The prevalence of diabetic dyslipidemia has gradually increased worldwide and individuals with hypertriglyceridemia often have a high polygenic burden of triglyceride (TG)-increasing variants. ...However, the contribution of genetic variants to dyslipidemia in patients with type 2 diabetes (T2D) remains limited. Therefore, in this study, we aimed to investigate the genetic characteristics of longitudinal changes in TG levels among patients with T2D and summarize the genetic effects of polygenic risk score (PRS) on TG trajectory and risk of diabetic complications.
We conducted a case-control study. A total of 11,312 patients with T2D with longitudinal TG and genetic data were identified from a large hospital database in Taiwan. We then performed a genome-wide association study and calculated the relative PRS.
In total, 21 single-nucleotide polymorphisms (SNPs) related to TG trajectory were identified and yielded an area under the receiver operating characteristic curve (ROC) of 0.712 for high TG trajectory risk among Taiwanese patients with T2D. A cumulative genetic effect was observed for high TG trajectory, even when considering the adherence of a lipid-lowering agent in stratified analysis. An increased PRS increases high TG trajectory risk in a logistic regression model (odds ratio = 1.55; 95% confidence interval CI = 1.31-1.83 in the validation cohort). The TG-specific PRS was associated with the risk of diabetic microvascular complications, including diabetic retinopathy and nephropathy (with hazard ratios of 1.11 95% CI = 1.01-1.21, P = 0.027 and 1.05 95% CI = 1.01-1.1, P = 0.018, respectively).
This study may contribute to the identification of patients with T2D who are at risk of abnormal TG levels and diabetic microvascular complications using polygenic information.
Background
Cognition impairment is well known in patients with chronic kidney disease (CKD). The relationship between brain structure and cognitive performance in CKD patients is still under ...investigation. The study aimed to quantitatively assess the relationship between brain structure and cognitive performance in patients with CKD.
Methods
We recruited 39 patients with CKD and 39 age‐ and sex‐matched control participants from a tertiary medical center. All participants underwent 3‐T MRI scan neuropsychological assessments, and renal function tests. FreeSurfer software was used for imaging processing and analysis, including measurement of cortical thickness and gray matter (GM) and white matter volumes.
Results
Compared with control subjects (73.1±7.5 years old), patients with CKD (76.4±8.4 years old) had significantly lower scores on the Mini‐Mental State Examination, and forward digit span test (P<.01). Patients with CKD had smaller cerebral GM volume, hippocampus, and decreased cortical thickness (P<.01) relative to the control group. Estimated glomerular filtration rate (eGFR) was correlated with cognitive performance, cortical thickness, GM volume, and hippocampal volume (P<.001). Linear regression analysis revealed that eGFR and GM volume were independently negatively associated with cognitive performance (P<.001), while eGFR and age were negatively associated with cortical thinning and GM volume after controlling for confounding factors.
Conclusions
This study demonstrated that impaired kidney function is associated not only with poor cognitive performance, but also with small cerebral GM volume and reduced cortical thickness.
The automatic establishment of image relationship between oblique images can be a challenging task. Feature based image matching (FBM) establishes this relationship by detecting and matching ...corresponding feature points. A robust matching is beneficial for many tasks including reconstruction, mapping and localization. The need of automatic processing of remotely sensed data, like very highresolution (VHR) satellite imagery, increased over the years. Furthermore, green vegetation and water are changing the physical properties with respect to the amount of light emitted, season and pollution. In addition, with human interaction, the change in appearance increases. The Normalized Differential Vegetation Index (NDVI) is a well-known and studied index in order to detect healthy green vegetation. The Normalized Differential Water Index (NDWI) can help identify water areas in an image. They can be used to preliminarily segment images into different categories for later process. This study proposes a novel framework to explore the potential of feature based stereo matching for very high-resolution satellite imagery with segmentation. The proposed framework will perform first, image segmentation with NDVI and NDWI on stereo VHR satellite image pairs. Then, classification by threshold to detect healthy green vegetation, water and image frame. Features within these three classes are masked out and kept from being processed during the feature matching step. The idea is that, features in these classes are easy to cause miss matching because they are more prone to be affected by different image and environmental conditions in the stereo image pairs. As a result, the amount of miss matches can be reduced on average by 7.5%. Furthermore, the segmentation decreases the total amount of detected features by 13.71%, so that the processing time decreases. This study has successfully proven that segmentation can lead to improved stereo matching. In future, segmentation driven can be utilized by AI matching processes as well as traditionally photogrammetric or computer vision tasks.
