Association between hypertension requiring medication and postoperative 30-day mortality in adult patients with tumor craniotomy: an analysis of data using propensity score matching.

Background: Reliable quantification of the association between hypertension requiring medication and postoperative 30-day mortality in adult patients who undergo craniotomy for tumor resection is limited. We aimed to explore the associations between these factors. Materials and methods: This work was a retrospective cohort study that used propensity score matching (PSM) among 18,642 participants from the American College of Surgeons National Surgical Quality Improvement Program database between 2012 and 2015. Hypertension requiring medication and postoperative 30-day mortality were the independent and dependent target variables, respectively. PSM was conducted via nonparsimonious multivariate logistic regression to balance the confounders. Robust estimation methods were used to investigate the association between hypertension requiring medication and postoperative 30-day mortality. Results: A total of 18,642 participants (52.6% male and 47.4% female) met our inclusion criteria; 7,116 (38.17%) participants with hypertension required medication and had a 3.74% mortality rate versus an overall mortality rate of 2.46% in the adult cohort of patients who underwent craniotomy for tumor resection. In the PSM cohort, the risk of postoperative 30-day mortality significantly increased by 39.0% among patients with hypertension who required medication (OR = 1.390, 95% confidence interval (CI): 1.071-1.804, p = 0.01324) after adjusting for the full covariates. Compared with participants without hypertension requiring medication, those with hypertension requiring medication had a 34.0% greater risk of postoperative 30-day mortality after adjusting for the propensity score (OR = 1.340, 95% CI: 1.040-1.727, p = 0.02366) and a 37.6% greater risk of postoperative 30-day mortality in the inverse probability of treatment weights (IPTW) cohort (OR = 1.376, 95% CI: 1.202, 1.576, p < 0.00001). Conclusion: Among U.S. adult patients undergoing craniotomy for tumor resection, hypertension requiring medication is a notable contributor to 30-day mortality after surgery, with odds ratios ranging from 1.34 to 1.39.

Do small effects matter more in vulnerable populations? an investigation using Environmental influences on Child Health Outcomes (ECHO) cohorts.

BACKGROUND: A major challenge in epidemiology is knowing when an exposure effect is large enough to be clinically important, in particular how to interpret a difference in mean outcome in unexposed/exposed groups. Where it can be calculated, the proportion/percentage beyond a suitable cut-point is useful in defining individuals at high risk to give a more meaningful outcome. In this simulation study we compute differences in outcome means and proportions that arise from hypothetical small effects in vulnerable sub-populations. METHODS: Data from over 28,000 mother/child pairs belonging to the Environmental influences on Child Health Outcomes Program were used to examine the impact of hypothetical environmental exposures on mean birthweight, and low birthweight (LBW) (birthweight < 2500g). We computed mean birthweight in unexposed/exposed groups by sociodemographic categories (maternal education, health insurance, race, ethnicity) using a range of hypothetical exposure effect sizes. We compared the difference in mean birthweight and the percentage LBW, calculated using a distributional approach. RESULTS: When the hypothetical mean exposure effect was fixed (at 50, 125, 167 or 250g), the absolute difference in % LBW (risk difference) was not constant but varied by socioeconomic categories. The risk differences were greater in sub-populations with the highest baseline percentages LBW: ranging from 3.1-5.3 percentage points for exposure effect of 125g. Similar patterns were seen for other mean exposure sizes simulated. CONCLUSIONS: Vulnerable sub-populations with greater baseline percentages at high risk fare worse when exposed to a small insult compared to the general population. This illustrates another facet of health disparity in vulnerable individuals.

A Gene Cluster of Mitochondrial Complexes Contributes to the Cognitive Decline of COVID-19 Infection.

"Brain fog," a persistent cognitive impairment syndrome, stands out as a significant neurological aftermath of coronavirus disease 2019 (COVID-19). Yet, the underlying mechanisms by which COVID-19 induces cognitive deficits remain elusive. In our study, we observed an upregulation in the expression of genes linked to the inflammatory response and oxidative stress, whereas genes associated with cognitive function were downregulated in the brains of patients infected with COVID-19. Through single-nucleus RNA sequencing (snRNA-seq) analysis, we found that COVID-19 infection triggers the immune responses in microglia and astrocytes and exacerbates oxidative stress in oligodendrocytes, oligodendrocyte progenitors (OPCs), and neurons. Further investigations revealed that COVID-19 infection elevates LUC7L2 expression, which inhibits mitochondrial oxidative phosphorylation (OXPHOS) and suppresses the expression of mitochondrial complex genes such as MT-ND1, MT-ND2, MT-ND3, MT-ND4L, MT-CYB, MT-CO3, and MT-ATP6. A holistic approach to protect mitochondrial complex function, rather than targeting a single molecular, should be an effective therapeutic strategy to prevent and treat the long-term consequences of "long COVID."

