Neuroendocrine carcinoma of the common hepatic duct coexisting with distal cholangiocarcinoma: A case report and review of literature.

BACKGROUND: Neuroendocrine carcinoma (NEC) of the extrahepatic bile duct is very rare, and the treatment and prognosis are unclear. Herein, we report the case of a middle-aged female with primary large cell NEC (LCNEC) of the common hepatic duct combined with distal cholangiocarcinoma (dCCA). Additionally, after a review of the relevant literature, we summarize and compare mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) and pure NEC to provide a reference for selecting the appropriate treatment and predicting the prognosis of this rare disease. CASE SUMMARY: A 62-year-old female presented to the hospital due to recurrent abdominal pain for 2 months. Physical examination showed mild tenderness in the upper abdomen and a positive Courvoisier sign. Blood tests showed elevated liver transaminase and carbohydrate antigen 199 levels. Imaging examination revealed a 1-cm tumour in the middle and lower segments of the common bile duct. Pancreaticoduodenectomy + lymph node dissection was performed, and hepatic duct tumours were unexpectedly found during surgery. Pathology suggested poorly differentiated LCNEC (approximately 0.5 cm × 0.5 cm × 0.4 cm), Ki-67 (50%), synaptophysin+, and chromogranin A+. dCCA pathology suggested moderately differentiated adenocarcinoma. The patient eventually developed lymph node metastasis in the liver, bone, peritoneum, and abdominal cavity and died 24 months after surgery. Gene sequencing methods were used to compare gene mutations in the two primary bile duct tumours. CONCLUSION: The prognosis of MiNEN and pure NEC alone is different, and the selection of treatment options needs to be differentiated.

Targeting Wavefront Discontinuity Lines for Scar-Related Ventricular Tachycardia Ablation: A Novel Functional Substrate Ablation Approach.

BACKGROUND: The boundaries of critical isthmuses for re-entrant ventricular tachycardia (VT) are formed by wave-front discontinuities (fixed lines of block, slow propagation, and rotational propagation) seen during baseline rhythm. It is unknown whether wavefront discontinuities can be automatically identified and targeted for ablation using electroanatomic mapping systems. OBJECTIVES: The purpose of this study was to assess the electrophysiologic characteristics of automatically projected wavefront discontinuity lines (WADLs) and outcomes of an ablation strategy targeting WADLs in a mixed cohort of VT patients. METHODS: Late activation substrate maps were analyzed from 1 or more baseline rhythm wavefronts. WADLs were identified using the Carto Extended Early Meets Late module. Number, total length, and distance to critical VT sites were measured. VT recurrence and VT-free survival were followed. RESULTS: In total, 49 patients underwent 52 ablations with 71 unique substrate maps analyzed (18.8% epicardial; 62.0% right ventricular paced, 28.2% sinus rhythm, 9.9% left ventricular paced). A total of 28 VT critical sites were identified in 24 patients. WADLs were present in 49 of 71 (69.0%) maps. WADLs were present regardless of cardiomyopathy etiology, mapping wavefront, or surface. At a WADL threshold of 30%, 73.9% of critical VT sites were in close proximity (≤15 mm) to a WADL. VT-free survival was 62% at 1 year, with a competing risk model estimating a 1-year risk of VT recurrence of 23%. CONCLUSIONS: WADLs can be automatically projected in a majority of patients in a mixed cohort of cardiomyopathy etiology, mapped wavefronts, and myocardial surfaces mapped. Targeting WADLs results in low rate of VT recurrence at 1 year.

Analysis of Health-Related Quality of Life in Elderly Patients with Stroke Complicated by Hypertension in China Using the EQ-5D-3L Scale.

