Miracle-dz/UniFAR-FTUs huggingface dataset:
A scintillation dosimeter with real‐time positional tracking information for in vivo dosimetry error detection in HDR brachytherapy

Abstract Purpose To evaluate the performance of an electromagnetic (EM)‐tracked scintillation dosimeter in detecting source positional errors of IVD in HDR brachytherapy treatment. Materials and Methods Two different scintillator dosimeter prototypes were coupled to 5 degrees‐of‐freedom (DOF) EM sensors read by an Aurora V3 system. The scintillators used were a 0.3 × 0.4 × 0.4 mm3 ZnSe:O and a BCF‐60 plastic scintillator of 0.5 mm diameter and 2.0 mm in length (Saint‐Gobain Crystals). The sensors were placed at the dosimeter's tip at 20.0 mm from the scintillator. The EM sampling rate was 40/s while the scintillator signal was sampled at 100 000/s using two photomultiplier tubes from Hamamatsu (series H10722) connected to a data acquisition board. A high‐pass filter and a low‐pass filter were used to separate the light signal into two different channels. All measurements were performed with an afterloader unit (Flexitron‐Elekta AB, Sweden) in full‐scattered (TG43) conditions. EM tracking was further used to provide distance/angle‐dependent energy correction for the ZnSe:O inorganic scintillator. For the error detection part, lateral shifts of 0.5 to 3 mm were induced by moving the source away from its planned position. Indexer length (longitudinal) errors between 0.5 to 10 mm were also introduced. The measured dose rate difference was converted to a shift distance, with and without using the positional information from the EM sensor. Results The inorganic scintillator had both a signal‐to‐noise‐ratio (SNR) and signal‐to‐background‐ratio (SBR) close to 70 times higher than those of the plastic scintillator. The mean absolute difference from the dose measurement to the dose calculated with TG‐43U1 was 1.5% ±0.7%. The mean absolute error for BCF‐60 detector was 1.7% ±1.2% when compared to TG‐43 calculations formalism. With the inorganic scintillator and EM tracking, a maximum area under the curve (AUC) gain of 24.0% was obtained for a 0.5‐mm lateral shift when using the EMT data with the ZnSe:O. Lower AUC gains were obtained for a 3‐mm lateral shifts with both scintillators. For the plastic scintillator, the highest gain from using EM tracking information occurred for a 0.5‐mm lateral shift at 20 mm from the source. The maximal gain (17.4%) for longitudinal errors was found at the smallest shifts (0.5 mm). Conclusions This work demonstrates that integrating EM tracking to in vivo scintillation dosimeters enables the detection of smaller shifts, by decreasing the dosimeter positioning uncertainty. It also serves to perform position‐dependent energy correction for the inorganic scintillator,providing better SNR and SBR, allowing detection of errors at greater distances from the source.
Executive Functions in a Population of Individuals with CHARGE Syndrome: Findings from Performance-Based and Rating Scale Measures According to a 3-Factor Model

ABSTRACT Purpose To identify possible predictors of executive functions of individuals with CHARGE syndrome, as these will be important targets for interventions. Methods A population-based cross-sectional study investigating the executive functions of a representative sample of 35 Norwegians with CHARGE syndrome divided into two subgroups to handle their inherent heterogeneity. Both performance-based measures and rating scale findings were included and organized according to the 3-factor model of Miyake and colleagues. Results Both measures showed comprehensive executive dysfunctions within the population, which were largely unrelated to deafblindness. Working memory stood out as a strength within the executive domain and the only factor presenting results within the normal range. Verbal working memory was a particular cognitive resource for participants with deafblindness, and, unlike those without deafblindness, unrelated to sensorimotor functions. Conclusions Individuals with CHARGE syndrome appear to be at risk for underdeveloped executive functions due to neurogenetic and environmental factors. Performance-based measures and ratings from caregivers gave unique and complementary knowledge and implied the need of both when investigating executive functioning in CHARGE syndrome. Participants with deafblindness presented strong verbal working memory despite their auditory impairments, indicating effective compensatory mechanisms The results also indicated an untapped cognitive potential in both subgroups. Because of their relatively advanced working memory significantly correlating with global cognition, the environment should assume equal learning potential of individuals with CHARGE syndrome regardless of their degree of sensory impairments.
Piperacetazine Directly Binds to the PAX3::FOXO1 Fusion Protein and Inhibits Its Transcriptional Activity

