Biomarker Periodic Repolarization Dynamics Indicates Enhanced Risk for Arrhythmias and Sudden Cardiac Death in Myocardial Infarction in Pigs.

BACKGROUND: Periodic repolarization dynamics (PRD) is an electrocardiographic biomarker that captures repolarization instability in the low frequency spectrum and is believed to estimate the sympathetic effect on the ventricular myocardium. High PRD indicates an increased risk for postischemic sudden cardiac death (SCD). However, a direct link between PRD and proarrhythmogenic autonomic remodeling has not yet been shown. METHODS AND RESULTS: We investigated autonomic remodeling in pigs with myocardial infarction (MI)-related ischemic heart failure induced by balloon occlusion of the left anterior descending artery (n=17) compared with pigs without MI (n=11). Thirty days after MI, pigs demonstrated enhanced sympathetic innervation in the infarct area, border zone, and remote left ventricle paralleled by altered expression of autonomic marker genes/proteins. PRD was enhanced 30 days after MI compared with baseline (pre-MI versus post-MI: 1.75±0.30 deg2 versus 3.29±0.79 deg2, P<0.05) reflecting pronounced autonomic alterations on the level of the ventricular myocardium. Pigs with MI-related ventricular fibrillation and SCD had significantly higher pre-MI PRD than pigs without tachyarrhythmias, suggesting a potential role for PRD as a predictive biomarker for ischemia-related arrhythmias (no ventricular fibrillation versus ventricular fibrillation: 1.50±0.39 deg2 versus 3.18±0.53 deg2 [P<0.05]; no SCD versus SCD: 1.67±0.32 deg2 versus 3.91±0.63 deg2 [P<0.01]). CONCLUSIONS: We demonstrate that ischemic heart failure leads to significant proarrhythmogenic autonomic remodeling. The concomitant elevation of PRD levels in pigs with ischemic heart failure and pigs with MI-related ventricular fibrillation/SCD suggests PRD as a biomarker for autonomic remodeling and as a potential predictive biomarker for ventricular arrhythmias/survival in the context of MI.

A transient in planta editing assay identifies specific binding of the splicing regulator PTB as a prerequisite for cassette exon inclusion.

The dynamic interaction of RNA-binding proteins (RBPs) with their target RNAs contributes to the diversity of ribonucleoprotein (RNP) complexes that are involved in a myriad of biological processes. Identifying the RNP components at high resolution and defining their interactions are key to understanding their regulation and function. Expressing fusions between an RBP of interest and an RNA editing enzyme can result in nucleobase changes in target RNAs, representing a recent addition to experimental approaches for profiling RBP/RNA interactions. Here, we have used the MS2 protein/RNA interaction to test four RNA editing proteins for their suitability to detect target RNAs of RBPs in planta. We have established a transient test system for fast and simple quantification of editing events and identified the hyperactive version of the catalytic domain of an adenosine deaminase (hADARcd) as the most suitable editing enzyme. Examining fusions between homologs of polypyrimidine tract binding proteins (PTBs) from Arabidopsis thaliana and hADARcd allowed determining target RNAs with high sensitivity and specificity. Moreover, almost complete editing of a splicing intermediate provided insight into the order of splicing reactions and PTB dependency of this particular splicing event. Addition of sequences for nuclear localisation of the fusion protein increased the editing efficiency, highlighting this approach's potential to identify RBP targets in a compartment-specific manner. Our studies have established the editing-based analysis of interactions between RBPs and their RNA targets in a fast and straightforward assay, offering a new system to study the intricate composition and functions of plant RNPs in vivo.

Patterns of infant fecal metabolite concentrations and social behavioral development in toddlers.

