bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of nuclear effects on the ultrafast dynamics of an organic/inorganic mixed-dimensional interface
Authors: Jacobs Matheus , Fidanyan Karen , Rossi Mariana , Cocchi Caterina
Published: May 2024

Electron dynamics at weakly bound interfaces of organic/inorganic materials are easily influenced by large-amplitude nuclear motion. In this work, we investigate the effects of different approximations to the equilibrium nuclear distributions on the ultrafast charge-carrier dynamics of a laser-excited hybrid organic/inorganic interface. By considering a prototypical system consisting of pyrene physisorbed on a MoSe2 monolayer, we analyze linear absorption spectra, electronic density currents, and charge-transfer dynamics induced by a femtosecond pulse in resonance with the frontier-orbital transition in the molecule. The calculations are based on ab initio molecular dynamics with classical and quantum thermostats, followed by time-dependent density-functional theory coupled to multi-trajectory Ehrenfest dynamics. We impinge the system with a femtosecond (fs) pulse of a few hundred GW cm−2 intensity and propagate it for 100 fs. We find that the optical spectrum is insensitive to different nuclear distributions in the energy range dominated by the excitations localized on the monolayer. The pyrene resonance, in contrast, shows a small blue shift at finite temperatures, hinting at an electron-phonon-induced vibrational-level renormalization. The electronic current density following the excitation is affected by classical and quantum nuclear sampling through suppression of beating patterns and faster decay times. Interestingly, finite temperature leads to a longer stability of the ultrafast charge transfer after excitation. Overall, the results show that the ultrafast charge-carrier dynamics are dominated by electronic rather than by nuclear effects at the field strengths and time scales considered in this work.
Analysis of mechanical stresses in silicone rubber joint tubes using a hyper-elastic model
Authors: Hamdan Mohammad A
Published: May 2024

A 2D model of a silicone rubber joint tube is proposed to calculate mechanical pressure. An analysis of radial and circumferential stresses within a joint tube based on a hyper-elastic model, employing finite element method is presented. This paper shows that assuming a constant elastic modulus for rubber leads to miscalculation of stresses within the joint tube. In addition, restricting the expansion ratio without considering the material’s elasticity could elevate the possibility of introducing high circumferential stress. Depending on the elastic modulus and expansion ratio, these circumferential stresses may approach 50% of the material’s tensile strength however, none of the simulated materials showed any critical values. A rigid semiconducting deflector could potentially generate significant circumferential stress, especially at the deflector-joint insulation interface, posing an increased risk if the material is relatively weak. Achieving the required pressure with stiffer materials necessitates a lower expansion ratio, while softer materials demand higher expansion ratios to accomplish the necessary pressure levels.
Unsupervised learning of quantum many-body scars using intrinsic dimension
Authors: Cao Harvey , Angelakis Dimitris G , Leykam Daniel
Published: May 2024

Quantum many-body scarred systems contain both thermal and non-thermal scar eigenstates in their spectra. When these systems are quenched from special initial states which share high overlap with scar eigenstates, the system undergoes dynamics with atypically slow relaxation and periodic revival. This scarring phenomenon poses a potential avenue for circumventing decoherence in various quantum engineering applications. Given access to an unknown scar system, current approaches for identification of special states leading to non-thermal dynamics rely on costly measures such as entanglement entropy. In this work, we show how two dimensionality reduction techniques, multidimensional scaling and intrinsic dimension estimation, can be used to learn structural properties of dynamics in the PXP model and distinguish between thermal and scar initial states. The latter method is shown to be robust against limited sample sizes and experimental measurement errors.
An Introduction to International Space Law
Authors: Bhat B. Sandeepa
Published: May 2024

The entry into outer space opened up a new horizon for humanity. However, the ColdWar backdrop of such an entry threatened the world order and posed multiple questions on the legal regulation of space activities. This resulted in a quick response from the United Nations (UN) to develop international norms to regulate space activities. The UN General Assembly resolutions, five space treaties and the set of principles to govern space activities, adopted during the twentieth century, form the foundation of international space law. The essential principles adopted under international space law still hold good despite a shift from State-oriented space activities to private sector-oriented space activities in the twenty-first century. Hence, probing into international space law and understanding its essentials in the right sense has become very important. This chapter, being introductory, provides an overview of international space law in terms of its development as well as its substance.
Introduction
Authors: Marchesi Ilaria
Published: May 2024

The chapter introduces the notion of social solecism—that is, of an improper behavior measured on grammatical correctness—as a distinctive feature of Martial’s self-construction as an epigrammatist. The notion is connected with the distinct anxiety about the abuse of signs that permeated Martial’s cultural environment, as manifested in the Lex Roscia epigrams as well as in poems about questionable sexual behaviors. A treatment of social and sexual disuniformity in terms of grammatical correctness distinctively matches the epigrammatist’s perception and recording of improprieties in the social sphere. The chapter thus establishes Martial’s interest in allusively appointing himself as a surrogate censor: someone who may complement with his competence in the rules of speech the work of the Emperor, in this case Domitian, the law-giving censor of the social body he controls.
Type 3: Shaping and Shifting
Authors: Marchesi Ilaria
Published: May 2024

