Projected lifetime cancer risk for patients undergoing spine surgery for isthmic spondylolisthesis.

BACKGROUND CONTEXT: Radiographs, fluoroscopy, and computed tomography (CT) are increasingly utilized in the diagnosis and management of various spine pathologies. Such modalities utilize ionizing radiation, a known cause of carcinogenesis. While the radiation doses such studies confer has been investigated previously, it is less clear how such doses translate to projected cancer risks, which may be a more interpretable metric. PURPOSE: (1) Calculate the lifetime cancer risk and the relative contributions of preference-sensitive selection of imaging modalities associated with the surgical management of a common spine pathology, isthmic spondylolisthesis (IS); (2) Investigate whether the use of intraoperative CT, which is being more pervasively adopted, increases the risk of cancer. STUDY DESIGN/SETTING: Retrospective cross-sectional study carried out within a large integrated health care network. PATIENT SAMPLE: Adult patients who underwent surgical treatment of IS via lumbar fusion from January 2016 through December 2021. OUTCOME MEASURES: (1) Effective radiation dose and lifetime cancer risk associated with each exposure to ionizing radiation; (2) Difference in effective radiation dose (and lifetime cancer risk) among patients who received intraoperative CT compared to other intraoperative imaging techniques. METHODS: Baseline demographics and differences in surgical techniques were characterized. Radiation exposure data were collected from the 2-year period centered on the operative date. Projected risk of cancer from this radiation was calculated utilizing each patient's effective radiation dose in combination with age and sex. Generalized linear modeling was used to adjust for covariates when determining the comparative risk of intraoperative CT as compared to alternative imaging modalities. RESULTS: We included 151 patients in this cohort. The range in calculated cancer risk exclusively from IS management was 1.3-13 cases of cancer per 1,000 patients. During the intraoperative period, CT imaging was found to significantly increase radiation exposure as compared to alternate imaging modalities (adjusted risk difference (ARD) 12.33mSv; IQR 10.04, 14.63mSv; p<.001). For a standardized 40 to 49-year-old female, this projects to an additional 0.72 cases of cancer per 1,000. For the entire 2-year perioperative care episode, intraoperative CT as compared to other intraoperative imaging techniques was not found to increase total ionizing radiation exposure (ARD 9.49mSv; IQR -0.83, 19.81mSv; p=.072). The effect of intraoperative imaging choice was mitigated in part due to preoperative (ARD 13.1mSv, p<.001) and postoperative CTs (ARD 22.7mSv, p<.001). CONCLUSIONS: Preference-sensitive imaging decisions in the treatment of IS impart substantial cancer risk. Important drivers of radiation exposure exist in each phase of care, including intraoperative CT and/or CT scans during the perioperative period. Knowledge of these data warrant re-evaluation of current imaging protocols and suggest a need for the development of radiation-sensitive approaches to perioperative imaging.

Treating osteoporosis: risks and management.

Osteoporosis, osteopenia and minimal trauma fractures are becoming increasingly common in the ageing population. Fractures cause increases in morbidity and mortality and have a significant financial impact on the healthcare system and society Addressing risk factors for osteoporosis early may prevent or delay the onset of fractures and use of drugs. Calcium and vitamin D supplementation may benefit people with a high risk of deficiency (e.g. institutionalised older people) but may not be required in people without risk factors. Impact and resistance exercises and physical activity can increase bone density and prevent falls Antiresorptive drugs such as bisphosphonates and denosumab remain first-line treatment options for osteoporosis. The ongoing need for bisphosphonates should be assessed after five years and treatment may then be interrupted in some patients. Progressive bone loss will recur slowly. Denosumab therapy should not be interrupted without switching to another therapy, as post-treatment bone loss can progress rapidly. All patients will need ongoing monitoring and most will require some long-term therapy once started Raloxifene may be considered in women who do not tolerate first-line antiresorptive drugs. Romosozumab is a new anabolic treatment for osteoporosis and, together with teriparatide, is subsidised as second-line therapy for individuals with severe disease and multiple fractures. Specialist referral should be considered for patients who sustain fractures while undergoing osteoporosis therapy.

