Antibiotic use and risk of autism spectrum disorder and attention-deficit/hyperactivity disorder: a population-based cohort study.

BACKGROUND: The gut microbiota is believed to influence neurodevelopment through the gut-brain axis, but prior studies have shown inconsistent results regarding early childhood antibiotic exposure and subsequent risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). The purpose of this study was to evaluate the hypothesis that exposure to antibacterial agents in the first 2 years of life increases the risk of ASD and/or ADHD. METHODS: This was a retrospective cohort study using 2003-2019 data from the National Health Insurance Research Database in Taiwan. Livebirths born between 2004 and 2016 were identified and separated into singleton, full sibling, and exposure-discordant sibling pair cohorts. The exposure group included children who filled at least one prescription for antibacterial agents between 0 and 2 years old in outpatient settings. The outcome, ASD and/or ADHD, was defined by at least one inpatient or outpatient diagnosis. The maximum follow-up age was 15 years in this study. Potential neonatal, maternal and paternal confounders were adjusted for. Cox proportional hazards models were used to estimate the relative event risk. RESULTS: The final sample contained 946,581 children in the singleton cohort, 1,142,693 children in the full sibling cohort, and 352,612 children in the exposure-discordant sibling pair cohort. Antibiotic exposure marginally increased the risk of ASD and/or ADHD in the singleton cohort (adjusted hazard ratio [aHR]: 1.06, 95% confidence interval [CI]: 1.04-1.07) and in the full sibling cohort (aHR: 1.03, 95% CI: 1.01-1.04). A slight decrease in the risk of ASD and/or ADHD was observed in the exposure-discordant sibling pair cohort (aHR: 0.92, 95% CI: 0.90-0.94). CONCLUSIONS: The results suggest that early life antibiotic exposure has minimal impact on the risk of ASD and/or ADHD. Given that the estimated effects are marginal and close to null, concerns about ASD and/or ADHD risk increase should not postpone or deter timely and reasonable antibiotic use.

Cigarette smoke promotes IL-6-dependent lung cancer migration and osteolytic bone metastasis.

Lung cancer stands as a major contributor to cancer-related fatalities globally, with cigarette smoke playing a pivotal role in its development and metastasis. Cigarette smoke is also recognized as a risk factor for bone loss disorders like osteoporosis. However, the association between cigarette smoke and another bone loss disorder, lung cancer osteolytic bone metastasis, remains largely uncertain. Our Gene Set Enrichment Analysis (GSEA) indicated that smokers among lung cancer patients exhibited higher expression levels of bone turnover gene sets. Both The Cancer Genome Atlas (TCGA) database and our clinic samples demonstrated elevated expression of the osteolytic factor IL-6 in ever-smokers with bone metastasis among lung cancer patients. Our cellular experiments revealed that benzo[α]pyrene (B[α]P) and cigarette smoke extract (CSE) promoted IL-6 production and cell migration in lung cancer. Activation of the PI3K, Akt, and NF-κB signaling pathways was involved in cigarette smoke-augmented IL-6-dependent migration. Additionally, cigarette smoke lung cancer-secreted IL-6 promoted osteoclast formation. Importantly, blocking IL-6 abolished cigarette smoke-facilitated lung cancer osteolytic bone metastasis in vivo. Our findings provide evidence that cigarette smoke is a risk factor for osteolytic bone metastasis. Thus, inhibiting IL-6 may be a valuable therapeutic strategy for managing osteolytic bone metastasis in lung cancer patients who smoke.

The expected changes with different periods of home-based resistance exercise in patients with chronic kidney disease.

