State-of-the-Science Data and Methods Need to Guide Place-Based Efforts to Reduce Air Pollution Inequity.

BACKGROUND: Recently enacted environmental justice policies in the United States at the state and federal level emphasize addressing place-based inequities, including persistent disparities in air pollution exposure and associated health impacts. Advances in air quality measurement, models, and analytic methods have demonstrated the importance of finer-scale data and analysis in accurately quantifying the extent of inequity in intraurban pollution exposure, although the necessary degree of spatial resolution remains a complex and context-dependent question. OBJECTIVE: The objectives of this commentary were to a) discuss ways to maximize and evaluate the effectiveness of efforts to reduce air pollution disparities, and b) argue that environmental regulators must employ improved methods to project, measure, and track the distributional impacts of new policies at finer geographic and temporal scales. DISCUSSION: The historic federal investments from the Inflation Reduction Act, the Infrastructure Investment and Jobs Act, and the Biden Administration's commitment to Justice40 present an unprecedented opportunity to advance climate and energy policies that deliver real reductions in pollution-related health inequities. In our opinion, scientists, advocates, policymakers, and implementing agencies must work together to harness critical advances in air quality measurements, models, and analytic methods to ensure success. https://doi.org/10.1289/EHP13063.

A comparison of the infant gut microbiome before versus after the start of the covid-19 pandemic.

The COVID-19 pandemic and resulting public health directives led to many changes in families' social and material environments. Prior research suggests that these changes are likely to impact composition of the gut microbiome, particularly during early childhood when the gut microbiome is developing most rapidly. Importantly, disruption to the gut microbiome during this sensitive period can have potentially long-lasting impacts on health and development. In the current study, we compare gut microbiome composition among a socioeconomically and racially diverse group of 12-month old infants living in New York City who provided stool samples before the pandemic (N = 34) to a group who provided samples during the first 9-months of the pandemic (March-December 2020; N = 20). We found that infants sampled during the pandemic had lower alpha diversity of the microbiome, lower abundance of Pasteurellaceae and Haemophilus, and significantly different beta diversity based on unweighted Unifrac distance than infants sampled before the pandemic. Exploratory analyses suggest that gut microbiome changes due to the pandemic occurred relatively quickly after the start of the pandemic and were sustained. Our results provide evidence that pandemic-related environmental disruptions had an impact on community-level taxonomic diversity of the developing gut microbiome, as well as abundance of specific members of the gut bacterial community.

Accurate and Fast Deep Learning Dose Prediction for a Preclinical Microbeam Radiation Therapy Study Using Low-Statistics Monte Carlo Simulations.

Microbeam radiation therapy (MRT) utilizes coplanar synchrotron radiation beamlets and is a proposed treatment approach for several tumor diagnoses that currently have poor clinical treatment outcomes, such as gliosarcomas. Monte Carlo (MC) simulations are one of the most used methods at the Imaging and Medical Beamline, Australian Synchrotron to calculate the dose in MRT preclinical studies. The steep dose gradients associated with the 50µm-wide coplanar beamlets present a significant challenge for precise MC simulation of the dose deposition of an MRT irradiation treatment field in a short time frame. The long computation times inhibit the ability to perform dose optimization in treatment planning or apply online image-adaptive radiotherapy techniques to MRT. Much research has been conducted on fast dose estimation methods for clinically available treatments. However, such methods, including GPU Monte Carlo implementations and machine learning (ML) models, are unavailable for novel and emerging cancer radiotherapy options such as MRT. In this work, the successful application of a fast and accurate ML dose prediction model for a preclinical MRT rodent study is presented for the first time. The ML model predicts the peak doses in the path of the microbeams and the valley doses between them, delivered to the tumor target in rat patients. A CT imaging dataset is used to generate digital phantoms for each patient. Augmented variations of the digital phantoms are used to simulate with Geant4 the energy depositions of an MRT beam inside the phantoms with 15% (high-noise) and 2% (low-noise) statistical uncertainty. The high-noise MC simulation data are used to train the ML model to predict the energy depositions in the digital phantoms. The low-noise MC simulations data are used to test the predictive power of the ML model. The predictions of the ML model show an agreement within 3% with low-noise MC simulations for at least 77.6% of all predicted voxels (at least 95.9% of voxels containing tumor) in the case of the valley dose prediction and for at least 93.9% of all predicted voxels (100.0% of voxels containing tumor) in the case of the peak dose prediction. The successful use of high-noise MC simulations for the training, which are much faster to produce, accelerates the production of the training data of the ML model and encourages transfer of the ML model to different treatment modalities for other future applications in novel radiation cancer therapies.

