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Noninvasive visualization of the distribution and persistence of mRNA vaccine antigen expression in mammalian systems has implications for the development and evaluation of future mRNA vaccines. Here, we genetically fuse E. coli dihydrofolate reductase (eDHFR) to the delta furin diproline modified SARS-CoV-2 spike glycoprotein (S2P ∆f ) mRNA vaccine and image its expression in female mice and male non-human primates using [ 18 F]fluoropropyl-trimethoprim ([ 18 F]FP-TMP). Whole body positron emission tomography (PET) imaging revealed transient expression of the vaccine antigen in the injection site and draining lymph nodes (dLNs). Fusion of eDHFR did not impact S2P immunogenicity and no humoral or cellular immune response was detected against eDHFR in either species. In this work, we show that eDHFR can be used as an mRNA-encoded PET reporter gene to monitor the spatiotemporal dynamics of mRNA vaccine antigen expression in vivo. This technique could be applied in clinical translation of future mRNA vaccines or therapeutics. mRNA vaccines have been successfully developed, but a better understanding of in vivo distribution of the encoded antigen may aid further improvements. Here the authors use PET imaging and demonstrate transient expression of the vaccine antigen in the injection site and draining lymph nodes in mice and non-human primates.

In this paper, the problem of multi-objective optimal design of hedge-algebras-based fuzzy controller (HAC) for structural vibration control with actuator saturation is presented. The main advantages of HAC are: (i) inherent order relationships among linguistic values of each linguistic variable are always ensured; (ii) instead of using any fuzzy sets, linguistic values of linguistic variables are determined by an isomorphism mapping called semantically quantifying mapping (SQM) based on a few fuzziness parameters of each linguistic variable and hence, the process of fuzzy inference is very simple due to SQM values occurring in the fuzzy rule base and (iii) when optimizing HAC, only a few design variables which are above fuzziness parameters are needed. As a case study, a HAC and optimal HACs (opHACs) based on multi-objective optimization view point have been designed to active control of a benchmark structure with active bracing system subjected to earthquake excitation. Control performance of controllers is also discussed in order to shown advantages of the proposed method.

Objective Acute visual impairment is the most feared complication of giant cell arteritis (GCA) but is challenging to predict. Magnetic resonance imaging (MRI) evaluates orbital pathology not visualized by an ophthalmologic examination. This study combined orbital and cranial vessel wall MRI to assess both orbital and cranial disease activity in patients with GCA, including patients without visual symptoms. Methods Patients with suspected active GCA who underwent orbital and cranial vessel wall MRI were included. In 14 patients, repeat imaging over 12 months assessed sensitivity to change. Clinical diagnosis of ocular or nonocular GCA was determined by a rheumatologist and/or ophthalmologist. A radiologist masked to clinical data scored MRI enhancement of structures. Results Sixty‐four patients with suspected GCA were included: 25 (39%) received a clinical diagnosis of GCA, including 12 (19%) with ocular GCA. Orbital MRI enhancement was observed in 83% of patients with ocular GCA, 38% of patients with nonocular GCA, and 5% of patients with non‐GCA. MRI had strong diagnostic performance for both any GCA and ocular GCA. Combining MRI with a funduscopic examination reached 100% sensitivity for ocular GCA. MRI enhancement significantly decreased after treatment (P < 0.01). Conclusion In GCA, MRI is a sensitive tool that comprehensively evaluates multiple cranial structures, including the orbits, which are the most concerning site of pathology. Orbital enhancement in patients without visual symptoms suggests that MRI may detect at‐risk subclinical ocular disease in GCA. MRI scores decreased following treatment, suggesting scores reflect inflammation. Future studies are needed to determine if MRI can identify patients at low risk for blindness who may receive less glucocorticoid therapy.

Background Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for Breast Cancer gene ( BRCA )-mutant HER2- breast cancer, and there is clinical interest in expanding indications to include homologous recombination deficient (HRD) breast cancers. Yet, response in these populations remains variable, suggesting clinical utility in developing a better biomarker to select patients for PARPi and predict response. Here, we evaluate a radiolabeled PARPi, [ 18 F]FluorThanatrace ([ 18 F]FTT), as a functional biomarker of PARPi response in breast cancer. Methods A single-arm prospective observational trial was conducted at the University of Pennsylvania. [ 18 F]FTT-PET uptake was measured in 24 women with untreated primary breast cancer and correlated with tumor HRD score. In a separate cohort of ten subjects with metastatic HER- breast cancer, [ 18 F]FTT-PET uptake was measured at baseline and after a short interval on a PARPi (a measure of drug-target engagement) and correlated to progression free survival (PFS). Results Here we show that baseline [ 18 F]FTT-PET uptake does not correlate to HRD tissue score, supporting that [ 18 F]FTT provides distinct information from genetic features. Baseline [ 18 F]FTT-PET uptake and the change in uptake from baseline to after PARPi initiation significantly correlates to PFS in woman with breast cancer who received a PARPi ( ρ  = 0.74, P  = 0.023 and ρ  = −0.86, P  = 0.012, respectively). Conclusions These early results suggest the potential of [ 18 F]FTT-PET to select patients for PARPi treatment and monitor in vivo pharmacodynamics after therapy start. Absence of association with HRD scores supports [ 18 F]FTT uptake as a novel measure that may be leveraged as a biomarker. Further studies are warranted. Plan Language Summary PARP inhibitors are an effective treatment for breast cancer; however, do not work in all patients. Our goal is to identify individuals with breast cancer who are likely to respond to this treatment, so we do not administer the drug to those who will not benefit and could experience side effects. We gave people a probe that is visible by imaging and that binds to the PARP protein in the body. We found that the amount of probe taken up by a person’s tumor was an indicator of whether they would respond well to PARP inhibitor treatment. Using such a probe could help doctors make decisions about whether to treat breast cancer patients with PARP inhibitors. Gitto, Pantel et al. evaluate a PARP-targeted PET imaging ligand, [18 F]FlourThanatrace, as a biomarker of response to PARP inhibitors in patients with breast cancer. There is [18 F]FlourThanatrace uptake in the tumor before treatment, and a decline in uptake after PARP inhibitor therapy initiation, correlating with patient progression free survival.