Purpose: To evaluate the health-related quality of life(HRQoL)status of elderly patients with hypertensive stroke, to understand the factors influencing it, and to provide a basis for the development of health intervention policies. Patients and Methods: This study used the EQ-5D-3L scale to assess the HRQoL among elderly patients who experienced a stroke related to high blood pressure. Various analytical methods were employed to examine the factors that influenced the patient's quality of life. Univariate analysis, Tobit regression, random forest, and XGBoost models were applied to analyze the HRQoL of the patients. Furthermore, to interpret the machine learning results, the SHAP method was utilized. This method involved assessing the importance of each feature, examining the effect of each feature on the prediction result of a single sample, and determining the impact of individual features on the overall prediction. Results: The study found that the median health utility value for elderly patients with hypertensive stroke was 0.427, with an interquartile range of 0.186 to 0.745. The results of the Tobit regression model, Random Forest, and XGBoost model were compared. The results of the model evaluation show that the performance of the machine learning model and the Tobit regression model are not very different. The XGBoost model performs slightly better relative to the random forest model. The factors that strongly influenced the health utility value of patients included BMI, social activities, smoking, education level, alcohol consumption, urban/rural residence, annual income, physical activity level, and hours of sleep at night. Conclusion: Health-related quality of life in hypertensive stroke patients is influenced by a variety of factors. Health-related quality of life can be positively influenced by modifying these factors and making lifestyle adjustments. Maintaining a healthy weight, being socially active, quitting smoking, improving living conditions, increasing physical activity levels and getting enough sleep are recommended. Lifestyle changes need to be developed for each individual on a case-by-case basis and by medical advice.

Rare subcommunity maintains the stability of ecosystem multifunctionality by deterministic assembly processes in subtropical estuaries.

Microorganisms, especially rare microbial species, are crucial in estuarine ecosystems for driving biogeochemical processes and preserving biodiversity. However, the understanding of the links between ecosystem multifunctionality (EMF) and the diversity of rare bacterial taxa in estuary ecosystems remains limited. Employing high-throughput sequencing and a variety of statistical methods, we assessed the diversities and assembly process of abundant and rare bacterioplankton and their contributions to EMF in a subtropical estuary. Taxonomic analysis revealed Proteobacteria as the predominant phylum among both abundant and rare bacterial taxa. Notably, rare taxa demonstrated significantly higher taxonomic diversity and a larger species pool than abundant taxa. Additionally, our findings highlighted that deterministic assembly processes predominantly shape microbial communities, with heterogeneous selection exerting a stronger influence on rare taxa. Further analysis reveals that rare bacterial beta-diversity significantly impacts to EMF, whereas alpha diversity did not. The partial least squares path modeling (PLS-PM) analysis demonstrated that the beta diversity of abundant and rare taxa, as the main biotic factor, directly affected EMF, while temperature and total organic carbon (TOC) were additional key factors to determine the relationship between beta diversity and EMF. These findings advance our understanding of the distribution features and ecological knowledge of the abundant and rare taxa in EMF in subtropical estuaries, and provide a reference for exploring the multifunctionality of different biospheres in aquatic environments.

Comparative Proteomics Identified EXOSC1 as a Target Protein of Anticancer Peptide LVTX-8 in Nasopharyngeal Carcinoma Cells.

Nasopharyngeal carcinoma (NPC) is a prevalent malignancy that usually occurs among the nose and throat. Due to mild initial symptoms, most patients are diagnosed in the late stage, and the recurrence rate of tumors is high, resulting in many deaths every year. Traditional radiotherapy and chemotherapy are prone to causing drug resistance and significant side effects. Therefore, searching for new bioactive drugs including anticancer peptides is necessary and urgent. LVTX-8 is a peptide toxin synthesized from the cDNA library of the spider Lycosa vittata, which is consisting of 25 amino acids. In this study, a series of in vitro cell experiments such as cell toxicity, colony formation, and cell migration assays were performed to exam the anticancer activity of LVTX-8 in NPC cells (5-8F and CNE-2). The results suggested that LVTX-8 significantly inhibited cell proliferation and migration of NPC cells. To find the potential molecular targets for the anticancer capability of LVTX-8, high-throughput proteomic and bioinformatics analysis were conducted on NPC cells. The results identified EXOSC1 as a potential target protein with significantly differential expression levels under LVTX-8+/LVTX-8- conditions. The results in this research indicate that spider peptide toxin LVTX-8 exhibits significant anticancer activity in NPC, and EXOSC1 may serve as a target protein for its anticancer activity. These findings provide a reference for the development of new therapeutic drugs for NPC and offer new ideas for the discovery of biomarkers related to NPC diagnosis. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (https://proteomecentral.proteomexchange.org) via the iProX partner repository with the data set identifier PXD050542.