BACKGROUND: Gut-derived metabolites, products of microbial and host co-metabolism, may inform mechanisms underlying children's neurodevelopment. We investigated whether infant fecal metabolites were related to toddler social behavior. METHODS: Stool samples collected from 6-week-olds (n = 86) and 1-year-olds (n = 209) in the New Hampshire Birth Cohort Study (NHBCS) were analyzed using nuclear magnetic resonance spectroscopy metabolomics. Autism-related behavior in 3-year-olds was assessed by caregivers using the Social Responsiveness Scale (SRS-2). To assess the association between metabolites and SRS-2 scores, we used a traditional single-metabolite approach, quantitative metabolite set enrichment (QEA), and self-organizing maps (SOMs). RESULTS: Using a single-metabolite approach and QEA, no individual fecal metabolite or metabolite set at either age was associated with SRS-2 scores. Using the SOM method, fecal metabolites of six-week-olds organized into four profiles, which were unrelated to SRS-2 scores. In 1-year-olds, one of twelve fecal metabolite profiles was associated with fewer autism-related behaviors, with SRS-2 scores 3.4 (95%CI: -7, 0.2) points lower than the referent group. This profile had higher concentrations of lactate and lower concentrations of short chain fatty acids than the reference. CONCLUSIONS: We uncovered metabolic profiles in infant stool associated with subsequent social behavior, highlighting one potential mechanism by which gut bacteria may influence neurobehavior. IMPACT: Differences in host and microbial metabolism may explain variability in neurobehavioral phenotypes, but prior studies do not have consistent results. We applied three statistical techniques to explore fecal metabolite differences related to social behavior, including self-organizing maps (SOMs), a novel machine learning algorithm. A 1-year-old fecal metabolite pattern characterized by high lactate and low short-chain fatty acid concentrations, identified using SOMs, was associated with social behavior less indicative of autism spectrum disorder. Our findings suggest that social behavior may be related to metabolite profiles and that future studies may uncover novel findings by applying the SOM algorithm.

Process evaluation of an integrated community-based intervention for promoting health equity in children in a new residential development area.

BACKGROUND: Reducing health inequities for children from a disadvantaged background is an important task in public health. While intersectoral partnerships are a promising way to achieve this, few studies have examined the factors influencing the success of these interventions. In this study, we conducted a process evaluation of the integrated community-based intervention Präventionskette Freiham that the city of Munich, Germany, has implemented in a new residential development area. The aim was to investigate the implementation process as well as barriers and facilitators. METHODS: Following a mixed methods approach, we collected data from different core groups making up Präventionskette Freiham from April 2020 to August 2022, exploring their perspective on the implementation process. We conducted repeated qualitative interviews with the network coordinators and eleven local professionals from institutions engaged with or relevant for the intervention. We also undertook a focus group with four members of the advisory group representing the three municipal departments guiding the intervention. Ego-centered network maps were drawn by the network coordinators to chart the development of the network. Subsequently, we also conducted an online survey with local network members. RESULTS: At the early stage of the implementation process, the intervention was able to integrate actors from different sectors, serving as a platform for mutual exchange. However, the network produced limited output. According to the interviews, this may be mainly attributable to the early development status of the area. We identified seven topics that may act as facilitators or barriers to implementation of Präventionskette Freiham: (1) availability of resources, (2) political and administrative support, (3) the network coordinators, (4) network-internal processes, (5) trans-institutional cooperation, (6) perceived benefits of engagement, and (7) the output of the network. CONCLUSIONS: The early development status of the area was a challenge for the intervention. This emphasizes the need to carefully consider context when planning and implementing integrated community-based public health interventions in new residential development areas.

Quantified retrospective biomonitoring of fetal and infant elemental exposure using LA-ICP-MS analysis of deciduous dentin in three contrasting human cohorts.

