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Background/Objectives: Immune effector cell-associated hematotoxicity (ICAHT) is a frequent adverse event after chimeric antigen receptor (CAR)-T cell therapy. Grade ≥ 3 thrombocytopenia occurs in around one-third of patients, and many of them become platelet transfusion-dependent. Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) able to accelerate megakaryopoiesis, which has been used successfully in patients with bone marrow failure and immune thrombocytopenia (ITP). Its role in managing thrombocytopenia and other cytopenias in CAR-T cell-treated patients has been scarcely addressed. Our aim was to report the safety and efficacy of this approach in patients included in the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC) registry. Methods: This is a retrospective, multicenter, observational study. Patients who developed platelet transfusion dependence subsequently to CAR-T cells and received eltrombopag to improve platelet counts were recruited in 10 Spanish hospitals. Results: Thirty-eight patients were enrolled and followed up for a median (interquartile range [IQR]) of 175 (99, 489) days since CAR-T cell infusion. At the moment eltrombopag was indicated, 18 patients had thrombocytopenia and another severe cytopenia, while 8 patients had severe pancytopenia. After 32 (14, 38) days on eltrombopag, 29 (76.3%) patients recovered platelet transfusion independence. The number of platelet units transfused correlated with the time needed to restore platelet counts higher than 20 × 109/L (Rho = 0.639, p < 0.001). Non-responders to eltrombopag required more platelet units (58 [29, 69] vs. 12 [6, 26] in responders, p = 0.002). Nineteen out of twenty-three (82.6%) patients recovered from severe neutropenia after 22 (11, 31) days on eltrombopag. Twenty-nine out of thirty-five (82.9%) patients recovered red blood cell (RBC) transfusion independence after 29 (17, 44) days. Seven patients recovered all cell lineages while on treatment. No thromboembolic events were reported. Only two transient toxicities (cholestasis, hyperbilirubinemia) were reported during eltrombopag treatment, none of which compelled permanent drug withdrawal. Conclusions: Eltrombopag could be safely used to manage thrombocytopenia and accelerate transfusion independence in CAR-T cell-treated patients. [ABSTRACT FROM AUTHOR]

Colony collapse disorder (CCD) has caused widespread death of honeybees, but the exact causes are not understood. Many scientists agree that pathogenic threats most likely contribute to CCD. Due to the integral ecosystem role bees fulfill, it is important to understand how honeybees respond immunologically to different factors to better inform practices to combat CCD. Quantifying the immunological cost of two different beekeeping approaches allows us to better understand how beekeeping practices affect bees' susceptibility to CCD. Within colonies, a plastic frame foundation provides structural support for the creation of honeycomb. Production of beeswax is energetically costly for colonies to produce, possibly causing energetic stress that may affect the colony's ability to fight pathogens. Two colonies were maintained, one with an internal plastic foundation on their frames and one without. We collected bees from each colony and extracted their hemolymph to quantify both their basal and activated immunological protein levels. Protein levels were higher in bees from the no foundation colony. Prophenoloxidase (PPO) activity trended toward higher levels in the no foundation colony, although this was not statistically significant. This suggests that lack of foundation causes the bees to have a higher protein turnover based on their energetic requirements, increasing their ability to fight off immunological threats. [ABSTRACT FROM AUTHOR]

The evolutionary expansion of sensory neuron populations detecting important environmental cues is widespread, but functionally enigmatic. We investigated this phenomenon through comparison of homologous olfactory pathways of Drosophila melanogaster and its close relative Drosophila sechellia, an extreme specialist for Morinda citrifolia noni fruit. D. sechellia has evolved species-specific expansions in select, noni-detecting olfactory sensory neuron (OSN) populations, through multigenic changes. Activation and inhibition of defined proportions of neurons demonstrate that OSN number increases contribute to stronger, more persistent, noni-odour tracking behaviour. These expansions result in increased synaptic connections of sensory neurons with their projection neuron (PN) partners, which are conserved in number between species. Surprisingly, having more OSNs does not lead to greater odour-evoked PN sensitivity or reliability. Rather, pathways with increased sensory pooling exhibit reduced PN adaptation, likely through weakened lateral inhibition. Our work reveals an unexpected functional impact of sensory neuron population expansions to explain ecologically-relevant, species-specific behaviour. Sensory neuron population expansions are common in evolution but of unclear function. Here, the authors show that, in drosophilid olfactory systems, increased sensory neuron number impacts interneuron dynamics, but not sensitivity, to promote olfactory-guided behaviour. [ABSTRACT FROM AUTHOR]

Overexpression of the agouti-signaling protein (asip1), an endogenous melanocortin antagonist, under the control of a constitutive promoter in zebrafish [Tg(Xla.Eef1a1:Cau.Asip1]iim4] (asip1-Tg) increases food intake by reducing sensitivity of the central satiety systems and abolish circadian activity rhythms. The phenotype also shows increased linear growth and body weight, yet no enhanced aggressiveness in dyadic fights is observed. In fact, asip1-Tg animals choose to flee to safer areas rather than face a potential threat, thus suggesting a potential anxiety-like behavior (ALB). Standard behavioral tests, i.e., the open field test (OFT), the novel object test (NOT), and the novel tank dive test (NTDT), were used to investigate thigmotaxis and ALB in male and female zebrafish. Results showed that the asip1-Tg strain exhibited severe ALB in every test, mainly characterized by pronounced freezing behavior and increased linear and angular swimming velocities. asip1-Tg animals exhibited low central serotonin (5-HT) and dopamine (DA) levels and high turnover rates, thus suggesting that central monoaminergic pathways might mediate melanocortin antagonist-induced ALB. Accordingly, the treatment of asip1-Tg animals with fluoxetine, a selective serotonin reuptake inhibitor (SSRI), reversed the ALB phenotype in NTDT as well as 5-HT turnover. Genomic and anatomical data further supported neuronal interaction between melanocortinergic and serotonergicsystems. These results suggest that inhibition of the melanocortin system by ubiquitous overexpression of endogenous antagonist has an anxiogenic effect mediated by serotonergic transmission. [ABSTRACT FROM AUTHOR]

