Excited-State Half-Lives in

The known I^{π}=8_{1}^{+}, E_{x}=2129-keV isomer in the semimagic nucleus ^{130}Cd_{82} was populated in the projectile fission of a ^{238}U beam at the Radioactive Isotope Beam Factory at RIKEN. The high counting statistics of the accumulated data allowed us to determine the excitation energy, E_{x}=2001.2(7) keV, and half-life, T_{1/2}=57(3) ns, of the I^{π}=6_{1}^{+} state based on γγ coincidence information. Furthermore, the half-life of the 8_{1}^{+} state, T_{1/2}=224(4) ns, was remeasured with high precision. The new experimental information, combined with available data for ^{134}Sn and large-scale shell model calculations, allowed us to extract proton and neutron effective charges for ^{132}Sn, a doubly magic nucleus far-off stability. A comparison to analogous information for ^{100}Sn provides first reliable information regarding the isospin dependence of the isoscalar and isovector effective charges in heavy nuclei.

Peripheral expression of brain-penetrant progranulin rescues pathologies in mouse models of frontotemporal lobar degeneration.

Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) pathology (FTLD-GRN). Multiple therapeutic strategies are in clinical development to restore PGRN in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution. We therefore developed an adeno-associated virus (AAV) targeting the liver (L) to achieve sustained peripheral expression of a transferrin receptor (TfR) binding, brain-penetrant (b) PGRN variant [AAV(L):bPGRN] in two mouse models of FTLD-GRN, namely, Grn knockout and GrnxTmem106b double knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS-administered AAVs and maintains sustained concentrations of PGRN in the brain after a single dose. AAV(L):bPGRN treatment reduced several FTLD-GRN-associated pathologies including severe motor function deficits, aberrant TDP-43 phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis, and neurodegeneration in the brain. The potential translatability of our findings was tested in an in vitro model using cocultured human induced pluripotent stem cell (hiPSC)-derived microglia lacking PGRN and TMEM106B and wild-type hiPSC-derived neurons. As in mice, aberrant TDP-43, lysosomal dysfunction, and neuronal loss were ameliorated after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our studies suggest that peripherally administered brain-penetrant PGRN replacement strategies ameliorate FTLD-GRN relevant phenotypes including TDP-43 pathology, neurodegeneration, and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD-GRN and potentially other CNS disorders.

Temperature Dependency of Insect's Wingbeat Frequencies: An Empirical Approach to Temperature Correction.

This study examines the relationship between the wingbeat frequency of flying insects and ambient temperature, leveraging data from over 302,000 insect observations obtained using a near-infrared optical sensor during an eight-month field experiment. By measuring the wingbeat frequency as well as wing and body optical cross-sections of each insect in conjunction with the ambient temperature, we identified five clusters of insects and analyzed how their average wingbeat frequencies evolved over temperatures ranging from 10 °C to 38 °C. Our findings reveal a positive correlation between temperature and wingbeat frequency, with a more pronounced increase observed at higher wingbeat frequencies. Frequencies increased on average by 2.02 Hz/°C at 50 Hz, and up to 9.63 Hz/°C at 525 Hz, and a general model is proposed. This model offers a valuable tool for correcting wingbeat frequencies with temperature, enhancing the accuracy of insect clustering by optical and acoustic sensors. While this approach does not account for species-specific responses to temperature changes, our research provides a general insight, based on all species present during the field experiment, into the intricate dynamics of insect flight behavior in relation to environmental factors.

Synaptic injury in the inner plexiform layer of the retina is associated with progression in multiple sclerosis.

While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression.

Metabolomic profiles of ovariectomized mice and their associations with body composition and frailty-related parameters in postmenopausal women.

BACKGROUND: Menopause, a dramatical estrogen-deficient condition, is considered the most significant milestone in women's health. PURPOSE: To investigate the metabolite changes attributed to estrogen deficiency using random forest (RF)-based machine learning (ML) modeling strategy in ovariectomized (OVX) mice as well as determine the clinical relevance of selected metabolites in older women. METHODS AND RESULTS: Untargeted and targeted metabolomic analyses revealed that metabolites related to TCA cycle, sphingolipids, phospholipids, fatty acids, and amino acids, were significantly changed in the plasma and/or muscle of OVX mice. Subsequent ML classifiers based on RF algorithm selected alpha-ketoglutarate (AKG), arginine, carnosine, ceramide C24, phosphatidylcholine (PC) aa C36:6, and PC ae C42:3 in plasma as well as PC aa 34:1, PC aa C34:3, PC aa C36:5, PC aa C32:1, PC aa C36:2, and sphingosine in muscle as top featured metabolites that differentiate the OVX mice from the sham-operated group. When circulating levels of AKG, arginine, and carnosine, which showed the most significant changes in OVX mice blood, were measured in postmenopausal women, higher plasma AKG levels were associated with lower bone mass, weak grip strength, poor physical performance, and increased frailty risk. CONCLUSIONS: Metabolomics- and ML-based methods identified the key metabolites of blood and muscle that were significantly changed after ovariectomy in mice, and the clinical implication of several metabolites was investigated by looking at their correlation with body composition and frailty-related parameters in postmenopausal women. These findings provide crucial context for understanding the diverse physiological alterations caused by estrogen deficiency in women.