Propensity score matching for estimating a marginal hazard ratio.

Propensity score matching is commonly used to draw causal inference from observational survival data. However, its asymptotic properties have yet to be established, and variance estimation is still open to debate. We derive the statistical properties of the propensity score matching estimator of the marginal causal hazard ratio based on matching with replacement and a fixed number of matches. We also propose a double-resampling technique for variance estimation that takes into account the uncertainty due to propensity score estimation prior to matching.

C9orf72-Associated Dipeptide Repeat Expansions Perturb ER-Golgi Vesicular Trafficking, Inducing Golgi Fragmentation and ER Stress, in ALS/FTD.

Hexanucleotide repeat expansions (HREs) in the chromosome 9 open reading frame 72 (C9orf72) gene are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both are debilitating neurodegenerative conditions affecting either motor neurons (ALS) in the brain and spinal cord or neurons in the frontal and/or temporal cortical lobes (FTD). HREs undergo repeat-associated non-ATG (RAN) translation on both sense and anti-sense strands, generating five distinct dipeptide repeat proteins (DPRs), poly-GA, -GR, -GP, -PA and -PR. Perturbed proteostasis is well-recognised in ALS pathogenesis, including processes affecting the endoplasmic reticulum (ER) and Golgi compartments. However, these mechanisms have not been well characterised for C9orf72-mediated ALS/FTD. In this study we demonstrate that C9orf72 DPRs polyGA, polyGR and polyGP (× 40 repeats) disrupt secretory protein transport from the ER to the Golgi apparatus in neuronal cells. Consistent with this finding, these DPRs also induce fragmentation of the Golgi apparatus, activate ER stress, and inhibit the formation of the omegasome, the precursor of the autophagosome that originates from ER membranes. We also demonstrate Golgi fragmentation in cells undergoing RAN translation that express polyGP. Furthermore, dysregulated ER-Golgi transport was confirmed in C9orf72 patient dermal fibroblasts. Evidence of aberrant ER-derived vesicles in spinal cord motor neurons from C9orf72 ALS patients compared to controls was also obtained. These data thus confirm that ER proteostasis and ER-Golgi transport is perturbed in C9orf72-ALS in the absence of protein over-expression. Hence this study identifies novel molecular mechanisms associated with the ER and Golgi compartments induced by the C9orf72 HRE.

Detection of Cadmium in Human Biospecimens by a Cadmium-Selective Whole-Cell Biosensor Based on Deoxyviolacein.

Cadmium poses a severe health risk, impacting various bodily systems. Monitoring human exposure is vital. Urine and blood cadmium serve as critical biomarkers. However, current urine and blood cadmium detection methods are expensive and complex. Being cost-effective, user-friendly, and efficient, visual biosensing offers a promising complement to existing techniques. Therefore, we constructed a cadmium whole-cell biosensor using CadR10 and deoxyviolacein pigment in this study. We assessed the sensor for time-dose response, specific response to cadmium, sensitivity response to cadmium, and stability response to cadmium. The results showed that (1) the sensor had a preferred signal-to-noise ratio when the incubation time was 4 h; (2) the sensor showed excellent specificity for cadmium compared to the group 12 metals and lead; (3) the sensor was responsive to cadmium down to 1.53 nM under experimental conditions and had good linearity over a wide range from 1.53 nM to 100 µM with good linearity (R2 = 0.979); and (4) the sensor had good stability. Based on the excellent results of the performance tests, we developed a cost-effective, high-throughput method for detecting urinary and blood cadmium. Specifically, this was realized by adding the blood or urine samples into the culture system in a particular proportion. Then, the whole-cell biosensor was subjected to culture, n-butanol extraction, and microplate reading. The results showed that (1) at 20% urine addition ratio, the sensor had an excellent curvilinear relationship (R2 = 0.986) in the range of 3.05 nM to 100 µM, and the detection limit could reach 3.05 nM. (2) At a 10% blood addition ratio, the sensor had an excellent nonlinear relationship (R2 = 0.978) in the range of 0.097-50 µM, and the detection limit reached 0.195 µM. Overall, we developed a sensitive and wide-range method based on a whole-cell biosensor for the detection of cadmium in blood and urine, which has the advantages of being cost-effective, ease of operation, fast response, and low dependence on instrumentation and has the potential to be applied in the monitoring of cadmium exposure in humans as a complementary to the mainstream detection techniques.