Hypertension-induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure. Our previous studies found that the activation of insulin-like growth factor receptor II ...(IGF-IIR) signaling was critical for hypertensive angiotensin II (ANG II)-induced cardiomyocyte apoptosis. However, the detailed mechanism by which ANG II regulates IGF-IIR in heart cells remains elusive. In this study, we found that ANG II activated its downstream kinase JNK to increase IGF-IIR expression through the ANG II receptor angiotensin type 1 receptor. JNK activation subsequently led to sirtuin 1 (SIRT1) degradation via the proteasome, thus preventing SIRT1 from deacetylating heat-shock transcription factor 1 (HSF1). The resulting increase in the acetylation of HSF1 impaired its ability to bind to the IGF-IIR promoter region (nt -748 to -585). HSF1 protected cardiomyocytes by acting as a repressor of IGF-IIR gene expression, and ANG II diminished this HSF1-mediated repression through enhanced acetylation, thus activating the IGF-IIR apoptosis pathway. Taken together, these results suggest that HSF1 represses IGF-IIR gene expression to protect cardiomyocytes. ANG II activates JNK to degrade SIRT1, resulting in HSF1 acetylation, which induces IGF-IIR expression and eventually results in cardiac hypertrophy and apoptosis. HSF1 could be a valuable target for developing treatments for cardiac diseases in hypertensive patients.
Mutations in the kinase domain of epidermal growth factor receptor (EGFR) are associated with clinical responsiveness to gefitinib in patients with non-small-cell lung cancers (NSCLC). Recently, we ...have identified many novel EGFR mutations in NSCLC tissues. In this study, we found that gefitinib could suppress the tyrosine phosphorylation of most EGFR mutants better than the wild-type receptor. However, gefitinib had quite variable growth-suppressive effects on different EGFR mutant-expressing cells. All tested EGFR mutants have high basal phosphorylation at multiple tyrosine residues. Upon EGF stimulation, the mutated EGFRs did not have apparently stronger phosphorylation at tyrosines 845, 992, 1,068, and 1,173 than the wild-type receptor. However, stronger phosphorylation at tyrosine 1,045 was observed in the S768I, L861Q, E709G, and G719S mutants. The E746-A750 deletion mutant was less responsive to EGF than the wild-type and other mutant receptors. The S768I, L861Q, E709G, and G719S mutants were refractory to EGF-induced ubiquitination and had more sustained tyrosine phosphorylation. E709G and G719S also lacked EGF-induced receptor downregulation. Our results indicate that, in addition to sensitivity to gefitinib, EGFR mutations also caused various changes in EGFR's regulatory mechanisms, which may contribute to the constitutive activation of EGFR mutants and oncogenesis in NSCLC.
Background
Patients treated with tumour necrosis factor (TNF) inhibitors are at risk of new‐onset tuberculosis (TB) or reactivation of latent tuberculosis infection (LTBI). Association between ...TB/LTBI and interleukin (IL)‐23 inhibitors for psoriasis is unclear. Patients with LTBI typically initiate LTBI therapy before receiving biologics.
Objectives
Safety in moderate‐to‐severe psoriasis patients with LTBI treated with guselkumab (IL‐23 inhibitor) and LTBI treatment was evaluated.
Methods
In the VOYAGE 1 & VOYAGE 2 studies, patients screened for LTBI were randomized to guselkumab, placebo, or adalimumab (TNF inhibitor) at baseline. Placebo → guselkumab crossover occurred at week 16 and adalimumab → guselkumab at week 52 (VOYAGE 1), or at week 28 or later (VOYAGE 2). Incidence of active TB, adverse events (AEs), serious AEs (SAEs), and markedly abnormal liver function tests alanine aminotransferase test (ALT); aspartate aminotransferase test (AST) were evaluated using pooled data through week 100 in guselkumab‐treated patients receiving and not receiving LTBI treatment.