Decreasing Prescribing Errors in Antimicrobial Stewardship Program-Restricted Medications.

OBJECTIVES: Antimicrobial stewardship programs (ASPs) restrict prescribing practices to regulate antimicrobial use, increasing the risk of prescribing errors. This quality improvement project aimed to decrease the proportion of prescribing errors in ASP-restricted medications by standardizing workflow. METHODS: The study took place on all inpatient units at a tertiary care children's hospital between January 2020 and February 2022. Patients <22 years old with an order for an ASP-restricted medication course were included. An interprofessional team used the Model for Improvement to design interventions targeted at reducing ASP-restricted medication prescribing errors. Plan-Do-Study-Act cycles included standardizing communication and medication review, implementing protocols, and developing electronic health record safety nets. The primary outcome was the proportion of ASP-restricted medication orders with a prescribing error. The secondary outcome was time between prescribing errors. Outcomes were plotted on control charts and analyzed for special cause variation. Outcomes were monitored for a 3-month sustainability period. RESULTS: Nine-hundred ASP-restricted medication orders were included in the baseline period (January 2020-December 2020) and 1035 orders were included in the intervention period (January 2021-February 2022). The proportion of prescribing errors decreased from 10.9% to 4.6%, and special cause variation was observed in Feb 2021. Mean time between prescribing errors increased from 2.9 days to 8.5 days. These outcomes were sustained. CONCLUSIONS: Quality improvement methods can be used to achieve a sustained reduction in the proportion of ASP-restricted medication orders with a prescribing error throughout an entire children's hospital.

Alterations in Lysosomal, Glial and Neurodegenerative Biomarkers in Patients with Sporadic and Genetic Forms of Frontotemporal Dementia.

Background: Frontotemporal dementia (FTD) is the most common cause of early-onset dementia with 10-20% of cases caused by mutations in one of three genes: GRN, C9orf72, or MAPT. To effectively develop therapeutics for FTD, the identification and characterization of biomarkers to understand disease pathogenesis and evaluate the impact of specific therapeutic strategies on the target biology as well as the underlying disease pathology are essential. Moreover, tracking the longitudinal changes of these biomarkers throughout disease progression is crucial to discern their correlation with clinical manifestations for potential prognostic usage. Methods: We conducted a comprehensive investigation of biomarkers indicative of lysosomal biology, glial cell activation, synaptic and neuronal health in cerebrospinal fluid (CSF) and plasma from non-carrier controls, sporadic FTD (symptomatic non-carriers) and symptomatic carriers of mutations in GRN, C9orf72, or MAPT, as well as asymptomatic GRN mutation carriers. We also assessed the longitudinal changes of biomarkers in GRN mutation carriers. Furthermore, we examined biomarker levels in disease impacted brain regions including middle temporal gyrus (MTG) and superior frontal gyrus (SFG) and disease-unaffected inferior occipital gyrus (IOG) from sporadic FTD and symptomatic GRN carriers. Results: We confirmed glucosylsphingosine (GlcSph), a lysosomal biomarker regulated by progranulin, was elevated in the plasma from GRN mutation carriers, both symptomatic and asymptomatic. GlcSph and other lysosomal biomarkers such as ganglioside GM2 and globoside GB3 were increased in the disease affected SFG and MTG regions from sporadic FTD and symptomatic GRN mutation carriers, but not in the IOG, compared to the same brain regions from controls. The glial biomarkers GFAP in plasma and YKL40 in CSF were elevated in asymptomatic GRN carriers, and all symptomatic groups, except the symptomatic C9orf72 mutation group. YKL40 was also increased in SFG and MTG regions from sporadic FTD and symptomatic GRN mutation carriers. Neuronal injury and degeneration biomarkers NfL in CSF and plasma, and UCHL1 in CSF were elevated in patients with all forms of FTD. Synaptic biomarkers NPTXR, NPTX1/2, and VGF were reduced in CSF from patients with all forms of FTD, with the most pronounced reductions observed in symptomatic MAPT mutation carriers. Furthermore, we demonstrated plasma NfL was significantly positively correlated with disease severity as measured by CDR+NACC FTLD SB in genetic forms of FTD and CSF NPTXR was significantly negatively correlated with CDR+NACC FTLD SB in symptomatic GRN and MAPT mutation carriers. Conclusions: In conclusion, our comprehensive investigation replicated alterations in biofluid biomarkers indicative of lysosomal function, glial activation, synaptic and neuronal health across sporadic and genetic forms of FTD and unveiled novel insights into the dysregulation of these biomarkers within brain tissues from patients with GRN mutations. The observed correlations between biomarkers and disease severity open promising avenues for prognostic applications and for indicators of drug efficacy in clinical trials. Our data also implicated a complicated relationship between biofluid and tissue biomarker changes and future investigations should delve into the mechanistic underpinnings of these biomarkers, which will serve as a foundation for the development of targeted therapeutics for FTD.