Scutellarein alleviates osteoarthritis progression through the PI3K/Akt/NF-kappaB signaling pathway: In vitro and in vivo studies.

Osteoarthritis (OA), a joint disease that is associated with inflammatory processes is involved in joint destruction. Scutellarein (Scu), a component of the medicinal herbs Scutellaria barbata D. Don and Erigeron breviscapus (vant) Hand Mass, has anti-inflammatory effects. We explored the role of Scu in the development of OA and the underlying mechanisms. CCK-8 assays, Calcein-AM/PI and EdU staining were used to determine chondrocyte viability after Scu exposure. Western blot, qPCR, as well as ELISA were utilized to measure extracellular matrix (ECM) degradation and inflammation. Immunofluorescence (IF), western blot and luciferase assays were used to examine the NF-kappaB (NF-κB) pathway. Scu interacting proteins were predicted using network pharmacology analysis and molecular docking. X-ray, H&E, Safranin O-Fast Green(S-O), toluidine blue, and immunohistochemistry analysis were used to examine the therapeutic effects of Scu in OA using destabilization of medial meniscus (DMM) models. Scu demonstrated inhibitory effects on ECM degradation and pro-inflammatory factor levels in chondrocytes treated with IL-1ß. Mechanistically, Scu inhibited the IL-1ß-induced activation of the PI3K/Akt/ NF-κB signaling pathway cascades. Furthermore, Scu has been shown to have significant binding capacities to PI3K. Additionally, Scu ameliorated the OA progression in DMM models. Our findings suggest that Scu may contribute to the amelioration of OA progression by targeting the PI3K/Akt/NF-κB signaling pathway, implying Scu possesses promising therapeutic potential for the treatment of OA.

Determination of Azole Fungicide Residues in Fresh Juice by Magnetic Solid Phase Extraction Based on Fe3O4@ZnAl-LDH@MIL-53(Al) Sorbent in Combination with High-Performance Liquid Chromatograph.

In this work, a magnetic adsorption material based on metal-organic framework (Fe3O4@ZnAl-LDH@MIL-53(Al)) was synthesized and used as an adsorbent in the process of magnetic solid phase extraction. Then, a high-performance liquid chromatograph was used to quantitatively detect triazole fungicides in samples. In order to verify the successful preparation of the material, a series of characterization analyses were carried out. Besides, the key parameters that may affect the extraction efficiency have been optimized, and under optimal conditions the three triazole fungicides showed good linearity in the range of 10-1000 µg/L (R2 ≥ 0.9796); Limit of detections were ranged from 0.013 to 0.030 µg/mL. Finally, the established method was applied to the detection of triazole fungicides in four fresh juice samples. The results showed that the target analyte was not detected in all the test samples. By detecting the recoveries (73.3-104.3%) and coefficient variation (RSD ≤ 6.8%) of triazole fungicides in fortified samples, it proved that this established method meets the requirements of pesticide residue analysis and showed excellent application potential.

Furosemide and Ductus Arteriosus Closure in Very-Low-Birth-Weight Preterm Infants: A Comprehensive Retrospective Study.

Ductus arteriosus closure may be delayed in preterm infants, and prostaglandin, a vasodilator, can affect ductal patency. Furosemide can increase renal prostaglandin synthesis, so its net effect on patent ductus arteriosus (PDA) is uncertain. Our goal is to explore the relationship between furosemide and spontaneous ductal closure in very-low-birth-weight preterm infants. Our treatment for PDA involves fluid restriction initially and furosemide administration for hemodynamically significant PDA until closure is confirmed by the echocardiogram. We enrolled 105 infants from 1 January 2019 to 30 June 2022 and evaluated the impact of furosemide on ductal closure, including exposure duration and cumulative dose. There is no correlation between furosemide exposure and spontaneous ductal closure (p = 0.384). Furosemide exposure does not delay the postmenstrual age at which spontaneous ductal closure occurs (p = 0.558). The time for spontaneous ductal closure is positively associated with furosemide prescription days (coefficient value = 0.547, p = 0.026) and negatively with gestational age (coefficient value = -0.384, p = 0.062). The prescription of furosemide does not impact the probability or time duration of ductus arteriosus spontaneous closure. The cumulative dose of furosemide has minimal impact on ductal closure. The correlation between furosemide exposure duration and ductal patency duration is likely due to our treatment protocol, with gestational age being a significant factor.