BACKGROUND: Spatial elemental analysis of deciduous tooth dentin combined with odontochronological estimates can provide an early life (in utero to ~2 years of age) history of inorganic element exposure and status. OBJECTIVE: To demonstrate the importance of data normalization to a certified reference material to enable between-study comparisons, using populations with assumed contrasting elemental exposures. METHODS: We used laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) of dentin to derive a history of elemental composition from three distinct cohort studies: a present day rural cohort, (the New Hampshire Birth Cohort Study (NHBCS; N = 154)), an historical cohort from an urban area (1958-1970), (the St. Louis Baby Tooth Study (SLBT; N = 78)), and a present-day Nigerian cohort established to study maternal HIV transmission (Dental caries and its association with Oral Microbiomes and HIV in young children-Nigeria (DOMHaIN; N = 31)). RESULTS: We report Li, Al, Mn, Cu, Zn, Sr, Ba and Pb concentrations (µg/g) and qualitatively examine As, Cd and Hg across all three cohorts. Rates of detection were highest, both overall and for each cohort individually, for Zn, Sr, Ba and Li. Zinc was detected in 100% of samples and was stably present in teeth at a concentration range of 64 - 86 µg/g. Mercury, As and Cd detection rates were the lowest, and had high variability within individual ablated spots. We found the highest concentrations of Pb in the pre- and postnatal dentin of the SLBT cohort, consistent with the prevalent use of Pb as an additive to gasoline prior to 1975. The characteristic decline in Mn after the second trimester was observed in all cohorts. IMPACT: Spatially resolved elemental analysis of deciduous teeth combined with methods for estimating crown formation times can be used to reconstruct an early-life history of elemental exposure inaccessible via other biomarkers. Quantification of data into absolute values using an external standard reference material has not been conducted since 2012, preventing comparison between studies, a common and highly informative component of epidemiology. We demonstrate, with three contrasting populations, that absolute quantification produces data with the lowest variability, compares well with available data and recommends that future tooth biomarker studies report data in this way.

Consented indicators for the evaluation of integrated strategies of community health promotion targeting children and adolescents: results of an eDelphi.

BACKGROUND: To date, there is no consensus on indicators for the evaluation of integrated community-based interventions for health promotion and prevention targeting children and adolescents. This study aims at consenting on a scoped set of indicators to evaluate integrated community-based interventions. METHODS: Out of 738 indicators derived from a literature search, we preselected 94 indicators allotted to 20 domains based on an internal quality appraisal and consensus process and conducted an eDelphi procedure to assess their relevance in view of experts. Experts were recruited in the field of public health, health sciences and communal health promotion in practice and were invited as participants in this eDelphi. During the eDelphi, 47 experts rated the relevance of 94 indicators in two rounds. Consensus was defined as agreement of 75% (or above). RESULTS: After round 1, 27 indicators among 11 consented subdomains reached a consensus on relevance. After round 2, a total of 36 indicators reached consensus on relevance in 9 subdomains (such as socioeconomic factors, health education, nutrition and physical activity, oral health, overall health status, specific health conditions, drug related behavior, exposure to drugs and violence, family factors). CONCLUSIONS: These identified indicators may provide a basis for evaluation concepts of integrated community-based interventions for children and adolescents to inform stakeholders about intervention impacts.

Atrial fibrosis heterogeneity is a risk for atrial fibrillation in pigs with ischaemic heart failure.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia and is associated with considerable morbidity and mortality. Ischaemic heart failure (IHF) remains one of the most common causes of AF in clinical practice. However, ischaemia-mediated mechanisms leading to AF are still incompletely understood, and thus, current treatment approaches are limited. To improve our understanding of the pathophysiology, we studied a porcine IHF model. METHODS: In pigs, IHF was induced by balloon occlusion of the left anterior descending artery for 90 min. After 30 days of reperfusion, invasive haemodynamic measurements and electrophysiological studies were performed. Masson trichrome and immunofluorescence staining were conducted to assess interstitial fibrosis and myofibroblast activation in different heart regions. RESULTS: After 30 days of reperfusion, heart failure with significantly reduced ejection fraction (left anterior obique 30°, 34.78 ± 3.29% [IHF] vs. 62.03 ± 2.36% [control], p < .001; anterior-posterior 0°, 29.16 ± 3.61% vs. 59.54 ± 1.09%, p < .01) was observed. These pigs showed a significantly higher susceptibility to AF (33.90% [IHF] vs. 12.98% [control], p < .05). Histological assessment revealed aggravated fibrosis in atrial appendages but not in atrial free walls in IHF pigs (11.13 ± 1.44% vs. 5.99 ± .86%, p < .01 [LAA], 8.28 ± .56% vs. 6.01 ± .35%, p < .01 [RAA]), which was paralleled by enhanced myofibroblast activation (12.09 ± .65% vs. 9.00 ± .94%, p < .05 [LAA], 14.37 ± .60% vs. 10.30 ± 1.41%, p < .05 [RAA]). Correlation analysis indicated that not fibrosis per se but its cross-regional heterogeneous distribution across the left atrium was associated with AF susceptibility (r = .6344, p < .01). CONCLUSION: Our results suggest that left atrial cross-regional fibrosis difference rather than overall fibrosis level is associated with IHF-related AF susceptibility, presumably by establishing local conduction disturbances and heterogeneity.