This chapter reviews examples of the ways in which Martial’s Epigrams depict and police three classes of women who find novel means to create, use, and exchange signs. These women engage in independent sign-making, sign-usage, and sign-circulation to affect the dynamics of cultural and social exchange in which they enter as an active constituency. Martial’s Epigrams offer many such figures: women who buy their identities through cosmetics or use language to work at cross purposes with their physically observable traits, who organize their own selves in carefully staged public performances, or even go so far as to replace a whole set of identifiers with new ones. These women are treated as semiotically confusing. Turning back time for themselves, turning the tables on controlling male gaze and social discourses, turning communication patterns on their head, they strive to shift out of the controlled play of signs in their world.
Validation of algorithms in studies based on routinely collected health data: general principles
Authors: Ehrenstein Vera , Hellfritzsch Maja , Kahlert Johnny , Langan Sinéad M , Urushihara Hisashi , Marinac-Dabic Danica , Lund Jennifer L , Sørensen Henrik Toft , Benchimol Eric I
Published: May 2024

Clinicians, researchers, regulators, and other decision-makers increasingly rely on evidence from real-world data (RWD), including data routinely accumulating in health and administrative databases. RWD studies often rely on algorithms to operationalize variable definitions. An algorithm is a combination of codes or concepts used to identify persons with a specific health condition or characteristic. Establishing the validity of algorithms is a prerequisite for generating valid study findings that can ultimately inform evidence-based health care. In this paper, we aim to systematize terminology, methods, and practical considerations relevant to the conduct of validation studies of RWD-based algorithms. We discuss measures of algorithm accuracy, gold/reference standards, study size, prioritization of accuracy measures, algorithm portability, and implications for interpretation. Information bias is common in epidemiologic studies, underscoring the importance of transparency in decisions regarding choice and prioritizing measures of algorithm validity. The validity of an algorithm should be judged in the context of a data source, and one size does not fit all. Prioritizing validity measures within a given data source depends on the role of a given variable in the analysis (eligibility criterion, exposure, outcome, or covariate). Validation work should be part of routine maintenance of RWD sources.

This article is part of a Special Collection on Pharmacoepidemiology.
Silicone Lymphadenopathy Following Augmentation Mammoplasty With Silicone Implants
Authors: Rosenthal Adaya , Goldbart Nahmias Adi , Heller Lior , Hadad Eran
Published: May 2024

Background

Silicone implants are by far the most widely used implant globally for breast augmentation. Despite technological advancements, complications persist, with silicone lymphadenopathy (siliconoma) being a noteworthy concern. This phenomenon has been inadequately addressed in the existing literature.

Objectives

The aim of this study was to characterize axillary siliconomas and identify potential risk factors to help reduce their occurrence.

Methods

The authors conducted a retrospective observational cross-sectional study spanning between 2011 and 2021 at the Shamir Assaf Harofeh Medical Center, Israel. Preoperative ultrasound examination was conducted, categorizing patients into those with siliconomas and those without.

Results

A total of 614 women (1209 breasts) met the inclusion criteria. The incidence of siliconomas was 13.6% (165 breasts). In univariate analysis, older age (47 years vs 43 years, P < .001), older implant age (12.2 years vs 11 years, P = .026), ruptured implants (59.4% vs 17.7%, P < .001), subpectoral placement (P = .019), severe capsular contracture, and the use of Mentor implants (Irvine, CA; P = .007) and Poly Implant Prothèse implants (PIP; La Seyne-sur-Mer, France; P = .001) correlated significantly with the presence of siliconomas. In a multivariate analysis, implant rupture (odds ratio [OR] = 6.342), and implant manufacturer—Mentor (OR = 3.047) and PIP (OR = 3.475)—were identified as independent risk factors associated with a higher incidence of siliconomas. Severe capsular contracture was also associated with a higher incidence of siliconomas (OR = 1.65).

Conclusions

Surgeons should inform candidates about the potential risk of silicone migration. Patients with ruptured implants, significant capsular contracture, and Mentor and PIP implants face an increased risk for developing siliconomas. Closer monitoring for the detection of siliconomas in the axilla for these patients is advisable, and potential prophylactic replacement or removal of implants may be warranted to mitigate siliconoma risk.

Level of Evidence: 3
P04 How fibroblasts and azathioprine prepare the soil for cutaneous squamous cell carcinoma
Authors: Kontou Ioanna , Pourzand Charareh , Walko Gernot , Jungwirth Ute
Published: May 2024

Introduction and aims

DNA damage-inducing immunosuppressive drugs such as azathioprine (AZA) act synergistically with ultraviolet (UV)A radiation and photosensitize the skin of immunosuppressed individuals, such as organ transplant recipients. These individuals have an increased risk of developing cutaneous squamous cell carcinoma (cSCC). The specific combination of AZA and UVA causes oxidative DNA damage that leaves behind a characteristic mutational signature in tumour keratinocytes of patients treated with AZA. However, as UVA radiation can penetrate the dermis, the impact of AZA/UVA on cells of the tumour microenvironment, such as fibroblasts, also need to be addressed. Fibroblasts are crucial for cSCC development and progression as they can switch to a protumourigenic phenotype.