Decreased serum levels of SETD1A protein in patients with schizophrenia.

OBJECTIVE: SET domain-containing protein 1A (SETD1A) histone lysine N-methyltransferase may serve as a biomarker for the auxiliary diagnosis and treatment assessment of schizophrenia (SCZ). The aim of this study was to compare serum levels of SETD1A protein between patients with SCZ and health controls. METHODS: Patients with SCZ and health controls were recruited from the Sixth Hospital of Changchun and the 'Survey on Chronic Diseases and Risk Factors among Adults in Jilin Province', respectively. The quantifications of lysine N-methyltransferase in peripheral serum were conducted by the ELISA method, and data was analyzed using the R software. RESULTS: Forty patients with SCZ (mean age: 33.97 ± 5.99 years) and forty healthy controls (mean age: 39.07 ± 4.62 years) were included. There was significantly lower concentration of SETD1A protein in the SCZ group compared with the control group (P < 0.001). This significant difference still exists after stratification by sex (P < 0.05). CONCLUSION: Our study demonstrates that decreased levels of serum SETD1A protein may be utilized as a possible peripheral biomarker for schizophrenia.

Robust analyzes for longitudinal clinical trials with missing and non-normal continuous outcomes.

Missing data is unavoidable in longitudinal clinical trials, and outcomes are not always normally distributed. In the presence of outliers or heavy-tailed distributions, the conventional multiple imputation with the mixed model with repeated measures analysis of the average treatment effect (ATE) based on the multivariate normal assumption may produce bias and power loss. Control-based imputation (CBI) is an approach for evaluating the treatment effect under the assumption that participants in both the test and control groups with missing outcome data have a similar outcome profile as those with an identical history in the control group. We develop a robust framework to handle non-normal outcomes under CBI without imposing any parametric modeling assumptions. Under the proposed framework, sequential weighted robust regressions are applied to protect the constructed imputation model against non-normality in the covariates and the response variables. Accompanied by the subsequent mean imputation and robust model analysis, the resulting ATE estimator has good theoretical properties in terms of consistency and asymptotic normality. Moreover, our proposed method guarantees the analysis model robust-ness of the ATE estimation in the sense that its asymptotic results remain intact even when the analysis model is misspecified. The superiority of the proposed robust method is demonstrated by comprehensive simulation studies and an AIDS clinical trial data application.

Screening of NSAIDs library identifies Tinoridine as a novel ferroptosis inhibitor for potential intervertebral disc degeneration therapy.

Low back pain (LBP) may profoundly impact the quality of life across the globe, and intervertebral disc degeneration (IVDD) is the major cause of LBP; however, targeted pharmaceutical interventions for IVDD are still lacking. Ferroptosis is a novel form of iron-dependent programmed cell death. Studies have showed that ferroptosis may closely associate with IVDD; thus, targeting ferroptosis may have great potential for IVDD therapy. Non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line medications for LBP, while nuclear factor-erythroid 2-related factor-2 (Nrf2) is a key inhibitory protein for ferroptosis. In the current study, we conducted a molecular docking screening between NSAIDs library and Nrf2 protein. Tinoridine was shown to have a high binding affinity to Nrf2. The in vitro study in nucleus pulposus (NP) cells showed that Tinoridine may promote the expression and activity of Nrf2, it may also rescue RSL3-induced ferroptosis in NP cells. Knockdown of Nrf2 reverses the protective effect of Tinoridine on RSL3-induced ferroptosis in NP cells, suggesting that the inhibitory effect of Tinoridine on ferroptosis is through Nrf2. In vivo study demonstrated that Tinoridine may attenuate the progression of IVDD in rats. As NSAIDs are already clinically used for LBP therapy, the current study supports Tinoridine's application from the view of ferroptosis inhibition.