Abstract The tumor-specific chromosomal translocation product, PAX3::FOXO1, is an aberrant fusion protein that plays a key role for oncogenesis in the alveolar subtype of rhabdomyosarcoma (RMS). PAX3::FOXO1 represents a validated molecular target for alveolar RMS and successful inhibition of its oncogenic activity is likely to have significant clinical applications. Even though several PAX3::FOXO1 function-based screening studies have been successfully completed, a directly binding small-molecule inhibitor of PAX3::FOXO1 has not been reported. Therefore, we screened small-molecule libraries to identify compounds that were capable of directly binding to PAX3::FOXO1 protein using surface plasmon resonance technology. Compounds that directly bound to PAX3::FOXO1 were further evaluated in secondary transcriptional activation assays. We discovered that piperacetazine can directly bind to PAX3::FOXO1 protein and inhibit fusion protein-derived transcription in multiple alveolar RMS cell lines. Piperacetazine inhibited anchorage-independent growth of fusion-positive alveolar RMS cells but not embryonal RMS cells. On the basis of our findings, piperacetazine is a molecular scaffold upon which derivatives could be developed as specific inhibitors of PAX3::FOXO1. These novel inhibitors could potentially be evaluated in future clinical trials for recurrent or metastatic alveolar RMS as novel targeted therapy options. Significance: RMS is a malignant soft-tissue tumor mainly affecting the pediatric population. A subgroup of RMS with worse prognosis harbors a unique chromosomal translocation creating an oncogenic fusion protein, PAX3::FOXO1. We identified piperacetazine as a direct inhibitor of PAX3::FOXO1, which may provide a scaffold for designing RMS-specific targeted therapy.
Microvascular dysfunction in women with a history of hypertensive disorders of pregnancy: A population-based retrospective cohort study.

OBJECTIVE To evaluate microvascular function in women with previous hypertensive disorders of pregnancy (HDP). DESIGN Retrospective population-based cohort study. SETTING Linköping, Sweden. POPULATION Women aged 50-65 years, participating in the Swedish CArdioPulmonary bioImage Study (SCAPIS) at one site (Linköping) 2016-18, who underwent microcirculatory assessment (N = 1222). METHODS Forearm skin comprehensive microcirculatory assessment was performed with a PeriFlux PF6000 EPOS (Enhanced Perfusion and Oxygen Saturation) system measuring oxygen saturation and total speed resolved perfusion. Obstetric records were reviewed to identify women with previous HDP. Data on cardiovascular risk factors, comorbidities, medication, lifestyle, anthropometric data, and biochemical analyses were obtained from SCAPIS. The microcirculatory data were compared between women with and without previous HDP. MAIN OUTCOME MEASURES Skin microcirculatory oxygen saturation and total speed resolved perfusion at baseline and post-ischaemic peak. RESULTS Women with previous pre-eclampsia displayed impaired post-ischaemic peak oxygen saturation compared with women with normotensive pregnancies (88%, interquartile range [IQR] 84-89% vs 91%, IQR 87-94%, p = 0.001) 6-30 years after pregnancy. The difference remained after multivariable adjustment (β -2.69, 95% CI -4.93 to -0.45). CONCLUSIONS The findings reveal microvascular dysfunction at long-term follow up in women with previous pre-eclampsia and strengthen the possible role of endothelial dysfunction as a link to the increased risk of cardiovascular disease in women with HDP.
SARS‐CoV‐2 vaccine immunogenicity for people living with HIV: A systematic review and meta‐analysis

Previous publications on the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccines in people living with HIV (PLWH) have reported inconsistent results. Additionally, a meta‐analysis investigating the immunogenicity in PLWH after the third SARS‐CoV‐2 vaccine dose is lacking. In this article we aim to provide a systematic review and a meta‐analysis studying the immunogenicity of SARS‐CoV‐2 vaccines in PLWH and to identify potential drivers for antibody response in PLWH.
Using social media research in health technology assessment: stakeholder perspectives and scoping review

