Regulation of capsule spine formation in castor.

Castor (Ricinus communis L.) is a dicotyledonous oilseed crop that can have either spineless or spiny capsules. Spines are protuberant structures that differ from thorns or prickles. The developmental regulatory mechanisms governing spine formation in castor or other plants have remained largely unknown. Herein, using map-based cloning in 2 independent F2 populations, F2-LYY5/DL01 and F2-LYY9/DL01, we identified the RcMYB106 (myb domain protein 106) transcription factor as a key regulator of capsule spine development in castor. Haplotype analyses demonstrated that either a 4,353-bp deletion in the promoter or a single nucleotide polymorphism leading to a premature stop codon in the RcMYB106 gene could cause the spineless capsule phenotype in castor. Results of our experiments indicated that RcMYB106 might target the downstream gene RcWIN1 (WAX INDUCER1), which encodes an ethylene response factor known to be involved in trichome formation in Arabidopsis (Arabidopsis thaliana) to control capsule spine development in castor. This hypothesis, however, remains to be further tested. Nevertheless, our study reveals a potential molecular regulatory mechanism underlying the spine capsule trait in a nonmodel plant species.

Non-generic bound states in the continuum in waveguides with lateral leakage channels.

For optical waveguides with a layered background which itself is a slab waveguide, a guided mode is a bound state in the continuum (BIC), if it coexists with slab modes propagating outwards in the lateral direction; i.e., there are lateral leakage channels. It is known that generic BICs in optical waveguides with lateral leakage channels are robust in the sense that they still exist if the waveguide is perturbed arbitrarily. However, the theory is not applicable to non-generic BICs which can be defined precisely. Near a BIC, the waveguide supports resonant and leaky modes with a complex frequency and a complex propagation constant, respectively. In this paper, we develop a perturbation theory to show that the resonant and leaky modes near a non-generic BIC have an ultra-high Q factor and ultra-low leakage loss, respectively. Recently, many authors studied merging-BICs in periodic structures through tuning structural parameters. It has been shown that resonant modes near a merging-BIC have an ultra-high Q factor. However, the existing studies on merging-BICs are concerned with specific examples and specific parameters. Moreover, we analyze an arbitrary structural perturbation given by δF(r) to waveguides supporting a non-generic BIC, where F(r) is the perturbation profile and δ is the amplitude, and show that the perturbed waveguide has two BICs for δ > 0 (or δ < 0) and no BIC for δ < 0 (or δ > 0). This implies that a non-generic BIC can be regarded as a merging-BIC (for almost any perturbation profile F) when δ is considered as a parameter. Our study indicates that non-generic BICs have interesting special properties that are useful in applications.

Bifurcation of bound states in the continuum in periodic structures.

In lossless dielectric structures with a single periodic direction, a bound state in the continuum (BIC) is a special resonant mode with an infinite quality factor (Q factor). The Q factor of a resonant mode near a typical BIC satisfies Q∼1/(ß-ß ∗)2, where ß and ß ∗ are the Bloch wavenumbers of the resonant mode and the BIC, respectively. However, for some special BICs with ß ∗=0 (referred to as super-BICs by some authors), the Q factor satisfies Q ∼ 1/ß6. Although super-BICs are usually obtained by merging a few BICs through tuning a structural parameter, they can be precisely characterized by a mathematical condition. In this Letter, we consider arbitrary perturbations to structures supporting a super-BIC. The perturbation is given by δF(r), where δ is the amplitude and F(r) is the perturbation profile. We show that for a typical F(r), the BICs in the perturbed structure exhibit a pitchfork bifurcation around the super-BIC. The number of BICs changes from one to three as δ passes through zero. However, for some special profiles F(r), there is no bifurcation, i.e., there is only a single BIC for δ around zero. In that case, the super-BIC is not associated with a merging process for which δ is the parameter.

Rolapitant treats lung cancer by targeting deubiquitinase OTUD3.