The SARS coronavirus 2 (SARS-CoV-2) epidemic remains globally active. The emergence of new variants of interest and variants of concern (VoCs), which are potentially more vaccine-resistant and less sensitive to existing treatments, is evident due to their high prevalence. The prospective spread of such variants and other coronaviruses with epidemic potential demands preparedness that can be met by developing fast-track workflows to find newcandidates that target viral proteins with a clear in vitro and in vivo phenotype. Mpro (or 3CLpro) is directly involved in the viral replication cycle and the production and function of viral polyproteins, whichmakes it an ideal target. The biological relevance of Mpro is highly conserved among betacoronaviruses like HCoV-OC43 and SARS-CoV-2, which makes the identification of new chemical scaffolds targeting them a good starting point for designing broad-spectrum antivirals. We report an optimizedmethodology based on orthogonal cell-free assays to identify smallmolecules that inhibit the binding pockets of both SARS-CoV-2-Mpro and HCoV-OC43-Mpro; this blockade correlates with antiviral activities in HCoV-OC43 cellular models. By using such a fast-tracking approach against the Open Global Health Library (Merck KGaA), we have found evidence of the antiviral activity of compound OGHL98. In silico studies dissecting intermolecular interactions between OGHL98 and both proteases and comprising docking and molecular dynamics simulations (MDSs) concluded that the binding mode was primarily governed by conserved H-bonds with their C-terminal amino acids and that the rational design of OGHL98 has potential against VoCs proteases resistant to current therapeutics. [ABSTRACT FROM AUTHOR]

Many research articles have explored the impact of surgical interventions on voice and speech evaluations, but advances are limited by the lack of publicly accessible datasets. To address this, a comprehensive corpus of 107 Spanish Castilian speakers was recorded, including control speakers and patients who underwent upper airway surgeries such as Tonsillectomy, Functional Endoscopic Sinus Surgery, and Septoplasty. The dataset contains 3,800 audio files, averaging 35.51 ± 5.91 recordings per patient. This resource enables systematic investigation of the effects of upper respiratory tract surgery on voice and speech. Previous studies using this corpus have shown no relevant changes in key acoustic parameters for sustained vowel phonation, consistent with initial hypotheses. However, the analysis of speech recordings, particularly nasalised segments, remains open for further research. Additionally, this dataset facilitates the study of the impact of upper airway surgery on speaker recognition and identification methods, and testing of anti-spoofing methodologies for improved robustness. [ABSTRACT FROM AUTHOR]

The development of algebraic reasoning from the earliest educational levels is an objective that has solid support both from the point of view of research and curricular development. Effectively incorporating algebraic content to enrich mathematical activity in schools requires considering the different degrees of generality of the objects and processes involved in algebraic practices. In this article, we present an expanded version of the model of levels of algebraization proposed within the framework of the onto-semiotic approach, establishing sublevels that provide a more microscopic view of the structures involved and the processes of generalization, representation, and analytical calculation at stake. We exemplify the model with mathematical activities that can be approached from primary education, classified according to the different sublevels of algebraization. The use of this expanded model can facilitate the development of didacticmathematical knowledge of teachers in training on algebraic reasoning and its teaching. [ABSTRACT FROM AUTHOR]

In 2021, the energy sector was put at risk by extreme weather in many different ways: North America and Spain suffered heavy winter storms that led to the collapse of the electricity network; California specifically experienced heavy droughts and heat-wave conditions, causing the operations of hydropower stations to halt; floods caused substantial damage to energy infrastructure in central Europe, Australia, and China throughout the year, and unusual wind drought conditions decreased wind power production in the United Kingdom by almost 40% during summer. The total economic impacts of these extreme weather events are estimated at billions of U.S. dollars. Here we review and assess in some detail the main extreme weather events that impacted the energy sector in 2021 worldwide, discussing some of the most relevant case studies and the meteorological conditions that led to them. We provide a perspective on their impacts on electricity generation, transmission, and consumption, and summarize estimations of economic losses. [ABSTRACT FROM AUTHOR]

Living organisms synchronize their biological activities with the earth's rotation through the circadian clock, a molecular mechanism that regulates biology and behavior daily. This synchronization factually maximizes positive activities (e.g., social interactions, feeding) during safe periods, and minimizes exposure to dangers (e.g., predation, darkness) typically at night. Beyond basic circadian regulation, some behaviors like sleep have an additional layer of homeostatic control, ensuring those essential activities are fulfilled. While sleep is predominantly governed by the circadian clock, a secondary homeostatic regulator, though not well-understood, ensures adherence to necessary sleep amounts and hints at a fundamental biological function of sleep beyond simple energy conservation and safety. Here we explore sleep regulation across seven Drosophila species with diverse ecological niches, revealing that while circadian-driven sleep aspects are consistent, homeostatic regulation varies significantly. The findings suggest that in Drosophilids, sleep evolved primarily for circadian purposes. The more complex, homeostatically regulated functions of sleep appear to have evolved independently in a species-specific manner, and are not universally conserved. This laboratory model may reproduce and recapitulate primordial sleep evolution. We all feel tired without sleep, but we still don't know why. Is tiredness a crucial, evolutionarily conserved feature of sleep? Joyce et al. show that some species have circadian but not homeostatic regulation of rest and suggest this is the ancestral drive of sleep evolution. [ABSTRACT FROM AUTHOR]

Organs have a distinctive yet often overlooked spatial arrangement in the body1–5. We propose that there is a logic to the shape of an organ and its proximity to its neighbours. Here, by using volumetric scans of many Drosophila melanogaster flies, we develop methods to quantify three-dimensional features of organ shape, position and interindividual variability. We find that both the shapes of organs and their relative arrangement are consistent yet differ between the sexes, and identify unexpected interorgan adjacencies and left–right organ asymmetries. Focusing on the intestine, which traverses the entire body, we investigate how sex differences in three-dimensional organ geometry arise. The configuration of the adult intestine is only partially determined by physical constraints imposed by adjacent organs; its sex-specific shape is actively maintained by mechanochemical crosstalk between gut muscles and vascular-like trachea. Indeed, sex-biased expression of a muscle-derived fibroblast growth factor-like ligand renders trachea sexually dimorphic. In turn, tracheal branches hold gut loops together into a male or female shape, with physiological consequences. Interorgan geometry represents a previously unrecognized level of biological complexity which might enable or confine communication across organs and could help explain sex or species differences in organ function.In fruit flies, three-dimensional organ arrangement is stereotypical, sexually dimorphic and actively maintained by muscle-vessel mechanochemical crosstalk. [ABSTRACT FROM AUTHOR]