Neurophysiology of sustained attention in early infancy: Investigating longitudinal relations with recognition memory outcomes.

The ability to sustain attention is a critical cognitive domain that emerges in infancy and is predictive of a multitude of cognitive processes. Here, we used a heart rate (HR) defined measure of sustained attention to assess corresponding changes in frontal electroencephalography (EEG) power at 3 months of age. Second, we examined how the neural underpinnings of HR-defined sustained attention were associated with sustained attention engagement. Third, we evaluated if neural or behavioral sustained attention measures at 3-months predicted subsequent recognition memory scores at 9 months of age. Seventy-five infants were included at 3 months of age and provided usable attention and EEG data and 25 infants returned to the lab at 9 months and provided usable recognition memory data. The current study focuses on oscillatory power in the theta (4-6 Hz) frequency band during phases of HR-defined sustained attention and inattention phases. Results revealed that theta power was significantly higher during phases of sustained attention. Second, higher theta power during sustained attention was positively associated with proportion of time in sustained attention. Third, longitudinal analyses indicated a significant positive association between theta power during sustained attention on 9-month visual paired comparison scores such that higher theta power predicted higher visual paired comparison scores at 9-months. These results highlight the interrelation of the attention and arousal systems which have longitudinal implications for subsequent recognition memory processes.

Sulfated glycosaminoglycans inhibit transglutaminase 2 by stabilizing its closed conformation.

Transglutaminases (TGs) catalyze the covalent crosslinking of proteins via isopeptide bonds. The most prominent isoform, TG2, is associated with physiological processes such as extracellular matrix (ECM) stabilization and plays a crucial role in the pathogenesis of e.g. fibrotic diseases, cancer and celiac disease. Therefore, TG2 represents a pharmacological target of increasing relevance. The glycosaminoglycans (GAG) heparin (HE) and heparan sulfate (HS) constitute high-affinity interaction partners of TG2 in the ECM. Chemically modified GAG are promising molecules for pharmacological applications as their composition and chemical functionalization may be used to tackle the function of ECM molecular systems, which has been recently described for hyaluronan (HA) and chondroitin sulfate (CS). Herein, we investigate the recognition of GAG derivatives by TG2 using an enzyme-crosslinking activity assay in combination with in silico molecular modeling and docking techniques. The study reveals that GAG represent potent inhibitors of TG2 crosslinking activity and offers atom-detailed mechanistic insights.

Stroke Caused by Arterial Thoracic Outlet Syndrome in an Adolescent.

Arterial thoracic outlet syndrome is a rare condition characterized by compression of the subclavian artery, often with post-stenotic aneurysm formation. Artery-to-artery embolic strokes related to thoracic outlet syndrome have been reported in the posterior circulation and in the ipsilateral anterior circulation. We present a case in which a thrombus secondary to thoracic outlet syndrome caused a contralateral anterior circulation stroke in an adolescent and postulate mechanisms of this rare occurrence. This case demonstrates that a subclavian thrombus due to thoracic outlet syndrome can take a circuitous path and cause an anterior circulation stroke contralateral to the diseased subclavian artery. In addition, this case illustrates the importance of a high index of suspicion for thoracic outlet syndrome in patients with stroke and associated arm pain or discoloration.

Maternal anxiety symptoms associated with increased behavioral synchrony in the early postnatal period.

