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Background Prognostic stratification of acute myocarditis (AM) presenting with normal left ventricular ejection fraction (LVEF) relies mostly on late gadolinium enhancement (LGE) characterization. Left ventricular peak global longitudinal strain (LV-GLS) measured by feature tracking analysis might improve prognostication of AM presenting with normal LVEF. Methods Data of patients undergoing cardiac magnetic resonance (CMR) for clinically suspected AM in seven European Centres (2013-2020) were retrospectively analysed. Patients with AM confirmed by CMR and LVEF >= 50% were included. LGE was visually characterized: localized versus. non-localized, subepicardial versus midwall. LV-GLS was measured by dedicated software. The primary outcome was the first occurrence of an adverse cardiovascular event (ACE) including cardiac death, life-threatening arrhythmias, development of heart failure or of LVEF Of 389 screened patients, 256 (66%) fulfilled inclusion criteria: median age 36 years, 71% males, median LVEF 60%, median LV-GLS -17.3%. CMR was performed at 4 days from hospitalization. At 27 months, 24 (9%) patients experienced >= 1 ACE (71% developed LVEF -20% or quartiles), non-localized and midwall LGE were associated with ACEs. Patients with LV-GLS = 50%, LV-GLS provides independent prognostic value over LGE characterization, improving risk stratification and representing a rationale for further studies of therapy in this cohort.

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important kinase of the innate immune system. Herein, we describe the optimization of a series of RIPK2 PROTACs which recruit members of the inhibitor of apoptosis (IAP) family of E3 ligases. Our PROTAC optimization strategy focused on reducing the lipophilicity of the early lead which resulted in the identification of analogues with improved solubility and increased human and rat microsomal stability. We identified a range of IAP binders that were successfully incorporated into potent RIPK2 PROTACs with attractive pharmacokinetic profiles. Compound 20 possessed the best overall profile with good solubility, potent degradation of RIPK2, and associated inhibition of TNFα release. A proof-of-concept study utilizing a slow release matrix demonstrated the feasibility of a long-acting parenteral formulation with >1 month duration. This represents an attractive alternative dosing paradigm to oral delivery, especially for chronic diseases where compliance can be challenging.

Objective Children with Sickle Cell Disease (SCD), who are predominantly Black, face academic disparities in part because of the impact of longstanding racially biased education systems. Adverse systemic factors in addition to neurologic complications put children with SCD at risk for poor academic outcomes. Providing caregivers with information on how to select quality schools and advocate for their child's specific educational needs may influence academic outcomes and reduce educational disparities. We aimed to provide information to caregivers of children with SCD on school selection/quality, enrollment, and special education options. Methods Forty-six caregivers of children with SCD between the ages of 2 and 5:11 years participated in a structured informational session. Caregivers' sense of empowerment regarding educational options for their child was assessed via survey before and after the structured informational session. Results Caregivers reported feeling more informed and empowered following their participation in an informational session on school selection/quality, enrollment, and special education options for their child than before the informational session. Conclusions It is essential that families of children with SCD have the knowledge, skills, and sense of empowerment to access quality schools beginning in early childhood. Future research will determine if this intervention will improve children's access to academic support and academic outcomes. We theorize improvements in academic outcomes along with addressing systemic disparities may ultimately create a positive impact on vocational and quality of life outcomes in the lives of children with SCD.

Off the southern coast of tasmania, Australia, lies a small island community and tourist hot spot called Bruny Island, known for its beautiful white sandy beaches, rugged coastline, and delicious produce (Figure 1). Just as the island population rises and falls with the holiday peaks, so, too, does the load on the undersea electricity cable connecting the island to mainland Tasmania, pushing the aging cable to its limits.