Early-life manganese exposure during multiple developmental periods and adolescent verbal learning and memory.

BACKGROUND: Manganese (Mn) is both an essential and toxic metal, and associations with neurodevelopment depend on exposure timing. Prospective data examining early life Mn with adolescent cognition are sparse. METHODS: We enrolled 140 Italian adolescents (10-14 years old) from the Public Health Impact of Metals Exposure study. Mn in deciduous teeth was measured using laser ablation-mass spectrometry to represent prenatal, postnatal and early childhood exposure. The California Verbal Learning Test for Children (CVLT-C) was administered to assess adolescent verbal learning and memory. Multivariable regression models estimated changes in CVLT-C scores and the odds of making an error per doubling in dentine Mn in each exposure period. Multiple informant models tested for differences in associations across exposure periods. RESULTS: A doubling in prenatal dentine Mn levels was associated with lower odds of making an intrusion error (OR = 0.23 [95% CI: 0.09, 0.61]). This beneficial association was not observed in other exposure periods. A doubling in childhood Mn was beneficially associated with short delay free recall: (ß = 0.47 [95% CI: -0.02, 0.97]), which was stronger in males (ß = 0.94 [95% CI: 0.05, 1.82]). Associations were null in the postnatal period. CONCLUSION: Exposure timing is critical for understanding Mn-associated changes in cognitive function.

Heterodimerization of Chemoreceptors TAS1R3 and mGlu2 in Human Blood Leukocytes.

The expression of canonical chemosensory receptors of the tongue, such as the heteromeric sweet taste (TAS1R2/TAS1R3) and umami taste (TAS1R1/TAS1R3) receptors, has been demonstrated in many extra-oral cells and tissues. Gene expression studies have revealed transcripts for all TAS1 and metabotropic glutamate (mGlu) receptors in different types of immune cells, where they are involved, for example, in the chemotaxis of human neutrophils and the protection of T cells from activation-induced cell death. Like other class-C G protein-coupling receptors (GPCRs), TAS1Rs and mGlu receptors form heteromers within their families. Since mGlu receptors and TAS1R1/TAS1R3 share the same ligand, monosodium glutamate (MSG), we hypothesized their hitherto unknown heteromerization across receptor families in leukocytes. Here we show, by means of immunocytochemistry and co-IP/Western analysis, that across class-C GPCR families, mGlu2 and TAS1R3 co-localize and heterodimerize in blood leukocytes. Expressing the recombinant receptors in HEK-293 cells, we validated their heterodimerization by bioluminescence resonance energy transfer. We demonstrate MSG-induced, mGlu2/TAS1R3 heteromer-dependent gain-of-function and pertussis toxin-sensitive signaling in luminescence assays. Notably, we show that mGlu2/TAS1R3 is necessary and sufficient for MSG-induced facilitation of N-formyl-methionyl-leucyl-phenylalanine-stimulated IL-8 secretion in neutrophils, using receptor-specific antagonists. In summary, our results demonstrate mGlu2/TAS1R3 heterodimerization in leukocytes, suggesting cellular function-tailored chemoreceptor combinations to modulate cellular immune responses.

In vitro modelling of the influence of alternative feeds (Hermetia illucens, Arthrospira platensis) on the resistance of different rainbow trout populations (Oncorhynchus mykiss) against the viral haemorrhagic septicaemia virus and Yersinia ruckeri.