Abstract Objectives The aim of this initiative was to examine collaboratively, in a multi-stakeholder team (health technology assessment (HTA) practitioners with patient involvement expertise, health technology industry, patient advocates, health policy experts, patient engagement experts), whether evidence generated through social media research (SMR) fills current information gaps relating to insights on specific aspects of patient experiences, preferences, or patient needs and delivers additional value to HTA. Methods The framing of the project was done in a co-creative, deliberative multi-stakeholder process. Challenge and refinement happened through discussions with 25 independent stakeholders from HTA bodies, industry, academia, and patient advocacy. For critical themes identified during the framing phase, scoping literature reviews were performed including the state of methods and examples for the use of SMR in HTA. Results The framing and stakeholder discussions specified a set of expectations and requirements, and the scoping reviews revealed the current state of methods and usage of SMR in health-policy decision making. Conclusions The project concluded that SMR can contribute new, relevant evidence to HTA. It is however recommended to evolve the science through defining best practices when planning, conducting, and using SMR and to conduct multi-stakeholder pilot SMR projects to address questions relevant to current HTAs and to validate and improve the proposed practices.
Changes in Self-Reported and Device-Measured Physical Activity Before Abdominal Resection Surgery: A Meta-Analysis

Objective To determine the effect of interventions on physical activity levels of patients awaiting abdominal resection surgery using self-reported as well as device-measured outcome measures. Data source PubMed and EMBASE databases were searched on the 18th of April 2023 up to April 2023 for studies on interventions to promote physical activity during the preoperative phase. Review methods Studies were included if pre- and post-intervention physical activity was measured between diagnosis and abdominal surgery. Risk of bias was assessed by the Physiotherapy Evidence Database (PEDro) assessment tool for trials. Meta-analyses were performed to assess the effect of the pre-surgery activity promoting interventions on self-reported and device-measured physical activity. Results Seventeen studies were included in the analysis with 452 subjects in the intervention groups. The random-effect meta-analysis showed a moderate improvement in intervention groups measures in pre-surgery physical activity levels compared to the baseline (SMD = 0.67, [CI = 0.30;1.03], I2 = 79%). The self-reported subgroup meta-analysis showed the largest increase in performed physical activity, (SMD = 0.78, [CI = 0.4;1.15], I2 = 79%) whilst non-significant increase was shown in the device-measured subgroup (SMD = 0.16, [CI = −0.64;0.97], I2 = 58%). Conclusion Increasing physical activity in the preoperative phase is feasible. Self-reported physical activity outcome measures show larger effects compared to device-measured outcome measures. More high-quality research should be performed utilizing objective measures.
Exploring the “misfolding problem” by systematic discovery and analysis of functional-but-degraded proteins

In both health and disease, the ubiquitin–proteasome system (UPS) degrades point mutants that retain partial function but have decreased stability compared with their wild-type counterparts. This class of UPS substrate includes routine translational errors and numerous human disease alleles, such as the most common cause of cystic fibrosis, ΔF508-CFTR. Yet, there is no systematic way to discover novel examples of these “minimally misfolded” substrates. To address that shortcoming, we designed a genetic screen to isolate functional-but-degraded point mutants, and we used the screen to study soluble, monomeric proteins with known structures. These simple parent proteins yielded diverse substrates, allowing us to investigate the structural features, cytotoxicity, and small-molecule regulation of minimal misfolding. Our screen can support numerous lines of inquiry, and it provides broad access to a class of poorly understood but biomedically critical quality-control substrates.
Ascertainment and Statistical Issues for Randomized Trials of Cardiovascular Interventions for Cognitive Impairment and Dementia

