Health care resource use in preschool children with cerebral palsy.

AIM: To estimate the burden of disease and evaluate which factors affect health care resource use (HCRU) in young children with cerebral palsy (CP). METHOD: Data were collected as part of a prospective, longitudinal cohort study of children with CP born in Queensland, Australia between 2006 and 2009. HCRU questionnaires were administered at six time points. Data on resource use, socio-demographics, and disease severity were collected. Costs were sourced from Medicare, the Australian National Hospital Cost Data Collection, and market prices. A generalized linear model was used to identify factors influencing CP-related costs. RESULTS: A total of 794 questionnaires were completed by 222 participants (mean = 3.6 per participant). Physiotherapy (94%, n = 208) was the most widely accessed allied health care therapy; almost half of the participants (45%; 354 of 794) reported one or more hospital admissions. From the health care funder perspective, a child with CP costs on average A$24 950 per annum (A$12 475 per 6 months). Higher costs were associated with increased motor impairment (Gross Motor Function Classification System, p < 0.001) and increased comorbidities (p = 0.012). INTERPRETATION: HCRU in preschool children with CP can be analysed according to disease severity. Both increased motor impairments and increased comorbidities were associated with higher health care costs.

State of the Art in Low-Grade Glioma Management: Insights From Isocitrate Dehydrogenase and Beyond.

Low-grade gliomas present a formidable challenge in neuro-oncology because of the challenges imposed by the blood-brain barrier, predilection for the young adult population, and propensity for recurrence. In the past two decades, the systematic examination of genomic alterations in adults and children with primary brain tumors has uncovered profound new insights into the pathogenesis of these tumors, resulting in more accurate tumor classification and prognostication. It also identified several common recurrent genomic alterations that now define specific brain tumor subtypes and have provided a new opportunity for molecularly targeted therapeutic intervention. Adult-type diffuse low-grade gliomas are frequently associated with mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), resulting in production of 2-hydroxyglutarate, an oncometabolite important for tumorigenesis. Recent studies of IDH inhibitors have yielded promising results in patients at early stages of disease with prolonged progression-free survival (PFS) and delayed time to radiation and chemotherapy. Pediatric-type gliomas have high rates of alterations in BRAF, including BRAF V600E point mutations or BRAF-KIAA1549 rearrangements. BRAF inhibitors, often combined with MEK inhibitors, have resulted in radiographic response and improved PFS in these patients. This article reviews emerging approaches to the treatment of low-grade gliomas, including a discussion of targeted therapies and how they integrate with the current treatment modalities of surgical resection, chemotherapy, and radiation.

Inelastic scattering of NO(A2Σ+) + CO2: rotation-rotation pair-correlated differential cross sections.

A crossed beam velocity-map ion-imaging apparatus has been used to determine differential cross sections (DCSs) for the rotationally inelastic scattering of NO(A2Σ+, v = 0, j = 0.5) with CO2, as a function of both NO(A, v = 0, N') final state and the coincident final rotational energy of the CO2. The DCSs are dominated by forward-peaked scattering for all N', with significant rotational excitation of CO2, and a small backward scattered peak is also observed for all final N'. However, no rotational rainbow scattering is observed and there is no evidence for significant product rotational angular momentum polarization. New ab initio potential energy surface calculations at the PNO-CCSD(T)-F12b level of theory report strong attractive forces at long ranges with significant anisotropy relative to both NO and CO2. The absence of rotational rainbow scattering is consistent with removal of low-impact-parameter collisions via electronic quenching, in agreement with the literature quenching rates of NO(A) by CO2 and recent electronic structure calculations. We propose that high-impact-parameter collisions, that do not lead to quenching, experience strong anisotropic attractive forces that lead to significant rotational excitation in both NO and CO2, depolarizing product angular momentum while leading to forward and backward glory scattering.

Geriatric proximal femur fracture updates.

Proximal femur fractures in the aging population present a variety of challenges. Physiologically, patients incurring this fracture are typically frail, with significant medical comorbidities, yet require early surgical treatment to restore mobility to prevent deterioration. Socioeconomically, the occurrence of a fragility fracture may be the beginning of the loss of independence, and the burdens of rehabilitation and support are borne by the individual patient and health care systems.

Robustness and classification capabilities of MRI radiomic features in identifying carotid plaque vulnerability.

