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Introduction Acute stroke patients presenting with large vessel occlusion secondary to intracranial atherosclerosis (ICAS‐LVO) may require rescue therapy (RT) in addition to mechanical thrombectomy (MT) to achieve and maintain successful recanalization. We performed a systematic review and meta‐analysis of comparative studies that reported outcomes of RT in ICAS‐LVO patients to evaluate its safety and efficacy. Methods Databases searched include PubMed, CINAHL Complete, and Scopus from database date of inception through August 17, 2021. We included comparative studies that reported the outcomes of ICAS‐LVO RT compared to outcomes of ICAS‐LVO patients who did not undergo RT or to those presenting with embolic LVO patients (non‐ICAS LVO). Meta‐analysis using the random effects model was used to combine estimates reporting odds ratios (OR) and 95% confidence intervals (CI). Results Total of 9 nonrandomized studies were included: 5 studies in ICAS‐LVO RT vs. ICAS‐LVO non‐RT analysis and 5 ICAS‐LVO RT vs. non‐ICAS LVO analysis. Rescue treatments included intra‐arterial antiplatelets, angioplasty, stenting or combination of treatments. Compared to non‐RT ICAS LVO, RT was associated with increased favorable 90‐day outcome (OR 3.19, 95% CI 1.91‐5.32, I2 14%) and decreased 90‐day mortality (OR 0.35, 95% CI 0.16‐0.76, I2 21%) (Figure 1). In the analysis of ICAS LVO vs embolic LVO, the incidence of favorable 90‐day outcome and 90‐day mortality did not differ between the ICAS‐LVO RT and non‐ICAS LVO (OR 0.97, 95% CI 0.58‐1.64, I2 50%) and (OR 1.22, 95% CI 0.90‐1.66, I2 0%), respectively. Conclusions Rescue treatment is associated with better outcomes in ICAS‐LVO patients. The outcomes of ICAS‐LVO patients who receive RT may be comparable to embolic LVO patients (non‐ICAS LVO).

ImportanceProgressive multifocal leukoencephalopathy can occur in the context of systemic sarcoidosis (S-PML) in the absence of therapeutic immune suppression and can initially be mistaken for neurosarcoidosis or other complications of sarcoidosis. Earlier recognition of S-PML could lead to more effective treatment of the disease.ObjectiveTo describe characteristics of patients with S-PML.Design, Setting, and ParticipantsFor this case series, records from 8 academic medical centers in the United States were reviewed from 2004 to 2022. A systematic review of literature from 1955 to 2022 yielded data for additional patients. Included were patients with S-PML who were not receiving therapeutic immune suppression. The median follow-up time for patients who survived the acute range of illness was 19 months (range, 2-99). Data were analyzed in February 2023.ExposuresSarcoidosis without active therapeutic immune suppression.Main Outcomes and MeasuresClinical, laboratory, and radiographic features of patients with S-PML.ResultsTwenty-one patients with S-PML not receiving therapeutic immune suppression were included in this study, and data for 37 patients were collected from literature review. The median age of the 21 study patients was 56 years (range, 33-72), 4 patients (19%) were female, and 17 (81%) were male. The median age of the literature review patients was 49 years (range, 21-74); 12 of 34 patients (33%) with reported sex were female, and 22 (67%) were male. Nine of 21 study patients (43%) and 18 of 31 literature review patients (58%) had simultaneous presentation of systemic sarcoidosis and PML. Six of 14 study patients (43%) and 11 of 19 literature review patients (58%) had a CD4+ T-cell count greater than 200/μL. In 2 study patients, a systemic flare of sarcoidosis closely preceded S-PML development. Ten of 17 study patients (59%) and 21 of 35 literature review patients (60%) died during the acute phase of illness. No meaningful predictive differences were found between patients who survived S-PML and those who did not.Conclusions and RelevanceIn this case series, patients with sarcoidosis developed PML in the absence of therapeutic immune suppression, and peripheral blood proxies of immune function were often only mildly abnormal. Systemic sarcoidosis flares may rarely herald the onset of S-PML. Clinicians should consider PML in any patient with sarcoidosis and new white matter lesions on brain magnetic resonance imaging.