Cocaine use disorder is a significant public health issue without an effective pharmacological treatment. Successful treatments are hindered in part by an incomplete understanding of the molecular mechanisms that underlie long-lasting maladaptive plasticity and addiction-like behaviors. Here, we leverage a large RNA sequencing dataset to generate gene coexpression networks across six interconnected regions of the brain's reward circuitry from mice that underwent saline or cocaine self-administration. We identify phosphodiesterase 1b (Pde1b), a Ca2+/calmodulin-dependent enzyme that increases cAMP and cGMP hydrolysis, as a central hub gene within a nucleus accumbens (NAc) gene module that was bioinformatically associated with addiction-like behavior. Chronic cocaine exposure increases Pde1b expression in NAc D2 medium spiny neurons (MSNs) in male but not female mice. Viral-mediated Pde1b overexpression in NAc reduces cocaine self-administration in female rats but increases seeking in both sexes. In female mice, overexpressing Pde1b in D1 MSNs attenuates the locomotor response to cocaine, with the opposite effect in D2 MSNs. Overexpressing Pde1b in D1/D2 MSNs had no effect on the locomotor response to cocaine in male mice. At the electrophysiological level, Pde1b overexpression reduces sEPSC frequency in D1 MSNs and regulates the excitability of NAc MSNs. Lastly, Pde1b overexpression significantly reduced the number of differentially expressed genes (DEGs) in NAc following chronic cocaine, with discordant effects on gene transcription between sexes. Together, we identify novel genemodules across the brain's reward circuitry associated with addiction-like behavior and explore the role of Pde1b in regulating the molecular, cellular, and behavioral responses to cocaine. [ABSTRACT FROM AUTHOR]

Healthy carriers of BRCA1/2 pathogenic variants (PVs) may benefit from risk-reducing measures of proven efficacy. The main approach to identify these individuals is cascade testing, and strategies to support this complex process are under investigation. In Italy, cascade testing has received little attention; therefore, we analyzed the uptake and characteristics of BRCA1/2 cascade testing in families diagnosed with HBOC between 2017 and 2019 at two Italian genetics centers. All blood relatives aged 18 years or older at September 2022 and who could be involved in the first step of cascade testing (i.e., all the living relatives closest to the proband) were included. In addition to first-degree relatives, individuals who were second-, third- or fourth-degree relatives were included if the closest relative(s) was/were deceased. Overall, 213 families were included (103, Genoa; 110, Bologna). Most probands were women affected by breast and/or ovarian cancer (86.4%, Genoa; 84.5%, Bologna), and the branch segregating the PV was known/suspected in 62% of families (62.1%, Genoa; 60.9%, Bologna). Overall, the uptake of cascade testing was 22.8% (25.8%, Genoa; 19.9%, Bologna; OR = 0.59: 95%CI 0.43–0.82). It was strongly associated with female gender (OR = 3.31, 95%CI 2.38–4.59), age ≤ 70 years (< 30 years OR = 3.48, 95%CI 1.85–6.56; 30–70 years OR = 3.08, 95%CI 2.01–4.71), first-degree relationship with the proband (OR = 16.61, 95%CI 10.50-26.28) and segregation of the PV in both the maternal (OR = 2.54, 95%CI 1.72–3.75) and the paternal branch (OR = 4.62, 95%CI 3.09–6.91). These real-world data may be important to inform the design and implementation of strategies aimed at improving the uptake of HBOC cascade testing in Italy. [ABSTRACT FROM AUTHOR]

High performance computing has entered the Exascale Age. Capable of performing over 1018 floating point operations per second, exascale computers, such as El Capitan, the National Nuclear Security Administration's first, have the potential to revolutionize the detailed in-depth study of highly complex science and engineering systems. However, in addition to these kind of whole machine "hero" simulations, exascale systems could also enable new paradigms in digital design by making petascale hero runs routine. Currently, untenable problems in complex system design, optimization, model exploration, and scientific discovery could all become possible. Motivated by the challenge of uncovering the next generation of robust high-yield inertial confinement fusion (ICF) designs, project ICECap (Inertial Confinement on El Capitan) attempts to integrate multiple advances in machine learning (ML), scientific workflows, high performance computing, GPU-acceleration, and numerical optimization to prototype such a future. Built on a general framework, ICECap is exploring how these technologies could broadly accelerate scientific discovery on El Capitan. In addition to our requirements, system-level design, and challenges, we describe some of the key technologies in ICECap, including ML replacements for multiphysics packages, tools for human-machine teaming, and algorithms for multifidelity design optimization under uncertainty. As a test of our prototype pre-El Capitan system, we advance the state-of-the art for ICF hohlraum design by demonstrating the optimization of a 17-parameter National Ignition Facility experiment and show that our ML-assisted workflow makes design choices that are consistent with physics intuition, but in an automated, efficient, and mathematically rigorous fashion. [ABSTRACT FROM AUTHOR]

Objective. The aim of this work is to investigate the response of the Roos chamber (type 34001) irradiated by clinical proton beams in magnetic fields. Approach. At first, a Fano test was implemented in Monte Carlo software package GATE version 9.2 (based on Geant4 version 11.0.2) using a cylindrical slab geometry in a magnetic field up to 1 T. In accordance to an experimental setup (Fuchs et al), the magnetic field correction factors k Q B ⃗ of the Roos chamber were determined at different energies up to 252 MeV and magnetic field strengths up to 1 T, by separately simulating the ratios of chamber signals M Q / M Q B ⃗ , without and with magnetic field, and the dose-conversion factors D w , Q B ⃗ / D w , Q in a small cylinder of water, with and without magnetic field. Additionally, detailed simulations were carried out to understand the observed magnetic field dependence. Main results. The Fano test was passed with deviations smaller than 0.25% between 0 and 1 T. The ratios of the chamber signals show both energy and magnetic field dependence. The maximum deviation of the dose-conversion factors from unity of 0.22% was observed at the lowest investigated proton energy of 97.4 MeV and B ⃗ = 1 T. The resulting k Q B ⃗ factors increase initially with the applied magnetic field and decrease again after reaching a maximum at around 0.5 T; except for the lowest 97.4 MeV beam that show no observable magnetic field dependence. The deviation from unity of the factors is also larger for higher proton energies, where the maximum lies at 1.0035(5), 1.0054(7) and 1.0069(7) for initial energies of E 0 = 152, 223.4 and 252 MeV, respectively. Significance. Detailed Monte Carlo studies showed that the observed effect can be mainly attributed to the differences in the transport of electrons produced both outside and inside of the air cavity in the presence of a magnetic field. [ABSTRACT FROM AUTHOR]

L-Lactate is an important bioanalyte in the food industry, biotechnology, and human healthcare. In this work, we report the development of a new L-lactate electrochemical biosensor based on the use of multiwalled carbon nanotubes non-covalently functionalized with avidin (MWCNT-Av) deposited at glassy carbon electrodes (GCEs) as anchoring sites for the bioaffinity-based immobilization of a new recombinant biotinylated lactate oxidase (bLOx) produced in Escherichia coli through in vivo biotinylation. The specific binding of MWCNT-Av to bLOx was characterized by amperometry, surface plasmon resonance (SPR), and electrochemical impedance spectroscopy (EIS). The amperometric detection of L-lactate was performed at −0.100 V, with a linear range between 100 and 700 µM, a detection limit of 33 µM, and a quantification limit of 100 µM. The proposed biosensor (GCE/MWCNT-Av/bLOx) showed a reproducibility of 6.0% and it was successfully used for determining L-lactate in food and enriched serum samples. [ABSTRACT FROM AUTHOR]

