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Background: Radiotherapy of the prostate and the pelvic lymph nodes (LN) is a part of the standard of care treatment for high‐risk prostate cancer. The independent translational and rotational (i.e., six‐degrees‐of‐freedom, [6DoF]) motion of the prostate and LN target during and between fractions can perturb the dose distribution. However, no standard dose reconstruction method accounting for differential 6DoF target motion is available. Purpose: We present a framework for monitoring motion‐induced dose perturbations for two independently moving target volumes in 6DoF. The framework was used to determine the dose perturbation for the prostate and the LN target caused by differential 6DoF motion for a cohort of high‐risk prostate cancer patients. As a potential first step toward real‐time dose‐guided high‐risk prostate radiotherapy, we furthermore investigated if the dose reconstruction was fast enough for real‐time application for both targets. Methods: Twenty high‐risk prostate cancer patients were treated with 3‐arc volumetric modulated arc therapy (VMAT). Kilovoltage intrafraction monitoring (KIM) with triggered kilovoltage (kV) images acquired every 3 throughout 7–10 fractions per patient was used for retrospective 6DoF intrafraction prostate motion estimation. The 6DoF interfraction LN motion was determined from a pelvic bone match between the planning CT and a post‐treatment cone beam CT (CBCT). Using the retrospectively extracted motion, real‐time 6DoF motion‐including dose reconstruction was simulated using the in‐house developed software DoseTracker. A data stream with the 6DoF target positions and linac parameters was broadcasted at a 3‐Hz frequency to DoseTracker. In a continuous loop, DoseTracker calculated the target dose increments including the specified motion and, for comparison, without motion. The motion‐induced change in D99.5% for the prostate CTV (ΔD99.5%) and in D98% for the LN CTV (ΔD98%) was calculated using the final cumulative dose of each fraction and averaged over all imaged fractions. The real‐time reconstructed dose distribution of DoseTracker was benchmarked against a clinical treatment planning system (TPS) and it was investigated whether the calculation speed was fast enough to keep up with the incoming data stream. Results: Translational motion was largest in cranio‐caudal (CC) direction (prostate: [‐5.9, +8.4] mm; LN: [‐9.9; +11.0] mm) and anterior–posterior (AP) direction (prostate:[‐5.6; +6.9] mm; LN: [‐9.6; +11.0] mm). The pitch was the largest rotation (prostate: [‐22.5; +25.2] deg; LN: [‐3.9; +5.5] deg). The prostate CTV ΔD99.5% was [‐16.2; +2.5]% for single fractions and [‐3.0; +1.7]% when averaged over all imaged fractions. The LN CTV ΔD98% was [‐19.8; +1.2]% for single fractions and [‐3.1; +0.9]% after averaging. Mean (Standard deviation) absolute dose errors in DoseTracker of 107.8% (Std: 1.9%) for the prostate and 105.5% (Std:1.4%) for the LN were corrected during dose reconstruction by automatically calculated normalization factors. It resulted in accurate calculation of the motion‐induced dose errors with relative differences between DoseTracker and TPS dose calculations of ‐0.1% (Std: 0.5%) (prostate CTV ΔD99.5%) and ‐0.2% (Std: 0.5%) (LN CTV ΔD98%). The DoseTracker calculation was fast enough to keep up with the incoming inputs for all but two out of 107 184 dose calculations. Conclusion: Using the developed framework for dose perturbation monitoring, we found that the differential 6DoF target motion caused substantial dose perturbation for individual fractions, which largely averaged out after several fractions. The framework was shown to provide reliable dose calculations and a sufficiently high‐dose reconstruction speed to be applicable in real‐time. [ABSTRACT FROM AUTHOR]