BACKGROUND: Lung cancer is cancer with the highest morbidity and mortality in the world and poses a serious threat to human health. Therefore, discovering new treatments is urgently needed to improve lung cancer prognosis. Small molecule inhibitors targeting the ubiquitin-proteasome system have achieved great success, in which deubiquitinase inhibitors have broad clinical applications. The deubiquitylase OTUD3 was reported to promote lung tumorigenesis by stabilizing oncoprotein GRP78, implying that inhibition of OTUD3 may be a therapeutic strategy for lung cancer. RESULTS: In this study, we identified a small molecule inhibitor of OTUD3, Rolapitant, by computer-aided virtual screening and biological experimental verification from FDA-approved drugs library. Rolapitant inhibited the proliferation of lung cancer cells by inhibiting deubiquitinating activity of OTUD3. Quantitative proteomic profiling indicated that Rolapitant significantly upregulated the expression of death receptor 5 (DR5). Rolapitant also promoted lung cancer cell apoptosis through upregulating cell surface expression of DR5 and enhanced TRAIL-induced apoptosis. Mechanistically, Rolapitant directly targeted the OTUD3-GRP78 axis to trigger endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP)-DR5 signaling, sensitizing lung cancer cells to TRAIL-induced apoptosis. In the vivo assays, Rolapitant suppressed the growth of lung cancer xenografts in immunocompromised mice at suitable dosages without apparent toxicity. CONCLUSION: In summary, the present study identifies Rolapitant as a novel inhibitor of deubiquitinase OTUD3 and establishes that the OTUD3-GRP78 axis is a potential therapeutic target for lung cancer.

T-cell lymphopenia is associated with an increased infecting risk in children after cardiopulmonary bypass.

BACKGROUND: children who undergo CPB operations are at an elevated risk of infection due to immunosuppression. This study aims to investigate the association between lymphopenia following CPB and early postoperative infection in children. METHODS: A retrospective analysis including 41 children under 2 years old underwent CPB. Among them, 9 subjects had an early postoperative infection, and 32 subjects were period-matched without infection. Inflammatory cytokines, serum CRP and PCT values were measured in plasma, additionally, circulating total leucocyte and lymphocyte subpopulations were counted. RESULTS: Infected subjects exhibited significantly higher levels of inflammatory cytokines, including IL-6, IL-8, IL-10, IL-1ß and TNF-α, than non-infected subjects after CPB. Additionally, lower absolute number of lymphocyte and their subpopulations CD3+ T cells, CD4+ T-helper cells and CD8+cytotoxic T-cells, were observed in infected subjects. The impairment of T-cells Immune was found to be associated with higher levels of inflammatory cytokines IL-10. The ROC demonstrated that the absolute number of CD3+ T-cells <1934/ul, CD4+ T helper cells <1203/ul and CD8+cytotoxic T-cells <327/ul were associated with early postoperative infection. CONCLUSION: Higher levels of inflammatory cytokines resulted in T-cells lymphopenia after CPB, which significantly increasing the risk of postoperative infection in infants and young children. IMPACT: Infection complications after cardiopulmonary bypass (CPB) in pediatric CHD patients are serious issues, identifing the infection from after CPB remains a challenging. CPB can release numerous inflammatory cytokines associated with T cells lymphopenia, which increases the risk of postoperative infection after surgery. Monitoring T cells lymphopenia maybe more beneficial to predict early postoperative infection than C-reactive protein and procalcitonin.

Sex differences in the frailty phenotype and mortality in the I-Lan longitudinal aging study cohort.