Due to the continuously growing demands from high-added-value sectors such as aerospace, e-mobility or biomedical bound-abrasive technologies are the key to achieving extreme requirements. During grinding, energy is rapidly dissipated as heat, generating thermal fields on the ground part which are characterized by high temperatures and very steep gradients. The consequences on the ground part are broadly known as grinding burn. Therefore, the measurement of workpiece temperature during grinding has become a critical issue. Many techniques have been used for temperature measurement in grinding, amongst which, the so-called grindable thermocouples exhibit great potential and have been successfully used in creep-feed grinding operations, in which table speed is low, and therefore, temperature gradients are not very steep. However, in conventional grinding operations with faster table speeds, as most industrial operations are, the delay in the response of the thermocouple results in large errors in the maximum measured value. In this paper, the need for accurate calibration of the response of grindable thermocouples is studied as a prior step for signal integration to correct thermal inertia. The results show that, if the raw signal is directly used from the thermocouples, the deviation in the maximum temperature with respect to the theoretical model is over 200 K. After integration using the calibration constants obtained for the ground junction, the error can be reduced to 93 K even for feed speeds as high as 40 m/min and below 20 K for lower feed speeds. The main conclusion is that, following the proposed procedure, maximum grinding temperatures can be effectively measured using grindable thermocouples even at high values of table speed. [ABSTRACT FROM AUTHOR]

There are numerous frameworks for implementing evidence-based practices (EBPs) in novel settings to achieve "fidelity." However, identifying appropriate referents for fidelity poses a challenge. The Core Functions and Forms paradigm offers a model that can inform adaptation decisions throughout all phases of the Exploration, Preparation, Implementation, Sustainment (EPIS) framework. We applied the Core Functions-Forms paradigm throughout the Exploration and Preparation phases of EPIS in the design of two EBPs targeting family protective factors among Latinos in San Diego, as well as describe plans for its use in Implementation and Sustainment. We employed a distinct approach for each intervention element to contrast adaptation decisions that prioritize adherence to either form or function fidelity. We describe our application of the functions-forms paradigm within the EPIS framework, focusing on the Preparation phase. We also provide functionsforms matrices that map out the relationship between individual intervention components (forms) and the essential processes (functions) by which components are theorized to exert their impact. This case study of how the core functions-forms framework can be mapped onto EPIS can support a conceptual shift from prioritizing form fidelity to also focusing on function fidelity. This might allow interventionists to target appropriate fidelity referents when adapting an EBP, rather than defaulting to maintaining fidelity to forms as described in the protocol. We see great promise for using this framework for guiding actions throughout all EPIS phases and informing future applications of this paradigm to foster more robust fidelity to function. [ABSTRACT FROM AUTHOR]

Introduction: Rectal temperature (RT) is the reference standard for clinical evaluation of body temperature in mammals. However, the use of a rectal thermometer to measure temperature can cause stress and other problems, especially in cats. There is a need for clinical techniques that reduce both stress and defensive behavior as part of the provision of better medical care. Subcutaneous temperature-sensing identification microchips fulfil the current legal requirements and provide a reading of subcutaneous temperature (MT). Methods: The clinical study tried to determine whether there is agreement between MT and RT in normal (n = 58), hospitalized (n = 26) and sedated/ anesthetized (n = 36) cats. Three measurements were taken using both methods (MT and RT) in each cat. Correlation between MT and RT, and differences between MT and RT, were estimated for pairs of data-points from the same individual, and all data pairs in each group were considered overall. Results: There was a strong positive correlation between MT and RT (r = 0.7 to 1.0) (p < 0.0005). The mean differences (d) were always negative and although statistically significant, these d values are likely of no biological importance. The overall d was -0.1°C in normal cats (p < 0.0005), -0.1°C in hospitalized cats (p = 0.001) and -0.1°C in sedated/anesthetized cats (p = 0.001). The limits of agreement between MT and RT appear narrow enough for MT to be acceptable estimate of RT. The overall limits of agreement (95%) were -0.71°C and 0.53°C (in normal cats); -0.51°C and 0.34°C (in hospitalized cats) and -0.60°C and 0.42°C (in sedated/anesthetized cats). Discussion: MT may provide a good alternative to RT measurement in cats. However, this study was mostly performed in animals that were normothermic. Therefore, further studies in larger groups of cats under different conditions are needed to compare trends and assess variation with time. [ABSTRACT FROM AUTHOR]

Background: Neutrophil extracellular traps (NETs) have repeatedly been related to COVID-19 severity and mortality. However, there is no consensus on their quantification, and there are scarce data on their evolution during the disease. We studied circulating NET markers in patients with COVID-19 throughout their hospitalization. Methods: We prospectively included 93 patients (201 blood samples), evaluating the disease severity in 3 evolutionary phases (viral, early, and late inflammation). Of these, 72 had 180 samples in various phases. We also evaluated 55 controls with similar age, sex and comorbidities. We measured 4 NET markers in serum: cfDNA, CitH3, and MPO-DNA and NE-DNA complexes; as well as neutrophil-related cytokines IL-8 and G-CSF. Results: The COVID-19 group had higher CitH3 (28.29 vs 20.29 pg/mL, p = 0.022), and cfDNA, MPO-DNA, and NE-DNA (7.87 vs 2.56 ng/mL; 0.80 vs 0.52 and 1.04 vs 0.72, respectively, p < 0.001 for all) than the controls throughout hospitalisation. cfDNA was the only NET marker clearly related to severity, and it remained higher in non-survivors during the 3 phases. Only cfDNA was an independent risk factor for mortality and need for intensive care. Neutrophil count, IL-8, and G-CSF were significantly related to severity. MPO-DNA and NE-DNA showed significant correlations (r: 0.483, p < 0.001), including all 3 phases and across all severity grades, and they only remained significantly higher on days 10–16 of evolution in those who died. Correlations among the other NET markers were lower than expected. Conclusions: The circulating biomarkers of NETs were present in patients with COVID-19 throughout hospitalization. cfDNA was associated with severity and mortality, but the three other markers showed little or no association with these outcomes. Neutrophil activity and neutrophil count were also associated with severity. MPO-DNA and NE-DNA better reflected NET formation. cfDNA appeared to be more associated with overall tissue damage; previous widespread use of this marker could have overestimated the relationship between NETs and severity. Currently, there are limitations to accurate NET markers measurement that make it difficult to assess its true role in COVID-19 pathogenesis. [ABSTRACT FROM AUTHOR]