Multi-omics and pharmacological characterization of patient-derived glioma cell lines.

Glioblastoma (GBM) is the most common brain tumor and remains incurable. Primary GBM cultures are widely used tools for drug screening, but there is a lack of genomic and pharmacological characterization for these primary GBM cultures. Here, we collect 50 patient-derived glioma cell (PDGC) lines and characterize them by whole genome sequencing, RNA sequencing, and drug response screening. We identify three molecular subtypes among PDGCs: mesenchymal (MES), proneural (PN), and oxidative phosphorylation (OXPHOS). Drug response profiling reveals that PN subtype PDGCs are sensitive to tyrosine kinase inhibitors, whereas OXPHOS subtype PDGCs are sensitive to histone deacetylase inhibitors, oxidative phosphorylation inhibitors, and HMG-CoA reductase inhibitors. PN and OXPHOS subtype PDGCs stably form tumors in vivo upon intracranial transplantation into immunodeficient mice, whereas most MES subtype PDGCs fail to form tumors in vivo. In addition, PDGCs cultured by serum-free medium, especially long-passage PDGCs, carry MYC/MYCN amplification, which is rare in GBM patients. Our study provides a valuable resource for understanding primary glioma cell cultures and clinical translation and highlights the problems of serum-free PDGC culture systems that cannot be ignored.

Discovery of KT-474─a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases.

Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential mediator of the IL-1R and TLR signaling pathways, both of which have been implicated in multiple autoimmune conditions. Hence, blocking the activity of IRAK4 represents an attractive approach for the treatment of autoimmune diseases. The activity of this serine/threonine kinase is dependent on its kinase and scaffolding activities; thus, degradation represents a potentially superior approach to inhibition. Herein, we detail the exploration of structure-activity relationships that ultimately led to the identification of KT-474, a potent, selective, and orally bioavailable heterobifunctional IRAK4 degrader. This represents the first heterobifunctional degrader evaluated in a nononcology indication and dosed to healthy human volunteers. This molecule successfully completed phase I studies in healthy adult volunteers and patients with atopic dermatitis or hidradenitis suppurativa. Phase II clinical trials in both of these indications have been initiated.

Maxillary impacted canine replacing a central incisor with root resorption: Multidisciplinary treatment in a preadolescent patient.

Maxillary canines are often impacted, which can result in tooth disorders and adversely affect occlusal and facial development. The case report describes complete bilateral impaction of maxillary canines and significant root resorption of a central incisor. The multidisciplinary approach is the optimal strategy for addressing impacted maxillary canines.

NAD+ metabolic enzyme inhibitor as radiosensitizer for malignant meningioma and its modulation of P53 expression.

Surgical resection followed by radiotherapy (RT) is recommended for malignant meningioma but poor outcome is unavoidable. To improve the efficacy of RT in malignant meningioma, a targeted radiosensitizer could be added. Nicotinamide phosphoribosyltransferase (NAMPT), highly expressed in high-grade meningiomas may have a role in determining the radioresponse. Here, we evaluated the impact of NAMPT inhibition on radiosensitivity in malignant meningioma in vivo and in vitro. IOMM-Lee and TTMM705 cells were treated with NAMPT inhibition (FK866 or shRNA NAMPT) before irradiation. The subsequent clonogenic assay demonstrated significantly increased radiosensitivity. Combination treatment with FK866 and irradiation significantly increased the number of G2/M-phase cells, the percentage of apoptotic cells and the γ-H2A.X level compared to FK866 or RT alone. We examined the effect of NAMPT inhibition on NMI and p53 expression in IOMM-Lee and TTMM705 cells. NAMPT inhibition by FK866 and shRNA treatment increased NMI, p53, CDKN1A and BAX expression. Additionally, we assessed the efficacy of FK866/RT combination treatment in vivo. The combination treatment exhibited increased antitumor efficacy compared to either treatment alone. The Ki-67 level was significantly lower and the p53 and γ-H2A.X level was significantly higher in the combination treatment group than in any of the other three groups. In conclusion, these results indicate that FK866 improves radiosensitivity in malignant meningioma, an effect that may be attributed to the increase in p53 expression.

