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This paper examines industrialization in developing countries. It introduces the GGDC/UNU-WIDER Economic Transformation Database, which provides consistent annual data of employment, real and nominal value added by 12 sectors in 51 economies for the period 1990-2018. Regressions that control for income and population indicate a manufacturing renaissance in several middle-income countries since the 2000s. We observe industrialization in many low-income Asian and sub-Saharan African countries. The industrial naissance in sub-Saharan Africa appears characterized by unregistered firms that expand employment. JEL Classification N10 * O14 * O47, 1 Introduction Historically, the reallocation of workers from craft to modern activities has driven sustained improvements in living standards. It was the industrial revolution that initiated a long period of [...]

The Single Biggest Problem in communication is the illusion that it has taken place. --George Bernard Shaw Shaw was a cynic, but he has a point: We believe we're communicating, [...]

The focus of healthcare mergers and acquisitions (M&A) transactions has been shifting today, with a growing emphasis on creating transformative partnerships aimed at improving value and overall cost effectiveness. As [...]

Facebook[sup.®] is a popular platform for hosting online support groups. The readily available, socially acceptable, and free platform holds many advantages for researchers designing and implementing interventions with social media. [...], Facebook[sup.®] is a popular platform for older adults, especially as they try to stay in contact with their family around the country. It is also a popular platform for hosting online support groups. The readily available, socially acceptable, and free platform holds many advantages not only for older adults but also for nurse researchers designing and implementing interventions for older adults. The literature is void of proven methods to measure individual engagement with the Facebook platform. The current article describes efforts to develop a measurement process and evaluate the impact that engagement with Facebook has on improved mental health outcomes for older adults. Scores were severely skewed and ranged from no engagement to very high engagement. Engagement differed based on sex, race, and living arrangements with patients. Further work in this area is needed if nurse researchers are to consider the role of engagement in social media interventions. [Journal of Gerontological Nursing, 48(7), 10?17.]

Eine Gingivitis ist bei der Mehrheit der Kinder und Jugendlichen in Deutschland zu beobachten, während andere parodontale Erkrankungen wie eine Parodontitis in dieser Altersgruppe hingegen nur selten vorkommen. Tritt eine Parodontitis jedoch auf, ist sie häufig mit einer schweren Allgemeinerkrankung oder einem Syndrom verbunden. Die frühzeitige Diagnosestellung - insbesondere durch die Erhebung des Parodontalen Screening Index - spielt eine entscheidende Rolle für eine erfolgreiche Therapie. Nekrotisierende Parodontalerkrankungen gehören zu den akuten Erkrankungsformen des Parodonts und können ein Hinweis auf eine schwerwiegende Immunerkrankung sein. In solchen Fällen ist eine allgemeinmedizinische Abklärung unerlässlich. Parodontale Rezessionen werden häufig nach einer kieferorthopädischen Behandlung festgestellt. Allerdings stellt diese nur einen von mehreren möglichen Risikofaktoren dar. Für eine chirurgische Rezessions-deckung sollte jedoch aufgrund des unvollständigen Wachstums das Erreichen des Erwachsenenalters abgewartet werden.© kittyfly / Stock.adobe.com (Symbolbild mit Fotomodell)

Health care worker well-being is critical to delivering optimal care to our patients. With greater understanding of these issues, evidence-informed models of employee well-being have been developed to guide efforts to improve well-being in the workplace. To ensure that organizational approaches resonate with staff needs, these models can be improved for local application by engaging employees in a co-creation process in which they actively participate in developing and refining the institutional framework for employee well-being. This article describes how the Mayo Clinic Employee Well-Being team, led by Mayo Clinic’s first organization-level medical director and administrator of Employee Well-Being, integrated employee input with existing well-being models through a comprehensive process to define a program structure reflecting the most important staff needs. The novel features of this approach are intended to serve as a guide for health care organizations as we work together to promote learning and working environments in medicine in which every member of the health care team can thrive.