The margin of stability is affected differently when walking under quasi-random treadmill perturbations with or without full visual support.

Background: Sensory-motor perturbations have been widely used to assess astronauts' balance in standing during pre-/post- spaceflight. However, balance control during walking, where most falls occur, was less studied in these astronauts. A study found that applying either visual or platform oscillations reduced the margin of stability (MOS) in the anterior-posterior direction (MOSap) but increased MOS in the medial-lateral direction (MOSml) as a tradeoff. This tradeoff induced an asymmetric gait. This study extended the current knowledge to investigate overall stability under unpredictable environments. This study aimed to determine (1) whether quasi-random treadmill perturbations with or without full vision support would result in a significant reduction in MOSap but an increase in MOSml and (2) regardless of whether vision support was provided, quasi-random treadmill perturbations might result in asymmetric gait patterns. Methods: Twenty healthy young adults participated in this study. Three experimental conditions were semi-randomly assigned to these participants as follows: (1) the control condition (Norm), walking normally with their preferred walking speed on the treadmill; (2) the treadmill perturbations with full vision condition (Slip), walking on the quasi-random varying-treadmill-belt-speeds with full vision support; and (3) the treadmill perturbations without full vision condition (Slip_VisionBlocked, blackout vision through customized vision-blocked goggles), walking on the quasi-random varying-treadmill-belt-speeds without full vision support. The dependent variables were MOSap, MOSml, and respective symmetric indices. A one-way repeated ANOVA measure or Friedman Test was applied to investigate the differences among the conditions mentioned above. Results: There was an increase in MOSap in Slip (p = 0.001) but a decrease in MOSap in Slip_VisionBlocked (p = 0.001) compared to Norm condition. The MOSml was significantly greater in both Slip and Slip_VisionBlocked conditions compared to the Norm condition (p = 0.011; p < 0.001). An analysis of Wilcoxon signed-rank tests revealed that the symmetric index of MOSml in Slip_VisionBlocked (p = 0.002) was greater than in the Norm condition. Conclusion: The novelty of this study was to investigate the effect of vision on the overall stability of walking under quasi-random treadmill perturbations. The results revealed that overall stability and symmetry were controlled differently with/without full visual support. In light of these findings, it is imperative to take visual support into consideration while developing a sensory-motor training protocol. Asymmetric gait also required extra attention while walking on the quasi-random treadmill perturbations without full vision support to maintain overall stability.

CRISPR-Cas9 and beyond: identifying target genes for developing disease-resistant plants.

Throughout the history of crop domestication, desirable traits have been selected in agricultural products. However, such selection often leads to crops and vegetables with weaker vitality and viability than their wild ancestors when exposed to adverse environmental conditions. Considering the increasing human population and climate change challenges, it is crucial to enhance crop quality and quantity. Accordingly, the identification and utilization of diverse genetic resources are imperative for developing disease-resistant plants that can withstand unexpected epidemics of plant diseases. In this review, we provide a brief overview of recent progress in genome-editing technologies, including zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) technologies. In particular, we classify disease-resistant mutants of Arabidopsis thaliana and several crop plants based on the roles or functions of the mutated genes in plant immunity and suggest potential target genes for molecular breeding of genome-edited disease-resistant plants. Genome-editing technologies are resilient tools for sustainable development and promising solutions for coping with climate change and population increases.

Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist.

Apolipoprotein E (APOE) is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD). APOE4 increases and APOE2 decreases risk relative to APOE3. In the P301S mouse model of tauopathy, ApoE4 increases tau pathology and neurodegeneration when compared with ApoE3 or the absence of ApoE. However, the role of ApoE isoforms and lipid metabolism in contributing to tau-mediated degeneration is unknown. We demonstrate that in P301S tau mice, ApoE4 strongly promotes glial lipid accumulation and perturbations in cholesterol metabolism and lysosomal function. Increasing lipid efflux in glia via an LXR agonist or Abca1 overexpression strongly attenuates tau pathology and neurodegeneration in P301S/ApoE4 mice. We also demonstrate reductions in reactive astrocytes and microglia, as well as changes in cholesterol biosynthesis and metabolism in glia of tauopathy mice in response to LXR activation. These data suggest that promoting efflux of glial lipids may serve as a therapeutic approach to ameliorate tau and ApoE4-linked neurodegeneration.

CT findings of inferior vena cava trauma according to the level of injury: a retrospective analysis of 19 cases in a single trauma centre.

AIM: To analyse the clinicoradiological characteristics of traumatic inferior vena cava (IVC) injury level on preoperative computed tomography (CT). MATERIALS AND METHODS: This retrospective study evaluated patients from a single trauma centre treated for traumatic IVC injury between January 2014 and January 2021. Data on demographics, mechanism of injury, Injury Severity Score, radiological findings on CT and angiography, IVC injury level in surgical findings, complications, and clinical outcomes were collected. RESULTS: During the 8-year study period, 36 patients presented with traumatic IVC injury: 19 underwent preoperative CT with 17 (89%) blunt and two (11%) penetrating injuries. The most common primary CT sign was contour abnormality (53%, n=10), followed by intraluminal flap and active extravasation (21%, n=4). Among the secondary signs, hepatic laceration (53%, n=10) and retroperitoneal haemorrhage (53%, n=10) were the most common. Frequencies of primary and secondary signs were higher in the infrarenal and suprarenal than in the retrohepatic vena cava injuries. Diagnostic capability of preoperative CT for IVC injury differed according to the IVC level. The detection rate was the highest for an infrarenal vena cava injury at 100% (n=4), followed by that for a suprarenal, suprahepatic, and retrohepatic vena cava injuries at 75% (n=3), 43% (n=3), and 25% (n=1), respectively. CONCLUSION: CT findings of traumatic IVC injuries may vary depending on the mechanism and anatomical site of injury. Familiarity with IVC injury imaging features may help in diagnosis and surgical treatment planning.

Postural Changes in Spinal Cord Stimulation Thresholds: Current and Voltage Sources.

OBJECTIVE: Spinal cord stimulation (SCS) thresholds are known to change with body position; however, these changes have not been fully characterized for both "constant-voltage" and "constant-current" pulse generators. This study aimed to evaluate and quantify changes in psychophysical thresholds resulting from postural changes that may affect both conventional paresthesia-based SCS and novel paresthesia-free SCS technologies. MATERIALS AND METHODS: We measured perceptual, usage, and discomfort thresholds in four body positions (prone, supine, sitting, standing) in 149 consecutive patients, with temporary lower thoracic percutaneous epidural electrodes placed for treating persistent low back and leg pain. We trialed 119 patients with constant-voltage stimulators and 30 patients with constant-current stimulators. RESULTS: Moving from supine to the sitting, standing, or prone positions caused all three thresholds (perceptual, usage, and discomfort) to increase by 22% to 34% for constant-voltage stimulators and by 44% to 82% for constant-current stimulators. Changing from a seated to a supine position caused stimulation to exceed discomfort threshold significantly more often for constant-current (87%) than for constant-voltage (63%) stimulators (p = 0.01). CONCLUSIONS: Posture-induced changes in SCS thresholds occurred consistently as patients moved from lying (supine or prone) to upright (standing or sitting) positions. These changes were more pronounced for constant-current than for constant-voltage pulse generators and more often led to stimulation-evoked discomfort. These observations are consistent with postural changes in spinal cord position measured in imaging studies, and with computer model predictions of neural recruitment for these different spinal cord positions. These observations have implications for the design, implantation, and clinical application of spinal cord stimulators, not only for conventional paresthesia-based SCS but also for paresthesia-free SCS.

Drug-induced aseptic meningitis after an interlaminar lumbar epidural steroid injection.