Methods

Cell viability and senescence assays were performed to investigate the impact of AZA in combination with or without UVA on neonatal (nonsun-exposed) and adult (sun-exposed) human dermal fibroblasts. In addition, the impact of AZA/UVA-treated fibroblasts on the clonal growth properties of different cSCC cell models was investigated using three-dimensional (co)culture models.

Results

We found that AZA and UVA synergistically reduce the viability of both UV-naïve neonatal and sun-exposed adult dermal fibroblasts. In addition, combined AZA and UVA treatments lead to an increased percentage of senescent fibroblasts. We hypothesize that the aberrant secretome of these senescent fibroblasts can impact the growth behaviour of tumour cells. In a soft agar assay, the more malignant cSCC cells (MET-1) formed more and larger clonal spheroids and were less dependent on growth factors compared with spheroids formed by premalignant (PM-1) keratinocytes.

Conclusions

AZA and UVA act synergistically and potentiate a UVA-induced senescent fibroblast phenotype. The changed characteristics of these fibroblasts can impact the stem cell-like properties from premalignant and malignant keratinocytes. Combining keratinocyte and fibroblast culture models enables us to study how AZA/UVA promote the initiation and progression of cSCC.
P33 Skinvaders: gamification of the skin barrier to engage school-age children in the biology of the skin
Authors: de Brito Marianne , Green Freddy , McCarthy Rebecca , Rees Martin , Balkwill Frances , O’Toole Edel Ann
Published: May 2024

Introduction and aims

Public engagement is an essential part of research design. It provides opportunities for both scientists and the public to learn, and inspires the next generation of researchers. We are fortunate to have a public engagement centre within our institution, which contains digital games, an established and effective way to engage children. We developed a new game for school-age children to engage them in the Paediatric Human Cell Atlas, a collaborative project that aims to map single-cell profiles and spatial characterization of gene expression across human tissues and organs throughout development. Our aim was to develop a game that involved different skin cell types, variation in skin colour and common skin disorders.

Methods

Initial steps included brainstorming with our public engagement staff about content and then developing a lay summary and agreeing on the following key themes: the skin as a barrier, the cells of the skin, and eczema, a common skin disorder. The game was based on the arcade game Breakout. It features a customizable paddle representing the skin, demonstrating how changes in quantities of different skin components can change appearance/function (e.g. melanin production, adipocytes, hair follicles), which players must move across the screen to keep pathogens and allergens out and keep water and protein in. In the last level, barrier function is impaired by eczema and the children can catch cream to repair the barrier.

Results

The game was developed for our public engagement centre where it has undergone testing by target audiences.

Conclusions

We have created a game as an innovative way to engage and educate paediatric communities in our research. It was challenging to simplify scientific content for use in a game while staying true to the scientific concepts. We will increase reach by adapting the game for desktop and app-based formats.
P38 Experimental evidence of ecto-5′-nucleotidase (CD73) modulation in psoriasis-like inflammation
Authors: De Palma Giacomo , Caiazzo Elisabetta , Ialenti Armando , Cicala Carla
Published: May 2024

Introduction and aims

Adenosine is an endogenous purine nucleoside that, by binding to adenosine receptors, modulates inflammation and immune responses. Psoriasis is a chronic immune-mediated inflammatory skin disease characterized by keratinocyte hyperproliferation and abnormal differentiation. A2A and A2B adenosine receptors modulate keratinocyte proliferation and their expression was found to be altered in psoriatic epidermis. Ecto-5′-nucleotidase (CD73) is an enzyme that hydrolyses extracellular adenosine monophosphate and represents a key control point for extracellular adenosine accumulation. CD73 is involved in the regulation of local immune response and tissue barrier function. As changes in CD73 expression and activity have been associated with other autoimmune diseases, the aim of this study was to investigate CD73 involvement in skin inflammation using in vitro and in vivo approaches.

Methods

In vitro experiments were performed on human keratinocyte (HaCaT) cell lines stimulated with tumour necrosis factor-α, interleukin (IL)-17A, IL-6 and IL-1α (10 ng mL−1 each), and in vivo, on the mouse model of imiquimod-induced psoriasis-like inflammation on the right ear, which was also performed on CD73−/− mice and their wildtype counterpart. CD73 expression in cell lysates and ear homogenates were evaluated using Western blot analysis.

Results

We found that CD73 expression was significantly increased (N = 3 wells, P < 0.05) in cytokine-treated HaCaTs compared with unstimulated cells. In vivo experiments showed increased CD73 expression on psoriatic lesions (P < 0.001, N = 3). In CD73−/− mice, imiquimod-induced lesions were exacerbated compared with the development of lesions in wildtype mice as shown by ear thickness (0.190 ± 0.02 mm, knockout mice vs. 0.138 ± 0.02 mm, wildtype mice; P < 0.05, N = 5), erythema and scaling.

