Renal protective effect of metformin in type 2 diabetes patients.

BACKGROUND: Inhibiting the development and progression of diabetic kidney disease (DKD) is an important issue, but the renoprotective effect of metformin is still controversial. AIMS: To assess the renoprotective effect of metformin in patients with type 2 diabetes. METHODS: This retrospective observational multicenter cohort study included 316,693 patients with type 2 diabetes from seven hospital. After age, gender, medical year, baseline estimated glomerular filtration rate (eGFR), urine protein (dipstick), glycated hemoglobin (HbA1C) and propensity score matching; a total of 13,096 metformin and 13,096 non-metformin patients were included. The main results were doubling of serum creatinine, eGFR ≤ 15 mL/min/1.73 m2 and end stage kidney disease (ESKD). RESULTS: After conducting a multivariable logistic regression analysis on the variables, the metformin group was revealed to have better renal outcomes than non-metformin group, including a lower incidence of doubling of serum creatinine (hazard ratio [HR], 0.71; 95% CI, 0.65-0.77), eGFR ≤ 15 mL/min/1.73 m2 (HR 0.61; 95% CI 0.53-0.71), and ESKD (HR 0.55; 95% CI 0.47-0.66). The subgroup analyses revealed a consistent renoprotective effect across patients with various renal functions. Furthermore, when considering factors such as age, sex, comorbidities, and medications in subgroup analyses, it consistently showed that the metformin group experienced a slower deterioration in renal function across nearly all patient subgroups. CONCLUSIONS: Metformin decreased the risk of renal function deterioration.

The Role of AKR1B10 in Lung Cancer Malignancy Induced by Sublethal Doses of Chemotherapeutic Drugs.

Chemotherapy remains a cornerstone in lung cancer treatment, yet emerging evidence suggests that sublethal low doses may inadvertently enhance the malignancy. This study investigates the paradoxical effects of sublethal low-dose chemotherapy on non-small-cell lung cancer (NSCLC) cells, emphasizing the role of Aldo-keto reductase family 1 member B10 (AKR1B10). We found that sublethal doses of chemotherapy unexpectedly increased cancer cell migration approximately 2-fold and invasion approximately threefold, potentially promoting metastasis. Our analysis revealed a significant upregulation of AKR1B10 in response to taxol and doxorubicin treatment, correlating with poor survival rates in lung cancer patients. Furthermore, silencing AKR1B10 resulted in a 1-2-fold reduction in cell proliferation and a 2-3-fold reduction in colony formation and migration while increasing chemotherapy sensitivity. In contrast, the overexpression of AKR1B10 stimulated growth rate by approximately 2-fold via ERK pathway activation, underscoring its potential as a target for therapeutic intervention. The reversal of these effects upon the application of an ERK-specific inhibitor further validates the significance of the ERK pathway in AKR1B10-mediated chemoresistance. In conclusion, our findings significantly contribute to the understanding of chemotherapy-induced adaptations in lung cancer cells. The elevated AKR1B10 expression following sublethal chemotherapy presents a novel molecular mechanism contributing to the development of chemoresistance. It highlights the need for strategic approaches in chemotherapy administration to circumvent the inadvertent enhancement of cancer aggressiveness. This study positions AKR1B10 as a potential therapeutic target, offering a new avenue to improve lung cancer treatment outcomes by mitigating the adverse effects of sublethal chemotherapy.

Risk Factors and Nomogram Model for Hepatocellular Carcinoma Development in Chronic Hepatitis B Patients with Low-Level Viremia.