Replacing fishmeal, a finite resource with high market demand, in the diet of carnivorous rainbow trout with proteins from alternative sources may be a challenge for these fish. Therefore, this study investigated whether replacing fishmeal with protein derived from Hermetia illucens or Arthrospira platensis could promote disease susceptibility in local trout populations with different growth performance. This was assessed in vitro by measuring susceptibility to infection with the viral haemorrhagic septicaemia virus (VHSV) or the bacterium Yersinia ruckeri. Analysis of fin tissue explants and primary cell cultures from scales from the three trout populations infected in vitro with VHSV and gill explants infected with Y. ruckeri showed no significant differences in virus replication or bacterial counts. Evaluation of the virucidal or bactericidal effect of skin mucus showed a significant reduction in viral load and bacterial count for all samples with mucus addition, but no significant difference was observed between the experimental groups. This study documents no apparent impairment of innate immune mechanisms in the skin and gills of trout after feeding a diet replacing fishmeal with Arthrospira or Hermetia proteins. This underlines the potential of these alternative protein sources for the further development of sustainable trout aquaculture.

A comparative study of social cognition in epilepsy, brain injury, and Parkinson's disease.

The brain regions involved in social cognition and the regulation of social behavior form a widely distributed cortico-subcortical network. Therefore, many neurological disorders could affect social cognition and behavior. A persistent lack of valid tests and a rigid neuropsychological focus on language, attention, executive function, and memory have contributed to a long-standing neglect of social cognition in clinical diagnostics, although the DSM-5 recognizes it as one of the six core dimensions in neurocognitive disorders. To assess for the first time the diagnostic yield of a comprehensive social cognition battery (Networks of Emotion Processing [NEmo]), we administered several emotion recognition and theory of mind tests to three incidental clinical samples with different neurological conditions: temporal lobe epilepsy (n = 30), acquired brain injury (n = 24), Parkinson's disease (n = 19), and a healthy control group (n = 67). A multivariate analysis of covariance was performed to test the effect of group on subscales of the NEmo test battery, controlling for age and performance IQ. The results showed statistically significant differences between clinical groups and healthy controls. No differences were found for gender and lateralization of the predominant lesion side. In our incidental samples, 86% of individuals with temporal lobe epilepsy, 57% of individuals with acquired brain lesion, and 14% of individuals with Parkinson's disease underperformed on tests of social cognition compared with controls. These findings suggest a differential impact of neurological disorders on the risk of impaired social cognition and highlight the need to consider social cognition in diagnostics, counselling, therapy, and rehabilitation.

Combination of immune-checkpoint inhibitors and targeted therapies for melanoma therapy: The more, the better?

The approval of immune-checkpoint inhibitors (CPI) and mitogen activated protein kinase inhibitors (MAPKi) in recent years significantly improved the treatment management and survival of patients with advanced malignant melanoma. CPI aim to counter-act receptor-mediated inhibitory effects of tumor cells and immunomodulatory cell types on effector T cells, whereas MAPKi are intended to inhibit tumor cell survival. In agreement with these complementary modes of action preclinical data indicated that the combined application of CPI and MAPKi or their optimal sequencing might provide additional clinical benefit. In this review the rationale and preclinical evidence that support the combined application of MAPKi and CPI either in concurrent or consecutive regimens are presented. Further, we will discuss the results from clinical trials investigating the sequential or combined application of MAPKi and CPI for advanced melanoma patients and their implications for clinical practice. Finally, we outline mechanisms of MAPKi and CPI cross-resistance which limit the efficacy of currently available treatments, as well as combination regimens.

Effects of Sex on the Susceptibility for Atrial Fibrillation in Pigs with Ischemic Heart Failure.

Atrial fibrillation (AF) is the most prevalent arrhythmia, often caused by myocardial ischemia/infarction (MI). Men have a 1.5× higher prevalence of AF, whereas women show a higher risk for new onset AF after MI. However, the underlying mechanisms of how sex affects AF pathophysiology are largely unknown. In 72 pigs with/without ischemic heart failure (IHF) we investigated the impact of sex on ischemia-induced proarrhythmic atrial remodeling and the susceptibility for AF. Electrocardiogram (ECG) and electrophysiological studies were conducted to assess electrical remodeling; histological analyses were performed to assess atrial fibrosis in male and female pigs. IHF pigs of both sexes showed a significantly increased vulnerability for AF, but in male pigs more and longer episodes were observed. Unchanged conduction properties but enhanced left atrial fibrosis indicated structural rather than electrical remodeling underlying AF susceptibility. Sex differences were only observed in controls with female pigs showing an increased intrinsic heart rate, a prolonged QRS interval and a prolonged sinus node recovery time. In sum, susceptibility for AF is significantly increased both in male and female pigs with ischemic heart failure. Differences between males and females are moderate, including more and longer AF episodes in male pigs and sinus node dysfunction in female pigs.