Intelligent Electromagnetic Sensors for Non-Invasive Trojan Detection.

Rapid growth of sensors and the Internet of Things is transforming society, the economy and the quality of life. Many devices at the extreme edge collect and transmit sensitive information wirelessly for remote computing. The device behavior can be monitored through side-channel emissions, including power consumption and electromagnetic (EM) emissions. This study presents a holistic self-testing approach incorporating nanoscale EM sensing devices and an energy-efficient learning module to detect security threats and malicious attacks directly at the front-end sensors. The built-in threat detection approach using the intelligent EM sensors distributed on the power lines is developed to detect abnormal data activities without degrading the performance while achieving good energy efficiency. The minimal usage of energy and space can allow the energy-constrained wireless devices to have an on-chip detection system to predict malicious attacks rapidly in the front line.

Guidelines on How to Perform a Systematic Review in Spine Surgery.

Primary literature can be contradictory due to a multitude of factors, including poorly designed studies, error types, and confounding factors, and thus literature reviews can be difficult and time-consuming. Systematic reviews are designed to provide unbiased and comprehensive comparisons of relevant primary studies. This method is considered superior to traditional literature reviews due to the unbiased consideration of a broad number of sources rather than a limited literature review. This article will provide guidance for performing a systematic review, including framing a question, selecting studies with inclusion and exclusion criteria, evaluating primary literature, and explaining analysis types.

Reconstruction of Lamb wave dispersion curves by sparse representation with continuity constraints.

Ultrasonic Lamb waves are a widely used research tool for nondestructive structural health monitoring. They travel long distances with little attenuation, enabling the interrogation of large areas. To analyze Lamb wave propagation data, it is often important to know precisely how they propagate. Yet, since wave propagation is influenced by many factors, including material properties, temperature, and other varying conditions, acquiring this knowledge is a significant challenge. In prior work, this information has been recovered by reconstructing Lamb wave dispersion curves with sparse wavenumber analysis. While effective, sparse wavenumber analysis requires a large number of sensors and is sensitive to noise in the data. In this paper, it extended and significantly improved by constraining the reconstructed dispersion curves to be continuous across frequencies. To enforce this constraint, it is included explicitly in a sparse optimization formulation, and by including in the reconstruction an edge detection step to remove outliers, and by using variational Bayesian Gaussian mixture models to predict missing values. The method is validated with simulation and experimental data. Significant improved performance is demonstrated over the original sparse wavenumber analysis approach in reconstructing the dispersion curves, in synthesizing noise-removed signals, in reducing the number of measurements, and in localizing damage.

The transcription factor PU.1 promotes alternative macrophage polarization and asthmatic airway inflammation.

The transcription factor PU.1 is involved in regulation of macrophage differentiation and maturation. However, the role of PU.1 in alternatively activated macrophage (AAM) and asthmatic inflammation has yet been investigated. Here we report that PU.1 serves as a critical regulator of AAM polarization and promotes the pathological progress of asthmatic airway inflammation. In response to the challenge of DRA (dust mite, ragweed, and Aspergillus) allergens, conditional PU.1-deficient (PU/ER(T)(+/-)) mice displayed attenuated allergic airway inflammation, including decreased alveolar eosinophil infiltration and reduced production of IgE, which were associated with decreased mucous glands and goblet cell hyperplasia. The reduced asthmatic inflammation in PU/ER(T)(+/-) mice was restored by adoptive transfer of IL-4-induced wild-type (WT) macrophages. Moreover, after treating PU/ER(T)(+/-) mice with tamoxifen to rescue PU.1 function, the allergic asthmatic inflammation was significantly restored. In vitro studies demonstrate that treatment of PU.1-deficient macrophages with IL-4 attenuated the expression of chitinase 3-like 3 (Ym-1) and resistin-like molecule alpha 1 (Fizz-1), two specific markers of AAM polarization. In addition, PU.1 expression in macrophages was inducible in response to IL-4 challenge, which was associated with phosphorylation of signal transducer and activator of transcription 6 (STAT6). Furthermore, DRA challenge in sensitized mice almost abrogated gene expression of Ym-1 and Fizz-1 in lung tissues of PU/ER(T)(+/-) mice compared with WT mice. These data, all together, indicate that PU.1 plays a critical role in AAM polarization and asthmatic inflammation.