Higher exploratory and vigilant behaviors related to higher central dopaminergic activities of Formosan wood mice (Apodemus semotus) in light-dark exploration tests.

Formosan wood mice (Apodemus semotus) are endemic rodents in Taiwan. Recently Formosan wood mice exhibit similar locomotor behaviors in the laboratory environment as in the field environment has shown. Contemporaneously, Formosan wood mice have higher moving distances of and central dopaminergic (DAergic) activities than C57BL/6 mice in behavioral test. This study tried to compare the behavioral responses between male Formosan wood mice and male C57BL/6 mice in the light-dark exploration tests. We also measured the levels of DA and 3,4-dihydroxyphenylacetic acid (DOPAC), the primary metabolite of DA, to assess the dopaminergic activity of the medial prefrontal cortex, striatum, and nucleus accumbens. Our data show that Formosan wood mice revealed higher exploration and central DAergic activities than did C57BL/6 mice in the light-dark exploration tests, and diazepam (an anxiolytics) treatment reduced the exploratory activity and central dopaminergic activities in Formosan wood mice, but not in C57BL/6 mice. After repeated exposure to light-dark exploration tests, the latency to dark zone was increased, and the duration in light zone as well as the central DAergic activity were decreased in C57BL/6 mice. This study provides comparative findings; Formosan wood mice showed the higher exploratory activities than C57BL/6 mice did, and their central DAergic activities were related to the behavioral responses in these two mice. This could potentially shed light on the reasons behind the prevalence of higher exploration and central dopaminergic activities. Using Formosan wood mice as a model to study human diseases related to hyperactivity adds significant value to the potential research.

Resource diversity disturbs marine Vibrio diversity and community stability, but loss of Vibrio diversity enhances community stability.

Vibrio is a salt-tolerant heterotrophic bacterium that occupies an important ecological niche in marine environments. However, little is known about the contribution of resource diversity to the marine Vibrio diversity and community stability. In this study, we investigated the association among resource diversity, taxonomic diversity, phylogenetic diversity, and community stability of marine Vibrio in the Beibu Gulf. V. campbellii and V. hangzhouensis were the dominant groups in seawater and sediments, respectively, in the Beibu Gulf. Higher alpha diversity was observed in the sediments than in the seawater. Marine Vibrio community assembly was dominated by deterministic processes. Pearson's correlation analysis showed that nitrite (NO2--N), dissolved inorganic nitrogen (DIN), ammonium (NH4+-N), and pH were the main factors affecting marine Vibrio community stability in the surface, middle, and bottom layers of seawater and sediment, respectively. Partial least-squares path models (PLS-PM) demonstrated that resource diversity, water properties, nutrients, and geographical distance had important impacts on phylogenetic and taxonomic diversity. Regression analysis revealed that the impact of resource diversity on marine Vibrio diversity and community stability varied across different habitats, but loss of Vibrio diversity increases community stability. Overall, this study provided insights into the mechanisms underlying the maintenance of Vibrio diversity and community stability in marine environments.

Nitrogen-Rich Triazine-Based Covalent Organic Frameworks as Efficient Visible Light Photocatalysts for Hydrogen Peroxide Production.

Covalent organic frameworks (COFs) have been widely used in photocatalytic hydrogen peroxide (H2O2) production due to their favorable band structure and excellent light absorption. Due to the rapid recombination rate of charge carriers, however, their applications are mainly restricted. This study presents the design and development of two highly conjugated triazine-based COFs (TBP-COF and TTP-COF) and evaluates their photocatalytic H2O2 production performance. The nitrogen-rich structures and high degrees of conjugation of TBP-COF and TTP-COF facilitate improved light absorption, promote O2 adsorption, enhance their redox power, and enable the efficient separation and transfer of photogenerated charge carriers. There is thus an increase in the photocatalytic activity for the production of H2O2. When exposed to 10 W LED visible light irradiation at a wavelength of 420 nm, the pyridine-based TTP-COF produced 4244 µmol h-1 g-1 of H2O2 from pure water in the absence of a sacrificial agent. Compared to TBP-COF (1882 µmol h-1 g-1), which has a similar structure but lacks pyridine sites, TTP-COF demonstrated nearly 2.5 times greater efficiency. Furthermore, it exhibited superior performance compared to most previously published nonmetal COF-based photocatalysts.