Background and aim: Patients with chronic hepatitis B patients (CHB) with low-level viremia (LLV) are not necessarily at low risk of developing hepatocellular carcinoma (HCC). The question of whether CHB patients with LLV require immediate antiviral agent (AVT) or long-term AVT remains controversial. The study aims to investigate the risk of HCC development and the risk factors in CHB patients with LLV and construct a nomogram model predicting the risk of HCC. Methods: We conducted a retrospective cohort study that enrolled 16,895 CHB patients from January 2008 to December 2020. The patients were divided into three groups for comparison: the LLV group, maintained virological response (MVR) group and HBV-DNA>2000 group. The cumulative incidence of progression to HCC was assessed. Cox regression analysis was performed to determine the final risk factors, and a nomogram model was constructed. The 10-fold Cross-Validation method was utilized for internal validation. Results: A total of 408 new cases of HCC occurred during the average follow-up period of 5.78 years. The 3, 5, and 10-year cumulative HCC risks in the LLV group were 3.56%, 4.96%, and 9.51%, respectively. There was a significant difference in the cumulative risk of HCC between the HBV-DNA level > 2000 IU/mL and LLV groups (p = 0.049). Independent risk factors for HCC development in LLV group included male gender, age, presence of cirrhosis, and platelets count. The Area Under the Curve (AUC) values for the 3-year and 5-year prediction from our HCC risk prediction model were 0.75 and 0.76, respectively. Conclusion: Patients with LLV and MVR are still at risk for developing HCC. The nomogram established for CHB patient with LLV, incorporating identified significant risk factors, serves as an effective tool for predicting HCC-free outcomes. This nomogram model provides valuable information for determining appropriate surveillance strategies and prescribing AVT.

ABE-ultramax for high-efficiency biallelic adenine base editing in zebrafish.

Advancements in CRISPR technology, particularly the development of base editors, revolutionize genetic variant research. When combined with model organisms like zebrafish, base editors significantly accelerate and refine in vivo analysis of genetic variations. However, base editors are restricted by protospacer adjacent motif (PAM) sequences and specific editing windows, hindering their applicability to a broad spectrum of genetic variants. Additionally, base editors can introduce unintended mutations and often exhibit reduced efficiency in living organisms compared to cultured cell lines. Here, we engineer a suite of adenine base editors (ABEs) called ABE-Ultramax (Umax), demonstrating high editing efficiency and low rates of insertions and deletions (indels) in zebrafish. The ABE-Umax suite of editors includes ABEs with shifted, narrowed, or broadened editing windows, reduced bystander mutation frequency, and highly flexible PAM sequence requirements. These advancements have the potential to address previous challenges in disease modeling and advance gene therapy applications.

Metabolic stress induces a double-positive feedback loop between AMPK and SQSTM1/p62 conferring dual activation of AMPK and NFE2L2/NRF2 to synergize antioxidant defense.

Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, the STK11-AMPK activity was also required for metabolic stress-induced expression and phosphorylation of SQSTM1, suggesting a double-positive feedback loop between AMPK and SQSTM1. Mechanistically, SQSTM1 expression was increased by the PPP2/PP2A-dependent dephosphorylation of TFEB and TFE3, which was induced by the lysosomal deacidification caused by low glucose metabolism and AMPK-dependent proton reduction. Furthermore, SQSTM1 phosphorylation was increased by MAP3K7/TAK1, which was activated by ROS and pH-dependent secretion of lysosomal Ca2+. Importantly, phosphorylation of SQSTM1 at S24 and S226 was critical for the activation of AMPK and NFE2L2. Notably, the effects caused by metabolic stress were abrogated by the protons provided by lactic acid. Collectively, our data reveal a novel double-positive feedback loop between AMPK and SQSTM1 leading to the dual activation of AMPK and NFE2L2, potentially explaining why co-occurring mutations in STK11 and KEAP1 happen and providing promising therapeutic strategies for lung cancer.Abbreviations: AMPK: AMP-activated protein kinase; BAF1: bafilomycin A1; ConA: concanamycin A; DOX: doxycycline; IP: immunoprecipitation; KEAP1: kelch like ECH associated protein 1; LN: low nutrient; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NSCLC: non-small cell lung cancer; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PPP2/PP2A: protein phosphatase 2; ROS: reactive oxygen species; PPP3/calcineurin: protein phosphatase 3; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TCL: total cell lysate; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; V-ATPase: vacuolar-type H+-translocating ATPase.