The presence of perinatal mood and anxiety disorders has typically been associated with decreases in the quality of mother-infant interactions. However, maternal anxiety symptoms during the postpartum period have been less studied than other mental health disorders like depression. In the current study, we examined associations among symptoms of maternal anxiety, maternal perceived stress, and mother-infant behavioral synchrony in the early postnatal period. Eighty-one mother-infant dyads participated in this study when the infants were 3 months old. Surveys were given to obtain demographic information and current maternal mental health symptoms, and dyads completed a 5-min free-play task to measure behavioral synchrony. Results indicated that maternal anxiety symptoms were positively associated with behavioral synchrony, but only for mothers reporting moderate levels of perceived stress. These findings highlight the differential impact of maternal postpartum mental health on behavioral synchrony and suggest that higher maternal anxiety symptoms during the postnatal period may play an adaptive role in fostering more dynamic mother-infant interactions.

The Presentation of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Not Influenced by the Presence or Absence of Joint Hypermobility.

OBJECTIVE: To examine demographic and clinical characteristics of individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with and without joint hypermobility We hypothesized that patients who were joint hypermobility-positive would have an earlier onset of ME/CFS symptoms as well as increased severity, a greater number of comorbid conditions, and a lower health-related quality of life. STUDY DESIGN: From an observational cohort study of 55 individuals meeting the Fukuda criteria for ME/CFS, we compared groups using a Beighton score cutoff of 4 or higher to indicate joint hypermobility. Chart data were collected to examine the age and type of onset of ME/CFS and the presence of comorbid conditions. The impact on quality of life was assessed through questionnaires that included the Peds QL, Functional Disability Inventory, Peds QL Multidimensional Fatigue Scale, and Anxiety Subscale of the Symptom Checklist 90. RESULTS: There was no significant difference between groups in mean ± SD age at onset of ME/CFS (13.3 ± 3.3 years vs 13.3 ± 2.3 years; P = .92), sex, frequency, and severity of ME/CFS symptoms, orthostatic intolerance symptoms, or comorbid conditions. There was no significant difference between the groups in measures of health-related quality of life using a Beighton score cutoff of 4 or a cutoff of 5 to define joint hypermobility. CONCLUSIONS: Despite being a risk factor for the development of ME/CFS, joint hypermobility as defined in this study was not associated with other clinical characteristics of the illness.

Within-person changes in basal cortisol and caregiving modulate executive attention across infancy.

One pathway by which environments of socioeconomic risk are thought to affect cognitive development is through stress physiology. The biological systems underpinning stress and attention undergo a sensitive period of development during infancy. Psychobiological theory emphasizes a dynamic pattern of context-dependent development, however, research has yet to examine how basal cortisol and attention dynamically covary across infancy in ecologically valid contexts. Thus, to address these gaps, we leveraged longitudinal, multilevel analytic methods to disentangle between- from within-person associations of hypothalamic-pituitary-adrenal (HPA) axis activity and executive attention behaviors across infancy. We use data from a large longitudinal sample (N = 1,292) of infants in predominantly low-income, nonurban communities at 7-, 15-, and 24-months of age. Using multilevel models, we investigated longitudinal associations of infant attention and basal cortisol levels and examined caregiving behaviors as moderators of this relationship. Results indicated a negative between- and within-person association between attention and cortisol across infancy and a within-person moderation by caregiver responsiveness. In other words, on the within-person level, higher levels of cortisol were concomitantly associated with lower infant attention across the first 2 years of life. However, variation in the caregiver's level of responsiveness either buffered or sensitized the executive attention system to the negative effects of physiological stress.

Identification of intracellular glycosaminoglycan-interacting proteins by affinity purification mass spectrometry.

