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Gianluca Dini,1 Giuseppe Di Cara,1 Pietro Ferrara,2 Pasquale Striano,3 Alberto Verrotti1 1Department of Pediatrics, University of Perugia, Perugia, Italy; 2Department of Pediatrics, Campus Bio-Medico University, Rome, Italy; 3Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto “G. Gaslini”, Genoa, ItalyCorrespondence: Gianluca Dini, Department of Pediatrics, University of Perugia, Piazzale Giorgio Menghini 1, Perugia, 06129, Italy, Tel +39 3337797213, Email gianlucadini90@gmail.comAbstract: Despite the introduction of new anti-seizure medications in recent years, approximately one-third of the epileptic population continues to experience seizures. Recently, the anti-obesity medication fenfluramine (FFA) has been successfully repurposed, and it has received approval from various regulatory agencies for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome. The potential antiseizure effects of FFA were initially observed in patients with photosensitive epilepsy in the 1980s but it was not rigorously explored as a treatment option until 30 years later. This narrative review aims to provide an overview of the historical progression of FFA’s use, starting from initial clinical observations to preclinical studies and, ultimately, successful clinical trials in the field of epilepsy.Keywords: fenfluramine, seizures, Dravet syndrome, drug-resistant epilepsy, serotonin

As environmental opportunistic pathogens, nontuberculous mycobacteria (NTM) can cause severe and difficult to treat pulmonary disease. In the United States, Hawai’i has the highest prevalence of infection. Rapid growing mycobacteria (RGM) such as Mycobacterium abscessus and M. porcinum and the slow growing mycobacteria (SGM) including M. intracellulare subspecies chimaera are common environmental NTM species and subspecies in Hawai’i. Although iron acquisition is an essential process of many microorganisms, iron acquisition via siderophores among the NTM is not well-characterized. In this study, we apply genomic and microbiological methodologies to better understand iron acquisition via siderophores for environmental and respiratory isolates of M. abscessus, M. porcinum, and M. intracellulare subspecies chimaera from Hawai’i. Siderophore synthesis and transport genes, including mycobactin (mbt), mmpL/S, and esx-3 were compared among 47 reference isolates, 29 respiratory isolates, and 23 environmental Hawai’i isolates. Among all reference isolates examined, respiratory isolates showed significantly more siderophore pertinent genes compared to environmental isolates. Among the Hawai’i isolates, RGM M. abscessus and M. porcinum had significantly less esx-3 and mbt genes compared to SGM M. chimaera when stratified by growth classification. However, no significant differences were observed between the species when grown on low iron culture agar or siderophore production by the chrome azurol S (CAS) assay in vitro. These results indicate the complex mechanisms involved in iron sequestration and siderophore activity among diverse NTM species.

Abstract Laser powder bed fusion (L-PBF) is increasingly used to fabricate functional parts used in safety-relevant applications. To ensure that the sophisticated part specifications are achieved, 100% quality inspections are performed subsequent to the buildup process. However, knowledge about the detectability of defects in L-PBF parts using NDT methods is limited. This paper analyzes the suitability of NDT techniques in an ex situ environment, in particular active infrared thermography, neutron grating interferometry (nGI), X-ray computed tomography, and ultrasonic testing for the examination of L-PBF parts made from Inconel 718. Based on a test specimen with artificially inserted defects with varying dimensions and depths, these NDT techniques were compared in terms of their attainable resolution and thus defect detection capability. The empirical studies revealed that nGI shows the highest resolution capability. It was possible to detect defects with a diameter of 100–200 m at a depth of 60–80 $${\upmu } \hbox {m}$$ μ m . The results are discussed with regard to their relevance for the examination of L-PBF parts and thus not only contribute to a better understanding of the potential of the NDT techniques in comparison but also assist stakeholders in additive manufacturing in evaluating the suitability of the NDT techniques investigated.