Disorder of neuroplasticity aggravates cognitive impairment via neuroinflammation associated with intestinal flora dysbiosis in chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) impairs cognitive function, yet its effects on brain structure and underlying mechanisms remain elusive. This study aims to explore the mechanisms behind cognitive impairment. METHODS: CHF models in rats were induced by ligation of the left anterior descending coronary artery. Cardiac function was analyzed by cardiac ultrasound and hemodynamics. ELISA, immunofluorescence, Western blot, Golgi staining and transmission electron microscopy were performed on hippocampal tissues. The alterations of intestinal flora under the morbid state were investigated via 16S rRNA sequencing. The connection between neuroinflammation and synapses is confirmed by a co-culture system of BV2 microglia and HT22 cells in vitro. Results: CHF rats exhibited deteriorated cognitive behaviors. CHF induced neuronal structural disruption, loss of Nissl bodies, and synaptic damage, exhibiting alterations in multiple parameters. CHF rats showed increased hippocampal levels of inflammatory cytokines and activated microglia and astrocytes. Furthermore, the study highlights dysregulated PDE4-dependent cAMP signaling and intestinal flora dysbiosis, closely associated with neuroinflammation, and altered synaptic proteins. In vitro, microglial neuroinflammation impaired synaptic plasticity via PDE4-dependent cAMP signaling. CONCLUSIONS: Neuroinflammation worsens CHF-related cognitive impairment through neuroplasticity disorder, tied to intestinal flora dysbiosis. PDE4 emerges as a potential therapeutic target. These findings provide insightful perspectives on the heart-gut-brain axis.

Impact of audiovestibular factors on prognosis in patients with sudden sensorineural hearing loss without vertigo.

PURPOSE: This study aimed to investigate the hearing outcomes in patients with sudden sensorineural hearing loss without vertigo (SSNHLwoV). METHODS: Patients with SSNHLwoV managed from December 2016 to March 2020 were prospectively enrolled in an academic tertiary referral center. Fifty-one patients with SSNHLwoV who completed high-dose steroid treatment. The hearing prognosis was analyzed using a multivariate Cox regression model. RESULTS: The rates of complete, partial, and no hearing recovery were 52.9%, 17.6%, and 29.4% in patients with SSNHLwoV, respectively. The video head impulse test (vHIT) of the posterior semicircular canal (PSC), high-tone hearing loss (4-8 kHz) ≥ 30 dB, and average hearing threshold (0.5-1-2-4 kHz) were significantly associated with incomplete recovery of hearing after treatment. In multivariate analysis, the vHIT of the PSC (hazard ratio [HR], 14.502; 95% confidence interval [CI], 1.371-153.355) and high-tone hearing loss ≥ 30 dB (HR, 9.170; 95% CI, 2.283-36.830) remained robust. CONCLUSIONS: Abnormal vestibular function tests were performed in 80.4% of the patients with SSNHLwoV. Abnormal vHIT of the PSC and high-tone hearing loss ≥ 30 dB were independent factors resulting in incomplete recovery of hearing in patients with SSNHLwoV. In the SSNHLwoV cohort, the caloric test was not significantly associated with hearing prognosis, and vHIT was a feasible predictor of treatment outcome.

Visible Light-Induced Radical Cascade Difluoromethylation/Cyclization of Unactivated Alkenes: Access to CF2H-Substituted Polycyclic Imidazoles.

An efficient and mild protocol for the visible light-induced radical cascade difluoromethylation/cyclization of imidazoles with unactivated alkenes using easily accessible and bench-stable difluoromethyltriphenylphosphonium bromide as the precursor of the -CF2H group has been developed to afford CF2H-substituted polycyclic imidazoles in moderate to good yields. This strategy, along with the construction of Csp3-CF2H/C-C bonds, is distinguished by mild conditions, no requirement of additives, simple operation, and wide substrate scope. In addition, the mechanistic experiments have indicated that the difluoromethyl radical pathway is essential for the methodology.

Key risk factors and adverse outcomes in metachronous vertebral osteomyelitis following periprosthetic joint infection: A 5-year retrospective study.