Associations of an industry-relevant metal mixture with verbal learning and memory in Italian adolescents: The modifying role of iron status.

BACKGROUND: Biomarker concentrations of metals are associated with neurodevelopment, and these associations may be modified by nutritional status (e.g., iron deficiency). No prior study on associations of metal mixtures with neurodevelopment has assessed effect modification by iron status. OBJECTIVES: We aimed to quantify associations of an industry-relevant metal mixture with verbal learning and memory among adolescents, and to investigate the modifying role of iron status on those associations. METHODS: We used cross-sectional data from 383 Italian adolescents (10-14 years) living in proximity to ferroalloy industry. Verbal learning and memory was assessed using the California Verbal Learning Test for Children (CVLT-C), and metals were quantified in hair (manganese, copper, chromium) or blood (lead) using inductively coupled plasma mass spectrometry. Serum ferritin, a proxy for iron status, was measured using immunoassays. Covariate-adjusted associations of the metal mixture with CVLT subtests were estimated using Bayesian Kernel Machine Regression, and modification of the mixture associations by ferritin was examined. RESULTS: Compared to the 50th percentile of the metal mixture, the 90th percentile was associated with a 0.12 standard deviation [SD] (95% CI = -0.27, 0.50), 0.16 SD (95% CI = -0.11, 0.44), and 0.11 SD (95% CI = -0.20, 0.43) increase in the number of words recalled for trial 5, long delay free, and long delay cued recall, respectively. For an increase from its 25th to 75th percentiles, copper was beneficially associated the recall trials when other metals were fixed at their 50th percentiles (for example, trial 5 recall: ß = 0.31, 95% CI = 0.14, 0.48). The association between copper and trial 5 recall was stronger at the 75th percentile of ferritin, compared to the 25th or 50th percentiles. CONCLUSIONS: In this metal mixture, copper was beneficially associated with neurodevelopment, which was more apparent at higher ferritin concentrations. These findings suggest that metal associations with neurodevelopment may depend on iron status, which has important public health implications.

Long-term prognostic impact of paravalvular leakage on coronary artery disease requires patient-specific quantification of hemodynamics.

Transcatheter aortic valve replacement (TAVR) is a frequently used minimally invasive intervention for patient with aortic stenosis across a broad risk spectrum. While coronary artery disease (CAD) is present in approximately half of TAVR candidates, correlation of post-TAVR complications such as paravalvular leakage (PVL) or misalignment with CAD are not fully understood. For this purpose, we developed a multiscale computational framework based on a patient-specific lumped-parameter algorithm and a 3-D strongly-coupled fluid-structure interaction model to quantify metrics of global circulatory function, metrics of global cardiac function and local cardiac fluid dynamics in 6 patients. Based on our findings, PVL limits the benefits of TAVR and restricts coronary perfusion due to the lack of sufficient coronary blood flow during diastole phase (e.g., maximum coronary flow rate reduced by 21.73%, 21.43% and 21.43% in the left anterior descending (LAD), left circumflex (LCX) and right coronary artery (RCA) respectively (N = 6)). Moreover, PVL may increase the LV load (e.g., LV load increased by 17.57% (N = 6)) and decrease the coronary wall shear stress (e.g., maximum wall shear stress reduced by 20.62%, 21.92%, 22.28% and 25.66% in the left main coronary artery (LMCA), left anterior descending (LAD), left circumflex (LCX) and right coronary artery (RCA) respectively (N = 6)), which could promote atherosclerosis development through loss of the physiological flow-oriented alignment of endothelial cells. This study demonstrated that a rigorously developed personalized image-based computational framework can provide vital insights into underlying mechanics of TAVR and CAD interactions and assist in treatment planning and patient risk stratification in patients.

Environmental Metal Exposure, Neurodevelopment, and the Role of Iron Status: a Review.