Simultaneous in vivo imaging of blood and lymphatic vessel growth in Prox1-GFP/Flk1::myr-mCherry mice.

The ability to visually observe angiogenesis and lymphangiogenesis simultaneously and repeatedly in living animals would greatly enhance our understanding of the inter-dependence of these processes. To generate a mouse model that allows such visualization via in vivo fluorescence imaging, we crossed Prox1-GFP mice with Flk1::myr-mCherry mice to generate Prox1-GFP/Flk1::myr-mCherry mice, in which lymphatic vessels emit green fluorescence and blood vessels emit red fluorescence. Corneal neovascularization was induced in these mice using three injury models: implantation of a vascular endothelial growth factor (VEGF) pellet, implantation of a basic fibroblast growth factor (bFGF) pellet, and alkali burn injury. Vessel growth was observed in vivo by stereomicroscopy on days 0, 3, 7 and 10 after pellet implantation or alkali injury as well as in flat-mounted corneas via confocal microscopy after the final in vivo imaging time point. We observed blood and lymphatic vessel growth in all three models, with the most significant growth occurring from days 0-7. Upon VEGF stimulation, the growth kinetics of blood and lymphatic vessels were similar. Blood vessels exhibited similar growth patterns in VEGF- and bFGF-stimulated corneas. Alkali burn injury induced robust angiogenesis and lymphangiogenesis. The intrinsic fluorescence of blood and lymphatic endothelial cells in Prox1-GFP/Flk1::myr-mCherry mice permitted simultaneous in vivo imaging of angiogenesis and lymphangiogenesis. This allowed us to differentiate the processes as well as observe their inter-dependence, and will be valuable in development of therapies targeting angiogenesis and/or lymphangiogenesis.

Corneal lymphangiogenesis in herpetic stromal keratitis.

Corneal lymphangiogenesis is the extension of lymphatic vessels into the normally alymphatic cornea, a process that compromises the cornea's immune-privileged state and facilitates herpetic stromal keratitis (HSK). HSK results most commonly from infection by herpes simplex virus-1 (HSV-1) and is characterized by immune- and inflammation-mediated damage to the deep layers of the cornea. Current research demonstrates the potential of anti-lymphangiogenic therapy to decrease and prevent herpes-induced lymphangiogenesis.

Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization.

Emerging concepts suggest that the functional phenotype of macrophages is regulated by transcription factors that define alternative activation states. We found that RBP-J, the main nuclear transducer of signaling via Notch receptors, augmented Toll-like receptor 4 (TLR4)-induced expression of key mediators of classically activated M1 macrophages and thus of innate immune responses to Listeria monocytogenes. Notch-RBP-J signaling controlled expression of the transcription factor IRF8 that induced downstream M1 macrophage-associated genes. RBP-J promoted the synthesis of IRF8 protein by selectively augmenting kinase IRAK2-dependent signaling via TLR4 to the kinase MNK1 and downstream translation-initiation control through eIF4E. Our results define a signaling network in which signaling via Notch-RBP-J and TLRs is integrated at the level of synthesis of IRF8 protein and identify a mechanism by which heterologous signaling pathways can regulate the TLR-induced inflammatory polarization of macrophages.

Notch- and transducin-like enhancer of split (TLE)-dependent histone deacetylation explain interleukin 12 (IL-12) p70 inhibition by zymosan.