BACKGROUND: Frailty is a common geriatric syndrome related to multiple adverse outcomes. Sex differences in its prevalence and impact on mortality remain incompletely understood. METHODS: This study was conducted with data from the I-Lan Longitudinal Aging Study, in which community-dwelling subjects aged > 50 years without coronary artery disease or diabetes were enrolled. Sex disparities in phenotypically defined frailty and sex-morality predictor interactions were evaluated. Sex- and frailty-stratified analyses of mortality were performed. RESULTS: The sample comprised 1371 subjects (51.4% women, median age 61 years). The median follow-up period was 6.3 (interquartile range, 5.8-7.0) years. The frailty prevalence did not differ between men (5.3%) and women (5.8%). Frail individuals were older and less educated and had poorer renal function than did non-frail individuals. Body composition trends differed between sexes, regardless of frailty. Relative to non-frail men, frail men had significantly lower body mass indices (BMIs; 24.5 vs. 23.4 kg/m2, p = 0.04) and relative appendicular skeletal muscle masses (7.87 vs. 7.05 kg/m2, p < 0.001). Frail women had significantly higher BMIs (25.2 vs. 23.9 kg/m2, p = 0.02) and waist circumferences (88 vs. 80 cm, p < 0.001) than did non-frail women. Frailty was an independent mortality predictor for men only [hazard ratio (95% confidence interval) = 3.395 (1.809-6.371), psex-frailty interaction = 0.03]. CONCLUSION: Frailty reflected poorer health in men than in women in the present cohort. This study revealed sex disparities in the impact of frailty on mortality among relatively healthy community-dwelling older adults.

MiR-124 synergism with ELAVL3 enhances target gene expression to promote neuronal maturity.

Neuron-enriched microRNAs (miRNAs), miR-9/9* and miR-124 (miR-9/9*-124), direct cell fate switching of human fibroblasts to neurons when ectopically expressed by repressing antineurogenic genes. How these miRNAs function after the repression of fibroblast genes for neuronal fate remains unclear. Here, we identified targets of miR-9/9*-124 as reprogramming cells activate the neuronal program and reveal the role of miR-124 that directly promotes the expression of its target genes associated with neuronal development and function. The mode of miR-124 as a positive regulator is determined by the binding of both AGO and a neuron-enriched RNA-binding protein, ELAVL3, to target transcripts. Although existing literature indicates that miRNA-ELAVL family protein interaction can result in either target gene up-regulation or down-regulation in a context-dependent manner, we specifically identified neuronal ELAVL3 as the driver for miR-124 target gene up-regulation in neurons. In primary human neurons, repressing miR-124 and ELAVL3 led to the down-regulation of genes involved in neuronal function and process outgrowth and cellular phenotypes of reduced inward currents and neurite outgrowth. Our results highlight the synergistic role between miR-124 and RNA-binding proteins to promote target gene regulation and neuronal function.

Versatile Use of V-Y Advancement Flap for Facial Defect Reconstruction: A Case Series in Asian Patients.

BACKGROUND: V-Y advancement flap (VYAF) is a commonly used flap for facial reconstruction, but it is not popular in Asian society with limited aesthetic outcome evaluation. OBJECTIVE: To demonstrate our experience of facial VYAF with the quantitative aesthetic outcome assessment. METHODS AND MATERIALS: From January 2013 to December 2022, patients who underwent facial VYAF reconstruction were reviewed. Postoperative photographs were collected and independently graded by three plastic surgeons, three nurses, and six non-medical personnel using Manchester scar scale (MSS). The representative preoperative images were selected for surgeons' reconstruction preferences survey. RESULTS: Forty-eight patients (27 females and 21 males), with a mean age of 66.8 (23-97) years, were included in this study. All flaps survived with no flap necrosis. Only six patients (12.5%) developed minor postoperative complications, and they were treated conservatively and resolved uneventfully. The total MSS score was 7.8 ± 1.9 (scale of 4 [best scar] to 24 [worst scar]) and the overall scar VAS rating was 1.9 ± 1.1 (0 [best scar] to 10 [worst scar]), indicating satisfactory postoperative scar condition. From the survey of 22 plastic surgeons and 11 scenarios, VYAF was rarely chosen among other local flaps which only accounted for 8.7%. CONCLUSION: VYAF is an easy and safe method for facial reconstruction with low morbidity, but its usefulness is underappreciated. With a proper design and cautious dissection, we believe that good aesthetic and functional outcomes can be achieved with VYAF. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

[Advances in molecular mechanisms and therapeutic strategies of white matter injury after intracerebral hemorrhage].