Results
At baseline, 130 randomized patients (guselkumab: n = 69; adalimumab: n = 36; placebo: n = 25) tested positive for LTBI and received concomitant LTBI treatments (LTBI+). No active TB was reported among guselkumab‐treated patients without LTBI (LTBI−) through week 100. Two cases of active TB occurred in LTBI− patients treated with adalimumab. Through week 16, across all treatment groups, greater proportions of LTBI+ patients reported ALT and AST elevations compared with LTBI− patients. Through week 100, proportions of patients experiencing AEs and SAEs were comparable between LTBI+ and LTBI− patients.
Conclusions
No cases of active TB, including reactivation of LTBI, were reported in patients with or without LTBI treated with guselkumab through up to 2 years. LTBI treatment was effective across all treatment groups in preventing reactivation of LTBI. Long‐term treatment with guselkumab was generally well‐tolerated through up to 2 years in patients receiving LTBI medications.
There have been several episodes of viral infection evolving into epidemics in recent decades, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the latest example. Its high ...infectivity and moderate mortality have resulted in an urgent need to find an effective treatment modality. Although the category of immunosuppressive drugs usually poses a risk of infection due to interference of the immune system, some of them have been found to exert antiviral properties and are already used in daily practice. Recently, hydroxychloroquine and baricitinib have been proposed as potential drugs for SARS-CoV-2. In fact, there are other immunosuppressants known with antiviral activities, including cyclosporine A, hydroxyurea, minocycline, mycophenolic acid, mycophenolate mofetil, leflunomide, tofacitinib, and thalidomide. The inherent antiviral activity could be a treatment choice for patients with coexisting rheumatological disorders and infections. Clinical evidence, their possible mode of actions and spectrum of antiviral activities are included in this review article.
Lay summary
Immunosuppressants often raise the concern of infection risks, especially for patients with underlying immune disorders. However, some disease-modifying antirheumatic drugs (DMARDs) with inherent antiviral activity would be a reasonable choice in the situation of concomitant viral infections and flare up of autoimmune diseases. This review covers DMARDs of treatment potential for SARS-CoV-2 in part I, and antiviral mechanisms plus trial evidence for viruses other than SARS-CoV-2 in part II.
The Tonga volcano eruption of 15 January 2022 unleashed a variety of atmospheric perturbations, coinciding with the recovery-phase of a geomagnetic storm. The ensuing thermospheric variations created ...rare display of extreme poleward-expanding conjugate plasma bubbles seen in the rate of total electron content index over 100–150°E, reaching ∼40°N geographic latitude. This is associated with fluctuations in FORMOSAT-7/COSMIC-2 (F7/C2) ion-density measurements and spread-F in ionograms. Preceding to this, an unusually strong pre-reversal enhancement (PRE) occurred in the global ionospheric specification (GIS) electron density profiles derived from F7/C2 observations. The GIS also revealed a decrease of equatorial ionization anomaly (EIA) crest density due to the storm impact. Reduced E-region conductivity by volcano-induced waves and enhanced F-region wind, further accelerated by reduced ion-drag over the EIA, apparently intensified the PRE.
Accompanied with the strong PRE, volcano-induced seed perturbations triggered the super plasma bubble activity.
Hypertension and pregnancy-related hypertension are major public health problems of largely unknown causes. We describe a mutation in the mineralocorticoid receptor (MR), S810L, that causes ...early-onset hypertension that is markedly exacerbated in pregnancy. This mutation results in constitutive MR activity and alters receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups, normally MR antagonists, becoming potent agonists. Structural and biochemical studies indicate that the mutation results in the gain of a van der Waals interaction between helix 5 and helix 3 that substitutes for interaction of the steroid 21-hydroxyl group with helix 3 in the wild-type receptor. This helix 5-helix 3 interaction is highly conserved among diverse nuclear hormone receptors, suggesting its general role in receptor activation.
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