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1.
J Genet Couns ; 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34665896

RESUMO

The public health impact of genomic screening can be enhanced by cascade testing. However, cascade testing depends on communication of results to family members. While the barriers and facilitators of family communication have been researched following clinical genetic testing, the factors impacting the dissemination of genomic screening results are unknown. Using the pragmatic Electronic Medical Records and Genomics Network-3 (eMERGE-3) study, we explored the reported sharing practices of participants who underwent genomic screening across the United States. Six eMERGE-3 sites returned genomic screening results for mostly dominant medically actionable disorders and surveyed adult participants regarding communication of results with first-degree relatives. Across the sites, 279 participants completed a 1-month and/or 6-month post-results survey. By 6 months, only 34% of the 156 respondents shared their results with all first-degree relatives and 4% did not share with any. Over a third (39%) first-degree relatives were not notified of the results. Half (53%) of participants who received their results from a genetics provider shared them with all first-degree relatives compared with 11% of participants who received their results from a non-genetics provider. The most frequent reasons for sharing were a feeling of obligation (72%) and that the information could help family members make medical decisions (72%). The most common reasons indicated for not sharing were that the family members were too young (38%), or they were not in contact (25%) or not close to them (25%). These data indicate that the professional returning the results may impact sharing patterns, suggesting that there is a need to continue to educate healthcare providers regarding approaches to facilitate sharing of genetic results within families. Finally, these data suggest that interventions to increase sharing may be universally effective regardless of the origin of the genetic result.

2.
Alzheimers Dement ; 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34581485

RESUMO

INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) has accumulated 15 years of clinical, neuroimaging, cognitive, biofluid biomarker and genetic data, and biofluid samples available to researchers, resulting in more than 3500 publications. This review covers studies from 2018 to 2020. METHODS: We identified 1442 publications using ADNI data by conventional search methods and selected impactful studies for inclusion. RESULTS: Disease progression studies supported pivotal roles for regional amyloid beta (Aß) and tau deposition, and identified underlying genetic contributions to Alzheimer's disease (AD). Vascular disease, immune response, inflammation, resilience, and sex modulated disease course. Biologically coherent subgroups were identified at all clinical stages. Practical algorithms and methodological changes improved determination of Aß status. Plasma Aß, phosphorylated tau181, and neurofilament light were promising noninvasive biomarkers. Prognostic and diagnostic models were externally validated in ADNI but studies are limited by lack of ethnocultural cohort diversity. DISCUSSION: ADNI has had a profound impact in improving clinical trials for AD.

3.
CJEM ; 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34537915

RESUMO

OBJECTIVE: To determine how many Level 1 and Level 2 trauma centres in Canada have implemented a resuscitative endovascular balloon occlusion of the aorta (REBOA) program, and to identify facilitators and barriers to successful implementation of REBOA programs. METHODS: An electronic survey was developed and administered in November 2019 (updated in July 2021) via email to directors at all 32 Level 1 and Level 2 trauma centres across Canada, and to the medical director in PEI (no Level 1 or Level 2 capacity). Survey responses were supplemented by an online search in PubMed and the grey literature. Responses were analyzed using simple descriptive statistics including frequencies and proportions. RESULTS: We received responses from directors at 22 sites (17 Level 1 trauma centres, 4 Level 2 trauma centres, PEI) for a response rate of 66.7%. There are 6 Level 1 trauma centres with REBOA programs; all were implemented between 2017 and 2019. One additional Level 1 trauma centre that did not respond was found to have a REBOA program; thus, 21.9% (7/32) of Canadian Level 1 and Level 2 trauma centres have an existing REBOA program. These programs are located in three provinces (British Columbia, Ontario, Quebec). Five other centres are planning on implementing a REBOA program in the next 2 years. The number of REBOA cases performed ranged from 0 to 30 (median 2). Factors contributing most to successful program implementation were having physician champions and patient populations with sufficient REBOA candidates, while cost and lack of expertise were the greatest barriers identified. CONCLUSION: As of July 2021, 21.9% (7/32) of Canadian Level 1 and Level 2 trauma centres have a REBOA program. Physician champions and a patient population with sufficient numbers of REBOA candidates were the most important factors contributing to successful implementation of these programs.