Background: As many as 2.4 million Americans are affected by chronic Hepatitis C Virus (HCV) in the United States.In 2018, the estimated number of adults with a history of HCV infection in San Diego County was 55,354 (95% CI: 25,411–93,329). This corresponded to a seroprevalence of 2.1% (95% CI: 2.1–3.4%). One-third of infections were among PWID. Published research has demonstrated that direct-acting antivirals (DAAs) have high efficacy and can now be used by primary care providers to treat HCV. In addition, limited evidence exists to support the effectiveness of simplified algorithms in clinical trial and real-world settings. Even with expanded access to HCV treatment in primary care settings, there are still groups, especially people who inject drugs (PWID) and people experiencing homelessness, who experience treatment disparities due to access and treatment barriers. The current study extends the simplified algorithm with a streetside 'one-stop-shop' approach with integrated care (including the offer of buprenorphine prescriptions and abscess care) using a mobile clinic situated adjacent to a syringe service program serving many homeless populations. Rates of HCV treatment initiation and retention will be compared between patients offered HCV care in a mobile clinic adjacent to a syringe services program (SSP) and homeless encampment versus those who are linked to a community clinic's current practice of usual care, which includes comprehensive patient navigation. Methods: A quasi-experimental, prospective, interventional, comparative effectiveness trial with allocation of approximately 200 patients who inject drugs and have chronic HCV to the "simplified care" pathway (intervention group) or the "usual care" pathway (control group). Block randomization will be performed with a 1:1 randomization. Discussion: Previous research has demonstrated acceptable outcomes for patients treated using simplified algorithms for DAAs and point-of-care testing in mobile medical clinics; however, there are opportunities to explore how these new, innovative systems of care impact treatment initiation rates or other HCV care cascade outcomes among PWID. Trial registration: We have registered our study with ClinicalTrials.gov, a resource of the United States National Library of Medicine. This database contains research studies from United States and other countries around the world. Our study has not been previously published. The ClinicalTrials.gov registration identifier is NCT04741750. [ABSTRACT FROM AUTHOR]

Radiomics allows the extraction of quantitative imaging features from clinical magnetic resonance imaging (MRI) and computerized tomography (CT) studies. The advantages of radiomics have primarily been exploited in oncological applications, including better characterization and staging of oncological lesions and prediction of patient outcomes and treatment response. The potential introduction of radiomics in the clinical setting requires the establishment of a standardized radiomics pipeline and a quality assurance program. Radiomics and texture analysis of the liver have improved the differentiation of hypervascular lesions such as adenomas, focal nodular hyperplasia, and hepatocellular carcinoma (HCC) during the arterial phase, and in the pretreatment determination of HCC prognostic factors (e.g., tumor grade, microvascular invasion, Ki-67 proliferation index). Radiomics of pancreatic CT and MR images has enhanced pancreatic ductal adenocarcinoma detection and its differentiation from pancreatic neuroendocrine tumors, mass-forming chronic pancreatitis, or autoimmune pancreatitis. Radiomics can further help to better characterize incidental pancreatic cystic lesions, accurately discriminating benign from malignant intrapancreatic mucinous neoplasms. Nonetheless, despite their encouraging results and exciting potential, these tools have yet to be implemented in the clinical setting. This non-systematic review will describe the essential steps in the implementation of the radiomics and feature extraction workflow from liver and pancreas CT and MRI studies for their potential clinical application. A succinct overview of reported radiomics applications in the liver and pancreas and the challenges and limitations of their implementation in the clinical setting is also discussed, concluding with a brief exploration of the future perspectives of radiomics in the gastroenterology field. [ABSTRACT FROM AUTHOR]

Temporal signals such as light and temperature cycles profoundly modulate animal physiology and behaviour. Via endogenous timing mechanisms which are regulated by these signals, organisms can anticipate cyclic environmental changes and thereby enhance their fitness. The pineal gland in fish, through the secretion of melatonin, appears to play a critical role in the circadian system, most likely acting as an element of the circadian clock system. An important output of this circadian clock is the locomotor activity circadian rhythm which is adapted to the photoperiod and thus determines whether animals are diurnal or nocturnal. By using a genetically modified zebrafish strain known as Tg (Xla.Eef1a1:Cau.asip1)iim04, which expresses a higher level of the agouti signalling protein 1 (Asip1), an endogenous antagonist of the melanocortin system, we observed a complete disruption of locomotor activity patterns, which correlates with the ablation of the melatonin daily rhythm. Consistent with this, in vitro experiments also demonstrated that Asip1 inhibits melatonin secretion from the zebrafish pineal gland, most likely through the melanocortin receptors expressed in this gland. Asip1 overexpression also disrupted the expression of core clock genes, including per1a and clock1a, thus blunting circadian oscillation. Collectively, these results implicate the melanocortin system as playing an important role in modulating pineal physiology and, therefore, circadian organisation in zebrafish. [ABSTRACT FROM AUTHOR]

This article discusses a pilot study that examined the differences in metabolites in patients with colorectal liver metastasis (CRLM) after surgery. The study analyzed plasma samples from 39 patients and identified specific metabolic changes associated with disease relapse and survival. These findings suggest that metabolomics could be used to create a risk score to predict disease progression and improve treatment outcomes for CRLM patients. However, further research is needed to validate these findings in larger groups of patients. [Extracted from the article]

RNA pol II assembly occurs in the cytoplasm before translocation of the enzyme to the nucleus. Affecting this assembly influences mRNA transcription in the nucleus and mRNA decay in the cytoplasm. However, very little is known about the consequences on ncRNA synthesis. In this work, we show that impairment of RNA pol II assembly leads to a decrease in cryptic non-coding RNAs (preferentially CUTs and SUTs). This alteration is partially restored upon overcoming the assembly defect. Notably, this drop in ncRNAs is only partially dependent on the nuclear exosome, which suggests a major specific effect of enzyme assembly. Our data also point out a defect in transcription termination, which leads us to propose that CTD phosphatase Rtr1 could be involved in this process. [ABSTRACT FROM AUTHOR]

Copyright of Revista de Cirugia is the property of Sociedad de Cirujanos de Chile and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The article presents a case study of a 49-year-old male with Cowden syndrome type 1 (CWS1) who was found to have a novel Phosphatase and Tensin Homolog (PTEN) gene variant, c.100G>C, leading to a missense mutation p.Ala34Pro. Topics discussed include the patient's clinical presentation with dermatologic and gastrointestinal features, the genetic analysis of the PTEN gene identifying the new variant, and the implications for genetic counseling and diagnosis in CWS1.