The fungal analog zymosan induces IL-23 and low amounts of IL-12 p70. This study addresses the molecular mechanisms underlying this cytokine pattern in human monocyte-derived dendritic cells. The transcriptional regulation of il23a, one of the chains of IL-23, depended on the activation of c-Rel and histone H3 phosphorylation, as judged from the association of c-Rel with the il23a promoter and the correlation between IL-23 production and Ser-10-histone H3 phosphorylation. Consistent with its reduced ability to produce IL-12 p70, zymosan induced a transient occupancy of the il12a promoter by c-Rel, blocked the production of IL-12 p70 and the transcription of il12a induced by other stimuli, and triggered the expression and nuclear translocation of the transcriptional repressors of the Notch family hairy and enhancer of split (Hes)-1, Hes5, hairy/enhancer-of-split related with YRPW motif protein (Hey)-1, and transducin-like enhancer of split (TLE). Zymosan also induced the interaction of Hes1 and TLE with histone H3 phosphorylated on Ser-10 and deacetylated on Lys-14. Inhibition of class III histone deacetylases increased the production of IL-12 p70 and partially blunted the inhibitory effect of zymosan on the production of IL-12 p70 elicited by LPS and IFN-γ. These results indicate that the selective induction of IL-23 by ß-glucans is explained by the activation of c-Rel associated with Ser-10-histone H3 phosphorylation in the il23a promoter mediated by mitogen- and stress-activated kinase and/or protein kinase A and inhibition of il12a transcription by a mechanism involving activation of several corepressors with the ability to bind TLE and to promote histone deacetylation.

Autoamplification of Notch signaling in macrophages by TLR-induced and RBP-J-dependent induction of Jagged1.

Several signaling pathways, including the Notch pathway, can modulate TLR activation to achieve responses most appropriate for the environment. One mechanism of TLR-Notch cross-talk is TLR-induced expression of Notch ligands Jagged and Delta that feed back to engage Notch receptors on TLR-activated cells. In this study, we investigated mechanisms by which TLRs induce Notch ligand expression in primary macrophages. TLRs induced Jagged1 expression rapidly and independently of new protein synthesis. Jagged1 induction was augmented by IFN-γ, was partially dependent on canonical TLR-activated NF-κB and MAPK signaling pathways, and elevated Jagged1 expression augmented TLR-induced IL-6 production. Strikingly, TLR-induced Jagged1 expression was strongly dependent on the Notch master transcriptional regulator RBP-J and also on upstream components of the Notch pathway γ-secretase and Notch1 and Notch2 receptors. Thus, Jagged1 is an RBP-J target gene that is activated in a binary manner by TLR and Notch pathways. Early and direct cooperation between TLR and Notch pathways leads to Jagged1-RBP-J-mediated autoamplification of Notch signaling that can modulate later phases of the TLR response.

CTNNB1 mutations and overexpression of Wnt/beta-catenin target genes in WT1-mutant Wilms' tumors.

Gain-of-function mutations in exon 3 of beta-catenin (CTNNB1) are specific for Wilms' tumors that have lost WT1, but 50% of WT1-mutant cases lack such "hot spot" mutations. To ask whether stabilization of beta-catenin might be essential after WT1 loss, and to identify downstream target genes, we compared expression profiles in WT1-mutant versus WT1 wild-type Wilms' tumors. Supervised and nonsupervised hierarchical clustering of the expression data separated these two classes of Wilms' tumor. The WT1-mutant tumors overexpressed genes encoding myogenic and other transcription factors (MOX2, LBX1, SIM2), signaling molecules (TGFB2, FST, BMP2A), extracellular Wnt inhibitors (WIF1, SFRP4), and known beta-catenin/TCF targets (FST, CSPG2, CMYC). Beta-Catenin/TCF target genes were overexpressed in the WT1-mutant tumors even in the absence of CTNNB1 exon 3 mutations, and complete sequencing revealed gain-of-function mutations elsewhere in the CTNNB1 gene in some of these tumors, increasing the overall mutation frequency to 75%. Lastly, we identified and validated a novel direct beta-catenin target gene, GAD1, among the WT1-mutant signature genes. These data highlight two molecular classes of Wilms' tumor, and indicate strong selection for stabilization of beta-catenin in the WT1-mutant class. Beta-Catenin stabilization can initiate tumorigenesis in other systems, and this mechanism is likely critical in tumor formation after loss of WT1.