BACKGROUND: The comprehensive impact of prolonged home-based resistance training on individuals grappling with chronic kidney disease (CKD) have yet to be fully elucidated. This study aimed to explore the outcomes of varying exercise durations on physical performance, nutritional status, and kidney function within this specific population, encompassing patients undergoing dialysis and those affected by severe sarcopenia. METHODS: This was a 1-year observational double cohort study following a 52-week longitudinal design, we enrolled 101 adult CKD outpatients. These participants were divided into two groups: the continuous group, comprising individuals who consistently exercised for over 6 months, and the interrupted group, which included those who did not sustain regular exercise for the same duration. The exercise regimen involved resistance exercises conducted at least 3 to 5 days per week, involving activities like lifting dumbbells and executing weighted wall squats. Physical activity assessments and biochemical blood tests were conducted at weeks 0, 4, 16, 28, 40, and 52 for all participants. RESULTS: The continuous exercise group exhibited better handgrip strength and sit-to-stand movement compared to the interrupted group. Their estimated glomerular filtration rate stayed steady while the interrupted group was declined. Additionally, those who exercised consistently had better metabolism: higher carbon dioxide levels, increased albumin, better nutritional scores, and lower levels of blood urea nitrogen, creatinine, fasting blood glucose, and body weight. Subsequent adjustments for potential confounding factors continued to show improved physical performance and kidney function over time. CONCLUSION: Our findings indicate the advantageous impact of extended resistance exercise training on overall health of CKD patients, even those on dialysis or with severe sarcopenia. Dedication to this exercise routine could improve kidney function, metabolism, and physical abilities in these patients.

Kidney outcomes with SGLT2is for type 2 diabetes patients: does background treatment with metformin or RASis matter?

Introduction: There is a lack of real-world evidence regarding the impact of concomitant metformin and renin-angiotensin system inhibitors (RASis) on sodium-glucose cotransporter-2 inhibitor (SGLT2i)-associated kidney outcomes. This study was aimed to investigate whether SGLT2i-associated kidney outcomes were modified by the concomitant use of metformin or RASis in patients with type 2 diabetes. Methods: SGLT2i users were identified from three electronic health record databases during May 2016 and December 2017 and categorized into those with and without concomitant use of metformin or RASis. Propensity score matching was performed to minimize baseline differences between groups. Study outcomes were mean estimated glomerular filtration rate (eGFR) change and time to 30%, 40%, and 50% eGFR reductions. A meta-analysis was performed to combine the estimates across databases. Results: After matching, there were 6,625 and 3,260 SGLT2i users with and without metformin, and 6,654 and 2,746 SGLT2i users with and without RASis, respectively. The eGFR dip was similar in SGLT2i users with and without metformin therapy, but was greater in SGLT2i users with RASis compared to those without RASis. Neither metformin nor RASi use had a significant effect on SGLT2i-associated eGFR reductions, as evidenced by the hazard ratios (95% CIs) of 30% eGFR reductions for SGLT2is with versus without metformin/RASis, namely 1.02 (0.87-1.20)/1.09 (0.92-1.31). Such findings were also observed in the outcomes of 40% and 50% eGFR reductions. Conclusion: Using metformin or RASis did not modify SGLT2i-associated kidney outcomes in type 2 diabetes.

Sex-specific associations between prolonged serum uric acid levels and risk of major adverse cardiovascular events.

Background: While hyperuricemia has been correlated with cardiovascular (CV) diseases, further evidence is required to evaluate the implications of stable serum uric acid (sUA) levels, especially concerning low sUA. This study aimed to investigate prolonged stable sUA levels and CV events/mortality. Methods: We conducted a retrospective cohort study at a medical center using electronic medical records linked with the national claims database. Patients with at least two sUA measurements, with intervals ranging from 6 months to 4 years, were included. The mean of the first two eligible sUA measurements were analyzed, stratified by sex. Outcomes of interest comprised major adverse cardiovascular events (MACE), heart failure hospitalization, CV and all-cause mortality. Results: This study included 33,096 patients (follow-up: men 6.6 years, women 6.4 years). After multivariable adjustment, cubic spline models showed that long-term high sUA levels were consistently associated with a higher risk of MACE, heart failure hospitalization, CV and all-cause mortality. A U-shaped association was observed between sUA levels and all-cause mortality in both sexes and between sUA levels and CV mortality in women. The impact of sUA, especially lower levels, on CV events and mortality was more pronounced in women than in men. Conclusion: Long-term high sUA levels are consistently associated with increased risk of CV events and mortality. A U-shaped association between sUA levels and all-cause mortality was observed in both men and women and was pronounced in women. The findings underscore the importance of considering sUA levels, especially in women, when assessing CV risk.

Incense-burning smoke ingredient Auramine enhances lincRNA-p21 expression for chemosensitization in p53-mutated non-small cell lung cancer.