Distributional imputation for the analysis of censored recurrent events.

Longitudinal clinical trials for which recurrent events endpoints are of interest are commonly subject to missing event data. Primary analyses in such trials are often performed assuming events are missing at random, and sensitivity analyses are necessary to assess robustness of primary analysis conclusions to missing data assumptions. Control-based imputation is an attractive approach in superiority trials for imposing conservative assumptions on how data may be missing not at random. A popular approach to implementing control-based assumptions for recurrent events is multiple imputation (MI), but Rubin's variance estimator is often biased for the true sampling variability of the point estimator in the control-based setting. We propose distributional imputation (DI) with corresponding wild bootstrap variance estimation procedure for control-based sensitivity analyses of recurrent events. We apply control-based DI to a type I diabetes trial. In the application and simulation studies, DI produced more reasonable standard error estimates than MI with Rubin's combining rules in control-based sensitivity analyses of recurrent events.

A highly sensitive ratiometric fluorescent probe for detecting HSO3-/SO32- and viscosity change based on FRET/TICT mechanism.

BACKGROUND: Sulfur dioxide (SO2) is a significant gas signaling molecule in organisms, and viscosity is a crucial parameter of the cellular microenvironment. They are both involved in regulating many physiological processes in the human body. However, abnormalities in SO2 and viscosity levels are associated with various diseases, such as cardiovascular disease, lung cancer, respiratory diseases, neurological disorders, diabetes and Alzheimer's disease. Hence, it is essential to explore novel and efficient fluorescent probes for simultaneously monitoring SO2 and viscosity in organisms. RESULTS: We selected quinolinium salt with good stability, high fluorescence intensity, good solubility and low cytotoxicity as the fluorophore and developed a highly sensitive ratiometric probe QQD to identify SO2 and viscosity changes based on Förster resonance energy transfer/twisted intramolecular charge transfer (FRET/TICT) mechanism. Excitingly, compared with other probes for SO2 detection, QQD not only identified HSO3-/SO32- with a large Stokes shift (218 nm), low detection limit (1.87 µM), good selectivity, high energy transfer efficiency (92 %) and wide recognition range (1.87-200 µM), but also identified viscosity with a 26-fold fluorescence enhancement and good linearity. Crucially, QQD was applied to detect HSO3-/SO32- and viscosity in actual water and food samples. In addition, QQD had low toxicity and good photostability for imaging HSO3-/SO32- and viscosity in cells. These results confirmed the feasibility and reliability of QQD for HSO3-/SO32- and viscosity imaging and environmental detection. SIGNIFICANCE: We reported a unique ratiometric probe QQD for detecting HSO3-/SO32- and viscosity based on the quinolinium skeleton. In addition to detecting HSO3-/SO32- and viscosity change in actual water and food samples, QQD could also monitor the variations of HSO3-/SO32- and viscosity in cells, which provided an experimental basis for further exploration of the role of SO2 derivatives and viscosity in biological systems.

Identifying Shared Neuroanatomic Architecture between Cognitive Traits through Multiscale Morphometric Correlation Analysis.

We introduce an informative metric, called morphometric correlation, as a measure of shared neuroanatomic similarity between two cognitive traits. Traditional estimates of trait correlations can be confounded by factors beyond brain morphology. To exclude these confounding factors, we adopt a Gaussian kernel to measure the morphological similarity between individuals and compare pure neuroanatomic correlations among cognitive traits. In our empirical study, we employ a multiscale strategy. Given a set of cognitive traits, we first perform morphometric correlation analysis for each pair of traits to reveal their shared neuroanatomic correlation at the whole brain (or global) level. After that, we extend our whole brain concept to regional morphometric correlation and estimate shared neuroanatomic similarity between two cognitive traits at the regional (or local) level. Our results demonstrate that morphometric correlation can provide insights into shared neuroanatomic architecture between cognitive traits. Furthermore, we also estimate the morphometricity of each cognitive trait at both global and local levels, which can be used to better understand how neuroanatomic changes influence individuals' cognitive status.