Intracerebral hemorrhage (ICH) is the most common subtype of stroke with high disability and high mortality rates. Due to the hypertension with arteriosclerosis, hemopathy and cerebrovascular amyloidosis, the influx of blood from ruptured vessels into the brain destroys the cerebral parenchyma and results in dysfunction of central nervous system because of hematoma compression and a series of toxic metabolites. The cerebral parenchyma consists of gray and white matter. The white matter consists of myelinated axons and oligodendrocytes, whereas the gray matter consists of neuronal cell bodies and dendrites. Currently, most of studies have explored the mechanisms of gray matter injury. But researches of white matter injury (WMI) are still in their infancy, which may be partially responsible for the failure of treatments with neuroprotectants targeting degenerating neuronal cells. In recent years, researchers have progressively identified pathophysiological mechanisms of WMI after ICH including mass effect, neuroinflammation and oxidative stress, but information on the molecular mechanisms of WMI and its effective treatment remains limited. In this paper, we will describe the structure and function of white matter, summarize pathology of WMI and focus on the research advances in the molecular mechanisms and therapeutic strategies of WMI after ICH.

GBDT_KgluSite: An improved computational prediction model for lysine glutarylation sites based on feature fusion and GBDT classifier.

BACKGROUND: Lysine glutarylation (Kglu) is one of the most important Post-translational modifications (PTMs), which plays significant roles in various cellular functions, including metabolism, mitochondrial processes, and translation. Therefore, accurate identification of the Kglu site is important for elucidating protein molecular function. Due to the time-consuming and expensive limitations of traditional biological experiments, computational-based Kglu site prediction research is gaining more and more attention. RESULTS: In this paper, we proposed GBDT_KgluSite, a novel Kglu site prediction model based on GBDT and appropriate feature combinations, which achieved satisfactory performance. Specifically, seven features including sequence-based features, physicochemical property-based features, structural-based features, and evolutionary-derived features were used to characterize proteins. NearMiss-3 and Elastic Net were applied to address data imbalance and feature redundancy issues, respectively. The experimental results show that GBDT_KgluSite has good robustness and generalization ability, with accuracy and AUC values of 93.73%, and 98.14% on five-fold cross-validation as well as 90.11%, and 96.75% on the independent test dataset, respectively. CONCLUSION: GBDT_KgluSite is an effective computational method for identifying Kglu sites in protein sequences. It has good stability and generalization ability and could be useful for the identification of new Kglu sites in the future. The relevant code and dataset are available at https://github.com/flyinsky6/GBDT_KgluSite .

NRP1 contributes to stemness and potentiates radioresistance via WTAP-mediated m6A methylation of Bcl-2 mRNA in breast cancer.

NRP1 is a transmembrane glycoprotein that is highly expressed in a variety of tumors. There is evidence that NRP1 can enhance the stem cell properties of tumor cells, which are thought to be resistant to radiotherapy. This study aims to elucidate the potential mechanism of NRP1 in radiation resistance. We transfected NRP1 siRNA and plasmid in breast cancer cells to detect the expression of cancer stem cell markers by western blot and qRT-PCR. The effect of NRP1 on radiotherapy resistance was assesses by immunofluorescence and flow cytometry. In vivo, we established xenograft tumor model treating with shRNA-NRP1 to assess radiotherapy sensitivity. We found that NRP1 could enhance the stem cell properties and confer radioresistance of breast cancer cells. Mechanistically, we proved that NRP1 reduced IR-induced apoptosis by downregulation of Bcl-2 via methyltransferase WTAP in m6A-depentent way. It is suggested that these molecules may be the therapeutic targets for improving the efficacy of radiotherapy for breast cancer.

Robust and non-robust bound states in the continuum in rotationally symmetric periodic waveguides.