Purpose: Periprosthetic joint infection (PJI) is a leading cause of joint arthroplasty failure, potentially leading to critical complications like vertebral osteomyelitis (VO). The factors contributing to VO after PJI and the outcomes for these patients are not well understood. Our study aims to (1) identify risk factors for VO following PJI and (2) assess the clinical outcomes in these cases. Methods: We included PJI patients treated surgically at our centre from January 2006 to December 2020, excluding those with simultaneous VO post-PJI. Our focus was on patients with VO occurring after PJI, monitored for at least 5 years. Analysis included patient comorbidities, PJI treatment approaches, pathogen identification and clinical outcomes. Results: Of 1701 PJI cases, 21 (1.23%) developed VO. Key risk factors for VO post-PJI were identified: systemic inflammatory response syndrome, substance misuse, polymicrobial infection and undergoing at least three stages of resection arthroplasty (odds ratios: 1.86, 54.28, 52.33 and 31.88, respectively). Adverse outcomes were noted in VO patients, with recurrent VO in 6/21 and repeated PJIs in 18/21 cases. Conclusions: Patients with PJI, especially those with certain risk factors, have an increased likelihood of developing VO and encountering negative outcomes. The potential role of bacteremia in the development of VO after PJI needs further exploration. Level of Evidence: Level III.

Monocyte distribution width as a promising biomarker for differential diagnosis of chronic hepatitis, cirrhosis, and hepatocellular carcinoma.

Objective: We aimed to investigate the association and diagnostic value of monocyte distribution width (MDW) for chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). Methods: MDW levels were measured in 483 individuals (103 CHB, 77 LC, 153 HCC, and 150 controls). MDW was detected using UniCel Dx900 for specific cell volume parameters and the distribution of cell volumes. Results: Our findings revealed a dynamic upward change in MDW levels across different stages of chronic liver disease, from CHB to LC and HCC. In CHB, MDW levels were highest among HBeAg-positive CHB patients and exhibited a negative correlation with HBV markers while positively correlating with ALT levels. In LC, MDW showed a positive association with the pathological progression of LC, demonstrating consistency with CP scores. MDW proved to be equally effective as traditional detection for diagnosing LC. In HCC, MDW was positively correlated with HCC occurrence and development, with higher levels observed in the high MDW group, which also exhibited elevated AFP levels, MELD scores, and 90-day mortality rates. MDW surpassed predictive models in its effectiveness for diagnosing HCC, as well as CHB and LC, with respective areas under the curve of 0.882, 0.978, and 0.973. Furthermore, MDW emerged as an independent predictor of HCC. Conclusion: MDW holds significant diagnostic efficacy in identifying CHB, LC, and HCC. These findings suggest that MDW could serve as a promising biomarker for predicting the severity of liver diseases and aid in rational clinical treatment strategies.

ABCD2-I Score Predicts Unplanned Emergency Department Revisits within 72 Hours Due to Recurrent Acute Ischemic Stroke.

BACKGROUND: the ABCD2 score is valuable for predicting early stroke recurrence after a transient ischemic attack (TIA), and Doppler ultrasound can aid in expediting stroke triage. The study aimed to investigate whether combining the ABCD2 score with carotid duplex results can enhance the identification of early acute ischemic stroke after TIA. METHODS: we employed a retrospective cohort design for this study, enrolling patients diagnosed with TIA who were discharged from the emergency department (ED). The modified ABCD2-I (c50) score, which incorporates a Doppler ultrasound assessment of internal carotid artery stenosis > 50%, was used to evaluate the risk of acute ischemic stroke within 72 h. Patients were categorized into three risk groups: low risk (with ABCD2 and ABCD2-I scores = 0-4), moderate risk (ABCD2 score = 4-5 and ABCD2-I score = 5-7), and high risk (ABCD2 score = 6-7 and ABCD2-I score = 8-9). RESULTS: between 1 January 2014, and 31 December 2019, 1124 patients with new neurological deficits were screened, with 151 TIA patients discharged from the ED and included in the analysis. Cox proportional hazards analysis showed that patients in the high-risk group, as per the ABCD2-I (c50) score, were significantly associated with revisiting the ED within 72 h due to acute ischemic stroke (HR: 3.12, 95% CI: 1.31-7.41, p = 0.0102), while the ABCD2 alone did not show significant association (HR: 1.12, 95% CI: 0.57-2.22, p = 0.7427). CONCLUSION: ABCD2-I (c50) scores effectively predict early acute ischemic stroke presentations to the ED within 72 h after TIA.