Background: Anifrolumab, a monoclonal antibody targeting the type 1 interferon (IFN-I) signaling pathway, holds promise as a therapeutic intervention for systemic lupus erythematosus (SLE). However, its use is associated with an increased risk of infections, particularly viral infections like herpes zoster (HZ). Results from the clinical trials on anifrolumab show yearly rates of upper respiratory tract infections of 34% and HZ of 6.1%. An increased frequency of other specific viral infections, including herpes simplex virus (HSV), was not reported. Case Reports: Here, we present 2 cases of patients with SLE treated with anifrolumab, both experiencing severe adverse reactions in the form of disseminated herpesvirus infections, specifically disseminated HSV-2 and varicella zoster virus (VZV, HZ encephalitis). To the best of our knowledge, no previous reports of severe disseminated HSV-2 or HZ have been published in anifrolumab-treated patients. The patient in case 1 experienced a primary HSV-2 infection following anifrolumab treatment, potentially explaining the severity of the infection. The patient in case 2 had a history of previous HZ skin infections, which may have increased her risk of disseminated infection. Both patients recovered from the infections with minor sequelae, but they still require prophylactic antiviral treatment. These cases highlight the critical role of IFN-I immunity in protecting against herpesvirus infections. Conclusions: Thorough risk assessment before anifrolumab initiation, considering the patient's viral infection history, vaccination status, and potential exposure risks, is essential. Administration of recombinant zoster vaccine before anifrolumab therapy may benefit susceptible individuals. [ABSTRACT FROM AUTHOR]

Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus exclusively infecting humans, causing two distinct pathologies: varicella (chickenpox) upon primary infection and herpes zoster (shingles) following reactivation. In susceptible individuals, VZV can give rise to more severe clinical manifestations, including disseminated infection, pneumonitis, encephalitis, and vasculopathy with stroke. Here, we describe a 3-year-old boy in whom varicella followed a complicated course with thrombocytopenia, hemorrhagic and necrotic lesions, pneumonitis, and intermittent encephalopathy. Hemophagocytic lymphohistiocytosis (HLH) was strongly suspected and as the condition deteriorated, HLH therapy was initiated. Although the clinical condition improved, longstanding hemophagocytosis followed despite therapy. We found that the patient carries a rare monoallelic variant in autocrine motility factor receptor (AMFR), encoding a ubiquitin ligase involved in innate cytosolic DNA sensing and interferon (IFN) production through the cyclic GMP-AMP synthase–stimulator of IFN genes (cGAS-STING) pathway. Peripheral blood mononuclear cells (PBMCs) from the patient exhibited impaired signaling downstream of STING in response dsDNA and 2'3'-cGAMP, agonists of cGAS and STING, respectively, and fibroblasts from the patient showed impaired type I IFN responses and significantly increased VZV replication. Overexpression of the variant AMFR R594C resulted in decreased K27-linked STING ubiquitination compared to WT AMFR. Moreover, ImageStream technology revealed reduced STING trafficking from ER to Golgi in cells expressing the patient AMFR R594C variant. This was supported by a dose-dependent dominant negative effect of expression of the patient AMFR variant as measured by IFN-β reporter gene assay. Finally, lentiviral transduction with WT AMFR partially reconstituted 2'3'-cGAMP-induced STING-mediated signaling and ISG expression in patient PBMCs. This work links defective AMFR-STING signaling to severe VZV disease and hyperinflammation and suggests a direct role for cGAS-STING in the control of viral infections in humans. In conclusion, we describe a novel genetic etiology of severe VZV disease in childhood, also representing the first inborn error of immunity related to a defect in the cGAS-STING pathway. [ABSTRACT FROM AUTHOR]

Long COVID (LC) is an emerging global health concern. The underlying mechanism and pathophysiology remain unclear. Presence of neutralizing autoantibodies against type 1 interferons (IFN) has been established as a predictor of critical COVID‐19. We hypothesized that persistent autoimmune activity with autoantibodies against type 1 IFN may contribute to symptoms in patients with LC. Plasma samples and clinical information were obtained from a Danish LC cohort consisting of adult patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. Information on symptoms and quality of life was derived from an LC‐specific questionnaire and the EQ‐5D‐5L questionnaire. Detection of type 1 IFN autoantibodies in plasma were performed by ELISA. Samples collected between June, 2020, and September, 2021, from 279 patients were analyzed and compared to a control group of 94 individuals with prior mild SARS‐CoV‐2 infection who did not develop LC symptoms. In total, five LC patients (1.8%) and 3 (3.2%) of the controls had detectable circulating type 1 IFN autoantibodies. Collectively, prevalence of autoantibodies against type 1 IFN subtypes in our LC cohort were primarily driven by men and did not exceed the prevalence in controls. Thus, in our cohort, anti‐type I IFN autoantibodies are unlikely to drive LC symptoms. [ABSTRACT FROM AUTHOR]