Conclusions

Our preliminary Results show involvement of CD73 in the development of psoriasis-like inflammation, suggesting that CD73 may represent a new therapeutic target in the treatment of skin diseases. Further investigations are needed to provide an in-depth study of CD73 localization in inflamed skin.
Minority Social Workers Share Their Previously Tacit Knowledge: Patterns and Importance of Sharing and the Context
Authors: Mahajne Ibrahim , Allassad Alhuzail Nuzha
Published: May 2024

The gap between fieldwork demands and academic knowledge necessitates the sharing of tacit knowledge to ensure continuity of context-appropriate professional knowledge. The research describes and explains patterns of minority social workers’ sharing of their previously tacit knowledge, the knowledge’s significance and the context where it was acquired. In data drawn from in-depth semi-structured interviews with twenty children and youth workers in Arab welfare bureaus throughout Israel, Arab social workers exposed tacit knowledge they had revealed and shared concerning prolonged institutional deprivation in out-of-home settings that dramatically limited their ability to ensure the minors’ rights. This knowledge was shared in four ways: retention, transmission between colleagues, documentation for the future and publication. Social workers invested insufficient efforts to share their tacit knowledge, due to inappropriate relevant professional training and lack of a suitable infrastructure and organisational culture. They were aware that sharing and dissemination of their previously tacit knowledge could serve three players in the Children and Youth Services: the target population (giving them a voice), professionals (uniting their ranks for collective action) and government institutions (reflecting the reality and equipping them with data concerning service gaps). Social work should reconsider the potential value of sharing such knowledge.
NMDA receptor autoantibodies primarily impair the extrasynaptic compartment
Authors: Jamet Zoe , Mergaux Camille , Meras Morgane , Bouchet Delphine , Villega Frédéric , Kreye Jakob , Prüss Harald , Groc Laurent
Published: May 2024

Autoantibodies directed against the N-methyl-D-aspartate receptor (NMDAR-Ab) are pathogenic immunoglobulins detected in patients suffering from NMDAR encephalitis. NMDAR-Ab alter the receptor membrane trafficking, synaptic transmission and neuronal network properties, leading to neurological and psychiatric symptoms in patients. Patients often have very little neuronal damage but rapid and massive (treatment-responsive) brain dysfunctions related to an unknown early mechanism of NMDAR-Ab. Our understanding of this early molecular cascade remains surprisingly fragmented.

Here, we used a combination of single molecule-based imaging of membrane proteins to unveil the spatiotemporal action of NMDAR-Ab on live hippocampal neurons.

We first demonstrate that different clones of NMDAR-Ab primarily affect extrasynaptic (and not synaptic) NMDARs. In the first minutes, NMDAR-Ab increase extrasynaptic NMDAR membrane dynamics, declustering its surface interactome. NMDAR-Ab also rapidly reshuffle all membrane proteins located in the extrasynaptic compartment. Consistent with this alteration of multiple proteins, effects of NMDAR-Ab were not mediated through the sole interaction between the NMDAR and EphB2 receptor. In the long term, NMDAR-Ab reduce the NMDAR synaptic pool by slowing down receptor membrane dynamics in a cross-linking-independent manner. Remarkably, exposing only extrasynaptic NMDARs to NMDAR-Ab was sufficient to produce their full-blown effect on synaptic receptors.

Collectively, we demonstrate that NMDAR-Ab initially impair extrasynaptic proteins, then the synaptic ones. These data thus shed new and unsuspected light on the mode of action of NMDAR-Ab and, probably, our understanding of (extra)synaptopathies.
Aortic remodelling based on false lumen communications in patients undergoing acute type I dissection repair with AMDS hybrid prosthesis: a substudy of the DARTS trial
Authors: EL-Andari Ryaan , Bozso Sabin J , Nagendran Jeevan , Chung Jennifer , Ouzounian Maral , Moon Michael C
Published: May 2024

OBJECTIVES

The Dissected Aorta Repair Through Stent (DARTS) Implantation trial demonstrated positive proximal aortic remodelling following aortic dissection repair with the AMDS hybrid prosthesis. In this study, we look to identify predictors of aortic remodelling following aortic dissection repair with AMDS including whether communications between branch vessels and the false lumen (FL) predict aortic growth.

METHODS

The DARTS implantation trial included patients who underwent acute DeBakey type I aortic dissection (ATAD I) repair with the AMDS from March 2017 to January 2019. Anatomic measurements were collected from original computerized tomography scans. Measurements were taken at zones 2, 3, 6 and 9. Patients were grouped based on the number of FL communications with the supra-aortic branch vessels or visceral branch vessels.

RESULTS

Forty-seven patients were included in the original DARTS implantation trial. Patients with FL communications with the supra-aortic branch vessels tended to have significant growth at zone 3 (P = 0.02–0.0018), while greater numbers of visceral FL communications tended to predict aortic growth at zones 3 (P = 0.003), 6 (P = 0.017–0.0087) and 9 (P = 0.0016–0.0003).

CONCLUSIONS

Aortic remodelling following ATAD I repair using the AMDS may be predicted by local FL communications with branch vessels. Patients undergoing ATAD I repair were more likely to experience significant aortic growth in zone 3 with more head vessel communications and in zones 3, 6 and 9 with more visceral FL communications. Predictors of aortic remodelling may help to guide initial surgical management for aortic dissection patients.
Analysis of the global burden of cervical cancer in young women aged 15–44 years old
Authors: Zhang Min , Chen Jiayi , Cui Meimei , Jia Jingjing , Zhao Ming , Zhou Dan , Zhu Liling , Luo Limei
Published: May 2024

Background

Understanding the burden of cervical cancer (CC) in young women aged 15–44 years old are essential for formulating effective preventive strategies.