AMPK targets PDZD8 to trigger carbon source shift from glucose to glutamine.

The shift of carbon utilization from primarily glucose to other nutrients is a fundamental metabolic adaptation to cope with decreased blood glucose levels and the consequent decline in glucose oxidation. AMP-activated protein kinase (AMPK) plays crucial roles in this metabolic adaptation. However, the underlying mechanism is not fully understood. Here, we show that PDZ domain containing 8 (PDZD8), which we identify as a new substrate of AMPK activated in low glucose, is required for the low glucose-promoted glutaminolysis. AMPK phosphorylates PDZD8 at threonine 527 (T527) and promotes the interaction of PDZD8 with and activation of glutaminase 1 (GLS1), a rate-limiting enzyme of glutaminolysis. In vivo, the AMPK-PDZD8-GLS1 axis is required for the enhancement of glutaminolysis as tested in the skeletal muscle tissues, which occurs earlier than the increase in fatty acid utilization during fasting. The enhanced glutaminolysis is also observed in macrophages in low glucose or under acute lipopolysaccharide (LPS) treatment. Consistent with a requirement of heightened glutaminolysis, the PDZD8-T527A mutation dampens the secretion of pro-inflammatory cytokines in macrophages in mice treated with LPS. Together, we have revealed an AMPK-PDZD8-GLS1 axis that promotes glutaminolysis ahead of increased fatty acid utilization under glucose shortage.

Impulse oscillometry in patients with persistent post-COVID-19 symptoms: A retrospective study.

Introduction: Impaired lung function has been observed in patients following COVID-19 infection, with studies reporting persistent lung volume and diffusing capacity impairments. Some studies have demonstrated significantly higher small airway resistance in COVID-19 positive cases. This retrospective study aims to examine impulse oscillometry (IOS) data of patients with persistent symptoms after COVID-19 infection, focusing on the relationship between time and symptoms. Material and Method: The study analyzed data from adult patients with persistent symptoms who underwent IOS testing within and after 84 days from the diagnosis date. Result: The results showed that patients within 84 days and those between 31 and 84 days had higher small airway resistance values, indicating peripheral airway disease. Patients with dyspnea exhibited higher IOS values compared to those with cough symptoms, suggesting more significant impairment in the peripheral airways. Conclusion: The study highlights the importance of using comprehensive diagnostic tools like IOS to assess respiratory impairments in post-COVID-19 patients, particularly in the small airways. Understanding the relationship between time and symptoms can provide valuable insights for the treatment of peripheral airway dysfunction in post-COVID-19 patients.

Dental treatments in patients with special needs provided by university medical center in Southern Taiwan: a retrospective study.

OBJECTIVES: We perform special-need dental treatment at outpatient department (OPD), under general anesthesia (GA) when necessary, and provide domiciliary dental care. We aim to evaluate the profile and the characteristics of special needs patients (SNPs). MATERIALS AND METHODS: We consecutively enrolled 3117 SNPs from January 1, 2019 to December 31, 2022. Eighty patients with rare or genetic diseases were excluded. Demographic data were retrospectively collected. RESULTS: There were totally 3037 SNPs (mean age: 48.2 years; range, 1-100; male-to-female ratio, 1.5); 89.1% (n = 2705) SNPs received dental care at the OPD (OPD-SNPs), 7.9% (n = 239) received dental treatment under GA, and 3.0% (n = 93) received domiciliary dental care. Among those SNPs who received dental treatment under GA (n = 239), 91.2% (n = 218) were mental/intellectual disabled, and most underwent cavity filling (69.5%) and dental extractions (56.5%). OPD-SNPs with mental/intellectual disabilities (n = 1340) received significantly more items of dental treatment than those without (n = 1365). SNPs with more severe disabilities received more fluoride application and ultrasonic scaling (both p < 0.001, trend tests). Interestingly, among OPD-SNPs with mental/intellectual disabilities (n = 1340), more severe patients received more fluoride application (p < 0.001) and ultrasonic scaling (p < 0.001) but fewer root canal treatment (p = 0.007, trend test). CONCLUSIONS: GA benefited SNPs with more dental procedures, including invasive items. SNPs with mental/intellectual disabilities can tolerate more measures and SNPs with more severe mental/intellectual disabilities received more preventive measures but less invasive measures. Similarly, more severe SNPs with other disabilities received more preventive measures but not invasive measures. CLINICAL RELEVANCE: Our findings may provide useful information for special needs dentists and for doctor-patient communication.