4.
BMC Med ; 19(1): 199, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34404389

RESUMO

BACKGROUND: The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings. METHODS: Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates' correction. RESULTS: Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility. CONCLUSIONS: This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.

5.
JAMA Pediatr ; 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34424265

RESUMO

Importance: Newborn genomic sequencing (nGS) may provide health benefits throughout the life span, but there are concerns that it could also have an unfavorable (ie, negative) psychosocial effect on families. Objective: To assess the psychosocial effect of nGS on families from the BabySeq Project, a randomized clinical trial evaluating the effect of nGS on the clinical care of newborns from well-baby nurseries and intensive care units. Design, Setting, and Participants: In this randomized clinical trial conducted from May 14, 2015, to May 21, 2019, at well-baby nurseries and intensive care units at 3 Boston, Massachusetts, area hospitals, 519 parents of 325 infants completed surveys at enrollment, immediately after disclosure of nGS results, and 3 and 10 months after results disclosure. Statistical analysis was performed on a per-protocol basis from January 16, 2019, to December 1, 2019. Intervention: Newborns were randomized to receive either standard newborn screening and a family history report (control group) or the same plus an nGS report of childhood-onset conditions and highly actionable adult-onset conditions (nGS group). Main Outcomes and Measures: Mean responses were compared between groups and, within the nGS group, between parents of children who received a monogenic disease risk finding and those who did not in 3 domains of psychosocial impact: parent-child relationship (Mother-to-Infant Bonding Scale), parents' relationship (Kansas Marital Satisfaction Scale), and parents' psychological distress (Edinburgh Postnatal Depression Scale anxiety subscale). Results: A total of 519 parents (275 women [53.0%]; mean [SD] age, 35.1 [4.5] years) were included in this study. Although mean scores differed for some outcomes at singular time points, generalized estimating equations models did not show meaningful differences in parent-child relationship (between-group difference in adjusted mean [SE] Mother-to-Infant Bonding Scale scores: postdisclosure, 0.04 [0.15]; 3 months, -0.18 [0.18]; 10 months, -0.07 [0.20]; joint P = .57) or parents' psychological distress (between-group ratio of adjusted mean [SE] Edinburgh Postnatal Depression Scale anxiety subscale scores: postdisclosure, 1.04 [0.08]; 3 months, 1.07 [0.11]; joint P = .80) response patterns between study groups over time for any measures analyzed in these 2 domains. Response patterns on one parents' relationship measure differed between groups over time (between-group difference in adjusted mean [SE] Kansas Marital Satisfaction Scale scores: postdisclosure, -0.19 [0.07]; 3 months, -0.04 [0.07]; and 10 months, -0.01 [0.08]; joint P = .02), but the effect decreased over time and no difference was observed on the conflict measure responses over time. We found no evidence of persistent negative psychosocial effect in any domain. Conclusions and Relevance: In this randomized clinical trial of nGS, there was no persistent negative psychosocial effect on families among those who received nGS nor among those who received a monogenic disease risk finding for their infant. Trial Registration: ClinicalTrials.gov Identifier: NCT02422511.

6.
J Perinatol ; 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290375

RESUMO

OBJECTIVE: To quantify changes in respiratory and glycemic control outcomes following antenatal corticosteroids (ANCS) exposure in late preterm neonates. DESIGN/METHODS: The study included 500 neonates born between 34 0/7 and 36 6/7 weeks of gestation. Study population was divided into two groups: an immature group (34 0/7-35 6/7 weeks) and a mature group (36 0/7-36 6/7 weeks). Respiratory and glycemic control outcomes were analyzed for each group independently. RESULTS: In the immature group, the odds of developing respiratory distress decreased in neonates exposed to ANCS within 7 days of delivery (aOR 0.42; p = 0.02). In the mature group, ANCS exposure did not change respiratory outcomes, but decreased lowest blood glucose levels (-1.5 ± 0.66 mg/dL per dose, p = 0.02). CONCLUSION: In our study cohort, ANCS administration was associated with improved neonatal respiratory outcomes only for infants in the immature 34 0/7-35 6/7 weeks of gestational age group. ANCS was associated with altered glycemic control only in infants in the mature 36 0/7-36 6/7 weeks of gestational age group.