From the most classic carbon materials (CMs) to the advanced ones, all of them integrate a promising catalyst set in terms of sustainability and energy efficiency for a greener future. Different synthetic strategies concerning to the catalytic synthesis of relevant N‐containing heterocycles are herein described to address the great potential of the referred catalysts flying over what has been done and all that remains to be done. Current trends in this field involve structure‐activity relationships establishment also considering the reaction mechanisms understanding and the identification of active catalytic sites, as function of both experimental datasets, emphasizing on operando characterization techniques, and theoretical studies which will significantly contribute to the design of custom‐made catalysts as a new horizon. [ABSTRACT FROM AUTHOR]

Multi-fidelity models provide a framework for integrating computational models of varying complexity, allowing for accurate predictions while optimizing computational resources. These models are especially beneficial when acquiring high-accuracy data is costly or computationally intensive. This review offers a comprehensive analysis of multi-fidelity models, focusing on their applications in scientific and engineering fields, particularly in optimization and uncertainty quantification. It classifies publications on multi-fidelity modeling according to several criteria, including application area, surrogate model selection, types of fidelity, combination methods and year of publication. The study investigates techniques for combining different fidelity levels, with an emphasis on multi-fidelity surrogate models. This work discusses reproducibility, open-sourcing methodologies and benchmarking procedures to promote transparency. The manuscript also includes educational toy problems to enhance understanding. Additionally, this paper outlines best practices for presenting multi-fidelity-related savings in a standardized, succinct and yet thorough manner. The review concludes by examining current trends in multifidelity modeling, including emerging techniques, recent advancements, and promising research directions. [ABSTRACT FROM AUTHOR]

Although several lines of evidence from different studies highlight sex differences in cardiovascular diseases, to date, most studies have been focused on males, with the idea that males and females are similar, differing only in the magnitude of the response. However, the principles learned in male models cannot and should not be extrapolated to women and, therefore, it is important to study in greater detail not only the differences between the sexes but also the physiological intertwining of the underlying genetic and hormonal mechanisms of sexual dimorphism. This review explores the sex disparities in the autonomic nervous system regulation of blood pressure (particularly baroreceptor function), with special emphasis on sex hormones and sex chromosome complement factors involved in sexually dimorphic autonomic blood pressure regulation. A more detailed understanding of the sources of physiological disparities between the sexes may also help in understanding the differences between the sexes in rates of cardiovascular disease and may also aid in designing future improvements for sex-tailored therapeutic treatments. [ABSTRACT FROM AUTHOR]

Background: Minoritized communities including refugees are at an increased risk of poorly controlled hypertension. Evidence indicates that self-measured blood pressure monitoring (SMBP) is an effective method to improve blood pressure control in patients with hypertension. However, it has not been studied among refugee populations. The objective of this study is to examine barriers and facilitators to SMBP among Arab refugees resettled in the United States (US) with diagnosed hypertension. Methods: A total of 109 participants were recruited through a Federally Qualified Health Center system that is a major provider of healthcare to refugees in San Diego, California. Participants completed a questionnaire and were interviewed using in-depth, semi-structured interviews. Interviews were transcribed and translated, and data were coded using inductive thematic analysis and organized based on the theory of care-seeking behavior. Results: Several barriers to engaging in effective SMBP monitoring were identified. Clinical and sociodemographic barriers included reliance on public monitors and poor hypertension literacy. Psychosocial barriers of affect, norms, and habits included fear and anxiety from hypertension, cultural stigma of illness, and conditional SMBP with symptoms, respectively. Utility psychosocial barriers included lack of SMBP prioritization in treatment and perceived inaccuracy of home monitors. Family members' support with home monitoring served as an important facilitator to SMBP. Conclusions: There are several barriers to effective SMBP among the US-resettled Arab refugee population that may reflect unique cultural and care-seeking behaviors. Tailored public health and clinical interventions are needed to support refugee patients and providers to improve hypertension self-management behaviors for this unique population. [ABSTRACT FROM AUTHOR]

Literature commonly links the role of informality in collective bargaining to industrial relations systems based on voluntarism and decentralized negotiation settings. According to this view, informal processes won't exist or at best play a marginal role in institutionally strong industrial relations systems, where formal rules define the roles, rights and duties of actors in the system. Yet, even in highly regulated contexts, formal and informal mechanisms very often co-exist and complement each other to help reach agreements or solve conflicts among actors. A relational approach and social network analysis applied to the study of the retail sector in Italy, Netherlands and Spain allows to understand the role of informality in countries with different industrial relations regimes. The analysis shows the importance of informal interactions and events in all countries, irrespectively of the industrial relations regime, and confirms the positive contribution of relational approaches to the study of collective bargaining linking with the literature on the embeddedness theory and structural holes. [ABSTRACT FROM AUTHOR]

Copyright of European Journal of Psychotraumatology is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

End-to-end deep learning models have shown promising results for the automatic screening of Parkinson's disease by voice and speech. However, these models often suffer degradation in their performance when applied to scenarios involving multiple corpora. In addition, they also show corpus-dependent clusterings. These facts indicate a lack of generalisation or the presence of certain shortcuts in the decision, and also suggest the need for developing new corpus-independent models. In this respect, this work explores the use of domain adversarial training as a viable strategy to develop models that retain their discriminative capacity to detect Parkinson's disease across diverse datasets. The paper presents three deep learning architectures and their domain adversarial counterparts. The models were evaluated with sustained vowels and diadochokinetic recordings extracted from four corpora with different demographics, dialects or languages, and recording conditions. The results showed that the space distribution of the embedding features extracted by the domain adversarial networks exhibits a higher intra-class cohesion. This behaviour is supported by a decrease in the variability and inter-domain divergence computed within each class. The findings suggest that domain adversarial networks are able to learn the common characteristics present in Parkinsonian voice and speech, which are supposed to be corpus, and consequently, language independent. Overall, this effort provides evidence that domain adaptation techniques refine the existing end-to-end deep learning approaches for Parkinson's disease detection from voice and speech, achieving more generalizable models. [ABSTRACT FROM AUTHOR]

Purpose: Differentiating subtalar and ankle instability in the clinical setting is challenging. This study aims to analyze the rotational laxity of the subtalar joint bilaterally in patients with asymptomatic and symptomatic ankle instability under simulated load and stress-induced position of the subtalar joint. Methods: A case–control study was conducted using an adjustable load device (ALD). Patients with chronic ankle instability and healthy volunteers were included. Each subject underwent a CT scan under mechanical stress and simulated weight-bearing conditions, maintaining maximum eversion and inversion hindfoot positions. The images were obtained in a single model, allowing calculations of the motion vector as well as the helical axis. The helical axis was defined by a rotation angle and a translation distance. Results: A total of 72 feet were included in the study. Thirty-one patients with unilateral symptoms and five healthy controls were selected, defining two groups: symptomatic (n = 31) and asymptomatic (n = 41). An absolute difference of 4.6º (95%CI 2–11.1) rotation angle was found on the helical axis of the symptomatic vs. asymptomatic group (p = 0.001). No significant differences were detected in the translation distance (n.s.) between the groups. Additionally, a significant positive correlation was found between the rotation angle and translation distance through the helical axis in the asymptomatic group (r = 0.397, p = 0.027). Conclusion: Patients with chronic ankle instability suspected of having subtalar joint instability showed a wider subtalar range of laxity in terms of rotation about the helical axis. Furthermore, differences in kinematics between symptomatic and asymptomatic hindfeet was demonstrated when both feet were compared. Level of evidence: III. [ABSTRACT FROM AUTHOR]