Establishment of a Mouse Model of Mycoplasma pneumoniae-Induced Plastic Bronchitis.

Plastic bronchitis (PB) constitutes a life-threatening pulmonary disorder, predominantly attributed to Mycoplasma pneumoniae (MP) infection. The pathogenic mechanisms involved remain largely unexplored, leading to the absence of reliable approaches for early diagnosis and clear treatment. Thus, the present investigation aimed to develop an MP-induced mouse model of PB, thereby enhancing our understanding of this complex condition. In the first stage, healthy BALB/c mice were utilized to investigate the optimal methods for establishing PB. This involved the application of nebulization (15-20 min) and intratracheal administration (6-50 µL) with 2-chloroethyl ethyl sulfide (CEES) concentrations ranging from 4.5% to 7.5%. Subsequently, the MP model was induced by administering an MP solution (2 mL/kg/day, 108 CFU/50 µL) via the intranasal route for a duration of five consecutive days. Ultimately, suitable techniques were employed to induce plastic bronchitis in the MP model. Pathological changes in lung tissue were analyzed, and immunohistochemistry was employed to ascertain the expression levels of vascular endothelial growth factor receptor 3 (VEGFR-3) and the PI3K/AKT/mTOR signaling pathway. The administration of 4.5% CEES via a 6 µL trachea was the optimal approach to establishing a PB model. This method primarily induced neutrophilic inflammation and fibrinous exudate. The MP-infected group manifested symptoms indicative of respiratory infection, including erect hair, oral and nasal secretions, and a decrease in body weight. Furthermore, the pathological score of the MP+CEES group surpassed that of the groups treated with MP or CEES independently. Notably, the MP+CEES group demonstrated significant activation of the VEGFR-3 and PI3K/AKT/mTOR signaling pathways, implying a substantial involvement of lymphatic vessel impairment in this pathology. This study successfully established a mouse model of PB induced by MP using a two-step method. Lymphatic vessel impairment is a pivotal element in the pathogenetic mechanisms underlying this disease entity. This accomplishment will aid in further research into treatment methods for patients with PB caused by MP.

Clinical outcome in hypertensive patients treated with amlodipine plus bisoprolol or plus valsartan.

OBJECTIVE: Several guidelines do not recommend beta-blocker as the first-line treatment for hypertension because of its inferior efficacy in stroke prevention. Combination therapy with beta-blocker is commonly used for blood pressure control. We compared the clinical outcomes in patients treated with amlodipine plus bisoprolol (A + B), a ß1-selective beta-blocker and amlodipine plus valsartan (A + V). METHODS: A population-based cohort study was performed using data from the Taiwan National Health Insurance Research Database. From 2012 to 2019, newly diagnosed adult hypertensive patients who received initial amlodipine monotherapy and then switched to A + V or A + B were included. The efficacy outcomes included all-cause death, atherosclerotic cardiovascular disease (ASCVD) event (cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization), hemorrhagic stroke, and heart failure. Multivariable Cox proportional hazards model was used to evaluate the relationship between outcomes and different treatments. RESULTS: Overall, 4311 patients in A + B group and 10980 patients in A + V group were included. After a mean follow-up of 4.34 ± 1.79 years, the efficacy outcomes were similar between the A + V and A + B groups regarding all-cause death (adjusted hazard ratio [aHR] 0.99, 95% confidence interval [CI] 0.83-1.18), ASCVD event (aHR 0.97, 95% CI 0.84-1.12), and heart failure (aHR 1.06, 95% CI 0.87-1.30). The risk of hemorrhagic stroke was lower in A + B group (aHR 0.70, 95% CI 0.52-0.94). The result was similar when taking death into consideration in competing risk analysis. The safety outcomes were similar between the 2 groups. CONCLUSIONS: There was no difference of all-cause death, ASCVD event, and heart failure in A + B vs. A + V users. But A + B users had a lower risk of hemorrhagic stroke.