Incense-burning smoke is a deleterious air pollutant that initiates cytotoxic effects by inducing apoptosis in lung epithelial cells and also acts as a risk factor for lung cancers. Auramine, an ingredient of incense smoke, has been implicated in tumor progression and cellular sensitivity in non-small cell lung cancer (NSCLC) towards anti-cancer agents through unclear mechanisms. Tumor protein p53 (TP53)-activated long intergenic non-coding RNA-p21 (lincRNA-p21) undertakes a pivotal role in regulating cell apoptosis and chemosensitivity. TP53 mutations prevalent in 50% of NSCLC, contribute to diminished therapeutic efficacy. However, the influence of auramine on chemotherapy-induced lincRNA-p21 expression and apoptosis in NSCLC with different TP53 genetic statuses remains unexplored. This study disclosed that both wild-type p53 (wtp53) and mutant p53 (mutp53) mediate lincRNA-p21 expression, albeit through distinct promoter enhancers, p53-response element (p53RE) and non-B DNA structure G-quadruplex (GQ), respectively. Intriguingly, auramine functions as an effective stabilizer of the GQ structure, augmenting mutp53-mediated lincRNA-p21 expression and enhancing apoptosis and cellular sensitivity to chemotherapy in mutp53-expressing NSCLC cells. These findings suggest a mechanism by which mutp53, in the presence of auramine, is endowed with tumor-suppressing function akin to wtp53, thereby aiding in combating chemoresistance in NSCLC cells harboring TP53 mutations.

Correction: Valuation of the EQ-5D-5L in Taiwan.

[This corrects the article DOI: 10.1371/journal.pone.0209344.].

Particulate matter facilitates amphiregulin-dependent lung cancer proliferation through glutamine metabolism.

Although many cohort studies have reported that long-term exposure to particulate matter (PM) causes lung cancer, the molecular mechanisms underlying the PM-induced increases in lung cancer progression remain unclear. We applied the lung cancer cell line A549 (Parental; A549.Par) to PM for an extended period to establish a mimic PM-exposed lung cancer cell line, A549.PM. Our results indicate that A549.PM exhibits higher cell growth and proliferation abilities compared to A549.Par cells in vitro and in vivo. The RNA sequencing analysis found amphiregulin (AREG) plays a critical role in PM-induced cell proliferation. We observed that PM increases AREG-dependent lung cancer proliferation through glutamine metabolism. In addition, the EGFR/PI3K/AKT/mTOR signaling pathway is involved in PM-induced solute carrier family A1 member 5 (SLC1A5) expression and glutamine metabolism. Our findings offer important insights into how lung cancer proliferation develops upon exposure to PM.

Skull base surgery for malignant tumors: The 2nd international collaborative study (1995-2015).

BACKGROUND: The current study presents the effort of a global collaborative group to review the management and outcomes of malignant tumors of the skull base worldwide. PATIENTS AND METHODS: A total of 28 institutions contributed data on 3061 patients. Analysis evaluated clinical variables, survival outcomes, and multivariable factors associated with outcomes. RESULTS: The median age was 56 years (IQR 44-67). The open surgical approach was used in 55% (n = 1680) of cases, endoscopic resection was performed in 36% (n = 1087), and the combined approach in 9.6% (n = 294). With a median follow-up of 7.1 years, the 5-year OS DSS and RFS were 65%, 71.7% and 53%, respectively. On multivariable analysis, older age, comorbidities, histology, dural/intracranial involvement, positive margins, advanced stage, and primary site were independent prognostic factors for OS, DSS, and RFS. Adjuvant RT was a protective prognostic factor. CONCLUSION: The progress across various disciplines may have contributed to improved OS and DSS in this study compared to previous reports.

Functional and structural investigation of a broadly neutralizing SARS-CoV-2 antibody.

Since its emergence, SARS-CoV-2 has been continuously evolving, hampering the effectiveness of current vaccines against COVID-19. mAbs can be used to treat patients at risk of severe COVID-19. Thus, the development of broadly protective mAbs and an understanding of the underlying protective mechanisms are of great importance. Here, we isolated mAbs from donors with breakthrough infection with Omicron subvariants using a single-B cell screening platform. We identified a mAb, O5C2, which possesses broad-spectrum neutralization and antibody-dependent cell-mediated cytotoxic activities against SARS-CoV-2 variants, including EG.5.1. Single-particle analysis by cryo-electron microscopy revealed that O5C2 targeted an unusually large epitope within the receptor-binding domain of spike protein that overlapped with the angiotensin-converting enzyme 2 binding interface. Furthermore, O5C2 effectively protected against BA.5 Omicron infection in vivo by mediating changes in transcriptomes enriched in genes involved in apoptosis and interferon responses. Our findings provide insights into the development of pan-protective mAbs against SARS-CoV-2.