AbstractBackgroundSmall coronary arteries containing stents pose a challenge in CT imaging due to metal‐induced blooming artifact. High spatial resolution imaging capability is as the presence of highly attenuating materials limits noninvasive assessment of luminal patency.PurposeThe purpose of this study was to quantify the effective lumen diameter within coronary stents using a clinical photon‐counting‐detector (PCD) CT in concert with a convolutional neural network (CNN) denoising algorithm, compared to an energy‐integrating‐detector (EID) CT system.MethodsSeven coronary stents of different materials and inner diameters between 3.43 and 4.72 mm were placed in plastic tubes of diameters 3.96–4.87 mm containing 20 mg/mL of iodine solution, mimicking stented contrast‐enhanced coronary arteries. Tubes were placed parallel with or perpendicular to the scanner's z‐axis in an anthropomorphic phantom emulating an average‐sized patient and scanned with a clinical EID‐CT and PCD‐CT. EID scans were performed using our standard coronary computed tomography angiography (cCTA) protocol (120 kV, 180 quality reference mAs). PCD scans were performed using the ultra‐high‐resolution (UHR) mode (120 × 0.2 mm collimation) at 120 kV with tube current adjusted so that CTDIvol was matched to that of EID scans. EID images were reconstructed per our routine clinical protocol (Br40, 0.6 mm thickness), and with the sharpest available kernel (Br69). PCD images were reconstructed at a thickness of 0.6 mm and a dedicated sharp kernel (Br89) which is only possible with the PCD UHR mode. To address increased image noise introduced by the Br89 kernel, an image‐based CNN denoising algorithm was applied to the PCD images of stents scanned parallel to the scanner's z‐axis. Stents were segmented based on full‐width half maximum thresholding and morphological operations, from which effective lumen diameter was calculated and compared to reference sizes measured with a caliper.ResultsSubstantial blooming artifacts were observed on EID Br40 images, resulting in larger stent struts and reduced lumen diameter (effective diameter underestimated by 41% and 47% for parallel and perpendicular orientations, respectively). Blooming artifacts were observed on EID Br69 images with 19% and 31% underestimation of lumen diameter compared to the caliper for parallel and perpendicular scans, respectively. Overall image quality was substantially improved on PCD, with higher spatial resolution and reduced blooming artifacts, resulting in the clearer delineation of stent struts. Effective lumen diameters were underestimated by 9% and 19% relative to the reference for parallel and perpendicular scans, respectively. CNN reduced image noise by about 50% on PCD images without impacting lumen quantification (<0.3% difference).ConclusionThe PCD UHR mode improved in‐stent lumen quantification for all seven stents as compared to EID images due to decreased blooming artifacts. Implementation of CNN denoising algorithms to PCD data substantially improved image quality.

Abstract Oncolytic virotherapy aims to activate host antitumor immunity, but the effectiveness of current intratumoral herpes-simplex virus (HSV) based monotherapy is limited. Here, to boost the potency of cancer cell targeting α-herpesviruses derived from HSV or Varicella-Zoster Virus (VZV), we coinjected them with myeloid cell-tropic β-herpesviruses derived from cytomegalovirus (CMV) which can powerfully modulate immune responses. Co-administered CMV was shown to promote intratumoral replication of HSV, increase local release of pro-inflammatory cytokines, inhibit adaptive antiviral immune responses, enhance systemic antitumor responses, and lead to superior control of both injected and contralateral tumors. CMV-encoded myeloid-tropic genes, NK evasins (i.e. the vMHC-I homolog), and the m02-m16 region (involved in downregulating classical MHC-I) were implicated in enhancing antitumor activities. CMV is a promising adjuvant to reshape and enhance the antitumor immune responses following α-herpesvirus therapy.

ImportanceTumor necrosis factor α (TNF) inhibitor–induced psoriasiform eruption is well recognized in adults, but few reports document this paradoxical effect in children.ObjectiveTo characterize the clinical features and the clinical time course of TNF inhibitor–induced psoriasiform eruptions in children.Design, Setting, and ParticipantsA multicenter retrospective case series of children younger than 18 years seen between January 1, 2000, and December 31, 2016, who developed a new-onset psoriasiform eruption while taking a TNF inhibitor for a nondermatologic disorder. Participating sites were members of the Pediatric Dermatology Research Alliance. Data were entered into a Research Electronic Data Capture database at the Mayo Clinic (ie, the coordinating center).ResultsPsoriasiform eruptions were identified in 103 TNF inhibitor–treated patients (median age, 13.8 years [IQR, 11.7-16.4 years]; 52 female patients [50%]; 57 White patients [55%]), with 67 patients (65%) treated with infliximab, 35 (34%) with adalimumab, and 1 (1%) with certolizumab pegol. Most patients had no personal history (101 [98%]) or family history of psoriasis (60 patients [58%]). Inflammatory bowel disease was the most common indication for treatment with TNF inhibitor (94 patients [91%]). The primary extracutaneous disease was under control in 95 patients (92%) who developed the eruption. Most patients (n = 85 [83%]) developed psoriasiform eruptions at multiple anatomic sites, with scalp involvement being most common (65 patients [63%]). Skin disease developed at a median of 14.5 months (IQR, 9-24 months) after TNF inhibitor initiation. To treat the psoriasiform eruption, topical steroidal and nonsteroidal medication was prescribed for all patients. Systemic therapy was added for 30 patients (29%): methotrexate for 24 patients (23%), oral corticosteroids for 8 patients (8%), and azathioprine for 1 patient (1%). For 26 patients (25%), suboptimal effectiveness with topical medications alone prompted discontinuation of the initial TNF inhibitor and a change to a second-line TNF inhibitor with cutaneous improvement in 23 patients (88%) by a median of 3 months (IQR, 2-4 months). Eight patients (31%) who started a second-line TNF inhibitor developed a subsequent TNF inhibitor–induced psoriasiform eruption at a median of 6 months (IQR, 4-8 months). Persistent skin disease in 18 patients (17%) prompted discontinuation of all TNF inhibitors; 11 patients changed to a non-TNF inhibitor systemic therapy, and 7 discontinued all systemic therapy.Conclusions and RelevanceIn this case series, paradoxical TNF inhibitor–induced psoriasiform eruptions were seen in children treated with TNF inhibitors for any indication, and there appears to be a class effect among the varying TNF inhibitors. The majority of these children were able to continue TNF inhibitor therapy with adequate skin-directed and other adjuvant therapies.

