Idiopathic pulmonary fibrosis is incurable, and its progression is difficult to control and thus can lead to pulmonary deterioration. Pan-histone deacetylase inhibitors such as SAHA have shown ...potential for modulating pulmonary fibrosis yet with off-target effects. Therefore, selective HDAC inhibitors would be beneficial for reducing side effects. Toward this goal, we designed and synthesized 24 novel HDAC6, HDAC8, or dual HDAC6/8 inhibitors and established a two-stage screening platform to rapidly screen for HDAC inhibitors that effectively mitigate TGF-β-induced pulmonary fibrosis. The first stage consisted of a mouse NIH-3T3 fibroblast prescreen and yielded five hits. In the second stage, human pulmonary fibroblasts (HPFs) were used, and four out of the five hits were tested for caco-2 permeability and liver microsome stability to give two potential leads: J27644 (15) and 20. This novel two-stage screen platform will accelerate the discovery and reduce the cost of developing HDAC inhibitors to mitigate TGF-β-induced pulmonary fibrosis.
Osteoporosis increases the fracture and mortality risk of patients and has a higher disease burden than some cancers. Therefore, global concerns regarding the prevention and treatment of osteoporosis ...have been raised. However, fast-aging Taiwan lacks national epidemiological data on osteoporosis in recent years. We aimed to establish and update epidemiological data on osteoporosis by analyzing national data from 2008 to 2019.
We estimated the prevalence and incidence of osteoporosis in patients aged ≥50 years based on claims data from Taiwan's National Health Insurance database from 2008 to 2019. We also analyzed the key parameters of fracture care (anti-osteoporosis medication use, bone mineral density examination rate, and length of hospital stay) to understand the secular trend of management and related clinical outcomes (imminent refracture rate and mortality).
The number of prevalent osteoporosis increased from 2008 to 2015 and remained constant until 2019; however, the age-standardized prevalence and incidence rates declined from 2008 to 2019 (3.77%–2.91% and 2.08%–1.02%, respectively). The overall incidence rates of hip and spine fractures decreased significantly by 34% and 27%, respectively. For patients with hip and spine fractures, the immanent refracture rates were 8.5% and 12.9% and the 1-year mortality rate remained stable at approximately 15% and 6%, respectively.
The age-standardized prevalence and incidence rates decreased remarkably from 2008 to 2019, while the number of prevalent osteoporosis remained steady. Patients with hip fractures encountered a high 1-year mortality rate, while the risk of imminent refracture was notable for patients with spine fractures.
In this study, we assessed plasma biomarkers to identify cognitive impairment in Parkinson's disease (PD) patients by applying ultra-sensitive immunomagnetic reduction-based immunoassay (IMR).
The ...study enrolled 60 PD patients and 28 age- and sex-matched normal controls. Complete cognitive function assessments were performed on participants using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating. PD patients with an MMSE score of ≦26 were defined as having cognitive impairment. Meanwhile, a 99mTc-TRODAT-1 scan was performed and plasma levels of Aβ-40, Aβ-42, T-tau, and α-synuclein were evaluated using IMR, subsequent correlation analyses were then performed.
Compared with normal adults, PD patients have higher plasma levels of α-synuclein and T-tau, and a lower level of Aβ-40 (
< 0.05). Plasma levels of α-synuclein (
= -0.323,
= 0.002), Aβ-40 (
= 0.276,
= 0.01), and T-tau (
= -0.322,
= 0.002) are significantly correlated with MMSE scores. The TRODAT scan results, including visual inspection and quantification, revealed significant correlations between Aβ-40 and PD. Multiple regression analysis showed that the plasma levels of Aβ-40 (OR = 0.921, 95% CI = 0.879-0.962), α-synuclein (OR = 3.016, 95% CI = 1.703-5.339), and T-tau (OR = 1.069, 95% CI = 1.026-1.115) were independently associated with PD patients with cognitive impairment. The cutoff values for predicting cognitive deficits in PD patients were 45.101 pg/ml of Aβ-40, (Area under curve (AUC) = 0.791), 0.389 pg/ml of α-synuclein, (AUC = 0.790), and 30.555 pg/ml of T-tau (AUC = 0.726).
Plasma levels of α-synuclein, Aβ-40, and T-tau are potential biomarkers to detect cognitive impairment in PD patients.
Adherence to anti-osteoporosis medications (AOMs) is crucial. National Health Insurance (NHI) in Taiwan has its own rules of reimbursement rule for AOMs. The midterm adherence remained inconclusive. ...Here we investigated the adherence according to the initially used AOMs, for three consecutive years.