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.

Effects of postoperative antioxidants on the salivary glands in patients with thyroid cancer undergoing radioactive iodine-131 treatment.

OBJECTIVE: This study aimed to evaluate the effects of three antioxidants, selenium yeast capsule, vitamin E and vitamin C, alone or in combination, on the salivary glands of patients with differentiated thyroid cancer (DTC) treated with iodine-131 ( 131 I). METHODS: A total of 69 postoperative DTC patients were randomly divided into three groups: vitamin E combined with vitamin C group (21 cases); selenium yeast group (23 cases); and selenium yeast combined with vitamin C group (25 cases). Salivary gland functional changes were assessed by salivary gland dynamic imaging functional parameters in the enrolled patients before and 1 month after 131 I treatment. RESULTS: Comparison of salivary gland function parameters before and after 131 I treatment in the three groups were evaluated. In the vitamin E combined with the vitamin C group, the left parotid gland excretion fraction (EF) value was significantly higher than that before treatment. In the selenium yeast group, the left parotid gland excretion part, bilateral parotid gland excretion ratio (ER), left submandibular gland maximum uptake ratio within 20 min (UR20), and the right submandibular gland ER values were significantly higher than that before treatment, while in the selenium yeast combined with vitamin C group, the bilateral parotid gland EF, bilateral submandibular gland UR20, EF, and left submandibular gland ER values were significantly higher than that before treatment (all P < 0.05). CONCLUSION: During high-dose 131 I treatment, vitamin E combined with vitamin C improved the excretory function of parotid glands in DTC patients; selenium supplementation had a protective effect on salivary glands; and the combination of selenium and vitamin C had a better effect.

Comparison of different direct oral anticoagulant regimens in atrial fibrillation patients with high bleeding risk.

BACKGROUND: The optimal dose of direct oral anticoagulants (DOACs) to prevent ischemic stroke (IS) and systemic thromboembolism (STE) in atrial fibrillation (AF) patients with a predisposing bleeding risk remains unclear. OBJECTIVE: The purpose of this study was to compare the effectiveness and safety of different DOAC dosage regimens in AF patients with high bleeding risk but low thrombosis risk. METHODS: This retrospective observational study was conducted with the National Health Insurance claims database in Taiwan to include AF patients aged 20 up to 75 years, under DOAC therapy, with CHA2DS2-VASc score of 1 for males and 2 for females and HAS-BLED score ≥3. Standard-dose regimen was defined as dabigatran 300 mg, rivaroxaban 20 mg, apixaban 10 mg, or edoxaban 60 mg per day. Any other lower-dose regimen were defined as the low-dose regimen. The primary outcomes were IS and major bleeding (MB). The secondary outcomes were STE, gastrointestinal bleeding, intracranial hemorrhage, and cardiovascular death. RESULTS: A total of 964 patients were included (52.1% standard-dose regimen). Median HAS-BLED score was 3 [interquartile range 3-3]. Compared with standard-dose group, patients in the low-dose group had a significantly increased risk of IS (adjusted hazard ratio [aHR] 5.13; 95% confidence interval 1.37-19.22) and STE (aHR 3.14 [1.05-9.37]) but similar risk of MB (aHR 0.45 [0.12-1.67]). The risks of other hemorrhage and cardiovascular death were similar between the 2 dose groups. CONCLUSION: Among patients with a predominant bleeding risk but relatively low thrombosis risk, the low-dose DOAC regimen is not a more appropriate selection than standard-dose regimen.

Bulk RNA-sequencing, single-cell RNA-sequencing analysis, and experimental validation reveal iron metabolism-related genes CISD2 and CYP17A1 are potential diagnostic markers for recurrent pregnancy loss.