PURPOSE OF REVIEW: Exposure to environmental metals, like lead (Pb), manganese (Mn), and methylmercury (Me-Hg), has consistently been implicated in neurodevelopmental dysfunction. Recent research has focused on identifying modifying factors of metal neurotoxicity in childhood, such as age, sex, and co-exposures. Iron (Fe) status is critical for normal cognitive development during childhood, and current mechanistic, animal, and human evidence suggests that Fe status may be a modifier or mediator of associations between environmental metals and neurodevelopment. The goals of this review are to describe the current state of the epidemiologic literature on the role of Fe status (i.e., hemoglobin, ferritin, blood Fe concentrations) and Fe supplementation in the relationship between metals and children's neurodevelopment, and to identify research gaps. RECENT FINDINGS: We identified 30 studies in PubMed and EMBASE that assessed Fe status as a modifier, mediator, or co-exposure of associations of Pb, Me-Hg, Mn, copper (Cu), zinc (Zn), arsenic (As), or metal mixtures measured in early life (prenatal period through 8 years of age) with cognition in children. In experimental studies, co-supplementation of Fe and Zn was associated with better memory and cognition than supplementation with either metal alone. Several observational studies reported interactions between Fe status and Pb, Mn, Zn, or As in relation to developmental indices, memory, attention, and behavior, whereby adverse associations of metals with cognition were worse among Fe-deficient children compared to Fe-sufficient children. Only two studies quantified joint associations of complex metal mixtures that included Fe with neurodevelopment, though findings from these studies were not consistent. Findings support memory and attention as two possible cognitive domains that may be both vulnerable to Fe deficiency and a target of metals toxicity. Major gaps in the literature remain, including evaluating Fe status as a modifier or mediator of metal mixtures and cognition. Given that Fe deficiency is the most common nutritional deficiency worldwide, characterizing Fe status in studies of metals toxicity is important for informing public health interventions.

Iatrogenic influence on prognosis of radiation-induced contrast enhancements in patients with glioma WHO 1-3 following photon and proton radiotherapy.

BACKGROUND AND PURPOSE: Radiation-induced contrast enhancements (RICE) are a common side effect following radiotherapy for glioma, but both diagnosis and handling are challenging. Due to the potential risks associated with RICE and its challenges in differentiating RICE from tumor progression, it is critical to better understand how RICE prognosis depends on iatrogenic influence. MATERIALS AND METHODS: We identified 99 patients diagnosed with RICE who were previously treated with either photon or proton therapy for World Health Organization (WHO) grade 1-3 primary gliomas. Post-treatment brain MRI-based volumetric analysis and clinical data collection was performed at multiple time points. RESULTS: The most common histologic subtypes were astrocytoma (50%) and oligodendroglioma (46%). In 67%, it was graded WHO grade 2 and in 86% an IDH mutation was present. RICE first occurred after 16 months (range: 1-160) in median. At initial RICE occurrence, 39% were misinterpreted as tumor progression. A tumor-specific therapy including chemotherapy or re-irradiation led to a RICE size progression in 86% and 92% of cases, respectively and RICE symptom progression in 57% and 65% of cases, respectively. A RICE-specific therapy such as corticosteroids or Bevacizumab for larger or symptomatic RICE led to a RICE size regression in 81% of cases with symptom stability or regression in 62% of cases. CONCLUSIONS: While with chemotherapy and re-irradiation a RICE progression was frequently observed, anti-edematous or anti-VEGF treatment frequently went along with a RICE regression. For RICE, correct diagnosis and treatment decisions are challenging and critical and should be made interdisciplinarily.

Tumor suppressive functions of WNT5A in rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a highly aggressive soft tissue malignancy that predominantly affects children. The main subtypes are alveolar RMS (ARMS) and embryonal RMS (ERMS) and the two show an impaired muscle differentiation phenotype. One pathway involved in muscle differentiation is WNT signaling. However, the role of this pathway in RMS is far from clear. Our recent data showed that the canonical WNT/ß­Catenin pathway serves a subordinate role in RMS, whereas non­canonical WNT signaling probably is more important for this tumor entity. The present study investigated the role of WNT5A, which is the major ligand of non­canonical WNT signaling, in ERMS and ARMS. Gene expression analysis showed that WNT5A was expressed in human RMS samples and that its expression is more pronounced in ERMS. When stably overexpressed in RMS cell lines, WNT5A decreased proliferation and migration of the cells as demonstrated by BrdU incorporation and Transwell migration or scratch assay, respectively. WNT5A also decreased the self­renewal capacity and the expression of stem cell markers and modulates the levels of muscle differentiation markers as shown by sphere assay and western blot analysis, respectively. Finally, overexpression of WNT5A can destabilize active ß­Catenin of RMS cells. A WNT5A knockdown has opposite effects. Together, the results suggest that WNT5A has tumor suppressive functions in RMS, which accompanies downregulation of ß­Catenin.