Humanity is facing a vast prevalence of neurodegenerative diseases, with Alzheimer's disease (AD) being the most dominant, without efficacious drugs, and with only a few therapeutic targets identified. In this scenario, we aim to find molecular entities that modulate imidazoline I2 receptors (I2-IRs) that have been pointed out as relevant targets in AD. In this work, we explored structural modifications of well-established I2-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature. We report the synthesis, the affinity in human I2-IRs, the brain penetration capabilities, the in silico ADMET studies, and the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of this new bunch of I2-IR ligands. Selected compounds showed neuroprotective properties and beneficial effects in an in vitro model of Parkinson's disease, rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine, and showed crucial anti-inflammatory effects in a cellular model of neuroinflammation. After a preliminary pharmacokinetic study, we explored the action of our representative 2-(benzo[b]thiophen-2-yl)-1H-imidazole LSL33 in a mouse model of AD (5xFAD). Oral administration of LSL33 at 2 mg/Kg for 4 weeks ameliorated 5XFAD cognitive impairment and synaptic plasticity, as well as reduced neuroinflammation markers. In summary, this new I2-IR ligand that promoted beneficial effects in a well-established AD mouse model should be considered a promising therapeutic strategy for neurodegeneration. [ABSTRACT FROM AUTHOR]

Objective Disparities exist in health care access, diagnosis, and treatment of chronic pain in Latino populations and other minority populations. Cognitive behavioral–based physical therapy (CBPT) interventions have been shown to be effective in predominantly non-Hispanic white populations with chronic spine pain. However, there is a need for culturally adapted CBPT interventions that focus on the conservative management of chronic spine pain. The primary purpose of the study described in this protocol is to test the efficacy of an adapted cognitive behavioral–based hybrid telerehabilitation intervention for Latino patients with chronic spine pain. Methods A single-blind, 2-arm parallel group, superiority randomized clinical trial is planned to compare an adapted CBPT intervention to Usual Care physical therapy. Goal Oriented Activity for Latinos with chronic Spine pain (GOALS/Metas) is an 8-week hybrid telerehabilitation intervention that integrates guideline-based physical therapy and pain management interventions using cognitive behavioral approaches and has been adapted for Latino patients with chronic spine pain. Usual Care physical therapy will be administered based on institutional standards at the referring health center. Outcome measures will be evaluated preintervention and at 1-week, 3-months, and 6-months postintervention. The primary outcome is pain-related disability 1-week postintervention using the Brief Pain Inventory Pain Interference subscale. Secondary outcome measures include behavioral measures of functional activity, social participation, physical activity, and sleep. Determinants of treatment effect, including pain-related psychological measures, posture and movement, self-efficacy, treatment expectancy, and therapeutic alliance, will be included in the secondary moderation and mediation analyses. Impact This clinical trial will provide information on the extent to which an adapted CBPT hybrid telerehabilitation intervention is effective in reducing pain-related disability for Latino patients with chronic spine pain. This information will be useful for clinicians to integrate in their practice, given the growing population of Latino patients who experience disparities in health care management of chronic pain. [ABSTRACT FROM AUTHOR]

The theoretical reflection on the nature of school algebra and the development of algebraic thinking from the first educational levels is a relevant topic in mathematics education. In this paper, we first summarize and clarify the positions held on this topic by two theoretical frameworks: the Theory of Objectification and the Onto-semiotic Approach. We identify concordances and complementarities in the respective conceptions of algebra and of the processes of developing algebraic thinking, as a result of applying these frameworks to analyse some students' responses to a task on numerical patterns. We also analyse and compare the didactic models proposed in both theoretical frameworks for developing algebraic thinking. The analysis of the algebraic thinking and learning episodes is also used to illustrate a general discussion on the identity and boundaries of these theoretical frameworks and the possibilities of coordination and integration. [ABSTRACT FROM AUTHOR]

Type 2 diabetes disproportionately impacts ethnic minorities and individuals from low socioeconomic status. Diabetes self-management education and support has been shown to improve clinical outcomes in these populations, and mobile health (mHealth) interventions can reduce barriers to access. Dulce Digital-Me (DD-Me) was developed to integrate adaptive mHealth technologies to enhance self-management and reduce disparities in the high-risk, underserved Hispanic population. The objective of the present study was to evaluate reach, adoption, and implementation of an mHealth diabetes self-management education and support intervention in this underrepresented population. The present analysis is a multimethod process evaluation using the Reach , Effectiveness, Adoption , Implementation, and Maintenance (RE-AIM) framework. The study was effective in reaching a sample that was representative of the intended population; only modest but significant differences were observed in sex and age. The DD-Me health coach (HC) cited several important facilitators of intervention adoption , including outreach frequency and personalization, and the automated HC report. Implementation fidelity was high, with participants receiving >90% of intended interventions. Participants who received DD-Me with support from a HC were most engaged, suggesting utility and acceptability of integrating HCs with mHealth interventions. Perceptions of implementation among study participants were positive and consistent across study arms. This evaluation revealed the target population was successfully reached and engaged in the digital health interventions, which was implemented with high fidelity. Further studies should evaluate the efficacy and maintenance of the study following the RE-AIM model to determine whether this intervention warrants expansion to additional settings and populations. [ABSTRACT FROM AUTHOR]