BACKGROUND: Recurrent pregnancy loss (RPL) is associated with variable causes. Its etiology remains unexplained in about half of the cases, with no effective treatment available. Individuals with RPL have an irregular iron metabolism. In the present study, we identified key genes impacting iron metabolism that could be used for diagnosing and treating RPL. METHODS: We obtained gene expression profiles from the Gene Expression Omnibus (GEO) database. The Molecular Signatures Database was used to identify 14 gene sets related to iron metabolism, comprising 520 iron metabolism genes. Differential analysis and a weighted gene co-expression network analysis (WGCNA) of gene expression revealed two iron metabolism-related hub genes. Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry were used on clinical samples to confirm our results. The receiver operating characteristic (ROC) analysis and immune infiltration analysis were conducted. In addition, we analyzed the distribution of genes and performed CellChat analysis by single-cell RNA sequencing. RESULTS: The expression of two hub genes, namely, CDGSH iron sulfur domain 2 (CISD2)and Cytochrome P450 family 17 subfamily A member 1 (CYP17A1), were reduced in RPL, as verified by both qPCR and immunohistochemistry. The Gene Ontology (GO) analysis revealed the genes predominantly engaged in autophagy and iron metabolism. The area under the curve (AUC) demonstrated better diagnostic performance for RPL using CISD2 and CYP17A1. The single-cell transcriptomic analysis of RPL demonstrated that CISD2 is expressed in the majority of cell subpopulations, whereas CYP17A1 is not. The cell cycle analysis revealed highly active natural killer (NK) cells that displayed the highest communications with other cells, including the strongest interaction with macrophages through the migratory inhibitory factor (MIF) pathway. CONCLUSIONS: Our study suggested that CISD2 and CYP17A1 genes are involved in abnormal iron metabolism, thereby contributing to RPL. These genes could be used as potential diagnostic and therapeutic markers for RPL.

The clinical application of traditional Chinese medicine NRICM101 in hospitalized patients with COVID-19.

BACKGROUND: The aim of this study was to assess the efficacy and safety of NRICM101 in hospitalized patients with COVID-19. RESEARCH DESIGN AND METHODS: We conducted a retrospective study from 20 April 2021 to 8 July 2021, and evaluated the safety and outcomes (mortality, hospital stay, mechanical ventilation, oxygen support, diarrhea, serum potassium) in COVID-19 patients. Propensity score matching at a 1:2 ratio was performed to reduce confounding factors. RESULTS: A total of 201 patients were analyzed. The experimental group (n = 67) received NRICM101 and standard care, while the control group (n = 134) received standard care alone. No significant differences were observed in mortality (10.4% vs. 14.2%), intubation (13.8% vs. 11%), time to intubation (10 vs. 11 days), mechanical ventilation days (0 vs. 9 days), or oxygen support duration (6 vs. 5 days). However, the experimental group had a shorter length of hospitalization (odds ratio = 0.12, p = 0.043) and fewer mechanical ventilation days (odds ratio = 0.068, p = 0.008) in initially severe cases, along with an increased diarrhea risk (p = 0.035). CONCLUSION: NRICM101 did not reduce in-hospital mortality. However, it shortened the length of hospitalization and reduced mechanical ventilation days in initially severe cases. Further investigation is needed.

The Report of Community-Based and Government-Endorsed Screening Program of Atrial Fibrillation in Taiwan.

BACKGROUND: Although international guidelines recommended opportunistic screening for atrial fibrillation (AF), the community-based AF screening program incorporated into the government-endorsed health care system is rarely reported in Asian countries. OBJECTIVES: We aimed to test the feasibility of adding AF screening into the preexistent adult health check program and report the AF detection rate and percentages of OAC prescriptions before and after AF screening with the involvement of public health care systems. METHODS: We performed this program in three counties (Chiayi county, Keelung City, and Yilan county) in Taiwan which have their own official preexistent adult health check programs conducted by public health bureaus for years. However, electrocardiography (ECG) was not included in these programs before. We cooperated with the public health bureaus of the three counties and performed single-lead 30-second ECG recording for every participant. RESULTS: From January to December 2020, AF screening was performed in 199 sessions with 23,572 participants. AF was detected in 278 subjects with a detection rate of 1.19% (age ≥65 years: 2.39%; ≥75 years: 3.73%). The mean CHA2DS2-VASc score of these 278 subjects was 2.36, with 91% of them had a score ≥1 (males) or ≥2 (females). The number needed to screen was 42 and 27 for subjects aged ≥65 and ≥75 years, respectively. The prescription rate of OACs significantly increased from 11.4 to 60.6% in Chiayi county and from 15.8 to 50.0% in Keelung City after screening (both p-values <0.001). CONCLUSION: This community-based and government-endorsed AF screening project in Taiwan demonstrated that incorporation of AF screening into the preexistent adult health check programs through co-operations with the government was feasible. Actions to detect AF, good education, and well-organized transferring plan after AF being detected with the involvement of public health care systems could result in a substantial increase in the prescription rate of OACs.