We propose two novel two-stage Volt/Var control schemes based on the affinely adjustable robust counterpart (AARC) methodology, to mitigate the over-voltage issues caused by integration of photovoltaic panels into distribution systems. To cope with different grid code requirements, our first approach formulates the unused capacity of residential inverters to provide reactive power support based on the real power deviation, while the second approach formulates them based on voltage magnitude deviation. In the first stage of both schemes, we make central measurements throughout the network to determine a linear function, mapping the operating point deviations to the reactive power of inverters. In the second stage, the local controllers use the provided linear functions to determine the required reactive power to keep the voltages within the safe limits. Unlike similar approaches, voltage limit constraints are directly incorporated into the AARC problem, preventing the second stage controllers from unnecessarily use of reactive powers. We compare the performance of our schemes using a Monte-Carlo simulation with four other existing techniques on a real-world 27-bus and the IEEE 906-bus LV feeders. Our simulations show that our approaches decrease the real power loss, reactive power usage, and line congestion compared to the other Volt/Var control schemes.

The increasing uptake of distributed energy resources (DER) is displacing the dispatchable generators responsible for providing frequency response in our power system. To compensate for the withdrawal of such generators, the market participation of DER fleets through aggregators has been suggested in the literature. Unfortunately, these works are either limited to price-taking aggregators or neglect the distribution network. The first limitation leads to inelastic bids which do not reflect DER flexibility, while the second results in bids that do not lie within the network boundaries. To mitigate these challenges, we propose a price-elastic aggregator bidding approach together with a network conforming layer. Our approach enables aggregators to offer a range of network-secure bid bands for different prices. To preserve the independent role of each stakeholder and share the computational burden, we decompose the problem into aggregator and network subproblems, solved sequentially. Moreover, we confer aggregators the possibility to provide reactive power support to enable the network to accept greater throughput. Finally, since our approach ensures network feasibility prior to bids reaching the market, it minimizes the disruption to existing wholesale market structures. Our results on a 141-bus network shows 19% higher benefits for aggregators, compared to the inelastic bidding approach.

This article reassesses J.-H. Rosny aine’s two sequential novels, Les Navigateurs de l’infini (1925) and Les Astronautes (1933; published posthumously in 1960), dealing with the exploratory voyage of three astronauts to Mars and humanity’s first encounter with a rational extraterrestrial race. The love story between the human first-person narrator, Jacques, and Grâce, an orificeless, six-eyed female tripedal creature, gradually eclipses the wider context of exploration and scientific advancement. The romance occupies much of the sequel, with the added complication of a love triangle with Violaine, the sister of one of the other voyagers. Through the perspective of this unusual relationship, Rosny calls into question European colonialism and pessimistic science fiction exemplified by H. G. Wells pitting human civilization against an alien enemy. The works may be contextualized as part of an interwar wave of science fiction involving Martians that critiqued imperialism. Above all, alterity is posited as an ultimately positive notion.

Introduction Studied have shown that continuous positive airway pressure(CPAP) adherence is lower in women. However, understanding of the specific challenges faced by woman when starting therapy remains poor. Specifically, is there any relationship between leak and women’s characteristics that could influence adherence? Methods The AWARE-study is a longitudinal pilot-study with the objective to identify in women modifiable barriers to initiating/adhering to treatment over 3-months. Adherence was considered when using CPAP for a minimum 4-hours 70% of the nights. But, is there any association between leak, mask type and other patient’s characteristics that could influence adherence in women? This is a secondary analysis looking at leak as a consequence of poor adherence in women within the AWARE-study. We gathered data directly from the PAP-data-base and evaluated adherence within the first 3-months after starting therapy and usage at-present-time. We investigated leakage (>25 L/min) and gathered information about severity of OSA, age, BMI, and race. Our aims: to evaluate for leak as a cause of poor adherence and to identify characteristics that could potentiate leak in women. Results Data from 49 women from the AWARE-study between the ages of 28-85, with a recent diagnosis of OSA who started CPAP was analyzed. Adherence, leakage, age, OSA severity, and mask type was gathered. Chi-squared test of independence suggests a relationship between leakage and present adherence, Chi2(1)=11.34, p=0.001. Of those women experiencing high leakage, 83% were non-adherent to therapy. Logistic regression was run to compute an odds ratio with 95% CI. Those experiencing high leakage have about 92% times lower odds to still be compliant than those not experiencing high leakage [OR=0.08, 95% CI: 0.007, 0.478]. Overall, mask type relates to adherence, 72% of nasal mask wearers were still being adherent versus 38% when using facial masks. The prediction of adherence from leakage does not significantly differ across mask type. Age was found to be related to adherence; 57% of women under 50-years were not adherent to CPAP versus 26% in women over 50-years. Conclusion This information could guide us in suggesting strategies for better mask choosing and possibly to implement more specific strategies that can increase adherence in women. Support (if any)