Spectral analysis enhanced net (SAE-Net) to classify breast lesions with BI-RADS category 4 or higher.

Early ultrasound screening for breast cancer reduces mortality significantly. The main evaluation criterion for breast ultrasound screening is the Breast Imaging-Reporting and Data System (BI-RADS), which categorizes breast lesions into categories 0-6 based on ultrasound grayscale images. Due to the limitations of ultrasound grayscale imaging, lesions with categories 4 and 5 necessitate additional biopsy for the confirmation of benign or malignant status. In this paper, the SAE-Net was proposed to combine the tissue microstructure information with the morphological information, thus improving the identification of high-grade breast lesions. The SAE-Net consists of a grayscale image branch and a spectral pattern branch. The grayscale image branch used the classical deep learning backbone model to learn the image morphological features from grayscale images, while the spectral pattern branch is designed to learn the microstructure features from ultrasound radio frequency (RF) signals. Our experimental results show that the best SAE-Net model has an area under the receiver operating characteristic curve (AUROC) of 12% higher and a Youden index of 19% higher than the single backbone model. These results demonstrate the effectiveness of our method, which potentially optimizes biopsy exemption and diagnostic efficiency.

Ultrasound wavelet spectra enable direct tissue recognition and full-color visualization.

Traditional brightness-mode ultrasound imaging is primarily constrained by the low specificity among tissues and the inconsistency among sonographers. The major cause is the imaging method that represents the amplitude of echoes as brightness and ignores other detailed information, leaving sonographers to interpret based on organ contours that depend highly on specific imaging planes. Other ultrasound imaging modalities, color Doppler imaging or shear wave elastography, overlay motion or stiffness information to brightness-mode images. However, tissue-specific scattering properties and spectral patterns remain unknown in ultrasound imaging. Here we demonstrate that the distribution (size and average distance) of scattering particles leads to characteristic wavelet spectral patterns, which enables tissue recognition and high-contrast ultrasound imaging. Ultrasonic wavelet spectra from similar particle distributions tend to cluster in the eigenspace according to principal component analysis, whereas those with different distributions tend to be distinguishable from one another. For each distribution, a few wavelet spectra are unique and act as a fingerprint to recognize the corresponding tissue. Illumination of specific tissues and organs with designated colors according to the recognition results yields high-contrast ultrasound imaging. The fully-colorized tissue-specific ultrasound imaging potentially simplifies the interpretation and promotes consistency among sonographers, or even enables the applicability for non-professionals.

Multi-Shell Nanourchin-Integrated Dual Mode Lateral Flow Immunoassay for Sensitive and Rapid Detection of Clinical Cardiac Myosin-Binding Protein C.

Cardiac myosin-binding protein C (cMyBP-C) is a novel cardiac marker of acute myocardial infarction (AMI) and acute cardiac injuries (ACI). Construction of point-of-care testing techniques capable of sensing cMyBP-C with high sensitivity and precision is urgently needed. Herein, we synthesized an Au@NGQDs@Au/Ag multi-shell nanoUrchins (MSNUs), and then applied it in a colorimetric/SERS dual-mode immunoassay for detection of cMyBP-C. The MSNUs displayed superior stability, colorimetric brightness, and SERS enhancement ability with an enhanced factor of 5.4 × 109, which were beneficial to improve the detection capability of test strips. The developed MSNU-based test strips can achieve an ultrasensitive immunochromatographic assay of cMyBP-C in both colorimetric and SERS modes with the limits of detection as low as 19.3 and 0.77 pg/mL, respectively. Strikingly, this strip was successfully applied to analyze actual plasma samples with significantly better sensitivity, negative predictive value, and accuracy than commercially available gold test strips. Notably, this method possessed a wide range of application scenarios via combining with a color recognizer application named Color Grab on the smartphone, which can meet various needs of different users. Overall, our MSNU-based test strip as a mobile health monitoring tool shows excellent sensitivity, reproducibility, and rapid detection of the cMyBP-C, which holds great potential for the early clinic diagnosis of AMI and ACI.