Introduction: The prognosis of relapsed B cell precursor acute lymphoblastic leukemia (B‐ALL) is poor and few patients can be successfully rescued with conventional therapies. Inotuzumab ozogamicin (IO), an antibody against the CD22 antigen linked to calicheamicin, has been approved as a rescue treatment in relapsed/refractory (R/R) B‐ALL. Patients and Methods: This was an observational, retrospective, multicenter study of adult patients included in the Spanish program of compassionate use of IO in centers from the PETHEMA group (Programa Español de Tratamientos en Hematología). Results: Thirty‐four patients with a median age of 43 years (range, 19–73) were included. Twenty patients (59%) were refractory to the last treatment, IO treatment was given as ≥3rd salvage treatment in 25 patients (73%) and 20 patients (59%) received allogeneic hematopoietic stem cell transplantation before IO treatment. After a median of 2 cycles of IO, 64% of patients achieved complete response (CR)/complete response with incomplete recovery. The median response duration, progression‐free survival and overall survival (OS) were 4.7 (95%CI, 2.4–7.0 months), 3.5 (95%CI, 1.0–5.0 months) and 4 months (95%CI, 1.9–6.1 months) respectively, with better OS for patients with relapsed B‐ALL versus refractory disease (10.4 vs. 2.5 months, respectively) (p =.01). There was a trend for better OS for patients with first CR duration >12 months (7.2 months [95%CI, 3.2–11.2] vs. 3 months [95% CI, 1.8–4.2] respectively) (p =.054). There was no sinusoidal obstruction syndrome (SOS) event during IO treatment, but three patients (9%) developed grade 3–4 SOS during alloHSCT after IO treatment. Conclusions: Our study showed slightly inferior outcomes of the pivotal trial probably due to poorer risk factors and late onset of IO therapy of recruited patients. Our results support early use of IO in relapsed/refractory ALL patients. [ABSTRACT FROM AUTHOR]

Background: Hypertension is a global leading cause of death which disproportionately affects refugees. This chronic disease increases the risk of heart disease, stroke, brain, and other end-organ disease, if left uncontrolled. The 2017 United States travel or "Muslim" ban prevented immigrants and refugees from seven Muslim-majority countries from entering the United States, including Syria and Iraq; two major contributors to the global refugee population. As of 2020, the United States has admitted more than 133,000 and 22,000 Iraqi and Syrian refugees, respectively. Studies on the health effects of this policy on refugees are lacking. This study qualitatively explores the impact of the refugee ban on United States resettled Syrian and Iraqi refugees with hypertension. Methods: Participants were recruited through a federally qualified health center system that is the largest healthcare provider for refugees in San Diego, CA. All participants were Arabic-speaking refugees diagnosed with hypertension from Syria and Iraq. In-depth interviews took place between April 2021 and April 2022. Inductive thematic analysis was used to analyze data from semi-structured interviews. Results: Participants (N = 109) include 53 women and 56 men (23 Syrian, 86 Iraqi). The average age was 61.3 years (SD: 9.7) and stay in the United States was 9.5 years (SD 5.92). Four themes emerged linking the travel ban's impact on health, in line with the society to cells framework: (1) family factors: the refugee ban resulted in family separation; (2) physiological factors: the refugee ban worsened participants' mental health, exacerbating hypertension and perceived health outcomes; (3) community factors: perpetuation of Islamophobia, xenophobia, and perceived discrimination were structural barriers with links to poorer health; and (4) individual factors: trickle down consequences led to worsened participant self-image and self-perception within their host community. Discussion: The refugee ban negatively impacted the mental and physical health of United States resettled Arabic-speaking refugees through perceived discrimination, stress, and poor social integration. It continues to have long-lasting effects years after the ban was instated. Centering family reunification within the United States Refugee Admissions Program and tailoring interventions through the healthcare and public health systems are warranted to reduce hypertension disparities in this growing and overlooked population. [ABSTRACT FROM AUTHOR]

Background: The clinical burden of Long COVID, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and other post-infectious fatiguing illnesses (PIFI) is increasing. There is a critical need to advance understanding of the effectiveness and sustainability of innovative approaches to clinical care of patients having these conditions. Methods: We aim to assess the effectiveness of a Long COVID and Fatiguing Illness Recovery Program (LC&FIRP) in a two-arm, single-blind, pragmatic, quality improvement, professional cluster, randomized controlled trial in which 20 consenting clinicians across primary care clinics in a Federally Qualified Health Center system in San Diego, CA, will be randomized at a ratio of 1:1 to either participate in (1) weekly multi-disciplinary team-based case consultation and peer-to-peer sharing of emerging best practices (i.e., teleECHO (Extension for Community Healthcare Outcomes)) with monthly interactive webinars and quarterly short courses or (2) monthly interactive webinars and quarterly short courses alone (a control group); 856 patients will be assigned to participating clinicians (42 patients per clinician). Patient outcomes will be evaluated according to the study arm of their respective clinicians. Quantitative and qualitative outcomes will be measured at 3- and 6-months post-baseline for clinicians and every 3-months post assignment to a participating clinician for patients. The primary patient outcome is change in physical function measured using the Patient-Reported Outcomes Measurement Information System (PROMIS)-29. Analyses of differences in outcomes at both the patient and clinician levels will include a linear mixed model to compare change in outcomes from baseline to each post-baseline assessment between the randomized study arms. A concurrent prospective cohort study will compare the LC&FIRP patient population to the population enrolled in a university health system. Longitudinal data analysis approaches will allow us to examine differences in outcomes between cohorts. Discussion: We hypothesize that weekly teleECHO sessions with monthly interactive webinars and quarterly short courses will significantly improve clinician- and patient-level outcomes compared to the control group. This study will provide much needed evidence on the effectiveness of a technology-enabled multi-disciplinary team-based care model for the management of Long COVID, ME/CFS, and other PIFI within a federally qualified health center. Trial registration: ClinicalTrials.gov, NCT05167227. Registered on December 22, 2021. [ABSTRACT FROM AUTHOR]

Over the last decade, the zebrafish has emerged as an important model organism for behavioural studies and neurological disorders, as well as for the study of metabolic diseases. This makes zebrafish an alternative model for studying the effects of energy disruption and nutritional quality on a wide range of behavioural aspects. Here, we used the zebrafish model to study how obesity induced by overfeeding regulates emotional and cognitive processes. Two groups of fish (n = 24 per group) were fed at 2% (CTRL) and 8% (overfeeding-induced obesity, OIO) for 8 weeks and tested for anxiety-like behaviour using the novel tank diving test (NTDT). Fish were first tested using a short-term memory test (STM) and then trained for four days for a long-term memory test (LTM). At the end of the experiment, fish were euthanised for biometric sampling, total lipid content, and triglyceride analysis. In addition, brains (eight per treatment) were dissected for HPLC determination of monoamines. Overfeeding induced faster growth and obesity, as indicated by increased total lipid content. OIO had no effect on anxiety-like behaviour. Animals were then tested for cognitive function (learning and memory) using the aversive learning test in Zantiks AD units. Results show that both OIO and CTRL animals were able to associate the aversive stimulus with the conditioned stimulus (conditioned learning), but OIO impaired STM regardless of fish sex, revealing the effects of obesity on cognitive processes in zebrafish. Obese fish did not show a deficiency in monoaminergic transmission, as revealed by quantification of total brain levels of dopamine and serotonin and their metabolites. This provides a reliable protocol for assessing the effect of metabolic disease on cognitive and behavioural function, supporting zebrafish as a model for behavioural and cognitive neuroscience. [ABSTRACT FROM AUTHOR]