Simulation-based learning (SBL) has been trialed and embedded in many disciplines and professions over many years to practice complex skills before embarking on real-life applications. Much research has confirmed the benefits of SBL and found simulations are among the most effective means to facilitate the learning of complex skills across domains. Yet, despite this evidence-based support for SBL, teacher education continues to be slow to adopt and embed SBL within their programs. This paper compares literature on two of the longest and widest adopted simulated programs in teacher education, Second Lifeand simSchool—to gain insight into the research types, findings and reasons for limited implementation. The findings support previously confirmed pedagogical benefits of SBL increasing student self-efficacy and reveal commonalities and differences between the two simulated platforms and a lack of adoption of SBL that centres around costs, accessibility and technical issues. The findings are positioned in practice-theory literature and highlight SBL’s ability to provide preservice teachers with a ‘third space’ where theory can be practiced, rehearsed and reviewed virtually before real classroom transference occurs. We offer recommendations that will stimulate future research and support wider adoption of SBL in Initial Teacher Education (ITE).

Purpose: The aim of this study was to assess the initial experience, technical success, and clinical benefit of AneuFix (TripleMed, Geleen, the Netherlands), a novel biocompatible and non-inflammatory elastomer that is directly injected into the aneurysm sac by a translumbar puncture in patients with a type II endoleak and a growing aneurysm.Materials and Methods: A multicenter, prospective, pivotal study was conducted (ClinicalTrials.gov:NCT02487290). Patients with a type II endoleak and aneurysm growth (>5 mm) were included. Patients with a patent inferior mesenteric artery connected to the endoleak were excluded for initial safety reasons. The endoleak cavity was translumbar punctured with cone-beam computed tomography (CT) and software guidance. Angiography of the endoleak was performed, all lumbar arteries connected to the endoleak were visualized, and AneuFix elastomer was injected into the endoleak cavity and short segment of the lumbar arteries. The primary endpoint was technical success, defined as successful filling of the endoleak cavity with computed tomography angiography (CTA) assessment within 24 hours. Secondary endpoints were clinical success defined as the absence of abdominal aortic aneurysm (AAA) growth at 6 months on CTA, serious adverse events, re-interventions, and neurological abnormalities. Computed tomography angiography follow-up was performed at 1 day and at 3, 6, and 12 months. This analysis reports the initial experience of the first 10 patients treated with AneuFix.Results: Seven men and 3 women with a median age of 78 years (interquartile range (IQR), 74-84) were treated. Median aneurysm growth after endovascular aneurysm repair (EVAR) was 19 mm (IQR, 8–23 mm). Technical success was 100%; it was possible to puncture the endoleak cavity of all treated patients and to inject AneuFix. Clinical success at 6 months was 90%. One patient showed 5 mm growth with persisting endoleak, probably due to insufficient endoleak filling. No serious adverse events related to the procedure or AneuFix material were reported. No neurological disorders were reported.Conclusion: The first results of type II endoleak treatment with AneuFix injectable elastomer in a small number of patients with a growing aneurysm show that it is technically feasible, safe, and clinically effective at 6 months.Clinical Impact Effective and durable embolization of type II endoleaks causing abdominal aortic aneurysms (AAA) growth after EVAR is challenging. A novel injectable elastic polymer (elastomer) was developed, specifically designed to treat type II endoleaks (AneuFix, TripleMed, Geleen, the Netherlands). Embolization of the type II endoleak was performed by translumbar puncture. The viscosity changes from paste-like during injection, into an elastic implant after curing. The initial experience of this multicentre prospective pivotal trial demonstrated that the procedure is feasible and safe with a technical success of 100%. Absence of AAA growth was observed in 9 out of 10 treated patients at 6 months.

Malaria continues to pose a significant burden on populations in endemic areas and requires innovative treatment options. Here, we report the synthesis and preclinical evaluation of the novel 3-hydroxypropanamidine (HPA) 2 (TKK130), which shows excellent antiplasmodial in vitroactivity against drug-sensitive and -resistant Plasmodium falciparumstrains. Moreover, in various human cell lines, the compound shows no cytotoxicity and excellent parasite selectivity. The compound inhibits synthetic hemozoin (β-hematin) formation, with IC50values lower than chloroquine (CQ), and its in vitrorate of activity is comparable with the fast-acting antimalarial drug dihydroartemisinin. Furthermore, selection studies reveal a very low propensity for resistance development. Based on initial in vivopharmacokinetic snapshot data, 2 (TKK130)has a long-lasting, linear pharmacokinetic profile. In vivo, this novel HPA exhibits curative activity in the Plasmodium bergheimouse model and potent activity in theP. falciparumSCID mouse model after oral administration.