Methods

Utilizing the Global Burden of Disease 2019 Study, we estimated incidence, disability-adjusted life-years (DALYs), years of life lost (YLLs) and years lived with disability (YLDs) due to CC among young women from 1990 to 2019. Additionally, we evaluated the temporal trends using estimated annual percentage changes (EAPCs) during this period. We conducted a decomposition analysis to assess the absolute contributions of three components: population growth, population age structure and epidemiologic changes.

Results

Globally, there were 187 609.22 incident cases of CC worldwide, resulting in 2621 917.39 DALYs in 2019. From1990 to 2019, the age-standardized rates were decline, only the age-standardized YLDs rate (EAPC = 0.02; 95% CI: −0.02 to 0.05) showed a stable trend. The largest increase in age-standardized incidence rate (ASIR) and age-standardized YLDs rate observed in the high-middle social demographic index (SDI) quintiles. Population growth and age structure changes were associated with substantial changes in cases of CC, especially in South Asia and East Asia.

Conclusions

Globally, the burden of CC in young women continues to increase, as measured by the absolute number. As populations are growing and age structure changes were associated with substantial changes in cases of CC, governments will face increasing demand for treatment, and support services for CC, especially in South Asia and East Asia.
De Novo Genome Assembly for the Coppery Titi Monkey (Plecturocebus cupreus): An Emerging Nonhuman Primate Model for Behavioral Research
Authors: Pfeifer Susanne P , Baxter Alexander , Savidge Logan E , Sedlazeck Fritz J , Bales Karen L
Published: May 2024

The coppery titi monkey (Plecturocebus cupreus) is an emerging nonhuman primate model system for behavioral and neurobiological research. At the same time, the almost entire absence of genomic resources for the species has hampered insights into the genetic underpinnings of the phenotypic traits of interest. To facilitate future genotype-to-phenotype studies, we here present a high-quality, fully annotated de novo genome assembly for the species with chromosome-length scaffolds spanning the autosomes and chromosome X (scaffold N50 = 130.8 Mb), constructed using data obtained from several orthologous short- and long-read sequencing and scaffolding techniques. With a base-level accuracy of ∼99.99% in chromosome-length scaffolds as well as benchmarking universal single-copy ortholog and k-mer completeness scores of >99.0% and 95.1% at the genome level, this assembly represents one of the most complete Pitheciidae genomes to date, making it an invaluable resource for comparative evolutionary genomics research to improve our understanding of lineage-specific changes underlying adaptive traits as well as deleterious mutations associated with disease.
U.S. Democratic Backsliding and the Decline of Democratic Support Abroad
Authors: Cavari Amnon , Magen Amichai , Yoel Benjamin
Published: May 2024

A burgeoning literature considers the domestic causes and consequences of democratic backsliding for public perceptions of democracy but has yet to fully examine the role of international factors in explaining these perceptions. Specifically, the effect of democratic backsliding in one democracy on public support for democratic principles in other countries has, thus far, defied theoretical and empirical investigation. Addressing this gap, we propose and test a theory of the effects of backsliding on global opinion in which information about democratic decline in one country can lead to increased support for authoritarian governance in another country. To test this, we use an original survey experiment in Israel where we test the effect of two narratives regarding the 2020 U.S. elections—one signaling democratic decline and one signaling democratic resilience—on support for authoritarian governance. We find that respondents exposed to the narrative of U.S. democratic decline were more supportive of authoritarian governance compared to respondents exposed to the narrative of democratic resilience. We further find marginal evidence that the respondents’ ideological preferences condition the effect of narrative exposure. Our findings suggest that the democratic backsliding literature has insufficiently explored the global consequences of domestic events and processes on democratic decline worldwide.
Tenofovir, emtricitabine, lamivudine and dolutegravir concentrations in plasma and urine following drug intake cessation in a randomized controlled directly observed pharmacokinetic trial to aid point-of-care testing
Authors: Else Laura J , Dickinson Laura , Edick Stacey , Zyhowski Ashley , Ho Ken , Meyn Leslie , Dilly-Penchala Sujan , Thompson Beth , Shaw Victoria , Khoo Saye , Brand Rhonda M
Published: May 2024

Background

Poor adherence to ART and pre-exposure prophylaxis (PrEP) can impact patient and public health. Point-of-care testing (POCT) may aid monitoring and adherence interventions.

Objectives

We report the pharmacokinetics of tenofovir [dosed as tenofovir disoproxil (TDF) and tenofovir alafenamide (TAF)], emtricitabine (FTC), lamivudine (3TC) and dolutegravir (DTG) in plasma and urine following drug cessation to evaluate adherence targets in urine for POCT.

Methods

Subjects were randomized (1:1) to receive DTG/FTC/TAF or DTG/3TC/TDF for 15 days. Plasma and spot urine were collected on Day 15 (0–336 h post final dose). Drug concentrations were quantified using LC-MS, and non-linear mixed-effects models applied to determine drug disposition between matrices and relationship with relevant plasma [dolutegravir protein-adjusted 90% inhibitory concentration (PA-IC90 = 64 ng/mL) and minimum effective concentration (MEC = 324 ng/mL)] and urinary thresholds [tenofovir disoproxil fumarate 1500 ng/mL].

