The Intersections of Race, Gender, Age, and Socioeconomic Status: Implications for Reporting Discrimination and Attributions to Discrimination.

This study employed an intersectional approach (operationalized as the combination of more than one social identity) to examine the relationship between aspects of social identity (i.e., race, gender, age, SES), self-reported level of mistreatment, and attributions for discrimination. Self-reported discrimination has been researched extensively and there is substantial evidence of its association with adverse physical and psychological health outcomes. Few studies, however, have examined the relationship of multiple demographic variables (including social identities) to overall levels self-reported mistreatment as well the selection of attributions for discrimination. A diverse community sample (N = 292; 42.12% Black; 47.26% male) reported on experiences of discrimination using the Everyday Discrimination Scale. General linear models were used to test the effect of sociodemographic characteristics (i.e., race, gender, age, SES) on total discrimination score and on attributions for discrimination. To test for intersectional relationships, we tested the effect of two-way interactions of sociodemographic characteristics on total discrimination score and attributions for discrimination. We found preliminary support for intersectional effects, as indicated by a significant race by age interaction on the selection of the race attribution for discrimination; gender by SES on the age attribution; age by gender on the education attribution; and race by SES on the economic situation attribution. Our study extends prior work by highlighting the importance of testing more than one factor as contributing to discrimination, particularly when examining to what sources individuals attribute discrimination

Single institution experience of MRI-guided radiotherapy for thoracic tumors and clinical characteristics impacting treatment duty cycle

IntroductionMRI-guided radiotherapy (MRgRT) allows for direct motion management and real-time radiation treatment plan adaptation. We report our institutional experience using low strength 0.35T MRgRT for thoracic malignancies, and evaluate changes in treatment duty cycle between first and final MRgRT fractions.MethodsAll patients with intrathoracic tumors treated with MRgRT were included. The primary reason for MRgRT (adjacent organ at risk [OAR] vs. motion management [MM] vs. other) was recorded. Tumor location was classified as central (within 2cm of tracheobronchial tree) vs. non-central, and further classified by the Expanded HILUS grouping. Gross tumor volume (GTV) motion, planning target volume expansions, dose/fractionation, treatment plan time, and total delivery time were extracted from the treatment planning system. Treatment plan time was defined as the time for beam delivery, including multileaf collimator (MLC) motion, and gantry rotation. Treatment delivery time was defined as the time from beam on to completion of treatment, including treatment plan time and patient respiratory breath holds. Duty cycle was calculated as treatment plan time/treatment delivery time. Duty cycles were compared between first and final fraction using a two-sample t-test.ResultsTwenty-seven patients with thoracic tumors (16 non-small cell lung cancer and 11 thoracic metastases) were treated with MRgRT between 12/2021 and 06/2023. Fifteen patients received MRgRT due to OAR and 11 patients received MRgRT for motion management. 11 patients had central tumors and all were treated with MRgRT due to OAR risk. The median dose/fractionation was 50 Gy/5 fractions. For patients treated due to OAR (n=15), 80% had at least 1 adapted fraction during their course of radiotherapy. There was no plan adaptation for patients treated due to motion management (n=11). Mean GTV motion was significantly higher for patients treated due to motion management compared to OAR (16.1mm vs. 6.5mm, p=0.011). Mean duty cycle for fraction 1 was 54.2% compared to 62.1% with final fraction (p=0.004). Mean fraction 1 duty cycle was higher for patients treated due to OAR compared to patients treated for MM (61% vs. 45.0%, p=0.012).DiscussionDuty cycle improved from first fraction to final fraction possibly due to patient familiarity with treatment. Duty cycle was improved for patients treated due to OAR risk, likely due to more central location and thus decreased target motion

In-vivo T-cell depleted reduced-intensity conditioned allogeneic haematopoietic stem-cell transplantation for patients with acute lymphoblastic leukaemia in first remission: results from the prospective, single-arm evaluation of the UKALL14 trial.