Herpesvirus infections can lead to a number of severe clinical manifestations, particularly when involving the central nervous system (CNS), causing encephalitis and meningitis. However, understanding of the host factors conferring increased susceptibility to these diseases and their complications remains incomplete. Previous studies have uncovered defects in the innate Toll-like receptor 3 pathway and production of type I interferon (IFN-I) in children and adults that predispose them to herpes simplex encephalitis. More recently, there is accumulating evidence for an important role of IFN-independent cell-autonomous intrinsic mechanisms, including small nucleolar RNAs, RNA lariat metabolism, and autophagy, in restricting herpesvirus replication and conferring protection against CNS infection. The present review first describes clinical manifestations of HSV infection with a focus on neurological complications and then summarizes the host–pathogen interactions and innate immune pathways responsible for sensing herpesviruses and triggering antiviral responses and immunity. Next, we review the current landscape of inborn errors of immunity and the underlying genetic defects and disturbances of cellular immune pathways that confer increased susceptibility to HSV infection in CNS. Ultimately, we discuss some of the present outstanding unanswered questions relating to inborn errors of immunity and HSV CNS infection together with some perspectives and future directions for research in the pathogenesis of these severe diseases in humans. [ABSTRACT FROM AUTHOR]

Background: During prostate stereotactic body radiation therapy (SBRT), prostate tumor translational motion may deteriorate the planned dose distribution. Most of the major advances in motion management to date have focused on correcting this one aspect of the tumor motion, translation. However, large prostate rotation up to 30° has been measured. As the technological innovation evolves toward delivering increasingly precise radiotherapy, it is important to quantify the clinical benefit of translational and rotational motion correction over translational motion correction alone. Purpose: The purpose of this work was to quantify the dosimetric impact of intrafractional dynamic rotation of the prostate measured with a six degrees‐of‐freedom tumor motion monitoring technology. Methods: The delivered dose was reconstructed including (a) translational and rotational motion and (b) only translational motion of the tumor for 32 prostate cancer patients recruited on a 5‐fraction prostate SBRT clinical trial. Patients on the trial received 7.25 Gy in a treatment fraction. A 5 mm clinical target volume (CTV) to planning target volume (PTV) margin was applied in all directions except the posterior direction where a 3 mm expansion was used. Prostate intrafractional translational motion was managed using a gating strategy, and any translation above the gating threshold was corrected by applying an equivalent couch shift. The residual translational motion is denoted as Tres$T_{res}$. Prostate intrafractional rotational motion Runcorr$R_{uncorr}$ was recorded but not corrected. The dose differences from the planned dose due to Tres$T_{res}$ + Runcorr$R_{uncorr}$, ΔD(Tres$T_{res}$ + Runcorr$R_{uncorr}$) and due to Tres$T_{res}$ alone, ΔD(Tres$T_{res}$), were then determined for CTV D98, PTV D95, bladder V6Gy, and rectum V6Gy. The residual dose error due to uncorrected rotation, Runcorr$R_{uncorr}$ was then quantified: ΔDResidual$\Delta D_{Residual}$ = ΔD(Tres$T_{res}$ + Runcorr$R_{uncorr}$) ‐ ΔD(Tres${T}_{\textit{res}}$). Results: Fractional data analysis shows that the dose differences from the plan (both ΔD(Tres$T_{res}$ + Runcorr$R_{uncorr}$) and ΔD(Tres$T_{res}$)) for CTV D98 was less than 5% in all treatment fractions. ΔD(Tres$T_{res}$ + Runcorr$R_{uncorr}$) was larger than 5% in one fraction for PTV D95, in one fraction for bladder V6Gy, and in five fractions for rectum V6Gy. Uncorrected rotation, Runcorr$R_{uncorr}$ induced residual dose error, ΔDResidual$\Delta D_{Residual}$, resulted in less dose to CTV and PTV in 43% and 59% treatment fractions, respectively, and more dose to bladder and rectum in 51% and 53% treatment fractions, respectively. The cumulative dose over five fractions, ∑D(Tres$T_{res}$ + Runcorr$R_{uncorr}$) and ∑D(Tres$T_{res}$), was always within 5% of the planned dose for all four structures for every patient. Conclusions: The dosimetric impact of tumor rotation on a large prostate cancer patient cohort was quantified in this study. These results suggest that the standard 3–5 mm CTV‐PTV margin was sufficient to account for the intrafraction prostate rotation observed for this cohort of patients, provided an appropriate gating threshold was applied to correct for translational motion. Residual dose errors due to uncorrected prostate rotation were small in magnitude, which may be corrected using different treatment adaptation strategies to further improve the dosimetric accuracy. [ABSTRACT FROM AUTHOR]