Purpose: Intersex people make up 1.7–4% of the population of North America. A recent scoping review of emergency department (ED) relevant literature for the care of sexual and gender minorities found almost no representation of this population. Intersex people have unique equity, diversity, and inclusion needs in the ED, so we undertook a review of international guidelines to identify ED-relevant recommendations. Methods: Using the PRISMA criteria, we systematically searched OVID Medline, EMBASE, CINAHL, and the gray literature for any clinical practice guideline (CPG) or best practice statement (BPS) published until Oct 21, 2022. We included articles in English, which included care of intersex people of any age, in any setting, region, or nation, and were of national or international in scope. We excluded primary research, systematic or narrative reviews, non-CPS or BPS statements, editorials, articles of regional or individual hospital scope, or if a more recent version had been published. Recommendations relevant to the ED were identified and the guideline and recommendations scored for quality using the AGREE-II and AGREE-REX tools respectively. Results: Of 1599 studies identified, 1400 studies were excluded, 199 full-text reviews completed, and 95 studies included for evaluation. There were no ED-relevant recommendations found among these guideline documents. Conclusion: A systematic review of the literature for ED-relevant guidelines for the care of Intersex populations returned no results. Given the risk of increasing barriers to care for intersex people, and the increasing use of the ED for primary care, the requirements of Intersex people need to be investigated and integrated into future development of a CPG for care of sexual and gender minority populations in the ED.

A physical model of a forward biased silicon phase shifter (FB-PS) in a 250 nm electronic-photonic integrated circuit (EPIC) BiCMOS technology was developed and fitted to measurement results. The model is implemented via VerilogA and SPICE to allow usage in all standard EDA software tools, enabling reliable simulations of electrooptical transmitter systems with FB-PSs. Physical effects inside the phase shifter (PS) are modelled individually by VerilogA/SPICE building blocks, allowing independent parametric modelling and fitting, as well as investigation of internal charges, currents, voltages and electromagnetic field parameters. Therefore, the presented FB-PS modelling is universally applicable and adoptable to FB-PSs in different technologies. The modelled FB-PS exhibits high efficiency, enabling very compact Mach-Zehnder modulators (MZM) with short PS length. All considered physical effects, measurement setups, model parameters, VerilogA implementations, and a bandwidth extension technique are presented. Validation of the model is done by means of electrooptical bandwidth measurements and non-return-to-zero signal generation experiments.

How do people react to ethnic (dis)similarity? Whereas prior studies on ethnic diversity and intergroup contact often focus on interpersonal outcomes such as prejudice and trust, we turn to an essential intrapersonal phenomenon: well-being. We argue that ethnic similarity in the local setting increases well-being for both the ethnic majority and ethnic minority but for theoretically different reasons. To test our argument, we combine Danish registry data with panel survey data from all fourth- to ninth-grade students in Danish public schools (N~700,000). Across different identification strategies, we find that higher levels of classroom ethnic similarity increase well-being. Further, whereas being in a dominant position promotes well-being among the ethnic majority, simply having someone increases minority students’ well-being. This points to the complex nature of intergroup integration but also suggests that local settings with some minority members may foster minorities’ well-being without substantively reducing the well-being of the ethnic majority.

The article summarizes the provisions of the 2017 Tax Cuts and Jobs Act (TCJA) that are scheduled to expire, speculates what tax reform may look like in 2025 and highlight trends and developments expected in the U.S. in 2025. Topics include key provisions that are set to expire at the end of 2025, business tax provisions in TCJA that are permanent, and policy proposals that may provide additional clues to what types of policies that the administration of President Donald Trump will support.