Results

Of 30 individuals enrolled, 29 were included (72% female at birth, 90% Caucasian). Median (range) predicted time to plasma dolutegravir PA-IC90 and MEC were 83.5 (41.0–152) and 49.0 h (23.7–78.9), corresponding to geometric mean (90%) urine concentrations of 5.42 (4.37–6.46) and 27.4 ng/mL (22.1–32.7). Tenofovir in urine reached 1500 ng/mL by 101 h (58.6–205) with an equivalent plasma concentration of 6.20 ng/mL (4.21–8.18).

Conclusions

These data support use of a urinary tenofovir threshold of <1500 ng/mL (tenofovir disoproxil fumarate-based regimens) as a marker of three or more missed doses for a POCT platform. However, due to low dolutegravir concentrations in urine, POCT would be limited to a readout of recent dolutegravir intake (one missed dose).
Mental Health Support Is an Unmet Need for Long-term Burn Survivors: A Web-based Survey
Authors: Ramsey Walter A , Cobler-Lichter Michael D , O’Neil Christopher F , Ishii Mary , Satahoo Shevonne S , Kaufman Joyce I , Pizano Louis R , Koru-Sengul Tulay , Szapocznik Jose , Schulman Carl I
Published: May 2024

A National Trauma Research Action Plan identified the involvement of burn survivors as critical informants to determine the direction of research. This study employed a web-based survey to identify care gaps in a sample of burn survivors. We surveyed burn survivors from around the United States through social media and email contact with the Phoenix Society for Burn Survivors. We elicited demographic info, burn history, and unmet needs. Statistical analysis was performed to test our hypothesis that lack of access to mental health support/professionals would be identified as an unmet need in long-term burn survivors. Of 178 survey respondents, most were at least 10 years removed from the date of their burn injury (n = 94, 53%). Compared with those less than 3 years from their burn injury, individuals greater than 10 years were at least 5 times more likely to note a lack of access to mental health support [11–20 years OR 8.7, P < .001; >20 years OR 5.7, P = .001]. About 60% of Spanish speakers reported lack of support group access was among their greatest unmet needs, compared with 37% of English speakers (P = .184). This study highlights the need for ongoing access to mental health resources in burn survivors. Our findings emphasize that burn injury is not just an acute ailment, but a complex condition that evolves into a chronic disease. Additional studies should focus on the experiences of Spanish-speaking burn survivors, given small sample size leading to a likely clinically significant but not statistically different lack of access to support groups.
Within-population plastic responses to combined thermal-nutritional stress differ from those in response to single stressors, and are genetically independent across traits in both males and females
Authors: Choy Yeuk Man Movis , Walter Greg M , Mirth Christen K , Sgrò Carla M
Published: May 2024

Phenotypic plasticity helps animals to buffer the effects of increasing thermal and nutritional stress created by climate change. Plastic responses to single and combined stressors can vary among genetically diverged populations. However, less is known about how plasticity in response to combined stress varies among individuals within a population or whether such variation changes across life-history traits. This is important because individual variation within populations shapes population-level responses to environmental change. Here, we used isogenic lines of Drosophila melanogaster to assess the plasticity of egg-to-adult viability and sex-specific body size for combinations of 2 temperatures (25 °C or 28 °C) and 3 diets (standard diet, low caloric diet, or low protein:carbohydrate ratio diet). Our results reveal substantial within-population genetic variation in plasticity for egg-to-adult viability and wing size in response to combined thermal-nutritional stress. This genetic variation in plasticity was a result of cross-environment genetic correlations that were often < 1 for both traits, as well as changes in the expression of genetic variation across environments for egg-to-adult viability. Cross-sex genetic correlations for body size were weaker when the sexes were reared in different conditions, suggesting that the genetic basis of traits may change with the environment. Furthermore, our results suggest that plasticity in egg-to-adult viability is genetically independent from plasticity in body size. Importantly, plasticity in response to diet and temperature individually differed from plastic shifts in response to diet and temperature in combination. By quantifying plasticity and the expression of genetic variance in response to combined stress across traits, our study reveals the complexity of animal responses to environmental change, and the need for a more nuanced understanding of the potential for populations to adapt to ongoing climate change.
Sun from Behind the Clouds: the Appeals Board of the European Centre for Medium-Range Weather Forecasts
Authors: Butler Graham
Published: May 2024

One of the lesser-known regional international organizations in Europe is the European Centre for Medium-Range Weather Forecasts (ECMWF). It has a mandate to undertake tasks such as the production of weather forecasts, conduct scientific research to improve meteorological projections, maintain extensive datasets, and to better coordinate European meteorological infrastructure. The Centre has three sites across three European states where it has over 400 staff, and given it is immune from suit, its staff members only have an internal justice mechanism to resort to in the event of employment/pensions disputes. Little is known about the ECMWF Appeals Board given its untransparent nature. As uncovered in this article, it has undergone partial reform, and simultaneously, there has been an uptick in the number of cases. This article analyses these developments and highlights that more must be done to align the ECMWF Appeals Boards with the features of other international administrative tribunals.
Some recollections of the early years of the Medical Research Council Statistical Research Unit
Authors: Armitage Peter
Published: May 2024

