previous studies have reported that antidepressant use during pregnancy increases the risk for gestational hypertension and preeclampsia, but the results of these studies are potentially confounded by important methodologic limitations. Furthermore, it remains unknown whether a higher cumulative dose of antidepressant increases the risk for hypertensive disorders of pregnancy. OBJECTIVE: This study aimed to investigate the association between prenatal antidepressant use and the risk for hypertensive disorders of pregnancy and the potential effect of a higher cumulative antidepressant dose. STUDY DESIGN: This retrospective cohort study used data from the Health and Welfare Database in Taiwan. Pregnant women with depression aged 18 to 49 years were enrolled as part of the study population. Prenatal antidepressant use was defined as at least 1 dispensing record of an antidepressant between the conception date and 20 weeks of gestation. Antidepressant users were further divided into groups according to the cumulative defined daily dose based on whether they took the defined daily dose for ≤10 weeks (low cumulative dose group ≤70 cumulative defined daily dose) or for >10 weeks (high cumulative dose group >70 cumulative defined daily dose). The primary outcome was hypertensive disorders of pregnancy defined as the diagnosis of either gestational hypertension or preeclampsia during the period from 20 weeks of gestation to delivery. Propensity score matching and stabilized inverse probability of treatment weighting were used to balance the confounders between the comparison groups. A robust Cox regression model was used to evaluate the association between exposure and outcome. RESULTS: A total of 5664 pregnant women with depression were included in the study (2832 antidepressant users matched to 2832 antidepressant nonusers). Prenatal antidepressant use was not associated with an increased risk for hypertensive disorders of pregnancy (adjusted hazard ratio, 0.89; 95% confidence interval, 0.67-1.18). However, among antidepressant users, the risk for hypertensive disorders of pregnancy was higher among women with a higher cumulative defined daily dose than among women with a lower cumulative defined daily dose (adjusted hazard ratio, 2.46; 95% confidence interval, 1.05-5.74). CONCLUSION: No association was found between antidepressant use and the development of hypertensive disorders of pregnancy. However, women taking higher cumulative doses of antidepressants were at greater risk. More frequent or regular monitoring of blood pressure may be warranted in women on high cumulative doses of antidepressants.