Glycosaminoglycans (GAGs) are essential functional components of the extracellular matrix (ECM). Artificial GAGs like sulfated hyaluronan (sHA) exhibit pro-osteogenic properties and boost healing processes. Hence, they are of high interest for supporting bone regeneration and wound healing. Although sulfated GAGs (sGAGs) appear intracellularly, the knowledge about intracellular effects and putative interaction partners is scarce. Here we used an affinity-purification mass spectrometry-based (AP-MS) approach to identify novel and particularly intracellular sGAG-interacting proteins in human bone marrow stromal cells (hBMSC). Overall, 477 proteins were found interacting with at least one of four distinct sGAGs. Enrichment analysis for protein localization showed that mainly intracellular and cell-associated interacting proteins were identified. The interaction of sGAG with α2-macroglobulin receptor-associated protein (LRPAP1), exportin-1 (XPO1), and serine protease HTRA1 (HTRA1) was confirmed in reverse assays. Consecutive pathway and cluster analysis led to the identification of biological processes, namely processes involving binding and processing of nucleic acids, LRP1-dependent endocytosis, and exosome formation. Respecting the preferentially intracellular localization of sGAG in vesicle-like structures, also the interaction data indicate sGAG-specific modulation of vesicle-based transport processes. By identifying many sGAG-specific interacting proteins, our data provide a resource for upcoming studies aimed at molecular mechanisms and understanding of sGAG cellular effects.

Osteogenic Potential of Mesenchymal Stem Cells from Adipose Tissue, Bone Marrow and Hair Follicle Outer Root Sheath in a 3D Crosslinked Gelatin-Based Hydrogel.

Bone transplantation is regarded as the preferred therapy to treat a variety of bone defects. Autologous bone tissue is often lacking at the source, and the mesenchymal stem cells (MSCs) responsible for bone repair mechanisms are extracted by invasive procedures. This study explores the potential of autologous mesenchymal stem cells derived from the hair follicle outer root sheath (MSCORS). We demonstrated that MSCORS have a remarkable capacity to differentiate in vitro towards the osteogenic lineage. Indeed, when combined with a novel gelatin-based hydrogel called Osteogel, they provided additional osteoinductive cues in vitro that may pave the way for future application in bone regeneration. MSCORS were also compared to MSCs from adipose tissue (ADMSC) and bone marrow (BMMSC) in a 3D Osteogel model. We analyzed gel plasticity, cell phenotype, cell viability, and differentiation capacity towards the osteogenic lineage by measuring alkaline phosphatase (ALP) activity, calcium deposition, and specific gene expression. The novel injectable hydrogel filled an irregularly shaped lesion in a porcine wound model displaying high plasticity. MSCORS in Osteogel showed a higher osteo-commitment in terms of calcium deposition and expression dynamics of OCN, BMP2, and PPARG when compared to ADMSC and BMMSC, whilst displaying comparable cell viability and ALP activity. In conclusion, autologous MSCORS combined with our novel gelatin-based hydrogel displayed a high capacity for differentiation towards the osteogenic lineage and are acquired by non-invasive procedures, therefore qualifying as a suitable and expandable novel approach in the field of bone regeneration therapy.

Impact of binding mode of low-sulfated hyaluronan to 3D collagen matrices on its osteoinductive effect for human bone marrow stromal cells.

Synthetically sulfated hyaluronan derivatives were shown to facilitate osteogenic differentiation of human bone marrow stromal cells (hBMSC) by application in solution or incorporated in thin collagen-based coatings. In the presented study, using a biomimetic three-dimensional (3D) cell culture model based on fibrillary collagen I (3D Col matrix), we asked on the impact of binding mode of low sulfated hyaluronan (sHA) in terms of adsorptive and covalent binding on osteogenic differentiation of hBMSC. Both binding modes of sHA induced osteogenic differentiation. Although for adsorptive binding of sHA a strong intracellular uptake of sHA was observed, implicating an intracellular mode of action, covalent binding of sHA to the 3D matrix induced also intense osteoinductive effects pointing towards an extracellular mode of action of sHA in osteogenic differentiation. In summary, the results emphasize the relevance of fibrillary 3D Col matrices as a model to study hBMSC differentiation in vitro in a physiological-like environment and that sHA can display dose-dependent osteoinductive effects in dependence on presentation mode in cell culture scaffolds.