BACKGROUND: This case report describes a rare instance of drug-induced aseptic meningitis after an interlaminar lumbar epidural steroid injection. CASE PRESENTATION: A 74 year-old female patient presented to the ED post-procedure day three after an L4-L5 interlaminar lumbar epidural steroid injection with fever, nausea, and vomiting. The patient had previously undergone numerous lumbar epidurals without complications and used identical medications, which included 1% lidocaine, iohexol contrast, methylprednisolone (Depo-medrol), and normal saline. Pertinent labs included a WBC of 15,000 cells/µL. Lumbar MRI revealed L4-S1 aseptic arachnoiditis. Two bone scans with Gallium and T-99 confirmed no infectious process. The patient then had a second admission months later with similar presenting symptoms and hospital course after repeating the lumbar epidural steroid injection. Lumbar MRI and CSF studies confirmed aseptic meningitis. CONCLUSION: This patient's repeated admissions from aseptic meningitis were likely caused by irritation of the meningeal layers from a medication used during the procedure.

Correction: Randomized nutrient bar supplementation improves exercise-associated changes in plasma metabolome in adolescents and adult family members at cardiometabolic risk.

[This corrects the article DOI: 10.1371/journal.pone.0240437.].

Dacomitinib in EGFR-mutant non-small-cell lung cancer with brain metastasis: a single-arm, phase II study.

INTRODUCTION: Dacomitinib showed superior progression-free survival (PFS) and overall survival compared to gefitinib in patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations in the ARCHER1050 study. However, because that study did not include patients with brain metastases, the efficacy of dacomitinib in patients with brain metastases has not been clarified. PATIENTS AND METHODS: This single-arm phase II study enrolled 30 patients with treatment-naïve advanced NSCLC harboring activating EGFR mutations from January 2021 to June 2021 and started them on dacomitinib (45 mg/day). All patients had non-irradiated brain metastases with a diameter of ≥5 mm. The primary endpoint was confirmed intracranial objective response rate (iORR). RESULTS: Patients had exon 19 deletions (46.7%) and L858R mutations in exon 21 (55.3%). The confirmed iORR was 96.7% (29/30), with an intracranial complete response of 63.3%. Median intracranial PFS (iPFS) was not reached, with 12- and 18-month iPFS rates of 78.6% [95% confidence interval (CI) 64.8% to 95.4%] and 70.4% (95% CI 54.9% to 90.1%), respectively. In the competing risk analysis, the 12-month cumulative incidence of intracranial progression was 16.7%. Regarding the overall efficacy for intracranial and extracranial lesions, the overall ORR was 96.7%, and the median PFS was 17.5 months (95% CI 15.2 months-not reached). Grade 3 or higher treatment-related adverse events were reported in 16.7% of patients, and 83.3% required a reduced dacomitinib dose to manage adverse events. However, none permanently discontinued dacomitinib treatment due to treatment-related adverse events. CONCLUSIONS: Dacomitinib has outstanding intracranial efficacy in patients with EGFR-mutant NSCLC with brain metastases.

New Developments in Image-Guided Percutaneous Irreversible Electroporation of Solid Tumors.

PURPOSE OF REVIEW: This review will describe the various applications, benefits, risks, and approaches of conventional irreversible electroporation (IRE), as well as highlight the new technological developments of this procedure along with their clinical applications. RECENT FINDINGS: Minimally invasive image-guided percutaneous IRE ablation has emerged as a newer, non-thermal ablation technique for tumors in the solid organs, particularly within the liver, pancreas, kidney, and prostate. IRE allows for ablation near heat-sensitive structures, including major blood vessels and nerves, and is not susceptible to the heat sink effect. However, it is limited by certain requirements, such as the need for precise parallel placement of at least two probes with a maximum inter-probe distance of 2.5 cm to reduce the risk of arching phenomenon, the requirement for general anesthesia with muscle relaxant, and the need for cardiac synchronization. However, new technological advancements in the ablation system and image guidance tools have been introduced to improve the efficiency and efficacy of IRE. IRE is a safe and effective treatment option for solid tumor ablation within the liver, pancreas, kidney, and prostate. Compared with other ablation techniques, IRE has several advantages, such as the absence of heat sink effect and minimal injury to blood vessels and bile ducts while activating the immune system. Novel techniques such as H-FIRE, needle placement systems, and robotics have enhanced the accuracy and performance in placement of IRE probes. IRE can be especially beneficial when combined with chemotherapy, immunomodulation, and immunotherapy.