OBJECTIVES: To assess how radiomic features may be combined with plaque morphological and compositional features identified by multi-contrast magnetic resonance imaging (MRI) to improve upon conventional risk assessment models in determining culprit lesions. METHODS: Fifty-five patients (mean age: 62.6; 35 males) with bilateral carotid stenosis who experienced transient ischaemic attack (TIA) or stroke were included from the CARE-II multi-centre carotid imaging trial (ClinicalTrials.gov Identifier: NCT02017756). They underwent MRI within 2 weeks of the event. Classification capability in distinguishing culprit lesions was assessed by machine learning. Repeatability and reproducibility of the results were investigated by assessing the robustness of the radiomic features. RESULTS: Radiomics combined with a relatively conventional plaque morphological and compositional metric-based model provided incremental value over a conventional model alone [area under curve (AUC), 0.819 ± 0.002 vs. 0.689 ± 0.019 respectively, p = 0.014]. The radiomic model alone also provided value over the conventional model [AUC, 0.805 ± 0.003 vs. 0.689 ± 0.019 respectively, p = 0.031]. T2-weighted imaging-based radiomic features had consistently higher robustness and classification capabilities compared with T1-weighted images. Higher-dimensional radiomic features outperformed first-order features. Grey Level Co-occurrence Matrix (GLCM), Grey Level Dependence Matrix (GLDM) and Grey Level Size Zone Matrix (GLSZM) sub-types were particularly useful in identifying textures which could detect vulnerable lesions. CONCLUSIONS: The combination of MRI-based radiomic features and lesion morphological and compositional parameters provided added value to the reference-standard risk assessment for carotid atherosclerosis. This may improve future risk stratification for individuals at risk of major adverse ischemic cerebrovascular events.

Altering biomolecular condensates as a potential mechanism that mediates cannabidiol effect on glioblastoma.

Glioblastoma (GBM) is an extremely aggressive primary brain tumor with poor prognosis, short survival time post-diagnosis and high recurrence. Currently, no cure for GBM exists. The identification of an effective therapeutic modality for GBM remains a high priority amongst medical professionals and researches. In recent studies, inhalant cannabidiol (CBD) has demonstrated promise in effectively inhibiting GBM tumor growth. However, exactly how CBD treatment affects the physiology of these tumor cells remains unclear. Stress granules (SG) (a sub-class of biomolecular condensates (BMC)) are dynamic, membrane-less intracellular microstructures which contain proteins and nucleic acids. The formation and signaling of SGs and BMCs plays a significant role in regulating malignancies. This study investigates whether inhaled CBD may play an intervening role towards SGs in GBM tumor cells. Integrated bioinformatics approaches were preformed to gain further insights. This includes use of Immunohistochemistry and flow cytometry to measure SGs, as well as expression and phosphorylation of eukaryotic initiation factor-2α (eIF2α). The findings of this study reveal that CBD receptors (and co-regulated genes) have the potential to play an important biological role in the formation of BMCs within GBM. In this experiment, CBD treatment significantly increased the volume of TIAR-1. This increase directly correlated with elevation in both eIF2α expression and p-eIF2α in CBD treated tissues in comparison to the placebo group (p < 0.05). These results suggest that inhalant CBD significantly up-regulated SGs in GBM, and thus support a theory of targeting BMCs as a potential therapeutic substrate for treating GBM.

Retinal small vessel pathology is associated with disease burden in multiple sclerosis.

BACKGROUND: Alterations of the superficial retinal vasculature are commonly observed in multiple sclerosis (MS) and can be visualized through optical coherence tomography angiography (OCTA). OBJECTIVES: This study aimed to examine changes in the retinal vasculature during MS and to integrate findings into current concepts of the underlying pathology. METHODS: In this cross-sectional study, including 259 relapsing-remitting MS patients and 78 healthy controls, we analyzed OCTAs using deep-learning-based segmentation algorithm tools. RESULTS: We identified a loss of small-sized vessels (diameter < 10 µm) in the superficial vascular complex in all MS eyes, irrespective of their optic neuritis (ON) history. This alteration was associated with MS disease burden and appears independent of retinal ganglion cell loss. In contrast, an observed reduction of medium-sized vessels (diameter 10-20 µm) was specific to eyes with a history of ON and was closely linked to ganglion cell atrophy. CONCLUSION: These findings suggest distinct atrophy patterns in retinal vessels in patients with MS. Further studies are necessary to investigate retinal vessel alterations and their underlying pathology in MS.

Molecular adaptations in response to exercise training are associated with tissue-specific transcriptomic and epigenomic signatures.