A fiber grating and a one-dimensional (1D) periodic array of spheres are examples of rotationally symmetric periodic (RSP) waveguides. It is well known that bound states in the continuum (BICs) may exist in lossless dielectric RSP waveguides. Any guided mode in an RSP waveguide is characterized by an azimuthal index m, the frequency ω, and Bloch wavenumber ß. A BIC is a guided mode, but for the same m, ω and ß, cylindrical waves can propagate to or from infinity in the surrounding homogeneous medium. In this paper, we investigate the robustness of nondegenerate BICs in lossless dielectric RSP waveguides. The question is whether a BIC in an RSP waveguide with a reflection symmetry along its axis z, can continue its existence when the waveguide is perturbed by small but arbitrary structural perturbations that preserve the periodicity and the reflection symmetry in z. It is shown that for m = 0 and m ≠ 0, generic BICs with only a single propagating diffraction order are robust and non-robust, respectively, and a non-robust BIC with m ≠ 0 can continue to exist if the perturbation contains one tunable parameter. The theory is established by proving the existence of a BIC in the perturbed structure mathematically, where the perturbation is small but arbitrary, and contains an extra tunable parameter for the case of m ≠ 0. The theory is validated by numerical examples for propagating BICs with m ≠ 0 and ß ≠ 0 in fiber gratings and 1D arrays of circular disks.

CircRNA hsa_circ_0071336 is associated with type 2 diabetes through targeting the miR-93-5p/GLUT4 axis.

Glucose transporter 4 (GLUT4) is a dominant regulator of whole-body glucose homeostasis. Accumulating evidence has shown that circular RNAs (circRNAs) play significant roles in the pathogenesis of disease. The aim of the present study was to identify the circRNA that can be used as a novel biomarker for type 2 diabetes (T2D) through regulating GLUT4. Based on previous microarray analysis comparing T2D cases and healthy controls, hsa_circ_0071336, which was predicted to be a regulator of GLUT4 by acting as a competitive endogenous RNAs (ceRNA) to sponge miR-93-5p, was selected for further validation. The clinical significance of circulating hsa_circ_0071336 was investigated in a large independent cohort. The results showed that circulating hsa_circ_0071336 was significantly downregulated in blood in T2D and had a high diagnostic accuracy for discriminating T2D and impaired fasting glucose (IFG) from healthy controls. Low expression of circ_0071336 was an independent predictor of T2D, IFG and insulin resistance. A luciferase reporter assay and western-blot analysis indicated that miR-93-5p was a direct target of hsa_circ_0071336, and miR-93-5p may negatively regulate the expression of GLUT4. The expression levels of hsa_circ_007136 were negatively related to miR-93-5p expression and positively correlated with the mRNA expression of GLUT4 in adipose tissues. In conclusion, hsa_circRNA_0071336 can be considered as a potential novel and stable biomarker for T2D and its early detection. hsa_circ_0071336 regulates the GLUT4 expression by sponging miR-93-5p and maybe involved in the pathogenesis of T2D. These findings may unveil new targets for the prevention, diagnosis and treatment of T2D.

Alterations of Spontaneous Cortical and Subcortical Activity in Type 2 Diabetes Mellitus with and without Depression.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) patients with depression have a higher risk of complications and mortality than T2DM without depression. However, the exact neuropathophysiological mechanism remains unclear. Consequently, the current study aimed to investigate the alteration of cortical and subcortical spontaneous neural activity in T2DM patients with and without depression. METHODS: The demographic data, clinical variables, neuropsychological tests, and functional and anatomical magnetic resonance imaging of depressed T2DM (n = 47) of non-depressed T2DM (n = 59) and healthy controls (n = 41) were collected and evaluated. The correlation analysis, stepwise multiple linear regression, and receiver operating characteristic curve were performed for further analysis. RESULTS: Abnormal neural activities in the bilateral posterior cingulate cortex (PCC) and hippocampus were observed in depressed and non-depressed T2DM and the right putamen of the depressed T2DM. Interestingly, the subcortical degree centrality (DC) of the right hippocampus and putamen were higher in depressed than non-depressed T2DM. Furthermore, the cortical amplitude of low-frequency fluctuation (ALFF) in PCC, subcortical DC in the putamen of depressed T2DM, and hippocampus of non-depressed T2DM was correlated with cognitive scores. In contrast, the cortical fractional ALFF in PCC of non-depressed T2DM was correlated with depression scores. CONCLUSIONS: The abnormalities of spontaneous cortical activity in PCC and subcortical activity in the hippocampus might represent the neurobiological feature of cerebral dysfunction in T2DM. Notably, the altered subcortical activity in the right putamen might mainly associate with negative emotion in T2DM, which could be a promising biomarker for recognizing early cerebral dysfunction in depressed T2DM. This study provided a novel insight into the neuropathophysiological mechanism of brain dysfunction in T2DM with and without depression.