BACKGROUND: The outcome of chemotherapy in patients older than 40 years with acute lymphoblastic leukaemia is poor and myeloablative allogeneic haematopoietic stem-cell transplantation (HSCT) has a high transplant-related mortality (TRM) in this age cohort. The aim of this study was to assess the activity and safety of reduced-intensity conditioned allogeneic HSCT in this patient population. METHODS: This was a single-arm, prospective study within the UKALL14 trial done in 46 centres in the UK, which recruited patients to the transplantation substudy. Participants in UKALL14 had B-cell or T-cell acute lymphoblastic leukaemia, were aged 25-65 years (BCR-ABL1-negative) or 18-65 years (BCR-ABL1-positive), and for this subcohort had a fit, matched sibling donor or an 8 out of 8 allelic matched unrelated donor (HLA-A, HLA-B, HLA-C, and HLA-DR). On June 20, 2014, the protocol was amended to allow 7 out of 8 matched unrelated donors if the patient had high risk cytogenetics or was minimal residual disease (MRD)-positive after the second induction course. Patients were given fludarabine, melphalan, and alemtuzumab (FMA; intravenous fludarabine 30 mg/m2 on days -6 to -2, melphalan 140 mg/m2 on day -2, and alemtuzumab 30 mg on day -1 [sibling donor] and days -2 and -1 [unrelated donor]) before allogeneic HSCT (aged ≥41 years patient pathway). Donor lymphocyte infusions were given from 6 months for mixed chimerism or MRD. The primary endpoint was event-free survival and secondary and transplantation-specific endpoints included overall survival, relapse incidence, TRM, and acute and chronic graft-versus-host disease (GVHD). This study is registered with ClinicalTrials.gov, NCT01085617. FINDINGS: From Feb 22, 2011, to July 26, 2018, 249 patients (236 aged ≥41 years and 13 younger than 41 years) considered unfit for a myeloablative allograft received an FMA reduced-intensity conditioned HSCT. 138 (55%) patients were male and 111 (45%) were female. 88 (35%) participants received transplantations from a sibling donor and 160 (64%) received transplantations from unrelated donors. 211 (85%) participants had B-precursor acute lymphoblastic leukaemia. High-risk cytogenetics were present in 43 (22%) and another 63 (25%) participants were BCR-ABL1-positive. At median follow-up of 49 months (IQR 36-70), 4-year event-free survival was 46·8% (95% CI 40·1-53·2) and 4-year overall survival was 54·8% (48·0-61·2). 4-year cumulative incidence of relapse was 33·6% (27·9-40·2) and 4-year TRM was 19·6% (15·1-25·3). 27 (56%) of 48 patients with TRM had infection as the named cause of death. Seven (15%) of 48 patients had fungal infections, 13 (27%) patients had bacterial infections (six gram-negative), and 11 (23%) had viral infections (three cytomegalovirus and two Epstein-Barr virus). Acute GVHD grade 2-4 occurred in 29 (12%) of 247 patients and grade 3-4 occurred in 12 (5%) patients. Chronic GVHD incidence was 84 (37%) of 228 patients (50 [22%] had extensive chronic GVHD). 49 (30%) of 162 patients had detectable end-of-induction MRD, which portended worse outcomes with event-free survival (HR 2·40 [95% CI 1·46-3·93]) and time-to-relapse (HR 2·41 [1·29-4·48]). INTERPRETATION: FMA reduced-intensity conditioned allogeneic HSCT in older patients with acute lymphoblastic leukaemia in first complete remission provided good disease control with moderate GVHD, resulting in better-than-expected event-free survival and overall survival in this high-risk population. Strategies to reduce infection-related TRM will further improve outcomes. FUNDING: Cancer Research UK

The correlation between reading and mathematics ability at age twelve has a substantial genetic component

Dissecting how genetic and environmental influences impact on learning is helpful for maximizing numeracy and literacy. Here we show, using twin and genome-wide analysis, that there is a substantial genetic component to children’s ability in reading and mathematics, and estimate that around one half of the observed correlation in these traits is due to shared genetic effects (so-called Generalist Genes). Thus, our results highlight the potential role of the learning environment in contributing to differences in a child’s cognitive abilities at age twelve

Exploring the cultural dimensions of environmental victimization

It has become increasingly clear in recent years that our understanding of ‘victimisation’ is informed by a whole range of societal and political factors which extend well beyond whatever particular form of words appears in any given directive, code or legislative instrument concerning crime, crime victims or criminal justice systems. In this paper, I will seek for the first time to apply recent developments in our understanding of so-called 'cultural victimology' to the issue of environmental harm and its impact on human and non-human animals. McCGarry and Waklate (2015) characterise cultural victimology as broadly comprising of two key aspects. These are the wider sharing and reflection of individual and collective victimisation experiences on the one hand and, on the other, the mapping of those experiences through the criminal justice process. In this discussion I will examine how environmental victimisation is viewed by and presented to society at large and will argue that such representations often fail, as a form of testimony, to adequately convey the traumas involved. Nor is this achieved through the application of present models of criminal, civil or administrative justice regimes in many jurisdictions. This lack of cultural acknowledgement of the harms vested on environmental victims, it is argued, afford us a clearer understand of the continued reticence amongst lawmakers, politicians and legal practitioners to adequately address the impacts of such victimisation through effective justice or regulatory mechanisms. This is unfortunate given that the often collective nature of environmental victimisation makes this particularly suited to a more cultural analysis and understanding. It is argued that various forms of environmental mediation processes might hold the key to this cultural reticence to accept environmental harm as a 'real' and pressing problem as compared to other criminal and civil justice concerns