Regular exercise has many physical and brain health benefits, yet the molecular mechanisms mediating exercise effects across tissues remain poorly understood. Here we analyzed 400 high-quality DNA methylation, ATAC-seq, and RNA-seq datasets from eight tissues from control and endurance exercise-trained (EET) rats. Integration of baseline datasets mapped the gene location dependence of epigenetic control features and identified differing regulatory landscapes in each tissue. The transcriptional responses to 8 weeks of EET showed little overlap across tissues and predominantly comprised tissue-type enriched genes. We identified sex differences in the transcriptomic and epigenomic changes induced by EET. However, the sex-biased gene responses were linked to shared signaling pathways. We found that many G protein-coupled receptor-encoding genes are regulated by EET, suggesting a role for these receptors in mediating the molecular adaptations to training across tissues. Our findings provide new insights into the mechanisms underlying EET-induced health benefits across organs.

Measuring Electrical Resistivity at the Nanoscale in Phase-Change Materials.

Electrical resistivity is the key parameter in the active regions of many current nanoscale devices, from memristors to resistive random-access memory and phase-change memories. The local resistivity of the materials is engineered on the nanoscale to fit the performance requirements. Phase-change memories, for example, rely on materials whose electrical resistance increases dramatically with a change from a crystalline to an amorphous phase. Electrical characterization methods have been developed to measure the response of individual devices, but they cannot map the local resistance across the active area. Here, we propose a method based on operando electron holography to determine the local resistance within working devices. Upon switching the device, we show that electrical resistance is inhomogeneous on the scale of only a few nanometers.

Long-acting intramuscular injections of ELQ-331, an antimalarial agent.

The overarching premise of this investigation is that injectable, long-acting antimalarial medication would encourage adherence to a dosage regimen for populations at risk of contracting the disease. To advance support for this goal, we have developed oil-based formulations of ELQ-331 (a prodrug of ELQ-300) that perform as long-acting, injectable chemoprophylactics with drug loading as high as 160 mg/ml of ELQ-331. In a pharmacokinetic study performed with rats, a single intramuscular injection of 12.14 mg/kg maintained higher plasma levels than the previously established minimum fully protective plasma concentration (33.25 ng/ml) of ELQ-300 for more than 4 weeks. The formulations were well tolerated by the rats and the tested dose produced no adverse reactions. We believe that by extending the length of time between subsequent injections, these injectable oil-based solutions of ELQ-331 can offer a more accessible, low-cost option for long-acting disease prevention and reduced transmission in malaria-endemic regions and may also be of use to travelers.

Comparative microplastic analysis in urban waters using µ-FTIR and Py-GC-MS: A case study in Amsterdam.

The contamination of freshwater with microplastics (MPs) has been established globally. While the analysis of MPs has predominantly involved spectroscopic methods for revealing particle numbers, the potential of employing spectroscopy for mass estimation has been underutilized. Consequently, there is a need to enhance our understanding of the mass loads of MPs and ensure the complementarity and comparability of various techniques for accurate quantification. This study presents the first comparative results on urban water samples using micro Fourier-transform infrared (µ-FTIR) imaging and pyrolysis-gas chromatography-mass spectrometry (Py-GC-MS) to identify and quantify MPs in both particle numbers and mass concentration. Two sampling campaigns in summer and winter were conducted at 11 locations within the Amsterdam canal network. An advanced in-situ volume-reducing sampling pump was employed to collect MPs from the surface water within the size fraction of 10-300 µm. The analysis revealed MP concentrations within the range of 16-107 MP/m3, estimated to be 2.0-789 µg/m3 by µ-FTIR imaging and 8.5-754 µg/m3 by Py-GC-MS. The results of the two analysis techniques showed good comparability in terms of the general trends of MP abundances, with variations in polymer compositions due to the inherent inter-methodological differences. Elevated MP concentrations were observed in the city center compared to the suburban areas. In addition, seasonal differences in MP abundances were noted at the locations with high human activity.

Structural basis of chemokine recognition by the class A3 tick evasin EVA-ACA1001.

Ticks produce chemokine-binding proteins, known as evasins, in their saliva to subvert the host's immune response. Evasins bind to chemokines and thereby inhibit the activation of their cognate chemokine receptors, thus suppressing leukocyte recruitment and inflammation. We recently described subclass A3 evasins, which, like other class A evasins, exclusively target CC chemokines but appear to use a different binding site architecture to control target selectivity among CC chemokines. We now describe the structural basis of chemokine recognition by the class A3 evasin EVA-ACA1001. EVA-ACA1001 binds to almost all human CC chemokines and inhibits receptor activation. Truncation mutants of EVA-ACA1001 showed that, unlike class A1 evasins, both the N- and C-termini of EVA-ACA1001 play minimal roles in chemokine binding. To understand the structural basis of its broad chemokine recognition, we determined the crystal structure of EVA-ACA1001 in complex with the human chemokine CCL16. EVA-ACA1001 forms backbone-backbone interactions with the CC motif of CCL16, a conserved feature of all class A evasin-chemokine complexes. A hydrophobic pocket in EVA-ACA1001, formed by several aromatic side chains and the unique disulfide bond of class A3 evasins, accommodates the residue immediately following the CC motif (the "CC + 1 residue") of CCL16. This interaction is shared with EVA-AAM1001, the only other class A3 evasins characterized to date, suggesting it may represent a common mechanism that accounts for the broad recognition of CC chemokines by class A3 evasins.