AbstractBackgroundPhoton‐counting‐detector CT (PCD‐CT) enables the production of virtual monoenergetic images (VMIs) at a high spatial resolution (HR) via simultaneous acquisition of multi‐energy data. However, noise levels in these HR VMIs are markedly increased.PurposeTo develop a deep learning technique that utilizes a lower noise VMI as prior information to reduce image noise in HR, PCD‐CT coronary CT angiography (CTA).MethodsCoronary CTA exams of 10 patients were acquired using PCD‐CT (NAEOTOM Alpha, Siemens Healthineers). A prior‐information‐enabled neural network (Pie‐Net) was developed, treating one lower‐noise VMI (e.g., 70 keV) as a prior input and one noisy VMI (e.g., 50 keV or 100 keV) as another. For data preprocessing, noisy VMIs were reconstructed by filtered back‐projection (FBP) and iterative reconstruction (IR), which were then subtracted to generate “noise‐only” images. Spatial decoupling was applied to the noise‐only images to mitigate overfitting and improve randomization. Thicker slice averaging was used for the IR and prior images. The final training inputs for the convolutional neural network (CNN) inside the Pie‐Net consisted of thicker‐slice signal images with the reinsertion of spatially decoupled noise‐only images and the thicker‐slice prior images. The CNN training labels consisted of the corresponding thicker‐slice label images without noise insertion. Pie‐Net's performance was evaluated in terms of image noise, spatial detail preservation, and quantitative accuracy, and compared to a U‐net‐based method that did not include prior information.ResultsPie‐Net provided strong noise reduction, by 95 ± 1% relative to FBP and by 60 ± 8% relative to IR. For HR VMIs at different keV (e.g., 50 keV or 100 keV), Pie‐Net maintained spatial and spectral fidelity. The inclusion of prior information from the PCD‐CT data in the spectral domain was able to improve a robust deep learning‐based denoising performance compared to the U‐net‐based method, which caused some loss of spatial detail and introduced some artifacts.ConclusionThe proposed Pie‐Net achieved substantial noise reduction while preserving HR VMI's spatial and spectral properties.

Abstract Myocardial infarction is a leading cause of morbidity and mortality. While reperfusion is now standard therapy, pathological remodeling leading to heart failure remains a clinical problem. Cellular senescence has been shown to contribute to disease pathophysiology and treatment with the senolytic navitoclax attenuates inflammation, reduces adverse myocardial remodeling and results in improved functional recovery. However, it remains unclear which senescent cell populations contribute to these processes. To identify whether senescent cardiomyocytes contribute to disease pathophysiology post-myocardial infarction, we established a transgenic model in which p16 (CDKN2A) expression was specifically knocked-out in the cardiomyocyte population. Following myocardial infarction, mice lacking cardiomyocyte p16 expression demonstrated no difference in cardiomyocyte hypertrophy but exhibited improved cardiac function and significantly reduced scar size in comparison to control animals. This data demonstrates that senescent cardiomyocytes participate in pathological myocardial remodeling. Importantly, inhibition of cardiomyocyte senescence led to reduced senescence-associated inflammation and decreased senescence-associated markers within other myocardial lineages, consistent with the hypothesis that cardiomyocytes promote pathological remodeling by spreading senescence to other cell-types. Collectively this study presents a novel demonstration that senescent cardiomyocytes are major contributors to myocardial remodeling and dysfunction following a myocardial infarction. Therefore, to maximize the potential for clinical translation, it is important to further understand the mechanisms underlying cardiomyocyte senescence and how to optimize senolytic strategies to target this cell lineage.