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Stream denitrification across biomes and its response to anthropogenic nitrate loading

Author Posting. © The Author(s), 2008. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature 452 (2008): 202-205, doi:10.1038/nature06686.Worldwide, anthropogenic addition of bioavailable nitrogen (N) to the biosphere is increasing and terrestrial ecosystems are becoming increasingly N saturated, causing more bioavailable N to enter groundwater and surface waters. Large-scale N budgets show that an average of about 20-25% of the N added to the biosphere is exported from rivers to the ocean or inland basins, indicating substantial sinks for N must exist in the landscape. Streams and rivers may be important sinks for bioavailable N owing to their hydrologic connections with terrestrial systems, high rates of biological activity, and streambed sediment environments that favor microbial denitrification. Here, using data from 15N tracer experiments replicated across 72 streams and 8 regions representing several biomes, we show that total biotic uptake and denitrification of nitrate increase with stream nitrate concentration, but that the efficiency of biotic uptake and denitrification declines as concentration increases, reducing the proportion of instream nitrate that is removed from transport. Total uptake of nitrate was related to ecosystem photosynthesis and denitrification was related to ecosystem respiration. Additionally, we use a stream network model to demonstrate that excess nitrate in streams elicits a disproportionate increase in the fraction of nitrate that is exported to receiving waters and reduces the relative role of small versus large streams as nitrate sinks.Funding for this research was provided by the National Science Foundation

Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures

Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 x 10(-23) and p = 6 x 10(-11), respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers. Germline biallelic pathogenic MUTYH variants predispose patients to colorectal cancer (CRC); however, approaches to identify MUTYH variant carriers are lacking. Here, the authors evaluated mutational signatures that could distinguish MUTYH carriers in large CRC cohorts, and found MUTYH-associated somatic mutations

Comparative analysis of rosaceous genomes and the reconstruction of a putative ancestral genome for the family

Abstract Background Comparative genome mapping studies in Rosaceae have been conducted until now by aligning genetic maps within the same genus, or closely related genera and using a limited number of common markers. The growing body of genomics resources and sequence data for both Prunus and Fragaria permits detailed comparisons between these genera and the recently released Malus × domestica genome sequence. Results We generated a comparative analysis using 806 molecular markers that are anchored genetically to the Prunus and/or Fragaria reference maps, and physically to the Malus genome sequence. Markers in common for Malus and Prunus, and Malus and Fragaria, respectively were 784 and 148. The correspondence between marker positions was high and conserved syntenic blocks were identified among the three genera in the Rosaceae. We reconstructed a proposed ancestral genome for the Rosaceae. Conclusions A genome containing nine chromosomes is the most likely candidate for the ancestral Rosaceae progenitor. The number of chromosomal translocations observed between the three genera investigated was low. However, the number of inversions identified among Malus and Prunus was much higher than any reported genome comparisons in plants, suggesting that small inversions have played an important role in the evolution of these two genera or of the Rosaceae.Apple genome research at FEM is supported by the research office of the Provincia autonoma di Trento. DJS and ELG acknowledge a grant from the East Malling Trust. Fragaria genomics at EMR is funded by the BBSRC. JMB is supported by a grant by Plant & Food Research's Excellence Programme. Apple genomics at Plant & Food Research is partially supported by the New Zealand Foundation for Research Science and Technology project C06X0812 "Exploiting Opportunities from Horticultural Genomics". Research conducted at IRTA was partly funded by the CONSOLIDER-INGENIO 2010 Program (CSD2007-00036) and project INIA-RTA2007-00063-00-00, both from the Spanish Ministry of Science and Innovation. RosCOS development at OSU/MSU was funded by the National Research Initiative Competitive Grant 2005-35300-15454 of USDA's National Institute of Food and Agriculture.Peer Reviewe