ForCEPSS-A framework for cardiac electrophysiology simulations standardization.

BACKGROUND AND OBJECTIVE: Simulation of cardiac electrophysiology (CEP) is an important research tool that is increasingly being adopted in industrial and clinical applications. Typical workflows for CEP simulation consist of a sequence of processing stages starting with building an anatomical model and then calibrating its electrophysiological properties to match observable data. While the calibration stages are common and generalizable, most CEP studies re-implement these steps in complex and highly variable workflows. This lack of standardization renders the execution of computational CEP studies in an efficient, robust, and reproducible manner a significant challenge. Here, we propose ForCEPSS as an efficient and robust, yet flexible, software framework for standardizing CEP simulation studies. METHODS AND RESULTS: Key processing stages of CEP simulation studies are identified and implemented in a standardized workflow that builds on openCARP1 Plank et al. (2021) and the Python-based carputils2 framework. Stages include (i) the definition and initialization of action potential phenotypes, (ii) the tissue scale calibration of conduction properties, (iii) the functional initialization to approximate a limit cycle corresponding to the dynamic reference state according to an experimental protocol, and, (iv) the execution of the CEP study where the electrophysiological response to a perturbation of the limit cycle is probed. As an exemplar application, we employ ForCEPSS to prepare a CEP study according to the Virtual Arrhythmia Risk Prediction protocol used for investigating the arrhythmogenic risk of developing infarct-related ventricular tachycardia (VT) in ischemic cardiomyopathy patients. We demonstrate that ForCEPSS enables a fully automated execution of all stages of this complex protocol. CONCLUSION: ForCEPSS offers a novel comprehensive, standardized, and automated CEP simulation workflow. The high degree of automation accelerates the execution of CEP simulation studies, reduces errors, improves robustness, and makes CEP studies reproducible. Verification of simulation studies within the CEP modeling community is thus possible. As such, ForCEPSS makes an important contribution towards increasing transparency, standardization, and reproducibility of in silico CEP experiments.

The development of brain metastases in patients with different therapeutic strategies for metastatic renal cell cancer.

A diagnosis of brain metastasis (BM) significantly affects quality of life in patients with metastatic renal cell cancer (mRCC). Although systemic treatments have shown efficacy in mRCC, active surveillance (AS) is still commonly used in clinical practice. In this single-center cohort study, we assessed the impact of different initial treatment strategies for metastatic RCC (mRCC) on the development of BM. All consecutive patients diagnosed with mRCC between 2011 and 2022 were included at the Erasmus MC Cancer Institute, the Netherlands, and a subgroup of patients with BM was selected. In total, 381 patients with mRCC (ECM, BM, or both) were identified. Forty-six patients had BM of whom 39 had metachronous BM (diagnosed ≥1 month after ECM). Twenty-five (64.1%) of these 39 patients with metachronous BM had received prior systemic treatment for ECM and 14 (35.9%) patients were treatment naive at BM diagnosis. The median BM-free survival since ECM diagnosis was significantly longer (p = .02) in previously treated patients (29.0 [IQR 12.6-57.0] months) compared to treatment naive patients (6.8 [IQR 1.0-7.0] months). In conclusion, patients with mRCC who received systemic treatment for ECM prior to BM diagnosis had a longer BM-free survival as compared to treatment naïve patients. These results emphasize the need for careful evaluation of treatment strategies, and especially AS, for patients with mRCC.

Interactions of the Immune System with Human Kidney Organoids.

Kidney organoids are an innovative tool in transplantation research. The aim of the present study was to investigate whether kidney organoids are susceptible for allo-immune attack and whether they can be used as a model to study allo-immunity in kidney transplantation. Human induced pluripotent stem cell-derived kidney organoids were co-cultured with human peripheral blood mononuclear cells (PBMC), which resulted in invasion of allogeneic T-cells around nephron structures and macrophages in the stromal cell compartment of the organoids. This process was associated with the induction of fibrosis. Subcutaneous implantation of kidney organoids in immune-deficient mice followed by adoptive transfer of human PBMC led to the invasion of diverse T-cell subsets. Single cell transcriptomic analysis revealed that stromal cells in the organoids upregulated expression of immune response genes upon immune cell invasion. Moreover, immune regulatory PD-L1 protein was elevated in epithelial cells while genes related to nephron differentiation and function were downregulated. This study characterized the interaction between immune cells and kidney organoids, which will advance the use of kidney organoids for transplantation research.