Conventional cancer therapy exploits sensitivity of dividing cells to DNA damage leading to apoptosis and tumor kill. Off-target normal tissue toxicity limits the maximum tolerated dose (MTD) and potential tumor ablation. We developed a targeted nanoparticle therapeutic platform that maximizes delivery of small molecules to tumor cells, including across the blood-brain barrier that normally prevents effective therapy with such agents. The core technology is a novel nanoparticle formulation that maximizes bioavailability and preferentially targets tumor cells while minimizing delivery to normal cells. Plasma irinotecan levels remain readily detectable for at least 48 hours, while free irinotecan is no longer detectable at 2 hours. Nanoparticles are readily imaged in tumor cells when virtually none are detectable in normal tissues. Targeting is achieved with antibodies that cause the nanoparticles to preferentially bind to tumor cells versus normal by a factor of at least 10. Levels of drug by quantitative mass spectroscopy are at least 15-fold greater in tumor vs normal tissue. As a result, the minimum effective dose (MED) is typically reduced ten-fold. Typical payloads include irinotecan, doxorubicin, and gemcitabine. Targeting antibodies include CD276 (B7H3) and CD99 (MIC2) for solid tumors. Compared to antibody-drug conjugates (ADCs), far greater drug doses per antibody molecule are delivered. In addition, the nanoparticles readily pass through the blood-brain barrier at least 15 times better than free drug alone. Consequently, the platform technology shows promise for treatment of both extra-cranial and intra-cranial tumors. In pre-clinical animal studies, survival of human PDX glioblastoma (GBM) bearing mice was prolonged by at least three-fold compared to free-drug treated animals when treated at a sub-optimal dose of 10mg/kg of irinotecan thrice weekly. Ewing sarcoma bearing mice showed indefinite survival at 2 mg/kg bi-weekly dosing, even for relapsed, treatment-resistant tumors. Treatment of hepatocellular carcinoma bearing mice biweekly at 5mg/kg resulted in no detectable tumor and 100% survival at 80 days, when all free irinotecan treated mice at the same dose were dead, with control animals dead at 50 days. Similarly, prostate cancer bearing mice treated at the same dose and regimen were all alive at 58 days when all untreated tumor bearing mice were dead. A similar result was obtained with ovarian cancer and the same treatment regimen, but tumor growth in treated animals was observed at 58 days when all untreated animals were dead. Perhaps most significantly, treated mice bearing pancreatic cancer showed 100 % survival at 80 days when all untreated animals were dead at day 59. At no time did any animal show evidence of treatment-related toxicity. Taken together, these results support a non-toxic cancer treatment approach with existing small molecule therapy that preferentially delivers drug to tumor with markedly improved efficacy. Citation Format: HyungGyoo Kang, Bryon Upton, Paul Scott, Mark Lewis, Jon Nagy, Timothy Triche. Targeted nanospheres for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 825.