The text of a presentation, given in 2003, regarding my recollections of the Medical Research Council’s Statistical Research Unit is provided.
Both biofilm cytotoxicity and monocytes’ adhesion may be used as estimators of enterococcal virulence
Authors: Daca Agnieszka , Piechowicz Lidia , Wiśniewska Katarzyna , Bryl Ewa , Witkowski Jacek M , Jarzembowski Tomasz
Published: May 2024

Our study aimed to identify markers of enterococci’s virulence potential by evaluating the properties of strains of different sites of isolation. Enterococcal strains were isolated as commensals from faeces and as invasive strains from the urine and blood of patients from the University Clinical Centre, Gdańsk, Poland. Changes in monocytes’ susceptibility to the cytotoxic activity of isolates of different origins and their adherence to biofilm were evaluated using a flow cytometer. The bacterial protein profile was estimated by matrix assisted laser desorption ionization-time of flight mass spectrometer. The cytotoxicity of biofilm and monocytes’ adherence to it were the most accurate factors in predicting the prevalence of the strain in the specific niche. Additionally, a bacterial protein with mass-to-charge ratio (m/z) 5000 was found to be responsible for the increased bacterial cytotoxicity, while monocytes’ decreased adherence to biofilm was linked with the presence of proteins either with m/z 3330 or 2435. The results illustrate that monocytes’ reaction when exposed to the bacterial biofilm can be used as an estimator of pathogens’ virulence potential. The observed differences in monocytes’ response are explainable by the bacterial proteins’ profile. Additionally, the results indicate that the features of both bacteria and monocytes impact the outcome of the infection.
Fatty acid oxidation-induced HIF-1α activation facilitates hepatic urate synthesis through upregulating NT5C2 and XDH
Authors: Liang Ningning , Yuan Xuan , Zhang Lili , Shen Xia , Zhong Shanshan , Li Luxiao , Li Rui , Xu Xiaodong , Chen Xin , Yin Chunzhao , Guo Shuyuan , Ge Jing , Zhu Mingjiang , Tao Yongzhen , Chen Shiting , Qian Yongbing , Dalbeth Nicola , Merriman Tony R , Terkeltaub Robert , Li Changgui , Xia Qiang , Yin Huiyong
Published: May 2024

Dyslipidemia affects approximately half of all people with gout, and prior Mendelian randomization analysis suggested a causal role for elevated triglycerides in hyperuricemia (HU), but the underlying mechanisms remain elusive. We hypothesize that dyslipidemia promotes hepatic urate biosynthesis in HU and gout and fatty acid (FA) oxidation (FAO) drives this process. Here we developed a targeted metabolomics to quantify major metabolites in purine metabolic pathway in the sera of a human cohort with HU, gout, and normaluricemic controls. We found that the levels of major purine metabolites and multiple FAs were significantly elevated in HU and gout groups compared to normouricemic controls, whereas hypoxathine showed opposite trend. Furthermore, the levels of multiple serum FAs were positively correlated with urate, xanthine, and inosine but negatively with hypoxanthine, which was also observed in a murine model of high-fat diet-induced HU. Using a stable isotope-labeled metabolic flux assay, we discovered that exogenous hypoxanthine plays a key role in urate synthesis. Moreover, FAO-induced hypoxia-inducible factor 1 alpha (HIF-1α) activation upregulated 5ʹ-nucleotidase II (NT5C2) and xanthine dehydrogenase (XDH) levels to facilitate hypoxanthine uptake from the blood to the liver and activation of urate biosynthesis. Our findings were further supported by data in human hepatocytes and 50 paired serum and liver tissues from liver transplant donors. Together, this study uncovers a mechanism by which FAO promotes hepatic urate synthesis by activating HIF-1α-NT5C2/XDH pathways, directly linking lipid metabolism to HU.
Evaluation of a Military Global Health Engagement Mission for Critical Wartime Surgical Specialty Readiness
Authors: Aryankalayil Joseph , Shields Margaret , Baird Michael , Gunasingha Rathnayaka M K D , Pullen W Michael , Johnson Mark , Fitch Jamie , Uber Ian , Worlton Tamara
Published: May 2024

Introduction

Surgical volume at Military Treatment Facilities (MTFs) has been gradually decreasing for roughly the past 2 decades. The Knowledge, Skills, and Abilities (KSA) Clinical Readiness Program linked surgical volume and readiness using a tool known as the KSA metric. However, the extent to which military medical missions contribute to the readiness of critical wartime specialties has not been evaluated using this metric.

Methods

In this study, a retrospective analysis was conducted using the surgical case logs from the US Naval Ship (USNS) Comfort missions in 2018 and 2019. The comprehensive case log data were categorized by year, surgeon, procedure, and location. The analysis focused on providing detailed descriptive statistics, including percentages pertaining to the types of procedures performed during these missions. The 2018 mission was 11 weeks in duration, and supported activities in Ecuador, Peru, Colombia, and Honduras. The USNS Comfort mission in 2019 lasted 6 months (June-November 2019), and visited 12 countries in Central America, South America, and the Caribbean.