Amylin, a member of the calcitonin family, acts via amylin receptors in the hindbrain and hypothalamus to suppress appetite. Native ligands of these receptors are peptides with short half-lives. Conjugating fatty acids to these peptides can increase their half-lives. The long-acting human amylin analog, NN1213, was generated from structure–activity efforts optimizing solubility, stability, receptor affinity, and selectivity, as well as in vivo potency and clearance. In both rats and dogs, a single dose of NN1213 reduced appetite in a dose-dependent manner and with a long duration of action. Consistent with the effect on appetite, studies in obese rats demonstrated that daily NN1213 dosing resulted in a dose-dependent reduction in body weight over a 21-day period. Magnetic resonance imaging indicated that this was primarily driven by loss of fat mass. Based on these data, NN1213 could be considered an attractive option for weight management in the clinical setting.

Fall detection systems can play an important role in assuring safe independent living for vulnerable people. These sensors not only have to detect falls but also have to recognize uncritical, normal activities of daily living in order to differentiate them from falls. Radar sensors are very attractive for human activity recognition thanks to their contactless capabilities and lack of plain videos recorded. In this article, a novel approach to recognize single activities in a continuous stream of radar data is proposed, whereby the stream is divided into windows of fixed length and, then, multilabel classification is used to recognize all activities taking place in these time segments. While the initial feasibility of this approach was presented in an earlier contribution presented at the 2023 IEEE SENSORS conference, in this extended work, additional in-depth studies on critical parameters are performed. Specifically, multiple combinations of different radar data domains/representations (e.g., range-time maps, range-Doppler maps, and spectrograms) and different radar nodes in a network of five cooperating sensors are considered as inputs to two considered multilabel classification networks. In addition, a parametric study on the probability thresholds of the networks to assign labels to specific classes is also performed.

Traf2- and Nck-interacting kinase (TNIK) has been identified as a promising therapeutic target for the treatment of fibrosis-driven diseases. Utilizing a structure-based drug design workflow, we developed a series of potent TNIK inhibitors that modulate the conformation of the gatekeeper Met105 side chain and access the TNIK back pocket. The lead optimization efforts culminated in the discovery of the recently reported compound 4(INS018_055), a novel TNIK inhibitor. This molecule demonstrated excellent activity in both enzymatic and cell-based assays, along with high selectivity in a kinome panel. Further, in vitroand in vivopreclinical studies revealed favorable in vitroand in vivoDMPK properties. Results from multiple cell-based and animal models proved that compound 4exhibits considerable antifibrotic and anti-inflammatory efficacy. Currently, phase II clinical trials of compound 4are underway for the treatment of idiopathic pulmonary fibrosis (IPF).

Radiation detection (dosimetry) most commonly uses scintillating materials in a wide array of fields, ranging from energy to medicine. Scintillators must be able to not only fluoresce owing to the presence of a suitable chromophore but also withstand damage from radiation over prolonged periods of time. While it is inevitable that radiation will cause damage to the physical and chemical properties of materials, there is limited understanding of features within solid-state scintillators that afford increased structural integrity upon exposure to gamma (γ) radiation. Even fewer studies have evaluated both physical- and atomistic-level properties of organic solid-state materials. Previous work demonstrated cocrystalline materials afford radiation resistance in comparison to the single component counterparts, as realized by trans-1,2-bis(4-pyridyl)ethylene (4,4′-bpe). To support the rational design of radiation-resistant scintillators, we have examined all symmetric and unsymmetric isomers of trans-1-(n-pyridyl)2-(m-pyridyl)ethylene (n,m′-bpe, where nand/or m= 2, 3, or 4) solid-state crystalline materials. Experimental methods employed include single-crystal, powder, and electron diffraction as well as solid-state fluorimetry. Periodic density functional theory (DFT) calculations were used to understand the atomistic-level differences in bond lengths, bond orders, and packing. Electron diffraction was also utilized to determine the structure of a nanocrystalline sample. The results provide insights into possible trends involving factors such as molecular symmetry which provides radiation resistance as well as information for rationally designing single and multicomponent scintillators with the intent of minimizing changes upon γ-radiation exposure.