Background: Hypofractionation in prostate radiotherapy is of increasing interest. Steep dose gradients and a large weight on each individual fraction emphasize the need for motion management. Real‐time motion management techniques such as multileaf collimator (MLC) tracking or couch tracking typically adjust for translational motion while rotations remain uncompensated with unknown dosimetric impact. Purpose: The purpose of this study is to demonstrate and validate dynamic real‐time rotation‐including dose reconstruction during radiotherapy experiments with and without MLC and couch tracking. Methods: Real‐time dose reconstruction was performed using the in‐house developed software DoseTracker. DoseTracker receives streamed target positions and accelerator parameters during treatment delivery and uses a pencil beam algorithm with water density assumption to reconstruct the dose in a moving target. DoseTracker's ability to reconstruct motion‐induced dose errors in a dynamically rotating and translating target was investigated during three different scenarios: (1) no motion compensation and translational motion correction with (2) MLC tracking and (3) couch tracking. In each scenario, dose reconstruction was performed online and in real time during delivery of two dual‐arc volumetric‐modulated arc therapy prostate plans with a prescribed fraction dose of 7 Gy to the prostate and simultaneous intraprostatic lesion boosts with doses of at least 8 Gy, but up to 10 Gy as long as the organs at risk dose constraints were fulfilled. The plans were delivered to a pelvis phantom that replicated three patient‐measured motion traces using a rotational insert with 21 layers of EBT3 film spaced 2.5 mm apart. DoseTracker repeatedly calculated the actual motion‐including dose increment and the planned static dose increment since the last calculation in 84 500 points in the film stack. The experiments were performed with a TrueBeam accelerator with MLC and couch tracking based on electromagnetic transponders embedded in the film stack. The motion‐induced dose error was quantified as the difference between the final cumulative dose with motion and without motion using the 2D 2%/2 mm γ‐failure rate and the difference in dose to 95% of the clinical target volume (CTV ΔD95%) and the gross target volume (GTV ΔD95%) as well as the difference in dose to 0.1 cm3 of the urethra, bladder, and rectum (ΔD0.1CC). The motion‐induced errors were compared between dose reconstructions and film measurements. Results: The dose was reconstructed in all calculation points at a mean frequency of 4.7 Hz. The root‐mean‐square difference between real‐time reconstructed and film‐measured motion‐induced errors was 3.1%‐points (γ‐failure rate), 0.13 Gy (CTV ΔD95%), 0.23 Gy (GTV ΔD95%), 0.19 Gy (urethra ΔD0.1CC), 0.09 Gy (bladder ΔD0.1CC), and 0.07 Gy (rectum ΔD0.1CC). Conclusions: In a series of phantom experiments, online real‐time rotation‐including dose reconstruction was performed for the first time. The calculated motion‐induced errors agreed well with film measurements. The dose reconstruction provides a valuable tool for monitoring dose delivery and investigating the efficacy of advanced motion‐compensation techniques in the presence of translational and rotational motion. [ABSTRACT FROM AUTHOR]