Objectives We conducted a systematic review and individual participant data meta-analysis of publications reporting the ophthalmologic presentation, clinical exam, and orbital MRI findings in patients with giant cell arteritis and ocular manifestations. Methods PubMed and Cochrane databases were searched up to January 16, 2022. Publications reporting patient-level data on patients with ophthalmologic symptoms, imaged with orbital MRI, and diagnosed with biopsy-proven giant cell arteritis were included. Demographics, clinical symptoms, exam, lab, imaging, and outcomes data were extracted. The methodological quality and completeness of reporting of case reports were assessed. Results Thirty-two studies were included comprising 51 patients (females = 24; median age, 76 years). Vision loss (78%) and headache (45%) were commonly reported visual and cranial symptoms. Ophthalmologic presentation was unilateral (41%) or bilateral (59%). Fundus examination most commonly showed disc edema (64%) and pallor (49%). Average visual acuity was very poor (2.28 logMAR ± 2.18). Diagnoses included anterior (61%) and posterior (16%) ischemic optic neuropathy, central retinal artery occlusion (8%), and orbital infarction syndrome (2%). On MRI, enhancement of the optic nerve sheath (53%), intraconal fat (25%), and optic nerve/chiasm (14%) was most prevalent. Among patients with monocular visual symptoms, 38% showed pathologic enhancement in the asymptomatic orbit. Six of seven cases reported imaging resolution after treatment on follow-up MRIs. Conclusions Vision loss, pallid disc edema, and optic nerve sheath enhancement are the most common clinical, fundoscopic, and imaging findings reported in patients diagnosed with giant cell arteritis with ocular manifestations, respectively. MRI may detect subclinical inflammation and ischemia in the asymptomatic eye and may be an adjunct diagnostic tool. Clinical relevance statement Brain and orbital MRIs may have diagnostic and prognostic roles in patients with suspected giant cell arteritis who present with ophthalmic symptoms.

INTRODUCTION Regional glucose hypometabolism resulting in glutamate loss has been shown as one of the characteristics of Alzheimer's disease (AD). Because the impact of AD varies between the sexes, we utilized glutamate‐weighted chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) for high‐resolution spatial mapping of cerebral glutamate and investigated subregional changes in a sex‐specific manner. METHODS Eight‐month‐old male and female AD mice harboring mutant amyloid precursor protein (APPNL‐F/NL‐F: n = 36) and wild‐type (WT: n = 39) mice underwent GluCEST MRI, followed by proton magnetic resonance spectroscopy (1H‐MRS) in hippocampus and thalamus/hypothalamus using 9.4T preclinical MR scanner. RESULTS GluCEST measurements revealed significant (p ≤ 0.02) glutamate loss in the entorhinal cortex (% change ± standard error: 8.73 ± 2.12%), hippocampus (11.29 ± 2.41%), and hippocampal fimbriae (19.15 ± 2.95%) of male AD mice. A similar loss of hippocampal glutamate in male AD mice (11.22 ± 2.33%; p = 0.01) was also observed in 1H‐MRS. DISCUSSIONS GluCEST MRI detected glutamate reductions in the fimbria and entorhinal cortex of male AD mice, which was not reported previously. Resilience in female AD mice against these changes indicates an intact status of cerebral energy metabolism. Highlights Glutamate levels were monitored in different brain regions of early‐stage Alzheimer's disease (AD) and wild‐type male and female mice using glutamate‐weighted chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI). Male AD mice exhibited significant glutamate loss in the hippocampus, entorhinal cortex, and the fimbriae of the hippocampus. Interestingly, female AD mice did not have any glutamate loss in any brain region and should be investigated further to find the probable cause. These findings demonstrate previously unreported sex‐specific glutamate changes in hippocampal sub‐regions using high‐resolution GluCEST MRI.