7.
Genome Med ; 13(1): 115, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34266500

RESUMO

The Global Alliance for Genomics and Health has approved a policy for the return of clinically actionable genomic research results, the first such policy approved by an international body. The policy acknowledges the potential medical benefits to millions of individuals who are participating in genomics research. It ties the pace of implementation to each country's clinical standards, including for the return of secondary findings, and urges funders to set aside resources to support responsible return.

9.
J Vis ; 21(7): 2, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34241621

RESUMO

Radial frequency (RF) patterns, circles which have had their radius modulated as a function of their polar angle, have been used in the examination of the integration of contour information around closed contour patterns. Typically, these patterns have been presented in a random orientation from trial-to-trial in order to maintain spatial uncertainty as to the location of the deformation on the pattern, as it may affect observer strategy and performance. However, the effect of fixed and random orientation (phase) on observer gaze strategies used to discriminate RF patterns has not been directly tested. This study compared fixation patterns across four conditions: fixed phase single cycle; random phase single cycle; fixed phase three cycle; and random phase three cycle RF3 patterns. The results showed that observers fixated on the known location of deformation for the fixed phase single cycle condition but used a more central fixation for the other three conditions. This strategy had a significant effect on observer thresholds for the fixed phase single cycle condition, with greater adherence to the strategy resulting in lower thresholds. It was also found that for the single cycle patterns observers tended to fixate on different locations on the pattern: on the maximum orientation difference from circular for the fixed phase pattern; and on the point of maximum curvature for the random phase pattern. These differences in gaze patterns are likely driven by the underlying local or global processing of the fixed or random phase single cycle patterns, respectively.

10.
J Genet Couns ; 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34309124

RESUMO

Much emphasis has been placed on participant's psychological safety within genomic research studies; however, few studies have addressed parental psychological health effects associated with their child's participation in genomic studies, particularly when parents meet the threshold for clinical concern for depression. We aimed to determine if parents' depressive symptoms were associated with their child's participation in a randomized-controlled trial of newborn exome sequencing. Parents completed the Edinburgh Postnatal Depression Scale (EPDS) at baseline, immediately post-disclosure, and 3 months post-disclosure. Mothers and fathers scoring at or above thresholds for clinical concern on the EPDS, 12 and 10, respectively, indicating possible Major Depressive Disorder with Peripartum Onset, were contacted by study staff for mental health screening. Parental concerns identified in follow-up conversations were coded for themes. Forty-five parents had EPDS scores above the clinical threshold at baseline, which decreased by an average of 2.9 points immediately post-disclosure and another 1.1 points 3 months post-disclosure (both p ≤ .014). For 28 parents, EPDS scores were below the threshold for clinical concern at baseline, increased by an average of 4.7 points into the elevated range immediately post-disclosure, and decreased by 3.8 points at 3 months post-disclosure (both p < .001). Nine parents scored above thresholds only at 3 months post-disclosure after increasing an average of 5.7 points from immediately post-disclosure (p < .001). Of the 82 parents who scored above the threshold at any time point, 43 (52.4%) were reached and 30 (69.7%) of these 43 parents attributed their elevated scores to parenting stress, balancing work and family responsibilities, and/or child health concerns. Only three parents (7.0%) raised concerns about their participation in the trial, particularly their randomization to the control arm. Elevated scores on the EPDS were typically transient and parents attributed their symptomatology to life stressors in the postpartum period rather than participation in a trial of newborn exome sequencing.