ObjectiveTo determine the proportion of patients undergoing hysterectomy for a benign indication who have unexpected malignancy (UM) on postoperative pathology and characterize the nature of UMs.MethodsThis was a multi-center, retrospective study of patients undergoing hysterectomy for a benign indication from July 2016 to December 2019 at 7 Ontario, Canada hospitals (4 academic, 3 community). Hysterectomies for invasive placentation, malignant, and premalignant indications were excluded. Primary outcome was rate of unexpected malignancy as defined by the number of patients with malignancy on final pathology divided by the total number of hysterectomy cases. Data was extracted from health records and electronic charts. Patient, surgical, and surgeon characteristics were compared between benign and UM groups using bivariate methods. Associations between UM status and perioperative variables were assessed using bivariate logistic regression.ResultsIn the study period, 2779 hysterectomies were performed. UM incidence was 1.8% (51 malignancies/2779 cases), with one patient having two malignancies (total UMs = 52). The most common UM types were endometrial (27/52, 51.9%) and sarcoma (13/52, 25%). Patients with UM were older (57.2 ± 11.4 years vs. 52.8 ± 12.5 years, p = .015), had more previous laparotomies (2 (1.25, 2.0) vs. 1 (1.0, 1.0), p < .001), and higher BMI (29.7 ± 7.2 kg/m2 vs. 28.0 ± 5.9 kg/m2, p = .049) and ASA class (p < .028). Regarding surgical factors, patients with UM had more adhesions (p = .001), transfusions (p = .020), and blood loss (p = .006) compared to those with benign pathology. Patient characteristics most strongly associated with UM were age (OR 2.57, 95% CI 1.78-3.72, p < .001) and preoperative diagnosis of pelvic mass (OR 2.76, 95% CI 1.11-6.20, p = .019).ConclusionIncidence of UM at hysterectomy for benign indication was 1.8%. Several perioperative variables are associated with an increased chance of UM.

Abstract Background With approximately 8 hours of one’s waking day spent at work, occupational tasks and environments are important influencers on an individual’s physical activity (PA) and sedentary behaviours. Little research has compared device-measured physical activity, sedentary behaviour and cardiometabolic outcomes between occupational groups. Objective To compare device-measured movement (sedentary time [ST], light intensity physical activity [LPA], moderate-to-vigorous intensity physical activity [MVPA], and steps) across occupations. The secondary objective was to examine whether cardiometabolic and fitness outcomes differed by occupation. Methods Five bibliographic databases were searched to identify all studies which included working age, employed adults from high-income countries, and reported on device-measured movement within occupations. Risk of bias within and across studies was assessed. Results were synthesized using meta-analyses and narrative syntheses. Results The review includes 132 unique studies with data from 15,619 participants. Working adults spent ~ 60% of their working and waking time engaged in sedentary behaviour; a very small proportion (~ 4%) of the day included MVPA. On average, workers accumulated 8124 steps/day. Office and call center workers’ steps/day were among the lowest, while those of postal delivery workers were highest. Office workers had the greatest ST and the lowest time in LPA both at work and during wakeful time. However, office workers had the greatest minutes sent in MVPA during wakeful hours. Laborers had the lowest ST and spent a significantly greater proportion of their work time in LPA and MVPA. Healthcare and protective services workers had higher levels of LPA at work compared to other occupations. Workers in driving-based occupations tended to have a higher body mass index and blood pressure. Conclusion This review identifies that occupational and wakeful time PA and ST differed between occupations. Future studies are needed to assess whether patterns differ by age and sex, describe leisure-time movement and movement patterns, and the relationship with cardiometabolic health. Systematic review registration PROSPERO CRD42017070448.

In binder jetting (BJ), an ink is inserted layerwise into a powder bed to selectively bond the particles in the cross-section of a part. By predicting the penetration depth of the ink, the ideal layer thickness for BJ can be set. Each layer should be penetrated with ink. Insufficient penetration will result in a poor layer bond and a low strength of the part; over-penetration will impede a dimensionally accurate production, as the ink will leak from the sides of the part and unintentionally solidify the powder in these areas. The Washburn equation has been used for the calculation of the penetration depth in various fields, such as hydrology or with loose powders. However, a transfer to the BJ process is difficult due to the preferably compact powder bed and the fine particles. In more compact powder beds, the small radii with their greater capillary pressure and their distribution in the layer have a high influence on the penetration depth. This work shows an adaptation of the Washburn equation for powder beds in BJ and a new approach to determine the effective pore radius for calculating the penetration depth. A weighted pore radius was introduced, which accounts for the spatial distribution of the pores in the powder bed and the acting capillary pressure. The validation was performed with two different powders by experimentally simulating the BJ process through the infiltration of a drop into a powder bed. The weighted radius was used in the Washburn equation to calculate the penetration depth. The results were compared with those models from the literature and experimental data, and a good agreement between the calculation and the experiment was found.