Purpose: Intrafractional motion during radiotherapy delivery can deteriorate the delivered dose. Dynamic rotational motion of up to 38 degrees has been reported during prostate cancer radiotherapy, but methods to determine the dosimetric consequences of such rotations are lacking. Here, we create and experimentally validate a dose reconstruction method that accounts for dynamic rotations and translations in a commercial treatment planning system (TPS). Interplay effects are quantified by comparing dose reconstructions with dynamic and constant rotations. Methods: The dose reconstruction accumulates the dose in points of interest while the points are moved in six degrees of freedom (6DoF) in a precalculated time‐resolved four‐dimensional (4D) dose matrix to emulate dynamic motion in a patient. The required 4D dose matrix was generated by splitting the original treatment plan into multiple sub‐beams, each representing 0.4 s dose delivery, and recalculating the dose of the split plan in the TPS (Eclipse). The dose accumulation was performed via TPS scripting by querying the dose of each sub‐beam in dynamically moving points, allowing dose reconstruction with any dynamic motion. The dose reconstruction was validated with film dosimetry for two prostate dual arc VMAT plans with intra‐prostatic lesion boosts. The plans were delivered to a pelvis phantom with internal dynamic rotational motion of a film stack (21 films with 2.5 mm separation). Each plan was delivered without motion and with three prostate motion traces. Motion‐including dose reconstruction was performed for each motion experiment using the actual dynamic rotation as well as a constant rotation equal to the mean rotation during the experiment. For each experiment, the 3%/2 mm γ failure rate of the TPS dose reconstruction was calculated with the film measurement being the reference. For each motion experiment, the motion‐induced 3%/2 mm γ failure rate was calculated using the static delivery as the reference and compared between film measurements and TPS dose reconstruction. DVH metrics for RT structures fully contained in the film volume were also compared between film and TPS. Results: The mean γ failure rate of the TPS dose reconstructions when compared to film doses was 0.8% (two static experiments) and 1.7% (six dynamic experiments). The mean (range) of the motion‐induced γ failure rate in film measurements was 35.4% (21.3–59.2%). The TPS dose reconstruction agreed with these experimental γ failure rates with root‐mean‐square errors of 2.1% (dynamic rotation dose reconstruction) and 17.1% (dose reconstruction assuming constant rotation). By DVH metrics, the mean (range) difference between dose reconstructions with dynamic and constant rotation was 4.3% (−0.3–10.6%) (urethra D2%), −0.6% (−5.6%–2.5%) (urethra D99%), 1.1% (−7.1–7.7%) (GTV D2%), −1.4% (−17.4–7.1%) (GTV D95%), −1.2% (−17.1–5.7%) (GTV D99%), and −0.1% (−3.2–7.6%) (GTV mean dose). Dose reconstructions with dynamic motion revealed large interplay effects (cold and hot spots). Conclusions: A method to perform dose reconstructions for dynamic 6DoF motion in a TPS was developed and experimentally validated. It revealed large differences in dose distribution between dynamic and constant rotations not identifiable through dose reconstructions with constant rotation. [ABSTRACT FROM AUTHOR]

Pattern recognition receptors (PRRs) induce host defense but can also induce exacerbated inflammatory responses. This raises the question of whether other mechanisms are also involved in early host defense. Using transcriptome analysis of disrupted transcripts in herpes simplex virus (HSV)-infected cells, we find that HSV infection disrupts the hypoxia-inducible factor (HIF) transcription network in neurons and epithelial cells. Importantly, HIF activation leads to control of HSV replication. Mechanistically, HIF activation induces autophagy, which is essential for antiviral activity. HSV-2 infection in vivo leads to hypoxia in CNS neurons, and mice with neuron-specific HIF1/2α deficiency exhibit elevated viral load and augmented PRR signaling and inflammatory gene expression in the CNS after HSV-2 infection. Data from human stem cell-derived neuron and microglia cultures show that HIF also exerts antiviral and inflammation-restricting activity in human CNS cells. Collectively, the HIF transcription factor system senses virus-induced hypoxic stress to induce cell-intrinsic antiviral responses and limit inflammation. [Display omitted] • HSV-1 and -2 disrupt the hypoxia-inducible factor (HIF) network in permissive cells • HIF activation induces autophagy, which exerts anti-HSV activity in neurons • Neuronal HIF activation regulates infection and inflammation in the infected brain Using transcriptome analysis of disrupted transcripts in herpes simplex virus-infected cells, Farahani et al. identify the hypoxia-inducible factor gene network to possess antiviral activity through induction of autophagy. This contributes to antiviral defense and regulation of inflammation during infection in the CNS. [ABSTRACT FROM AUTHOR]