The nationwide cohort study from 2008 to 2018, based on Taiwan's National Health Insurance Research Database, included 336,229 patients. Their adherence, indicated by medication possession ratio (MPR), to the initial AOMs was investigated yearly for three consecutive years. The overall MPRs (OMPR), including the switched AOMs, were also calculated in the first year. The Sankey diagram further visualized the patient flows toward different adherence according to the initial AOMs.
The OMPR in the first year improved if the patients used AOMs with longer dosing intervals. 100%, 68.9%, 40.7%, and 34.0% of the patients started the treatment with zoledronate, denosumab, alendronate, and raloxifene, respectively, had OMPR ≥75% in the first year. In the 3rd year, only 20.89%, 24.13%, and 12.83% of the patients continuously treated with zoledronate, denosumab, and alendronate, respectively, had MPR ≥75%. From the Sankey diagram, we also observed that patients who had poor adherence at one year were inclined to have poor adherence or discontinue antiosteoporosis treatment in the next year.
The initial AOMs and the observed adherence may provide clues for optimizing patient treatment. The real-world adherence in Taiwan was far from satisfactory in our study.
Background
Both nonoperative and operative treatments for spinal metastasis are expensive interventions. Patients' expected 3‐month survival is believed to be a key factor to determine the most ...suitable treatment. However, to the best of our knowledge, no previous study lends support to the hypothesis. We sought to determine the cost‐effectiveness of operative and nonoperative interventions, stratified by patients' predicted probability of 3‐month survival.
Methods
A Markov model with four defined health states was used to estimate the quality‐adjusted life years (QALYs) and costs for operative intervention with postoperative radiotherapy and radiotherapy alone (palliative low‐dose external beam radiotherapy) of spine metastases. Transition probabilities for the model, including the risks of mortality and functional deterioration, were obtained from secondary and our institutional data. Willingness to pay thresholds were prespecified at $100,000 and $150,000. The analyses were censored after 5‐year simulation from a health system perspective and discounted outcomes at 3% per year. Sensitivity analyses were conducted to test the robustness of the study design.
Results
The incremental cost‐effectiveness ratios were $140,907 per QALY for patients with a 3‐month survival probability >50%, $3,178,510 per QALY for patients with a 3‐month survival probability <50%, and $168,385 per QALY for patients with independent ambulatory and 3‐month survival probability >50%.
Conclusions
This study emphasizes the need to choose patients carefully and estimate preoperative survival for those with spinal metastases. In addition to reaffirming previous research regarding the influence of ambulatory status on cost‐effectiveness, our study goes a step further by highlighting that operative intervention with postoperative radiotherapy could be more cost‐effective than radiotherapy alone for patients with a better survival outlook. Accurate survival prediction tools and larger future studies could offer more detailed insights for clinical decisions.
The Cu(I)-catalyzed alkyne−azide 2 + 3 cycloaddition has been demonstrated to be an effective and orthogonal conjugation reaction to covalently immobilize biomolecules on magnetic nanoparticles ...(MNPs). The azido group on the MNP surface provides better conjugation efficiency with alkynated molecules. Moreover, the C-terminal alkynated protein was site-specifically immobilized on MNP. The protein binding activity presented by site-specific immobilization is higher than that by random amide bond formation.
Objective
The aim of this study was to develop an artificial intelligence–based model to detect the presence of acute respiratory distress syndrome (ARDS) using clinical data and chest X-ray (CXR) ...data.
Method
The transfer learning method was used to train a convolutional neural network (CNN) model with an external image dataset to extract the image features. Then, the last layer of the model was fine-tuned to determine the probability of ARDS. The clinical data were trained using three machine learning algorithms—eXtreme Gradient Boosting (XGB), random forest (RF), and logistic regression (LR)—to estimate the probability of ARDS. Finally, ensemble-weighted methods were proposed that combined the image model and the clinical data model to estimate the probability of ARDS. An analysis of the importance of clinical features was performed to explore the most important features in detecting ARDS. A gradient-weighted class activation mapping (Grad-CAM) model was used to explain what our CNN sees and understands when making a decision.
Results
The proposed ensemble-weighted methods improved the performances of the ARDS classifiers (XGB + CNN, area under the curve AUC = 0.916; RF + CNN, AUC = 0.920; LR + CNN, AUC = 0.920; XGB + RF + LR + CNN, AUC = 0.925). In addition, the ML model using clinical data to present the top 15 important features to identify the risk factors of ARDS.