In this paper, a practical ambient-frequency-data-based inertia estimation method using a physical equation is proposed and validated by real measurement data from Hawaii island grids. With high renewable penetration, accurate inertia estimation is important and urgent. Ambient frequency oscillation always exists in power grids, so the proposed method has advantages of real-time inertia estimation and no need for additional disturbances. This paper first developed the physical equation for inertia estimation to offer a clear mechanism for easy implementation in practice. To apply the proposed method in actual grids, a practical method to extract the ambient frequency oscillation from frequency measurement is further proposed. The inertia estimation using the physical equation is validated by KIUC simulation data and HECO field data, in which error rates are around 2% and 8%, respectively. Practical inertia estimation is challenging due to the large amounts of resources contributing to the power grid's effective inertia, but the method provided in this paper can offer a novel way for practical inertia estimation, which can help renewable penetration to boost carbon-free grid.

AbstractThis three-day unit engages students in the exploration of light behavior and makes connections to the advanced idea of the wave–particle duality of light. Students begin by exploring the behaviors of marbles (particles) as they interact with different materials through reflection (bouncing off), absorption (getting stuck), and transmission (rolling through them). Then students investigate Slinkys (waves) and how they go through similar interactions. Students draw connections between Slinky (waves) and marble (particle) movement to build an understanding of reflection, absorption, and transmission. Finally, students observe light interacting with a variety of materials and draw connections between the way the light interacts with various materials and the interactions of the marble and Slinky. By building on concrete experiences, we help students consider the abstract idea that light behaves both like a particle (marble) and a wave (Slinky), while at the same time drawing their attention to how their learning relates to the work of scientists studying these fields.

The risk of inducing hypoglycaemia (low blood glucose) constitutes the main challenge associated with insulin therapy for diabetes1,2. Insulin doses must be adjusted to ensure that blood glucose values are within the normal range, but matching insulin doses to fluctuating glucose levels is difficult because even a slightly higher insulin dose than needed can lead to a hypoglycaemic incidence, which can be anything from uncomfortable to life-threatening. It has therefore been a long-standing goal to engineer a glucose-sensitive insulin that can auto-adjust its bioactivity in a reversible manner according to ambient glucose levels to ultimately achieve better glycaemic control while lowering the risk of hypoglycaemia3. Here we report the design and properties of NNC2215, an insulin conjugate with bioactivity that is reversibly responsive to a glucose range relevant for diabetes, as demonstrated in vitro and in vivo. NNC2215 was engineered by conjugating a glucose-binding macrocycle4and a glucoside to insulin, thereby introducing a switch that can open and close in response to glucose and thereby equilibrate insulin between active and less-active conformations. The insulin receptor affinity for NNC2215 increased 3.2-fold when the glucose concentration was increased from 3 to 20 mM. In animal studies, the glucose-sensitive bioactivity of NNC2215 was demonstrated to lead to protection against hypoglycaemia while partially covering glucose excursions.

Thermal denaturation (TD), known as antigen retrieval, heats tissue samples in a buffered solution to expose protein epitopes. Thermal denaturation of formalin-fixed paraffin-embedded samples enhances on-tissue tryptic digestion, increasing peptide detection using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS). We investigated the tissue-dependent effects of TD on peptide MALDI IMS and liquid chromatography-tandem mass spectrometry signal in unfixed, frozen human colon, ovary, and pancreas tissue. In a triplicate experiment using time-of-flight, orbitrap, and Fourier-transform ion cyclotron resonance mass spectrometry platforms, we found that TD had a tissue-dependent effect on peptide signal, resulting in a (22.5%) improvement in peptide detection from the colon, a (73.3%) improvement in ovary tissue, and a (96.6%) improvement in pancreas tissue. Biochemical analysis of identified peptides shows that TD facilitates identification of hydrophobic peptides.