Background Although larger hematoma volume is associated with worse outcome after intracerebral hemorrhage (ICH), the association between perihematomal edema (PHE) volume and outcome remains uncertain, as does the impact of sex on PHE and outcome. Here we aimed to determine whether larger PHE volume is associated with worse outcome and whether PHE volume trajectories differ by sex. Methods We conducted a post hoc analysis of the Factor VIIa for Acute Hemorrhagic Stroke Treatment (FAST) trial, which randomized patients with ICH to receive recombinant activated factor VIIa or placebo. Computerized planimetry calculated PHE and ICH volumes on serial computed tomography (CT) scans (at baseline [within 3 h of onset], at 24 h, and at 72 h). Generalized estimating equations examined interactions between sex, CT time points, and FAST treatment arm on PHE and ICH volumes. Mixed and multivariable logistic models examined associations between sex, PHE, and outcomes. Results A total of 781 patients with supratentorial ICH (mean age 65 years) were included. Compared to women ( n  = 296), men ( n  = 485) had similar median ICH (14.9 vs. 13.6 mL, p  = 0.053) and PHE volumes (11.1 vs. 10.5 mL, p  = 0.56) at baseline but larger ICH and PHE volumes at 24 h (19.0 vs. 14.0 mL, p  < 0.001; 22.2 vs. 15.7 mL, p  < 0.001) and 72 h (16.0 vs. 11.8 mL, p  < 0.001; 28.7 vs. 19.9 mL, p  < 0.001). Men had higher absolute early PHE expansion ( p  < 0.001) and more hematoma expansion (growth ≥ 33% or 6 mL at 24 h, 33% vs. 22%, p  < 0.001). An interaction between sex and CT time points on PHE volume ( p  < 0.001), but not on ICH volume, confirmed a steeper PHE trajectory in men. PHE expansion (per 5 mL, odds radio 1.19, 95% confidence interval 1.10–1.28), but not sex, was associated with poor outcome. Conclusions Early PHE expansion and trajectory in men were significantly higher. PHE expansion was associated with poor outcomes independent of sex. Mechanisms leading to sex differences in PHE trajectories merit further investigation.

Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for Breast Cancer gene (BRCA)-mutant HER2- breast cancer, and there is clinical interest in expanding indications to include homologous recombination deficient (HRD) breast cancers. Yet, response in these populations remains variable, suggesting clinical utility in developing a better biomarker to select patients for PARPi and predict response. Here, we evaluate a radiolabeled PARPi, [18F]FluorThanatrace ([18F]FTT), as a functional biomarker of PARPi response in breast cancer.BACKGROUNDPoly (ADP-ribose) polymerase inhibitors (PARPi) are approved for Breast Cancer gene (BRCA)-mutant HER2- breast cancer, and there is clinical interest in expanding indications to include homologous recombination deficient (HRD) breast cancers. Yet, response in these populations remains variable, suggesting clinical utility in developing a better biomarker to select patients for PARPi and predict response. Here, we evaluate a radiolabeled PARPi, [18F]FluorThanatrace ([18F]FTT), as a functional biomarker of PARPi response in breast cancer.A single-arm prospective observational trial was conducted at the University of Pennsylvania. [18F]FTT-PET uptake was measured in 24 women with untreated primary breast cancer and correlated with tumor HRD score. In a separate cohort of ten subjects with metastatic HER- breast cancer, [18F]FTT-PET uptake was measured at baseline and after a short interval on a PARPi (a measure of drug-target engagement) and correlated to progression free survival (PFS).METHODSA single-arm prospective observational trial was conducted at the University of Pennsylvania. [18F]FTT-PET uptake was measured in 24 women with untreated primary breast cancer and correlated with tumor HRD score. In a separate cohort of ten subjects with metastatic HER- breast cancer, [18F]FTT-PET uptake was measured at baseline and after a short interval on a PARPi (a measure of drug-target engagement) and correlated to progression free survival (PFS).Here we show that baseline [18F]FTT-PET uptake does not correlate to HRD tissue score, supporting that [18F]FTT provides distinct information from genetic features. Baseline [18F]FTT-PET uptake and the change in uptake from baseline to after PARPi initiation significantly correlates to PFS in woman with breast cancer who received a PARPi (ρ = 0.74, P = 0.023 and ρ = -0.86, P = 0.012, respectively).RESULTSHere we show that baseline [18F]FTT-PET uptake does not correlate to HRD tissue score, supporting that [18F]FTT provides distinct information from genetic features. Baseline [18F]FTT-PET uptake and the change in uptake from baseline to after PARPi initiation significantly correlates to PFS in woman with breast cancer who received a PARPi (ρ = 0.74, P = 0.023 and ρ = -0.86, P = 0.012, respectively).These early results suggest the potential of [18F]FTT-PET to select patients for PARPi treatment and monitor in vivo pharmacodynamics after therapy start. Absence of association with HRD scores supports [18F]FTT uptake as a novel measure that may be leveraged as a biomarker. Further studies are warranted.CONCLUSIONSThese early results suggest the potential of [18F]FTT-PET to select patients for PARPi treatment and monitor in vivo pharmacodynamics after therapy start. Absence of association with HRD scores supports [18F]FTT uptake as a novel measure that may be leveraged as a biomarker. Further studies are warranted.