There has been considerable progress in the prevention and treatment of cardiovascular disease, reducing the population burden of cardiovascular morbidity and mortality. Recently, some randomized trials, including the SPRINT (Systolic Blood Pressure Intervention Trial), have suggested that improvements in cardiovascular risk factors may also slow cognitive decline and reduce the eventual development of dementia. Unfortunately, the randomized trial template that has been used repeatedly to successfully demonstrate reductions in major adverse cardiac events faces several design and analytic obstacles when applied in the context of cognitive decline and dementia. Here, we review these obstacles, motivated by SPRINT and the context of selecting an appropriate cognitive end point for future preventive randomized trials. A few options are available, spanning neuropsychological test scores or composites reflecting specific domains of cognitive function, adjudicated cognitive impairment, or potentially physiological biomarkers. This choice entails considerations around statistical power, modes of ascertainment, the clinical relevance of treatment effects, a myriad of statistical issues (interval censoring, missing data, the competing risk of death, practice effects, etc), as well as ethical considerations around equipoise. Collectively, these considerations indicate that trials aiming to mitigate the cardiovascular contribution to cognitive decline and dementia will generally need to be large, inclusive of a wide age range of older adults, and with multiple years of follow-up.
degQ associated with the degS/degU two‐component system regulates biofilm formation, antimicrobial metabolite production, and biocontrol activity in Bacillus velezensis DMW1

Abstract The gram‐positive bacterium Bacillus velezensis strain DMW1 produces a high level of antimicrobial metabolites that can suppress the growth of phytopathogens. We investigated the mechanism used by degQ and the degS/degU two‐component system to regulate the biocontrol characteristics of DMW1. When degQ and degU were deleted, the biofilm formation, cell motility, colonization activities, and antifungal abilities of ΔdegQ and ΔdegU were significantly reduced compared to wild‐type DMW1. The expression levels of biofilm‐related genes (epsA, epsB, epsC, and tasA) and swarming‐related genes (swrA and swrB) were all down‐regulated. We also evaluated the impact on secondary metabolites of these two genes. The degQ and degU genes reduced surfactin and macrolactin production and up‐regulated the production of fengycin, iturin, bacillaene, and difficidin metabolites. The reverse transcription‐quantitative PCR results were consistent with these observations. Electrophoretic mobility shift assay and microscale thermophoresis revealed that DegU can bind to the promoter regions of these six antimicrobial metabolite genes and regulate their synthesis. In conclusion, we provided systematic evidence to demonstrate that the degQ and degU genes are important regulators of multicellular behaviour and antimicrobial metabolic processes in B. velezensis DMW1 and suggested novel amenable strains to be used for the industrial production of antimicrobial metabolites.
Prognostic and Pharmacotypic Heterogeneity of Hyperdiploidy in Childhood ALL

PURPOSE High hyperdiploidy, the largest and favorable subtype of childhood ALL, exhibits significant biological and prognostic heterogeneity. However, factors contributing to the varied treatment response and the optimal definition of hyperdiploidy remain uncertain. METHODS We analyzed outcomes of patients treated on two consecutive frontline ALL protocols, using six different definitions of hyperdiploidy: chromosome number 51-67 (Chr51-67); DNA index (DI; DI1.16-1.6); United Kingdom ALL study group low-risk hyperdiploid, either trisomy of chromosomes 17 and 18 or +17 or +18 in the absence of +5 and +20; single trisomy of chromosome 18; double trisomy of chromosomes 4 and 10; and triple trisomy (TT) of chromosomes 4, 10, and 17. Additionally, we characterized ALL ex vivo pharmacotypes across eight main cytotoxic drugs. RESULTS Among 1,096 patients analyzed, 915 had B-ALL and 634 had pharmacotyping performed. In univariate analysis, TT emerged as the most favorable criterion for event-free survival (EFS; 10-year EFS, 97.3% v 86.8%; P = .0003) and cumulative incidence of relapse (CIR; 10-year CIR, 1.4% v 8.8%; P = .002) compared with the remaining B-ALL. In multivariable analysis, accounting for patient numbers using the akaike information criterion (AIC), DI1.16-1.6 was the most favorable criterion, exhibiting the best AIC for both EFS (hazard ratio [HR], 0.45; 95% CI, 0.23 to 0.88) and CIR (HR, 0.45; 95% CI, 0.21 to 0.99). Hyperdiploidy and subgroups with favorable prognoses exhibited notable sensitivities to asparaginase and mercaptopurine. Specifically, asparaginase sensitivity was associated with trisomy of chromosomes 16 and 17, whereas mercaptopurine sensitivity was linked to gains of chromosomes 14 and 17. CONCLUSION Among different definitions of hyperdiploid ALL, DI is optimal based on independent prognostic impact and also the large proportion of low-risk patients identified. Hyperdiploid ALL exhibited particular sensitivities to asparaginase and mercaptopurine, with chromosome-specific associations. We assessed survival outcomes and drug sensitivities across various definitions of hyperdiploidy in childhood ALL.
Modulation of Neuroinflammation: Advances in Roles and Mechanisms of the IL-33/ST2 Axis Involved in Ischemic Stroke