First extensive study of silver-doped lanthanum manganite nanoparticles for inducing selective chemotherapy and radio-toxicity enhancement.

Nanoparticles have a great potential to increase the therapeutic efficiency of several cancer therapies. This research examines the potential for silver-doped lanthanum manganite nanoparticles to enhance radiation therapy to target radioresistant brain cancer cells, and their potential in combinational therapy with magnetic hyperthermia. Magnetic and structural characterisation found all dopings of nanoparticles (NPs) to be pure and single phase with an average crystallite size of approximately 15 nm for undoped NPs and 20 nm for silver doped NPs. Additionally, neutron diffraction reveals that La0.9Ag0.1MnO3 (10%-LAGMO) NPs exhibit residual ferromagnetism at 300 K that is not present in lower doped NPs studied in this work, indicating that the Curie temperature may be manipulated according to silver doping. This radiobiological study reveals a completely cancer-cell selective treatment for LaMnO3, La0.975Ag0.025MnO3 and La0.95Ag0.05MnO3 (0, 2.5 and 5%-LAGMO) and also uncovers a potent combination of undoped lanthanum manganite with orthovoltage radiation. Cell viability assays and real time imaging results indicated that a concentration of 50 µg/mL of the aforementioned nanoparticles do not affect the growth of Madin-Darby Canine Kidney (MDCK) non-cancerous cells over time, but stimulate its metabolism for overgrowth, while being highly toxic to 9L gliosarcoma (9LGS). This is not the case for 10%-LAGMO nanoparticles, which were toxic to both non-cancerous and cancer cell lines. The nanoparticles also exhibited a level of toxicity that was regulated by the overproduction of free radicals, such as reactive oxygen species, amplified when silver ions are involved. With the aid of fluorescent imaging, the drastic effects of these reactive oxygen species were visualised, where nucleus cleavage (an apoptotic indicator) was identified as a major consequence. The genotoxic response of this effect for 9LGS and MDCK due to 10%-LAGMO NPs indicates that it is also causing DNA double strand breaks within the cell nucleus. Using 125 kVp orthovoltage radiation, in combination with an appropriate amount of NP-induced cell death, identified undoped lanthanum manganite as the most ideal treatment. Real-time imaging following the combination treatment of undoped lanthanum manganite nanoparticles and radiation, highlighted a hinderance of growth for 9LGS, while MDCK growth was boosted. The clonogenic assay following incubation with undoped lanthanum manganite nanoparticles combined with a relatively low dose of radiation (2 Gy) decreased the surviving fraction to an exceptionally low (0.6 ± 6.7)%. To our knowledge, these results present the first biological in-depth analysis on silver-doped lanthanum manganite as a brain cancer selective chemotherapeutic and radiation dose enhancer and as a result will propel its first in vivo investigation.

Compassionate leadership: how to support your team when fixing the problem seems impossible.

Stress, suboptimal mental health and an inadequate work-life balance are underlying and serious issues in the nursing profession, affecting staff recruitment and retention and potentially having a detrimental effect on patient care. While compassion towards patients is central to the nursing role, often 'compassion towards the compassionate' is lacking. The need for compassion is even more important now, and in the months ahead, due to the additional stressors experienced by nurses during the COVID-19 pandemic, whether they are on the front line, furloughed or shielding. This article includes reflections from nursing staff and uses their stories to encourage reflection on ethical and moral dilemmas experienced during the pandemic. The Compassion in the Workplace model is suggested as a tool that can be used by nurse managers to examine their compassion levels and to support the development of a compassionate workplace. In addition, this article offers some practical ideas on what compassionate leadership might look like in day-to-day practice.

Deprivation and threat as developmental mediators in the relation between early life socioeconomic status and executive functioning outcomes in early childhood.