High SARS-CoV-2 incidence and asymptomatic fraction during Delta and Omicron BA.1 waves in The Gambia.

Little is known about SARS-CoV-2 infection risk in African countries with high levels of infection-driven immunity and low vaccine coverage. We conducted a prospective cohort study of 349 participants from 52 households in The Gambia between March 2021 and June 2022, with routine weekly SARS-CoV-2 RT-PCR and 6-monthly SARS-CoV-2 serology. Attack rates of 45% and 57% were seen during Delta and Omicron BA.1 waves respectively. Eighty-four percent of RT-PCR-positive infections were asymptomatic. Children under 5-years had a lower incidence of infection than 18-49-year-olds. One prior SARS-CoV-2 infection reduced infection risk during the Delta wave only, with immunity from ≥2 prior infections required to reduce the risk of infection with early Omicron lineage viruses. In an African population with high levels of infection-driven immunity and low vaccine coverage, we find high attack rates during SARS-CoV-2 waves, with a high proportion of asymptomatic infections and young children remaining relatively protected from infection.

Enzyme-cargo encapsulation peptides bind between tessellating tiles of the bacterial microcompartment shell.

Bacterial microcompartments are prokaryotic organelles comprising encapsulated enzymes within a thin protein shell. They facilitate metabolic processing including propanediol, choline, glycerol, and ethanolamine utilization, and they accelerate carbon fixation in cyanobacteria. Enzymes targeted to the inside of the microcompartment frequently possess a cargo-encapsulation peptide, but the site to which the peptide binds is unclear. We provide evidence that the encapsulation peptides bind to the hydrophobic groove formed between tessellating subunits of the shell proteins. In silico docking studies provide a compelling model of peptide binding to this prominent hydrophobic groove. This result is consistent with the now widely accepted view that the convex side of the shell oligomers faces the lumen of the microcompartment. Binding of the encapsulation peptide to the groove between tessellating shell protein tiles explains why it has been difficult to define the peptide binding site using other methods, provides a mechanism by which encapsulation-peptide bearing enzymes can promote shell assembly, and explains how the presence of cargo affects the size and shape of the bacterial microcompartment. This knowledge may be exploited in engineering microcompartments or in disease prevention by hampering cargo-encapsulation.

The influence of sex, hemoglobin mass, and skeletal muscle characteristics on cycling critical power.

Critical power (CP) represents an important threshold for exercise performance and fatiguability. We sought to determine the extent to which sex, hemoglobin mass (Hbmass), and skeletal muscle characteristics influence CP. Prior to CP determination (i.e., 3-5 constant work rate trials to task failure), Hbmass and skeletal muscle oxidative capacity (τ) were measured and vastus lateralis muscle biopsy samples were collected from 12 females and 12 males matched for aerobic fitness relative to fat-free mass (mean (SD); V̇O2max: 59.2 (7.7) vs. 59.5 (7.1) mL·kg FFM-1·min-1, respectively). Males had a significantly greater CP than females in absolute units (225 (28) vs. 170 (43) W; p=0.001) but not relative to body mass (3.0 (0.6) vs. 2.7 (0.6) W·kg BM-1; p=0.267) or FFM (3.6 (0.7) vs. 3.7 (0.8) W·kg FFM-1; p=0.622). Males had significantly greater W' (p ≤ 0.030) and greater Hbmass (p ≤ 0.016) than females, regardless of the normalization approach; however, there were no differences in mitochondrial protein content (p=0.375), τ (p=0.603), or MHC I proportionality (p=0.574) between males and females. Whether it was expressed in absolute or relative units, CP was positively correlated with Hbmass (0.444≤r≤0.695; p<0.05), mitochondrial protein content (0.413≤r≤0.708; p<0.05), and MHC I proportionality (0.506≤r≤0.585; p<0.05), and negatively correlated with τ when expressed in relative units only (-0.588≤r≤-0.527; p<0.05). Overall, CP was independent of sex but variability in CP was related to Hbmass and skeletal muscle characteristics. The extent to which manipulations in these physiological parameters influence CP warrants further investigation to better understand factors underpinning CP.