A Superhydrophobic Trifluoromethyl-Containing Covalent Organic Framework Membrane for Efficient Oil/Water Separation.

Oily water caused in the process of industry leads to not only the waste of resources, but also environmental pollution. Membrane separation, as a facile and efficient separation technology, has attracted widespread attention in the field of oil/water separation. The development of membrane materials with high separation performance is one of the key elements to improve separation efficiency. In this work, a superhydrophobic membrane composited with a trifluoromethyl-containing covalent organic framework (COF) is prepared, which exhibits excellent performance on separations of oil/water mixtures and water-in-oil emulsions. For different composition of oil/water mixtures, the highest flux of oil is up to 32 000 L m-2  h-1 and oil/water separation efficiency is above 99%. Moreover, the high oil/water separation efficiency remains unchanged after successive cycles. This work provides a feasible scheme for the design of high-efficiency oil/water separation membranes.

Clinical Efficacy of Tandospirone on Functional Dyspepsia Patients with Anxiety: A Randomized, Placebo-Controlled Study.

BACKGROUND: Functional dyspepsia (FD) is characterized with multiple symptoms of indigestion and often accompanied with anxiety. However, there is currently an absence of effective treatment. Tandospirone is commonly used to treat generalized anxiety disorders. Whether tandospirone can improve the clinical symptoms of FD remain unknown. AIMS: The present study was designed to explore the pharmacological effect of tandospirone on FD patient with anxiety, and the potential mechanisms were also elucidated. METHODS: FD patients with anxiety were randomly divided into placebo and tandospirone treatment groups. Healthy volunteers were simultaneously recruited as control group. The gastrointestinal symptom score (GIS) and Hamilton anxiety scale (HAM-A) were performed before and after treatments with placebo or tandospirone. The serum levels of brain-derived neurotrophic factor (BDNF) and multiple inflammatory cytokines including tumor necrosis factor-α (TNF-α), and interleukin (IL)-6, IL-4, IL-1ß, and IL-10 were determined. Regression analyses relating BDNF levels and gastrointestinal symptoms were performed. RESULTS: Tandospirone significantly alleviated the gastrointestinal and anxiety symptoms of FD patient, as evidenced by reductions of GIS index and HAM-A scores. Compared with the healthy volunteers, FD patients had lower BDNF and IL-10 levels, but higher levels of IL-6 and TNF-α. Importantly, tandospirone increased serum BDNF and IL-10 and decreased IL-6 levels in FD patients. Relative analysis revealed that BDNF level was negatively associated with gastrointestinal symptoms in FD patients. CONCLUSION: Tandospirone effectively improved both anxiety and gastrointestinal symptoms of patients with FD, and these therapeutic effects may be associated with the modulation of BDNF and inflammatory cytokines.

Is use of a long-term proton pump inhibitor or histamine-2 receptor antagonist a risk factor for iron-deficiency anaemia in Taiwan? A neglected clinical drug-drug interaction.