Interleukin (IL)-33 was initially recognized as a constituent of the IL-1 cytokine family in 2005. It exerts pleiotropic effects by regulating immune responses via its binding to the receptor ST2 (IL-33R). The IL-33/ST2 pathway has been linked to several inflammatory disorders. In human and rodents, the broad expression of IL-33 in spinal cord tissues and brain indicates its central nervous system-specific functions. Growing evidence supports the protective effects of the IL-33/ST2 pathway in ischemic stroke, along with a better understanding of the underlying mechanisms. IL-33 plays a crucial role in the regulation of the release of inflammatory molecules from glial cells in response to neuropathological lesions. Moreover, IL-33/ST2-mediated neuroprotection following cerebral ischemia may be linked to T-cell function, specifically regulatory T cells. Soluble ST2 (sST2) acts as a decoy receptor in the IL-33/ST2 axis, blocking IL-33 signaling through the membrane ST2 receptor. sST2 has also been identified as a potential inflammatory biomarker of ischemic stroke. Targeting sST2 specifically to eliminate its inhibition of the protective IL-33/ST2 pathway in ischemic brain tissues is a promising approach for the treatment of ischemic stroke.
Effects of short‐term supervised exercise training on liver fat in adolescents with obesity: a randomized controlled trial

The objective of this study was to quantify the effects of a 4‐week, supervised, high‐intensity interval training (HIIT) on intrahepatic triglyceride content (IHTG, percentage), cardiorespiratory fitness (CRF), and cardiometabolic markers in adolescents with obesity.
Effects of epicatechin on cardiovascular function in middle-aged diet-induced obese rat models of metabolic syndrome

The current study aimed to investigate the cardiovascular effects of epicatechin, a flavonoid found in green tea and cocoa, in attenuating complications associated with metabolic syndrome in diet-induced obese rats. Male Wistar-Kyoto (WKY) rats aged 16 weeks were fed either standard rat chow or given a high-fat-high-carbohydrate (HFHC) diet for 20 weeks. Epicatechin treatment (5 mg/kg/d) was administered to a subset of WKY rats commencing at week 8 of the 20 week HFHC feeding period. Body weights, food, water and energy intakes, blood pressure, heart rate and glucose tolerance were measured throughout the treatment period. Oxidative stress and inflammatory markers, lipid levels, cardiac collagen deposition, cardiac electrical function, aortic and mesenteric vessel reactivity were examined after the treatment. Twenty weeks of HFHC feeding in WKY rats resulted in the development of metabolic syndrome indicated by the presence of abdominal obesity, dyslipidaemia, glucose intolerance and increased blood pressure. Epicatechin treatment was found to enhance the oxidative stress status in HFHC groups through an increase in serum nitric oxide levels and a decrease in 8-isoprostane concentrations. Furthermore, WKY-HFHC rats displayed a decrease in IL-6 levels. The lipid profiles in HFHC groups showed improvement, with a decrease in LDL-cholesterol and TAG and an increase in HDL-cholesterol levels observed in WKY-HFHC rats. However, epicatechin was not effective in preventing weight gain, glucose intolerance or hypertension in HFHC fed rats. Overall, the results of this study suggest that epicatechin has the potential to improve the underlying mechanisms associated with metabolic syndrome in obese rats.