Quantitative assessment of radionuclide production yields in in-beam and offline PET measurements at different proton irradiation facilities.

Objective. Reliable radionuclide production yield data are a prerequisite for positron-emission-tomography (PET) basedin vivoproton treatment verification. In this context, activation data acquired at two different treatment facilities with different imaging systems were analyzed to provide experimentally determined radionuclide yields in thick targets and were compared with each other to investigate the impact of the respective imaging technique.Approach.Homogeneous thick targets (PMMA, gelatine, and graphite) were irradiated with mono-energetic proton pencil-beams at two distinct energies. Material activation was measured (i)in-beamduring and after beam delivery with a double-head prototype PET camera and (ii)offlineshortly after beam delivery with a commercial full-ring PET/CT scanner. Integral as well as depth-resolvedß+-emitter yields were determined for the dominant positron-emitting radionuclides11C,15O,13N and (in-beamonly)10C.In-beamdata were used to investigate the qualitative impact of different monitoring time schemes on activity depth profiles and their quantitative impact on count rates and total activity.Main results.Production yields measured with thein-beamcamera were comparable to or higher compared to respectiveofflineresults. Depth profiles of radionuclide-specific yields obtained from thedouble-headcamera showed qualitative differences to data acquired with thefull-ringcamera with a more convex profile shape. Considerable impact of the imaging timing scheme on the activity profile was observed for gelatine only with a range variation of up to 3.5 mm. Evaluation of the coincidence rate and the total number of observed events in the considered workflows confirmed a strongly decreasing rate in targets with a large oxygen fraction.Significance. The observed quantitative and qualitative differences between the datasets underline the importance of a thorough system commissioning. Due to the lack of reliable cross-section data, in-house phantom measurements are still considered a gold standard for careful characterization of the system response and to ensure a reliable beam range verification.

Radiation-induced contrast enhancement following proton radiotherapy for low-grade glioma depends on tumor characteristics and is rarer in children than adults.

BACKGROUND AND PURPOSE: Proton beam radiotherapy (PRT) is used in the treatment of low-grade glioma (LGG) to mitigate long-term sequelae. Following PRT, increased rates of radiation-induced contrast enhancements (RICE) are suspected but poorly understood. MATERIALS AND METHODS: We analyzed consecutive 227 patients (42 children and 185 adults) treated with PRT (54 Gy RBE) for LGG from 2010 to 2020 and followed with serial clinical exams and magnetic resonance imaging for in median 5.6 years. RESULTS: Tumors were graded WHO 1 in a minority (n = 22, 12%) of adults, but a majority of children (n = 29, 69%). In contrast, tumors were graded WHO 2 in the majority (n = 160, 87%) of adults and a minority of children (n = 10, 24%). Five-year overall survival following PRT was 81% in adults and 91% in children. The risk of RICE was 5-fold more frequent in adults (25%) vs. children (5%; p = 0.0043). In children and adults, RICE were symptomatic in 50% and 55% (n = 1 and 26) of cases with CTCAE grade 0 in 47% (n = 23), grade 1 in 25% (n = 12), 0% grade 2 (n = 0) and 29% grade 3 (n = 14), respectively. In adults, RICE risk was associated to WHO grading (8% in WHO grade 1 vs. 24% in WHO grade 2, p = 0.026), independent of age (p = 0.44) and irradiation dose (p = 0.005), but not independent of IDH mutational status. CONCLUSIONS: These data demonstrate effectiveness of PRT for LGG in both children and adults. The RICE risk is lower in children which are a main target group for PRT and differs with WHO grading.