Scaffold-based non-viral CRISPR delivery platform for efficient and prolonged gene activation to accelerate tissue regeneration.

Clustered regularly interspaced short palindromic repeat activation (CRISPRa) technology has emerged as a precise genome editing tool for activating endogenous transgene expression. While it holds promise for precise cell modification, its translation into tissue engineering has been hampered by biosafety concerns and suboptimal delivery methods. To address these challenges, we have developed a CRISPRa non-viral gene delivery platform by immobilizing non-viral CRISPRa complexes into a biocompatible hydrogel/nanofiber (Gel/NF) composite scaffold. The Gel/NF scaffold facilitates the controlled and sustained release of CRISPRa complexes and also promotes cell recruitment to the scaffold for efficient and localized transfection. As a proof of concept, we employed this CRISPRa delivery platform to activate the vascular endothelial growth factor (VEGF) gene in a rat model with full-thickness skin defects. Our results demonstrate sustained upregulation of VEGF expression even at 21 days post-implantation, resulting in enhanced angiogenesis and improved skin regeneration. These findings underscore the potential of the Gel/NF scaffold-based CRISPRa delivery platform as an efficient and durable strategy for gene activation, offering promising prospects for tissue regeneration. STATEMENT OF SIGNIFICANCE: Translation of clustered regularly interspaced short palindromic repeat activation (CRISPRa) therapy to tissue engineering is limited by biosafety concerns and unsatisfactory delivery strategy. To solve this issue, we have developed a CRISPRa non-viral gene delivery platform by immobilizing non-viral CRISPRa complexes into a biocompatible hydrogel/nanofiber (Gel/NF) composite scaffold. This scaffold enables controlled and sustained release of CRISPRa and can induce cell recruitment for localized transfection. As a proof of concept, we activated vascular endothelial growth factor (VEGF) in a rat model with full-thickness skin defects, leading to sustained upregulation of VEGF expression, enhanced angiogenesis and improved skin regeneration in vivo. These findings demonstrate the potential of this platform for gene activation, thereby offering promising prospects for tissue regeneration.

How Impulsivity is Associated with Adolescent Depression: The Role of Substance Use, Gender and Social Support.

Background: Some risk/protective factors of adolescent depression have been proposed but have not been comprehensively studied. Recent advances in neuroimaging techniques have provided greater insight into the underlying neuropsychiatric mechanisms of depression-related factors such as impulsivity, substance use, gender difference and social support. However, how these factors are interconnected and how they affect depression in the real world is poorly understood. This study aimed to explore the relationships between adolescent depression with trait impulsivity, substance use and gender. We also tested the hypothesis that social support may play a buffering role in preventing depression. By expanding the diathesis-stress model. Methods: The adolescents enrolled in this study were grade 1 senior high school students from northern Taiwan (N = 5879), and they were assessed for depression, trait impulsivity, and tobacco/alcohol use. Hierarchical multiple linear regression was performed to control possible confounders, including other depression-related diathesis and sociodemographic variables. Gender differences were also analyzed by separately examining variables significantly associated with depression. Results: A higher level of depression was associated with female gender, trait impulsivity, low self-esteem, negative attitude towards the future, tobacco use, alcohol use, family discord and difficulty in basic family needs. Good parental health, living with their biological family and social support were protective factors. Trait impulsivity was significantly associated with depression after controlling for the confounding factors. Gender-specific analysis showed that trait impulsivity and tobacco use had a significant synergistic interaction on female depression. Social support from parents/peers was significantly associated with depression, but social support from other family members/teachers was not. Conclusion: The current study advances the understanding of adolescent depression and highlights that trait impulsivity, addictive substance use, social support and their interaction may play an influential role in the emergence of adolescent depression. Gender-specific research and treatment approach are also crucial, and more investigations are necessary.