In some proteins, a unique class of nonconserved positions is characterized by their ability to generate diverse functional outcomes through single amino acid substitutions. Due to their ability to tune protein function, accurately identifying such “rheostat” positions is crucial for protein design, for understanding the impact of mutations observed in humans, and for predicting the evolution of pathogen drug resistance. However, identifying rheostat positions has been challenging, due—in part—to the absence of a clear structural relationship with binding sites. In this study, experimental data from our previous study of the Escherichia colilactose repressor protein (LacI) was used to identify rheostat positions for which mutations tune in vivo EC50for the allosteric ligand “IPTG.” We next used the rheostat assignments to test the hypothesis that rheostat positions have unique dynamic features that will enable their identification. To that end, we integrated all-atom molecular dynamics simulations with perturbation residue response analysis. Results first revealed distinct dynamic behavior in IPTG-bound LacI compared with apo LacI, which was consistent with IPTG’s role as an allosteric inducer. Next, we used a variety of dynamic features to build a classification model that discriminates experimentally characterized rheostat positions in LacI from positions with other types of substitution outcomes. In parallel, we built a second classifier model based on the 3D structural “static” network features of LacI. In comparative studies, the dynamic model better identified rheostat positions that were >8 Å from the binding site. In summary, our study provides insights into the dynamic characteristics of rheostat positions and suggests that models built on dynamic features may be useful for predicting the locations of rheostat positions in a wide range of proteins.

Ultrasound is a high-resolution, real-time imaging modality that is frequently used for image-guided procedures. Due to the highly complex anatomy of the foot and ankle, ultrasound should be considered a first-line imaging modality for injections and procedures in this region.

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Next Generation Science Standards (NGSS) notes that all students can benefit from knowledge of engineering design practices: defining problems, developing solutions, and optimizing (NGSS, 2013). Design activities provide a useful [...]

Schools across the United States are creating teacher teams in ever-greater numbers. "Teaming" refers to assembling a group of teachers from different disciplines and/or grade levels who work together as a "core group" responsible for teaching a subset of the school's population. This brief examines some of the potential conflicts between teacher teaming and the development of schoolwide professional community. Drawing on the actual experiences of teachers and administrators in schools, the brief illustrates some of the more common dilemmas faced by schools with a strong commitment to teams. The first section summarizes what has been learned about professional community and its importance to schools. The following sections examine four middle schools that participated in research on school restructuring. In all four schools, teachers expressed enthusiastic support for teaching, but when researchers from the Center on Organization and Restructuring of Schools began looking at teacher teams in hopes of gaining insight into how teachers think about their work, another important pattern emerged. Teachers reported that teams tended to undermine the ability of the whole faculty to deal with the business of the whole school. The following specific dilemmas sidetracked teachers' attention to schoolwide issues and the development of a schoolwide professional community: time conflicts between team or whole-school issues; increased involvement with their group of students; limited time for peer observation; competition between teams; and the tendency within teams to compromise rather than risk serious disagreement, possibly leading to important issues being watered down. It is hoped that by presenting examples of problems that other schools encounter, teachers, principals, and other educators will learn from their colleagues' experiences and use them as a guide in developing or assessing their own schools and programs. (LMI)

Byline: Matthew Kruse I arrived in the state of Minas Gerais, Brazil this week, just in time for planting to begin. Our farm here received around one inch of rain [...]

Relaxin-2 is a peptide hormone with important roles in human cardiovascular and reproductive biology. Its ability to activate cellular responses such as vasodilation, angiogenesis, and anti-inflammatory and antifibrotic effects has led to significant interest in using relaxin-2 as a therapeutic for heart failure and several fibrotic conditions. However, recombinant relaxin-2 has a very short serum half-life, limiting its clinical applications. Here, we present protein engineering efforts targeting the relaxin-2 hormone in order to increase its serum half-life while maintaining its ability to activate the G protein-coupled receptor RXFP1. To achieve this, we optimized a fusion between relaxin-2 and an antibody Fc fragment, generating a version of the hormone with a circulating half-life of around 3 to 5 days in mice while retaining potent agonist activity at the RXFP1 receptor both in vitro and in vivo.