There has been a shift in the study of childhood adversity towards a focus on dimensions of adversity as opposed to a focus on cumulative risk or specific adversities. The Dimensional Model of Adversity and Psychopathology (DMAP) proposes deprivation and threat as core dimensions of childhood adversity. Previous work using DMAP has found links between deprivation and cognitive development and threat and emotional development in adolescence, but few studies have applied this framework to a poverty context, in which children are at heightened risk for adversity experiences, and none have examined outcomes in early childhood. We use data from the Family Life Project (n = 1292) to examine deprivation and threat at child age 24 months as developmental mediators in the association between socioeconomic status (SES) measured at 15 months and executive functions (EF) measured at 48 months. In a multiple mediation model, lower SES was related to higher deprivation and threat. Deprivation was negatively associated with EF, and threat was not associated with EF. Deprivation fully mediated association between SES and EF. These results expand previous work using the DMAP and point to new directions in understanding children's cognitive adaptations to adversity.

Early Life Stress and the Development of the Infant Gut Microbiota: Implications for Mental Health and Neurocognitive Development.

PURPOSE OF REVIEW: We review the state of the literature examining associations between early life stress (ELS), gut microbiota, and neurocognitive development and mental health in animals and humans. We identify gaps in current models and areas for future research. RECENT FINDINGS: ELS is associated with changes in gut microbiota, which correspond to changes in affective and cognitive functioning in both animals and humans. Some of these ELS-induced psychological changes can be remedied by supplementation with probiotics in early life, suggesting a potential area for intervention for ELS-exposed children. Prenatal stress exposure is rarely studied in humans in relation to gut microbiota, but animal work has suggested important associations between prenatal stress and fetal programming that should be tested in humans. The gut microbiota plays an important role in the association between ELS, neurocognitive development, and mental health. More work is needed to fully understand these associations in humans.

Toward personalized synchrotron microbeam radiation therapy.

Synchrotron facilities produce ultra-high dose rate X-rays that can be used for selective cancer treatment when combined with micron-sized beams. Synchrotron microbeam radiation therapy (MRT) has been shown to inhibit cancer growth in small animals, whilst preserving healthy tissue function. However, the underlying mechanisms that produce successful MRT outcomes are not well understood, either in vitro or in vivo. This study provides new insights into the relationships between dosimetry, radiation transport simulations, in vitro cell response, and pre-clinical brain cancer survival using intracerebral gliosarcoma (9LGS) bearing rats. As part of this ground-breaking research, a new image-guided MRT technique was implemented for accurate tumor targeting combined with a pioneering assessment of tumor dose-coverage; an essential parameter for clinical radiotherapy. Based on the results of our study, we can now (for the first time) present clear and reproducible relationships between the in vitro cell response, tumor dose-volume coverage and survival post MRT irradiation of an aggressive and radioresistant brain cancer in a rodent model. Our innovative and interdisciplinary approach is illustrated by the results of the first long-term MRT pre-clinical trial in Australia. Implementing personalized synchrotron MRT for brain cancer treatment will advance this international research effort towards clinical trials.

Childhood Adversity and Dimensional Variations in Adult Sustained Attention.

BACKGROUND AND OBJECTIVE: Sustained attention is a transdiagnostic phenotype linked with most forms of psychopathology. We sought to understand factors that influence the development of sustained attention, by looking at the relationship between childhood adversity and adult sustained attention. PARTICIPANTS SETTING AND METHODS: Participants were 5,973 TestMyBrain.org visitors from English-speaking countries who completed a continuous performance task (gradCPT) of sustained attention and a childhood adversity questionnaire. We analyzed gradCPT performance using a signal detection approach. RESULTS: Discrimination ability (the main metric of performance on the gradCPT) was associated with total childhood adversity load, even when controlling for covariates related to age, gender, parental education, race, country of origin, and relative socioeconomic status (ß = -0.079, b = -0.032). CONCLUSION: Our results demonstrate that attention differences related to childhood adversity exposure can (1) be measured using brief, performance-based measures of sustained attention, (2) persist into adulthood, and (3) be detected at the population level. These results, paired with the well-documented associations between sustained attention and psychopathology, indicate that sustained attention may be an important mechanism for understanding early influences on mental health.