BACKGROUND: Proton pump inhibitors (PPIs) and histamine-2 receptor (H2) antagonists change the gastric pH and reduce the intestinal absorption of nonheme iron. Case reports and case-control studies have demonstrated that absorption of iron is affected by gastric acidity, but the clinical importance of these drug-drug interactions has remained uncertain. OBJECTIVES: The present case-control study employed 2 million longitudinal claims in 2011-2018 in the Taiwan National Health Insurance Research Database to investigate the impact of PPIs/H2 antagonists on the occurrence of iron-deficiency anaemia (IDA). METHODS: The present study retrospectively compared exposure to PPIs/H2 antagonists for 1 year among 5,326 cases with IDA and 21,304 matched controls. The postdiagnosis prescribing pattern was also calculated to understand current practice. RESULTS: Long-term (≥2 month) use of PPIs/H2 antagonists resulted in a higher risk of developing IDA than noncontinuous use/nonuse of those drugs (adjusted odds ratio [aOR] = 2.36, 95% confidence interval [CI] = 1.94-2.86, P < 0.001). There were significant changes in the postdiagnosis prescribing patterns of PPIs/H2 antagonists. The risk of developing IDA remained significant in the female subgroup (aOR = 2.16, 95% CI = 1.73-2.70, P < 0.001) and was even more prominent in those aged ≥ 50 years (aOR = 2.68, 95% CI = 1.94-3.70, P < 0.05). CONCLUSIONS: This study found that long-term use of PPIs/H2 antagonists increased the risk of developing IDA, and there was strong evidence of prescription pattern adjustments postdiagnosis. Physicians and pharmacists should be aware of this risk when patients are expected to take or have been taking PPIs/H2 antagonists for the long term.

Proton pump inhibitors (PPIs) and histamine-2 receptor (H2) antagonists, 2 kinds of gastric suppressants commonly used for gastroesophageal reflux disease, decrease iron absorption in the gut and thus increase the risk of developing iron-deficiency anaemia (IDA). We constructed a retrospective matched case-control study within the Taiwan National Health Insurance Research Database. The longer period of PPIs/H2 antagonists used, the higher risk of IDA was, with the highest risk in female elderly groups (adjusted odds ratio = 2.68 in females aged ≥ 50). PPI users had a higher risk than H2 antagonist users during the 1-year follow-up. The prescription patterns postdiagnosis of IDA witnessed considerable drops for both groups, with less than a 10th of original users remaining the usages (1.72% and 9.85% taking PPIs and H2 antagonists within 90 days after receiving a diagnosis, respectively). Physicians and pharmacists should be aware of the risk of developing IDA in patients currently undergoing or expected to take long-term gastric acid suppressants.

MicroRNA153 induces apoptosis by targeting NFATc3 to improve vascular remodeling in pulmonary hypertension.

BACKGROUND: The present study aimed to investigate the effect of microRNA153 (miRNA153) on pulmonary hypertension (PH). METHODS: PH was induced by a single subcutaneous injection of sugen5416 (SU5416) combined with hypoxia exposure for 3 weeks (SuHx) in rats, while pulmonary arterial smooth muscle cells (PASMCs) obtained from rats were exposed to hypoxia to establish an in vitro model. Through observing the characteristic hemodynamic index in rats and by analyzing the physiological function, vascular remodeling and right ventricular hypertrophy were identified. The regulatory effects of miRNA153 on the nuclear factor of activated T cell isoform c3 (NFATc3) were measured by RT-qPCR, western blot, and immunofluorescence. Cell apoptosis was evaluated by flow cytometry. RESULTS: The miRNA153 expression was reduced and unclear translation of NFATc3 was increased in both the in vivo and in vitro models of PH. In vivo, the pulmonary arterial pressure, right ventricle/(left ventricle + interventricular septum) (RV/(LV+S)), and media vascular thickness were increased in rats with PH; however, all these parameters were suppressed by prophylactic administration of miRNA153agomir. The upregulation of NFATc3 and downregulation of the potassium voltage-gated channel subfamily A member 5 (Kv1.5) were also reversed by transfection with miRNA153agomir. In vitro, miRNA153 increased the level of Kv1.5 in hypoxic PASMCs by targeting NFATc3 and inhibiting their proliferation and apoptosis resistance. CONCLUSION: Our results confirmed that the therapeutic administration of miRNA153 promotes apoptosis and inhibits the proliferation of PASMCs to ameliorate PH, and that the NFATc3/Kv1.5 channel pathway may be involved in this process.

Explainable Machine Learning Techniques To Predict Amiodarone-Induced Thyroid Dysfunction Risk: Multicenter, Retrospective Study With External Validation.