Conclusion
This study developed combined machine learning models with clinical data and CXR images to detect ARDS. According to the results of the Shapley Additive exPlanations values and the Grad-CAM techniques, an explicable ARDS diagnosis model is suitable for a real-life scenario.
The respiratory dysfunction of patients with Parkinson's disease (PD) has drawn increasing attention. This study evaluated the relationship between gray matter volume (GMV), as determined by ...voxel-based morphometry (VBM), and respiratory dysfunction in patients with PD and correlated it with systemic inflammatory markers.
Whole-brain VBM analysis was performed on 3-dimensional T1-weighted images in 25 PD patients with abnormal pulmonary function (13 men, 12 women; mean age: 62.9 ± 10.8 years) and, for comparison, on 25 sex- and age-matched PD patients with normal pulmonary function (14 men, 11 women; mean age: 62.3 ± 6.9 years). Inflammatory markers were determined by flow cytometry. The differences and correlations in regional GMV, clinical severity and inflammatory markers were determined after adjusting for age, gender and total intracranial volume (TIV).
Compared with the normal pulmonary function group, the abnormal pulmonary function group had smaller GMV in several brain regions, including the left parahippocampal formation, right fusiform gyrus, right cerebellum crus, and left postcentral gyri. Forced expiratory volume in 1 s (FEV1) and maximal expiratory flow after expiration of 50% of forced vital capacity (MEF50) were positively correlated with regional GMV. There were no significant differences in the level of serum inflammatory markers between two groups.
Our findings suggested that involvement of the central autonomic network and GM loss may underlie the respiratory dysfunction in PD patients.
Introduction. Systemic inflammation with elevated oxidative stress causing neuroinflammation is considered a major factor in the pathogenesis of Parkinson’s disease (PD). The interface between ...systemic circulation and the brain parenchyma is the blood-brain barrier (BBB), which also plays a role in maintaining neurovascular homeostasis. Vascular cell adhesion molecule-1 (VCAM-1) and microRNAs (miRNAs) regulate brain vessel endothelial function, neoangiogenesis, and, in turn, neuronal homeostasis regulation, such that their dysregulation can result in neurodegeneration, such as gray matter atrophy, in PD. Objective. Our aim was to evaluate the associations among specific levels of gray matter atrophy, peripheral vascular adhesion molecules, miRNAs, and clinical disease severity in order to achieve a clearer understanding of PD pathogenesis. Methods. Blood samples were collected from 33 patients with PD and 27 healthy volunteers, and the levels of VCAM-1 and several miRNAs in those samples were measured. Voxel-based morphometry (VBM) analysis was performed using 3 T magnetic resonance imaging (MRI) and SPM (Statistical Parametric Mapping software program). The associations among the vascular parameter, miRNAs, gray matter volume, and clinical disease severity measurements were evaluated by partial correlation analysis. Results. The levels of VCAM-1, miRNA-22, and miRNA-29a expression were significantly elevated in the PD patients. The gray matter volume atrophy in the left parahippocampus, bilateral posterior cingulate gyrus, fusiform gyrus, left temporal gyrus, and cerebellum was significantly correlated with increased clinical disease severity, the upregulation of miRNA levels, and increased vascular inflammation. Conclusion. Patients with PD seem to have abnormal levels of vascular inflammatory markers and miRNAs in the peripheral circulation, and these levels are correlated with specific brain volume changes. This study reinforces the associations among peripheral inflammation, the BBB interface, and gray matter atrophy in PD and further demonstrates that BBB dysfunction with neurovascular impairment may play an important role in PD progression.
Indoleamine 2,3-dioxygenase-1 (IDO1) is a potential target for the next generation of cancer immunotherapies. We describe the development of two series of IDO1 inhibitors incorporating a ...N-hydroxy-thiophene-carboximidamide core generated by knowledge-based drug design. Structural modifications to improve the cellular activity and pharmacokinetic (PK) properties of the compounds synthesized, including extension of the side chain of the N-hydroxythiophene-2-carboximidamide core, resulted in compound 27a, a potent IDO1 inhibitor which demonstrated significant (51%) in vivo target inhibition on IDO1 in a human SK-OV-3 ovarian xenograft tumor mouse model. This strategy is expected to be applicable to the discovery of additional IDO1 inhibitors for the treatment of other diseases susceptible to modulation of IDO1.
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•The N-hydroxythiophene-2-carboximidamides were identified as novel IDO1 inhibitors.•The highest IDO1 gene expression was found in human SK-OV-3 cells by CCLE dataset.•Compound 27a decreased 51% of the kyn/trp ratio in SK-OV-3 xenograft tumor tissues.
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