Objectives: Chronic pain and mental illness in youth and parents are poised to reach new heights amidst the societal and healthcare impacts of the COVID-19 pandemic. Evidence from natural disasters (i.e., hurricanes) suggests that a degree of personal impact and individual personality may moderate the effects of high stress events, such as the COVID-19 pandemic, on mental health. Methods: In a pre-existing cohort of 84 youth with chronic pain (Mage = 14.39; 12–18 years; 67.8% female) and 90 parents (86.7% female), we examined changes in youth pain interference and youth and parent mental health (depression, anxiety) from before to during the first wave of the COVID-19 pandemic, and the influence of personal impact of the pandemic (i.e., financial, familial, health, social, occupational, and educational domains) and individual personality (neuroticism, conscientiousness, extroversion). Results: Overall, youth reported significantly lower pain interference and anxiety as compared to pre-pandemic; however, those more personally impacted by the pandemic reported worsening pain interference and anxiety symptoms. Overall, parents reported greater depressive symptoms as compared to pre-pandemic; however, those more personally impacted by the pandemic reported increased anxiety symptoms. Personality traits (high neuroticism, and low conscientiousness and extroversion) predicted worsened pain and mental health, and exacerbated effects of COVID-19-related personal impact on youth and parent anxiety symptoms. Discussion: Identifying risk and resilience profiles in youth and parents at high risk for worsening pain and mental health may better inform matching interventions to individual need.

Coaxial Laser Metal Deposition with wire (LMD-w) is a valuable complement to the already established Additive Manufacturing processes in production because it allows a direction-independent process with high deposition rates and high deposition accuracy. However, there is a lack of knowledge regarding the adjustment of the process parameters during process development to build defect-free parts. Therefore, in this work, a process development for coaxial LMD-w was conducted using an aluminum wire AlMg4,5MnZr and a stainless steel wire AISI 316L. At first, the boundaries for parameter combinations that led to a defect-free process were identified. The proportion between the process parameters energy per unit length and speed ratio proved crucial for a defect-free process. Then, the influence of the process parameters on the height and width of single beads for both materials was analyzed using a regression analysis. It was shown that linear models are suitable for describing the correlation between the process parameters and the dimensions of the beads. Lastly, a material-independent formula is presented to calculate the height increment per layer needed for an additive process. For future studies, the results of this work will be an aid for process development with different materials.

CD8+ T cell tolerance to self-proteins prevents autoimmunity but represents an obstacle to generating T cell responses to tumor-associated antigens. We have made a T cell receptor (TCR) transgenic mouse specific for a tumor antigen and crossed TCR-TG mice to transgenic mice expressing the tumor antigen in hepatocytes (gag-TG). TCRxgag mice showed no signs of autoimmunity despite persistence of high avidity transgenic CD8+ T cells in the periphery. Peripheral CD8+ T cells expressed phenotypic markers consistent with antigen encounter in vivo and had upregulated the antiapoptotic molecule Bcl-2. TCRxgag cells failed to proliferate in response to antigen but demonstrated cytolytic activity and the ability to produce interferon gamma. This split tolerance was accompanied by inhibition of Ca(2+) flux, ERK1/2, and Jun kinase phosphorylation, and a block in both interleukin 2 production and response to exogenous interleukin 2. The data suggest that proliferation and expression of specific effector functions characteristic of reactive cells are not necessarily linked in CD8+ T cell tolerance.

Water-based processing of electrodes is associated with an enhanced environmental footprint for lithium-ion battery (LIB) production in conjunction with reduced costs. This trend is accompanied by an increasing demand for electrode dispersion processing in inkjet printing. However, most of the dispersion components show a low inherent dispersibility with poor stability in aqueous formulations. This is particularly important when it comes to qualifying electrode dispersions for use in inkjet printing, since the effect of agglomeration and sedimentation effects must be effectively prevented. Therefore, additives are needed to improve the dispersive behavior. This paper analyzes the suitability of dispersants for organic electrode components, in particular graphite and carbon black. An empirical approach was devised on the basis of comprehensive theoretical considerations. Empirical investigations revealed that the utilization of polyvinylpyrrolidone (PVP) favored the enhanced stabilization of graphite nanoparticles. The addition of Triton X-100 (TX-100) resulted in an improved stabilization of carbon black. Based on these empirical studies, a methodology was derived, which supports the application of suitable dispersants in printable dispersions.