11.
PLoS One ; 16(7): e0254153, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34324495

RESUMO

Newer data platforms offer increased opportunity to share multidimensional health data with research participants, but the preferences of participants for which data to receive and how is evolving. Our objective is to describe the preferences and expectations of participants for the return of individual research results within Project Baseline Health Study (PBHS). The PBHS is an ongoing, multicenter, longitudinal cohort study with data from four initial enrollment sites. PBHS participants are recruited from the general population along with groups enriched for heart disease and cancer disease risk. Cross-sectional data on return of results were collected in 2017-2018 from an (1) in-person enrollment survey (n = 1,890), (2) benchmark online survey (n = 1,059), and (3) participant interviews (n = 21). The main outcomes included (1) preferences for type of information to be added next to returned results, (2) participant plans for sharing returned results with a non-study clinician, and (3) choice to opt-out of receiving genetic results. Results were compared by sociodemographic characteristics. Enrollment and benchmark survey respondents were 57.1% and 53.5% female, and 60.0% and 66.2% white, respectively. Participants preferred the following data types be added to returned results in the future: genetics (29.9%), heart imaging, (16.4%), study watch (15.8%), and microbiome (13.3%). Older adults (OR 0.60, 95% CI: 0.41-0.87) were less likely to want their genetic results returned next. Forty percent of participants reported that they would not share all returned results with their non-study clinicians. Black (OR 0.64, 95% CI 0.43-0.95) and Asian (OR 0.47, 95% CI 0.30-0.73) participants were less likely, and older participants more likely (OR 1.45-1.61), to plan to share all results with their clinician than their counterparts. At enrollment, 5.8% of participants opted out of receiving their genetics results. The study showed that substantial heterogeneity existed in participant's preferences and expectations for return of results, and variations were related to sociodemographic characteristics.

12.
Genet Med ; 23(10): 1977-1983, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34113000

RESUMO

PURPOSE: How primary care providers (PCPs) respond to genomic secondary findings (SFs) of varying clinical significance (pathogenic, uncertain significance [VUS], or benign) is unknown. METHODS: We randomized 148 American Academy of Family Physicians members to review three reports with varying significance for Lynch syndrome. Participants provided open-ended responses about the follow-up they would address and organized the SF reports and five other topics in the order they would prioritize responding to them (1 = highest priority, 6 = lowest priority). RESULTS: PCPs suggested referrals more often for pathogenic variants or VUS than benign variants (72% vs. 16%, p < 0.001). PCPs were also more likely to address further workup, like a colonoscopy or esophagogastroduodenoscopy, in response to pathogenic variants or VUS than benign variants (43% vs. 4%, p < 0.001). The likelihoods of addressing referrals or further workup were similar when PCPs reviewed pathogenic variants and VUS (both p > 0.46). SF reports were prioritized highest for pathogenic variants (2.7 for pathogenic variants, 3.6 for VUS, 4.3 for benign variants, all p ≤ 0.014). CONCLUSION: Results suggest that while PCPs appreciated the differences in clinical significance, disclosure of VUS as SFs would substantially increase downstream health-care utilization.

13.
Nat Med ; 27(6): 1012-1024, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34099924

RESUMO

Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10-7), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10-28), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10-15), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10-9) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10-4). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.


Assuntos
Envelhecimento/genética , Doenças Transmissíveis/genética , Pneumonia/genética , Sepse/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Bancos de Espécimes Biológicos , Aberrações Cromossômicas , Doenças Transmissíveis/complicações , Doenças Transmissíveis/microbiologia , Doenças do Sistema Digestório/epidemiologia , Doenças do Sistema Digestório/genética , Doenças do Sistema Digestório/microbiologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mosaicismo , Pneumonia/epidemiologia , Pneumonia/microbiologia , Fatores de Risco , Sepse/epidemiologia , Sepse/microbiologia , Anormalidades Urogenitais/epidemiologia , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/microbiologia , Adulto Jovem
14.
J Burn Care Res ; 2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34091669