Results

The 2019 mission case log, spanning 6 months, was evaluated using the KSA score in order to assess readiness and compare against 6 months of MTF KSA values within the same calendar year. In 2019, the orthopedic surgeon aboard the USNS Comfort had a total KSA score of 44,006, but the 6-month USNS Comfort mission only contributed 5,364 points (12% of the annual score). The general surgery practice aboard the USNS Comfort produced lower KSA scores compared to each surgeon’s respective MTF practice (Table III). Analyzing the cases logged by general surgeons also highlights minimal surgical diversity during these missions, with more than 90% of cases being hernia repairs or laparoscopic cholecystectomies (Table I). In addition, 35% of total procedures performed in 2018 and 2019 were performed laparoscopically.

Conclusions

The analysis of operative data from the 2019 USNS Comfort mission, in comparison with the surgeons’ work at their respective MTFs, reveals limited benefit in the ability of hospital-ship missions to bolster surgical readiness as measured by the KSA score. However, this is not a reflection on the value of Global Health Engagement (GHE) itself but a review of the way in which it is leveraged to support surgical readiness. Military surgeons participate in GHE as part of a larger strategy to strengthen relationships with partner nations, improve military medical force interoperability, and bolster partner nation medical capacity and capabilities. The KSA score offers an excellent tool to compare readiness metrics across significantly different GHE missions, and facilitates the opportunity for future prospective studies to improve case volume, diversity, and ultimately readiness.
Dietary and homeostatic controls of Zn isotopes in rats: a controlled feeding experiment and modeling approach
Authors: Bourgon Nicolas , Tacail Théo , Jaouen Klervia , Leichliter Jennifer N , McCormack Jeremy , Winkler Daniela E , Clauss Marcus , Tütken Thomas
Published: May 2024

The stable isotope composition of zinc (δ66Zn), which is an essential trace metal for many biological processes in vertebrates, is increasingly used in ecological, archeological, and paleontological studies to assess diet and trophic level discrimination among vertebrates. However, the limited understanding of dietary controls and isotopic fractionation processes on Zn isotope variability in animal tissues and biofluids limits precise dietary reconstructions. The current study systematically investigates the dietary effects on Zn isotope composition in consumers using a combined controlled feeding experiment and box-modeling approach. For this purpose, 21 rats were fed one of seven distinct animal- and plant-based diets and a total of 148 samples including soft and hard tissue, biofluid, and excreta samples of these individuals were measured for δ66Zn. Relatively constant Zn isotope fractionation is observed across the different dietary groups for each tissue type, implying that diet is the main factor controlling consumer tissue δ66Zn values, independent of diet composition. Furthermore, a systematic δ66Zn diet-enamel fractionation is reported for the first time, enabling diet reconstruction based on δ66Zn values from tooth enamel. In addition, we investigated the dynamics of Zn isotope variability in the body using a box-modeling approach, providing a model of Zn isotope homeostasis and inferring residence times, while also further supporting the hypothesis that δ66Zn values of vertebrate tissues are primarily determined by that of the diet. Altogether this provides a solid foundation for refined (paleo)dietary reconstruction using Zn isotopes of vertebrate tissues.
Landscape of Invasive Fusariosis in Pediatric Cancer Patients: Results of a Multicenter Observational Study From Latin America
Authors: Carlesse Fabianne , Paixão de Sousa da Silva Adriana Maria , Sztajnbok Jaques , Litivinov Nadia , Peron Karina , Otsuka Marcelo , Volpe Arnoni Mariana , Schirmer Marcelo , de Oliveira Costa Patricia , Munhoz Cavalcanti de Albuquerque Ana Lucia , Morales Hugo , Lopez-Medina Eduardo , A. Portilla Carlos , Valenzuela Romina , Motta Fabrizio , Motta Fabio Araújo , de Almeida Junior João Nobrega , Santolaya Maria Elena , Lopes Colombo Arnaldo
Published: May 2024

Invasive fusariosis (IF) is a life-threatening opportunistic infection that affects vulnerable hosts. We conducted a multicenter and multinational retrospective study to characterize the natural history and clinical management of IF in pediatric cancer patients. We selected patients <18 years old who were sequentially hospitalized in 10 Latin American medical centers with a diagnosis of IF between 2002 and 2021. Data were collected using an electronic case report form complemented by a dictionary of terms. We assessed mortality rates at 30, 60, and 90 days. We collected data from 60 episodes of IF (median age, 9.8 years) that were mostly documented in patients with hematologic cancer (70%). Other risk conditions found were lymphopenia (80%), neutropenia (76.7%), and corticosteroid exposure (63.3%). IF was disseminated in 55.6% of patients. Skin lesions was present in 58.3% of our patients, followed by pulmonary involvement in 55%, sinusitis in 21.7%, bone/joint involvement in 6.7% and 1 case each of endocarditis and brain abscess. Positive blood and skin biopsy cultures were detected in 60% and 48.3% of cases, respectively. Fusarium solani complex was the most commonly identified agent (66.6%). The majority of patients received monotherapy within the first 72 hours (71.6%), either with voriconazole or amphotericin B formulation. The mortality rates at 30, 60, and 90 days were 35%, 41.6%, and 45%, respectively. An important factor affecting mortality rates appears to be disseminated disease. The high percentage of patients with fungal involvement in multiple organs and systems highlights the need for extensive workup for additional sites of infection in severely immunocompromised children.