Beyond 10-year lead-times in EQ-5D-5L: leveraging alternative lead-times in willingness-to-accept questions to capture preferences for worse-than-dead states and their implication.

BACKGROUND: A fixed 10-year lead-time in composite time-trade-off (C-TTO) tasks might compromise the precision of utility values below - 1. This study explored how alternative lead-times (ALTs) influence EQ-5D-5L value sets and their implications in economic evaluations. METHODS: Leveraging data from Taiwan's EQ-5D-5L valuation and capitalizing on its exploratory willingness-to-accept question, we explored participants' quantification of "worse-than-dead (WTD)" health states with ALTs up to 50 years. We then derived alternative value sets incorporating these ALTs through interval regression and compared them against those from conventional models. To evaluate their impact on health change valuation, we simulated utility differences for all possible EQ-5D-5L health-state-pairs using each value set. RESULTS: With a salient floor effect observed in the C-TTO values, the model with ALT led to a wider range of predicted utilities ( - 2.3897 ~ 1), compared with those of conventional models (generalized least squares (GLS): - 0.7773 ~ 1; Tobit-GLS: - 0.9583 ~ 1). Compared to the Tobit-GLS model, the model with ALT increased the numerical distance in 80% of health-state-pairs, with 11% decreasing and 9% altering direction (e.g., positive to negative) in utility differences. CONCLUSIONS: While ALTs offer insights into patient preferences, their integration into economic evaluations might require rescaling. Future research should prioritize advanced rescaling methods or enhanced elicitation strategies for populations with substantial censoring. This is pivotal for improving the elicitation of extreme WTD states and accurately discerning the relative distances between health states. Countries developing EQ-5D-5L value sets should consider pilot studies and incorporating region-specific questions on social determinants, especially where pronounced floor effects are suspected.

Clinical Application of a Graphene Oxide-Based Surface Plasmon Resonance Biosensor to Measure First-Trimester Serum Pregnancy-Associated Plasma Protein-A/A2 Ratio to Predict Preeclampsia.

Background: Preeclampsia, a major cause of adverse pregnancy outcomes, involves metalloproteinases pregnancy-associated plasma protein (PAPP)-A and PAPP-A2 from placental trophoblasts. The graphene oxide (GO)-based surface plasmon resonance (SPR) biosensor has higher sensitivity, affinity, and selective ability than the traditional SPR biosensor. The aim of this study was to explore the feasibility of measuring first-trimester serum PAPP-A/PAPP-A2 ratio as a novel predictor of preeclampsia using the GO-SPR biosensor. Methods: This prospective case-control study of pregnant women was conducted at MacKay Memorial Hospital, Taipei, Taiwan between January 2018 and June 2020. The SPR angle shifts of first-trimester serum PAPP-A, PAPP-A2, and PAPP-A/PAPP-A2 ratio measured using the GO-SPR biosensor were compared between preeclampsia and control groups. Results: Serum samples from 185 pregnant women were collected, of whom 30 had preeclampsia (5 early-onset; 25 late-onset). The response time between the antibody-antigen association and dissociation only took about 200 seconds. The SPR angle shift of PAPP-A in the preeclampsia group was significantly smaller than that in the control group (median (interquartile range): 5.33 (4.55) versus 6.89 (4.10) millidegrees (mDeg), P = 0.008). Conversely, the SPR angle shift of PAPP-A2 in the preeclampsia group was significantly larger than that in the control group (5.70 (3.81) versus 3.63 (2.38) mDeg, P < 0.001). Receiver operating characteristic (ROC) curve analysis revealed a cut-off PAPP-A/PAPP-A2 ratio to predict all preeclampsia of ≤ 0.76, with an area under the ROC curve (AUC) of 0.79 (95% CI 0.73-0.85, P < 0.001). Sub-group analysis revealed a cut-off PAPP-A/PAPP-A2 ratio to predict early-onset preeclampsia of ≤ 0.53 (AUC 0.99, 95% CI 0.96-1.00, P < 0.001), and ≤ 0.73 to predict late-onset preeclampsia (AUC 0.75, 95% CI 0.68-0.81, P < 0.001). Conclusion: Measuring first-trimester serum PAPP-A/PAPP-A2 ratio using the GO-SPR biosensor could be a valuable method for early prediction of preeclampsia.