Purpose: In radiotherapy, tumor motion may deteriorate the planned dose distribution. However, the dosimetric consequences of the motion are normally unknown for individual treatments. We here present a method for real‐time motion‐including tumor dose reconstruction and demonstrate its use for simulated stereotactic body radiotherapy (SBRT) of patients with liver cancer previously treated with Calypso‐guided gating. Methods: Real‐time motion‐including dose reconstruction was performed using in‐house developed software, DoseTracker, on offline replays of previous clinical treatments. The patient cohort consisted of fifteen patients previously treated in our clinic with three‐fraction SBRT to the liver using conformal or IMRT plans. The tumor motion at treatment was monitored with implanted electromagnetic transponders. The dose reconstruction was performed for both the actual gated treatments and simulated nongated treatments using a 21 Hz data stream containing accelerator parameters and the recorded motion. The dose was reconstructed in the same calculation points within the planning target volume (PTV) as used by the treatment planning system (TPS). The reconstructed doses were compared with calculations performed in the TPS, in which the motion was modeled as a series of isocenter shifts. The comparison included point doses as a function of treatment time and the dose volume histogram (DVH) for the clinical target volume (CTV). The motion‐induced reduction in the dose to 95% of the CTV, ΔD95%, and in the mean CTV dose, ΔDMean, was compared between DoseTracker and the TPS for each simulated fraction. DoseTracker currently assumes water density within the patient contour, so for comparison, the TPS calculations were performed with both CT density and water density. The calculation times were additionally analyzed. Results: Dose reconstruction was carried out for ninety SBRT sessions with calculation volumes ranging from 9.9 to 366.4 cm3 and median calculation times of 55–155 ms (equivalent to 18.2–6.5 Hz). Time‐resolved trends of doses to a single calculation point in the patient were well replicated and dose differences between actual and planned calculations matched well. ΔDMean had a range of −0.1%–30.7%‐points and was estimated by DoseTracker with a root‐mean‐square deviation (RMSD) to the TPS calculations of 0.43%–points (water density) and 0.79%‐points (CT density). Similarly, ΔD95% had a range of 0.0%–35.2%‐points and was estimated by DoseTracker with an RMSD of 0.80%‐points (water density) and 1.33%‐points (CT density). DoseTracker predicted losses in tumor dose coverage above 5%‐points with high sensitivity (91.7%) and specificity (97.6%). Conclusions: Real‐time dose reconstruction to moving tumors was demonstrated on offline replays of previous clinical treatments. DVHs of actually delivered dose are made available immediately after the end of treatment fractions. It shows promising results for liver SBRT with accurate estimation of CTV dose deteriorations caused by motion during treatment. [ABSTRACT FROM AUTHOR]