Learning pathways composed of core subjects with features of reducing cognitive load have better learning outcomes.

BACKGROUND: Changing the course duration or timing of subjects in learning pathways would influence medical students' learning outcomes. Curriculum designers need to consider the strategy of reducing cognitive load and evaluate it continuously. Our institution underwent gradual curricular changes characterized by reducing cognitive load since 2000. Therefore, we wanted to explore the impact of this strategy on our previous cohorts. METHODS: This cohort study explored learning pathways across academic years of more than a decade since 2000. Eight hundred eighty-two medical students between 2006 and 2012 were included eventually. Learning outcomes included an average and individual scores of subjects in different stages. Core subjects were identified as those where changes in duration or timing would influence learning outcomes and constitute different learning pathways. We examined whether the promising learning pathway defined as the pathway with the most features of reducing cognitive load has higher learning outcomes than other learning pathways in the exploring dataset. The relationship between features and learning outcomes was validated by learning pathways selected in the remaining dataset. RESULTS: We found nine core subjects, constituting four different learning pathways. Two features of extended course duration and increased proximity between core subjects of basic science and clinical medicine were identified in the promising learning pathway 2012, which also had the highest learning outcomes. Other pathways had some of the features, and pathway 2006 without such features had the lowest learning outcomes. The relationship between higher learning outcomes and cognitive load-reducing features was validated by comparing learning outcomes in two pathways with and without similar features of the promising learning pathway. CONCLUSION: An approach to finding a promising learning pathway facilitating students' learning outcomes was validated. Curricular designers may implement similar design to explore the promising learning pathway while considering potential confounding factors, including students, medical educators, and learning design of the course.

Zedoary turmeric oil injection ameliorates lung inflammation via platelet factor 4 and regulates gut microbiota disorder in respiratory syncytial virus-infected young mice.

BACKGROUND: Respiratory syncytial virus (RSV)-induced lung inflammation is one of the main causes of hospitalization and easily causes disruption of intestinal homeostasis in infants, thereby resulting in a negative impact on their development. However, the current clinical drugs are not satisfactory. Zedoary turmeric oil injection (ZTOI), a patented traditional Chinese medicine (TCM), has been used for clinical management of inflammatory diseases. However, its in vivo efficacy against RSV-induced lung inflammation and the underlying mechanism remain unclear. PURPOSE: The present study was designed to confirm the in vivo efficacy of ZTOI against lung inflammation and intestinal disorders in RSV-infected young mice and to explore the potential mechanism. STUDY DESIGN AND METHODS: Lung inflammation was induced by RSV, and cytokine antibody arrays were used to clarify the effectiveness of ZTOI in RSV pneumonia. Subsequently, key therapeutic targets of ZTOI against RSV pneumonia were identified through multi-factor detection and further confirmed. The potential therapeutic material basis of ZTOI in target tissues was determined by non-target mass spectrometry. After confirming that the pharmacological substances of ZTOI can reach the intestine, we used 16S rRNA-sequencing technology to study the effect of ZTOI on the intestinal bacteria. RESULTS: In the RSV-induced mouse lung inflammation model, ZTOI significantly reduced the levels of serum myeloperoxidase, serum amyloid A, C-reactive protein, and thymic stromal lymphoprotein; inhibited the mRNA expression of IL-10 and IL-6; and decreased pathological changes in the lungs. Immunofluorescence and qPCR experiments showed that ZTOI reduced RSV load in the lungs. According to cytokine antibody arrays, platelet factor 4 (PF4), a weak chemotactic factor mainly synthesized by megakaryocytes, showed a concentration-dependent change in lung tissues affected by ZTOI, which could be the key target for ZTOI to exert anti-inflammatory effects. Additionally, sesquiterpenes were enriched in the lungs and intestines, thereby exerting anti-inflammatory and regulatory effects on gut microbiota. CONCLUSION: ZTOI can protect from lung inflammation via PF4 and regulate gut microbiota disorder in RSV-infected young mice by sesquiterpenes, which provides reference for its clinical application in RSV-induced lung diseases.