The adductor magnus ischiocondylar origin (AM‐IO) tendon has often been described as a third proximal hamstring tendon due to its common origin on the ischial tuberosity as well as similar function. Prior studies have described the magnetic resonance imaging characteristics of the AM‐IO; however, its appearance on ultrasound has not been well‐detailed. The purpose of our study is to describe the sonographic appearance of the AM‐IO and provide a structured scanning protocol for complete evaluation of the tendon. Access the CME test hereand search by article title.

Polymer entanglements─topological constraints to chain motion─are fundamental features of polymers, whose presence is believed to improve materials properties such as modulus and toughness, essential for most applications of soft materials. However, precise examination of the relationship between how the chains are entangled and material properties has remained elusive due to both difficulty in synthesizing materials with controlled entanglement topologies and an inability to spectroscopically detect the entanglements within the resulting polymer. Here, we use phenanthroline–copper(I) complexes as supramolecular templates installed in a poly(ethylene glycol) (PEG) network to form organogels with templated entanglements. When coordinated with copper, the storage moduli of both the entangled and the control materials are comparable to one another. Upon copper removal, unveiling the trapped entanglements, the gels with templated entanglements have a storage modulus 50–91% greater than the controls. Additionally, we discovered that both “entangled” and control gels form a fluorescent phenanthroline-based exciplex upon removal of solvent, indicative of proximity of phenanthroline moieties.

The multitarget stool RNA (mt-sRNA) test (ColoSense) is a noninvasive diagnostic test that screens for colorectal cancer and advanced adenomas in average-risk individuals aged 45 years and older. The mt-sRNA test incorporates a commercially available fecal immunochemical test, concentration of eight RNA transcripts, and participant-reported smoking status. As part of the CRC-PREVENT (Colorectal Cancer and Pre-Cancerous Adenoma Non-Invasive Detection Test) clinical trial, 12 analytical validation studies were conducted to assess analytical sensitivity, linearity, precision, interfering substances, cross-reactivity, carry-over, cross-contamination, and robustness. Analytical validation of the mt-sRNA test demonstrated limit of blank, limit of detection, and limit of quantification of <0.6, <0.7, and ≤2.5 copies/μL for all markers, respectively. The mt-sRNA test demonstrated linearity between 2.5 and 2500 copies/μL, and <20% coefficient of variation, and/or ≥95% concordance with regard to precision, interfering substances, carry-over, cross-contamination, and robustness. There was no significant impact of cross-reactivity from non–colorectal cancer diseases. These data provide a framework for laboratories to complete analytical validation for RNA-based panels that require premarket approval as a class III medical device from the US Food and Drug Administration.

Polymers can inherently entangle with each other, but the understanding of the physics of entanglements in polymer networks remains incomplete due to the challenges in both installation and characterization of these topological crosslinks.Installation of trapped entanglements in polymer networks can be achieved through various methods, including incorporation of long polymer chains, polymer interpenetration, or the use of supramolecular templates.Spectroscopic and mechanical testing technologies have enabled the mostly indirect characterization of polymer entanglements.Recent advances in the installation and characterization of polymer entanglements have spurred the development of novel materials with desirable mechanical properties, like elevated toughness.

Here, we describe the development of the FGF21 analog zalfermin (NNC0194-0499, 15), intended for once-weekly sc dosing. Protein engineering was needed to address inherent druggability issues of the natural FGF21 hormone. Thus, deamidation of Asp121 was solved by mutation to glutamine, and oxidation of Met168 was solved by mutation to leucine. N-terminal region degradation by dipeptidyl peptidase IV was prevented by alanine residue elongation. To prevent inactivating metabolism by fibroblast activation protein and carboxypeptidase-like activity in the C-terminal region, and to achieve t1/2extension (53 h in cynomolgus monkeys), we introduced a C18 fatty diacid at the penultimate position 180. The fatty diacid binds albumin in a reversible manner, such that the free fraction of zalfermin potently activates the FGF-receptor complex and retains receptor selectivity compared with FGF21, providing strong efficacy on body weight loss in diet-induced obese mice. Zalfermin is currently being clinically evaluated for the treatment of metabolic dysfunction-associated steatohepatitis.