Purpose: In radiotherapy, dose deficits caused by tumor motion often far outweigh the discrepancies typically allowed in plan‐specific quality assurance (QA). Yet, tumor motion is not usually included in present QA. We here present a novel method for online treatment verification by real‐time motion‐including four‐dimensional (4D) dose reconstruction and dose evaluation and demonstrate its use during stereotactic body radiotherapy (SBRT) delivery with and without MLC tracking. Methods: Five volumetric‐modulated arc therapy (VMAT) plans were delivered with and without MLC tracking to a motion stage carrying a Delta4 dosimeter. The VMAT plans have previously been used for (nontracking) liver SBRT with intratreatment tumor motion recorded by kilovoltage intrafraction monitoring (KIM). The motion stage reproduced the KIM‐measured tumor motions in three dimensions (3D) while optical monitoring guided the MLC tracking. Linac parameters and the target position were streamed to an in‐house developed software program (DoseTracker) that performed real‐time 4D dose reconstructions and 3%/3 mm γ‐evaluations of the reconstructed cumulative dose using a concurrently reconstructed planned dose without target motion as reference. Offline, the real‐time reconstructed doses and γ‐evaluations were validated against 4D dosimeter measurements performed during the experiments. Results: In total, 181,120 dose reconstructions and 5,237 γ‐evaluations were performed online and in real time with median computation times of 30 ms and 1.2 s, respectively. The mean (standard deviation) difference between reconstructed and measured doses was −1.2% (4.9%) for transient doses and −1.5% (3.9%) for cumulative doses. The root‐mean‐square deviation between reconstructed and measured motion‐induced γ‐fail rates was 2.0%‐point. The mean (standard deviation) sensitivity and specificity of DoseTracker to predict γ‐fail rates above a given threshold was 96.8% (3.5%) and 99.2% (0.4%), respectively, for clinically relevant thresholds between 1% and 30% γ‐fail rate. Conclusions: Real‐time delivery‐specific QA during radiotherapy of moving targets was demonstrated for the first time. It allows supervision of treatment accuracy and action on treatment discrepancy within 2 s with high sensitivity and specificity. [ABSTRACT FROM AUTHOR]

Abstract: Negative regulation of immune pathways is essential to achieve resolution of immune responses and to avoid excess inflammation. DNA stimulates type I IFN expression through the DNA sensor cGAS, the second messenger cGAMP, and the adaptor molecule STING. Here, we report that STING degradation following activation of the pathway occurs through autophagy and is mediated by p62/SQSTM1, which is phosphorylated by TBK1 to direct ubiquitinated STING to autophagosomes. Degradation of STING was impaired in p62‐deficient cells, which responded with elevated IFN production to foreign DNA and DNA pathogens. In the absence of p62, STING failed to traffic to autophagy‐associated vesicles. Thus, DNA sensing induces the cGAS‐STING pathway to activate TBK1, which phosphorylates IRF3 to induce IFN expression, but also phosphorylates p62 to stimulate STING degradation and attenuation of the response. [ABSTRACT FROM AUTHOR]

In this paper, the lightning shielding performance of a newly designed 400-k \textV double-circuit composite tower is investigated. Based on a revised electrogeometric model (EGM) method, traditional shielding failure regions located at both sides of a traditional tower are no longer a big issue for the fully composite tower, due to its unusual ^\prime Y^\prime configuration. Instead, a new unprotected region exists in the tower center. The maximum lightning current that can lead to shielding failure and the shielding failure rate of the new tower are calculated. To verify results from the revised EGM method, a scale model test is conducted. Spatial shielding failure probability around the tower is calculated based on the ratio of discharge paths recorded in the test. Moreover, based on test results, the maximum shielding failure lightning currents are obtained. Analysis and results derived from the revised EGM method and scale model test have a small deviation, verifying the feasibility of these two methods in the lightning performance evaluation of the fully composite tower. Both methods confirm that the unusual negative shielding angle of -\text60^\circ in the newly composite tower provides good lightning shielding performance. The feasibility of the novel composite tower is verified from the lightning protection point of view. [ABSTRACT FROM PUBLISHER]

In recent years, there has been an increasing interest in immunomodulatory therapy as a means to treat various conditions, including infectious diseases. For instance, Toll-like receptor (TLR) agonists have been evaluated for treatment of genital herpes. However, although the TLR7 agonist imiquimod was shown to have antiviral activity in individual patients, no significant effects were observed in clinical trials, and the compound also exhibited significant side effects, including local inflammation. Cytosolic DNA is detected by the enzyme cyclic GMP-AMP (2’3’-cGAMP) synthase (cGAS) to stimulate antiviral pathways, mainly through induction of type I interferon (IFN)s. cGAS is activated upon DNA binding to produce the cyclic dinucleotide (CDN) 2’3’-cGAMP, which in turn binds and activates the adaptor protein Stimulator of interferon genes (STING), thus triggering type I IFN expression. In contrast to TLRs, STING is expressed broadly, including in epithelial cells. Here we report that natural and non-natural STING agonists strongly induce type I IFNs in human cells and in mice in vivo, without stimulating significant inflammatory gene expression. Systemic treatment with 2’3’-cGAMP reduced genital herpes simplex virus (HSV) 2 replication and improved the clinical outcome of infection. More importantly, local application of CDNs at the genital epithelial surface gave rise to local IFN activity, but only limited systemic responses, and this treatment conferred total protection against disease in both immunocompetent and immunocompromised mice. In direct comparison between CDNs and TLR agonists, only CDNs acted directly on epithelial cells, hence allowing a more rapid and IFN-focused immune response in the vaginal epithelium. Thus, specific activation of the STING pathway in the vagina evokes induction of the IFN system but limited inflammatory responses to allow control of HSV2 infections in vivo. [ABSTRACT FROM AUTHOR]