In energy absorption applications, architectured metallic materials generally suffer from unrecoverable deformation as a result of local yield damage or inelastic buckling. Nitinol (NiTi) offers recoverable deformation and energy dissipation due to its unique superelasticity, which can change the way we design and additively manufacture energy-absorbing architectured materials. The interplay between microstructure, mesoscopic deformation, and macroscopic thermomechanical response of NiTi architectured materials is still not studied in depth. In this work, NiTi architectured materials featuring anisotropic superelastic response, recoverable energy absorption and damping were successfully modeled and manufactured using laser powder bed fusion (L-PBF). Extensive numerical models demonstrated that NiTi architectured materials exhibit temperature-dependent superelasticity and effective transformation stress which can be controlled by the relative density and cell architecture. An effective transformation surface was developed based on the extended Hill's model, illustrating anisotropy is temperature-independent. Stable cyclic behavior with 2.8 % of reversible strain and damping behavior was successfully achieved in cyclic compressive tests without yielding damage or plastic buckling, which further illustrates that the progressive martensitic transformation is the main deformation and energy dissipation mechanism. A comparative study between designed herein body centered cubic (BCC) and octet structures showed that local microstructures significantly affect the deformation modes. The integrated computational and experimental study enables tailoring the superelasticity by combining structural design and microstructural control. Architectured materials designed in this study are potentially applicable as reusable impact absorbers in aerospace, automotive, maritime and vibration-proof structures.

Reducing the required frequence of drug dosing can improve the adherence of patients to chronic treatments. Hence, drugs with longer in vivo half-lives are highly desirable. One of the most promising approaches to extend the in vivo half-life of drugs is conjugation to human serum albumin (HSA). In this work, we describe the use of AlbuBinder 1, a small-molecule noncovalent HSA binder, to extend the in vivo half-life and pharmacology of small-molecule BMP1/TLL inhibitors in humanized mice (HSA KI/KI). A series of conjugates of AlbuBinder 1 with BMP1/TLL inhibitors were prepared. In particular, conjugate c showed good solubility and a half-life extension of >20-fold versus the parent molecule in the HSA KI/KI mice, reaching half-lives of >48 h with maintained maximal inhibition of plasma BMP1/TLL. The same conjugate showed a half-life of only 3 h in the wild-type mice, suggesting that the half-life extension was principally due to specific interactions with HSA. It is envisioned that conjugation to AlbuBinder 1 should be applicable to a wide range of small molecule or peptide drugs with short half-lives. In this context, AlbuBinders represent a viable alternative to existing half-life extension technologies.

Conceptualisation and theoretical understanding of slow journalism has developed over more than a decade in reaction to the fast-paced journalism so prevalent in contemporary, mainstream media. Art...

Laser Powder Bed Fusion process is regarded as the most versatile metal additive manufacturing process, which has been proven to manufacture near net shape up to 99.9% relative density, with geometrically complex and high-performance metallic parts at reduced time. Steels and iron-based alloys are the most predominant engi-neering materials used for structural and sub-structural applications. Availability of steels in more than 3500 grades with their wide range of properties including high strength, corrosion resistance, good ductility, low cost, recyclability etc., have put them in forefront of other metallic materials. However, LPBF process of steels and iron-based alloys have not been completely established in industrial applications due to: (i) limited insight available in regards to the processing conditions, (ii) lack of specific materials standards, and (iii) inadequate knowledge to correlate the process parameters and other technical obstacles such as dimensional accuracy from a design model to actual component, part variability, limited feedstock materials, manual post-processing and etc. Continued efforts have been made to address these issues. This review aims to provide an overview of steels and iron-based alloys used in LPBF process by summarizing their key process parameters, describing thermophysical phenomena that is strongly linked to the phase transformation and microstructure evolution during solidifica-tion, highlighting metallurgical defects and their potential control methods, along with the impact of various post-process treatments; all of this have a direct impact on the mechanical performance. Finally, a summary of LPBF processed steels and iron-based alloys with functional properties and their application perspectives are presented. This review can provide a foundation of knowledge on LPBF process of steels by identifying missing information from the existing literature.

The 2021-2026 Strategic Plan of the National Institute of Neurological Disorders and Stroke began with a vision, a mission, and strategic objectives elaborated from within the institute. This plan is a collaborative product of the institute and its many stakeholders, emphasizing cross-cutting operational principles including scientific rigor, communication, workforce culture, and equity.