BACKGROUND: Machine learning offers new solutions for predicting life-threatening, unpredictable amiodarone-induced thyroid dysfunction. Traditional regression approaches for adverse-effect prediction without time-series consideration of features have yielded suboptimal predictions. Machine learning algorithms with multiple data sets at different time points may generate better performance in predicting adverse effects. OBJECTIVE: We aimed to develop and validate machine learning models for forecasting individualized amiodarone-induced thyroid dysfunction risk and to optimize a machine learning-based risk stratification scheme with a resampling method and readjustment of the clinically derived decision thresholds. METHODS: This study developed machine learning models using multicenter, delinked electronic health records. It included patients receiving amiodarone from January 2013 to December 2017. The training set was composed of data from Taipei Medical University Hospital and Wan Fang Hospital, while data from Taipei Medical University Shuang Ho Hospital were used as the external test set. The study collected stationary features at baseline and dynamic features at the first, second, third, sixth, ninth, 12th, 15th, 18th, and 21st months after amiodarone initiation. We used 16 machine learning models, including extreme gradient boosting, adaptive boosting, k-nearest neighbor, and logistic regression models, along with an original resampling method and 3 other resampling methods, including oversampling with the borderline-synthesized minority oversampling technique, undersampling-edited nearest neighbor, and over- and undersampling hybrid methods. The model performance was compared based on accuracy; Precision, recall, F1-score, geometric mean, area under the curve of the receiver operating characteristic curve (AUROC), and the area under the precision-recall curve (AUPRC). Feature importance was determined by the best model. The decision threshold was readjusted to identify the best cutoff value and a Kaplan-Meier survival analysis was performed. RESULTS: The training set contained 4075 patients from Taipei Medical University Hospital and Wan Fang Hospital, of whom 583 (14.3%) developed amiodarone-induced thyroid dysfunction, while the external test set included 2422 patients from Taipei Medical University Shuang Ho Hospital, of whom 275 (11.4%) developed amiodarone-induced thyroid dysfunction. The extreme gradient boosting oversampling machine learning model demonstrated the best predictive outcomes among all 16 models. The accuracy; Precision, recall, F1-score, G-mean, AUPRC, and AUROC were 0.923, 0.632, 0.756, 0.688, 0.845, 0.751, and 0.934, respectively. After readjusting the cutoff, the best value was 0.627, and the F1-score reached 0.699. The best threshold was able to classify 286 of 2422 patients (11.8%) as high-risk subjects, among which 275 were true-positive patients in the testing set. A shorter treatment duration; higher levels of thyroid-stimulating hormone and high-density lipoprotein cholesterol; and lower levels of free thyroxin, alkaline phosphatase, and low-density lipoprotein were the most important features. CONCLUSIONS: Machine learning models combined with resampling methods can predict amiodarone-induced thyroid dysfunction and serve as a support tool for individualized risk prediction and clinical decision support.

The effects of short-term exposure to air pollution on mortality in Baotou, China, during 2015-2019.

Air pollution was considered one of the main causes linked to increased morbidity and mortality around the world. This study aimed to estimate the effect of air pollutants on daily death in Baotou city of Inner Mongolia. Daily deaths data were provided by Baotou Centers for Disease Control and Prevention for the years 2015-2019 (Baotou CDC). The air pollutants, PM2.5, PM10, NO2, SO2, CO and maximum 8-h average concentrations of O3, came from the eight environmental monitoring stations in Baotou city. Time-series plots were used to exploit the trend of air pollutants at calendar time. Generalized additive model was used to estimate the effect of air pollutants on daily death. Restricted cubic spline was employed to investigate non-line relationships between air pollutants and daily death. After adjusting the meteorological factors, non-accidental daily deaths were related to PM2.5 (ER = 0.074%) and PM10 (ER = 0.023%), respectively. In stratified analysis, population aged over 65 years and females were more sensitive to air pollutants exposure and warm season might make people more susceptible to air pollutants compared with cold season. PM2.5 and PM10 increase the risk of non-accidental and cardiovascular daily death, but not respiratory daily death.