This paper deal with the electrical performance of a newly proposed fully composite pylon in Denmark, which has a unibody composite cross-arm at 420 kV highest system voltage level. Electric field consideration along the insulations of the novel unibody cross-arm is one of the most important requirements in the design process of a non-traditional pylon. In this paper, ANSYS finite element software is used to calculate the electric field and potential distribution around and inside the fully composite pylon. Electric field criteria related to the design of composite cross-arms are reviewed and applied for interpreting the electrical performance of the unibody cross-arm at power frequency stresses. Three different designs of non-conductive conductor clamp are assumed for the attachment points between phase conductors and the unibody cross-arm. The side effects of conductor clamp are included in 2D modeling in order to determine the minimum required height for phase conductors at the top of the unibody cross-arm. Considering the side effects of phase conductors at both sides of conductor clamp, the application of steel enclosures with an appropriate diameter is introduced to be used around the phase conductors in order to reduce the electric field magnitudes in the region of the conductor clamp. Finally, the feasibility of utilizing steel enclosures for modifying electric stresses inside the conductor clamp and unibody cross-arm is investigated by a 3D finite element analysis. [ABSTRACT FROM AUTHOR]

Investigates the phylogenetic relationship of intercellular fish pathogen Ichthyophonus hoferi. Rosette agent and choanoflagellates as ancestors of the parasite; Close relationship between animals and fungi; I. hoferi as not a member of the Fungi.

This study validates a method of fast motion-including dose reconstruction for proton pencil beam scanning in the liver. The method utilizes a commercial treatment planning system (TPS) and calculates the delivered dose for any translational 3D target motion. Data from ten liver patients previously treated with photon radiotherapy with intrafraction tumour motion monitoring were used. The dose reconstruction method utilises an in-house developed program to incorporate beam's-eye-view tumour motion by shifting each spot in the opposite direction of the tumour and in-depth motion as beam energy changes for each spot. The doses are then calculated on a single CT phase in the TPS. Two aspects of the dose reconstruction were assessed: (1) The accuracy of reconstruction, by comparing dose reconstructions created using 4DCT motion with ground truth doses obtained by calculating phase specific doses in all 4DCT phases and summing up these partial doses. (2) The error caused by assuming 4DCT motion, by comparing reconstructions with 4DCT motion and actual tumour motion. The CTV homogeneity index (HI) and the root-mean-square (rms) dose error for all dose points receiving  >70%, >80% and  >90% of the prescribed dose were calculated. The dose reconstruction resulted in mean (range) absolute CTV HI errors of 1.0% (0.0–3.0)% and rms dose errors of 2.5% (1.0%–5.3%), 2.1% (0.9%–4.5%), and 1.8% (0.7%–3.7%) for  >70%, >80% and  >90% doses, respectively, when compared with the ground truth. The assumption of 4DCT motion resulted in mean (range) absolute CTV HI errors of 5.9% (0.0–15.0)% and rms dose errors of 6.3% (3.9%–12.6%), 5.9% (3.4%–12.5%), and 5.4% (2.6%–12.1%) for  >70%, >80% and  >90% doses, respectively. The investigated method allows tumour dose reconstruction with the actual tumour motion and results in significantly smaller dose errors than those caused by assuming that motion at treatment is identical to the 4DCT motion. [ABSTRACT FROM AUTHOR]