RESUMO

Respiratory failure and acute respiratory distress syndrome can occur in burn patients with or without inhalational injury, and can significantly increase mortality. For patients with severe respiratory failure who fail conventional therapy with mechanical ventilation, the use of veno-venous extracorporeal membrane oxygen (ECMO) may be a lifesaving salvage therapy. There have been a series of case reports detailing the use of ECMO in burn patients over the last twenty years, but very little is currently known about the status of ECMO use at burn centers in North America. Using a web-based survey of burn center directors in Canada and the United States, we examined the rate of usage of ECMO in burn care, barriers to its use, and the perioperative management of burn patients receiving ECMO therapy. Our findings indicate that approximately half of burn centers have used ECMO in the care of burn patients, but patient volume is very low on average (less than 1 per year). Of centers that do use ECMO in burn care, only 40% have a specified protocol for doing so. Approximately half have operated on patients being actively treated with ECMO therapy, but perioperative management of anticoagulation varies widely. A lack of experience and institutional support, and a perceived lack of evidence to support ECMO use in burn patients were the most commonly identified barriers to more widespread uptake. Better collaboration between burn centers will allow for the creation of consensus statements and protocols to improve outcomes for burn patients who require ECMO.

15.
J Community Health ; 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34106371

RESUMO

Traumatic brain injury (TBI) is a leading cause of death and disability among adults. Falls and motor vehicle collisions (MVCs) are the most common causes of TBI hospitalizations in Canada. The purpose of this study was to determine whether, at the provincial level, there have been significant changes in the injury rate and causes of major TBI. This was a retrospective cohort study of all patients in Nova Scotia who presented with major TBI (Abbreviated Injury Scale Head score ≥ 3) between 2002 and 2018. Prospectively entered data were collected from the Nova Scotia Trauma Registry. Annual injury rates were calculated based on 100,000 population (all ages) using population estimates from Statistics Canada. Linear regression was performed to analyze annual trends of major TBI within the province. There were 5590 major TBI patients in Nova Scotia during the 16-year study period. The overall annual rate of major TBI was 37 per 100,000 population. There was a 39% increase in the rate of major TBI over the study period (r = - 0.72, R2 = 0.51, p < 0.002). Patients had a mean age of 51 ± 25 years; 72% were male. The proportion of TBIs in males decreased significantly from 76% in 2002 to 69% in 2017 (p < 0.001). Mechanisms of injury were predominantly falls (45%) and MVCs (29%); the proportion of violent injuries was 11.5%. The rate of fall-related TBIs more than doubled between 2002 and 2017, increasing from 9.1 to 20.5 injuries per 100,000 (p < 0.001). Our findings demonstrate an increasing incidence of major TBI over a 16-year period with a greater than two-fold increase in the rate of fall-related TBI. These results are important for targeting TBI prevention efforts in reducing falls, especially in older adults.

16.
J Perinatol ; 41(6): 1432-1440, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34035456

RESUMO

OBJECTIVE: To identify the prevalence of renal insufficiency (RI) in children with a history of prematurity and acute kidney injury (AKI). STUDY DESIGN: This prospective cohort study evaluated renal function in children born preterm at 5-9 years of age. Univariable analyses compared perinatal and follow-up data from subjects with and without AKI history, and with and without current RI. Regression analyses were attempted to model RI as a function of AKI and other clinical risk factors. RESULTS: Fifteen of 43 (35%) participants had previously undiagnosed RI. Only children with no AKI history or neonatal stage 1 AKI presented for follow-up. Children born preterm with a history of stage 1 AKI had higher serum creatinine (sCr) at follow-up, but were not more likely to have RI compared to children without stage 1 AKI history (RI prevalence 30% and 36% in AKI and non-AKI group, respectively). CONCLUSION: The high prevalence of RI in this preterm cohort at middle childhood follow-up highlights the need for routine kidney health assessments in this population. Large multicenter studies are needed to further characterize the impact of premature birth and mild AKI on renal function throughout childhood.


Assuntos
Injúria Renal Aguda , Nascimento Prematuro , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Criança , Feminino , Humanos , Gravidez , Estudos Prospectivos
17.
Phys Rev Lett ; 126(18): 187602, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34018782

RESUMO

Antiferromagnetic order is a common and robust ground state in the parent (undoped) phase of several strongly correlated electron systems. The progressive weakening of antiferromagnetic correlations upon doping paves the way for a variety of emergent many-electron phenomena including unconventional superconductivity, colossal magnetoresistance, and collective charge-spin-orbital ordering. In this study, we explored the use of oxygen stoichiometry as an alternative pathway to modify the coupled magnetic and electronic ground state in the family of rare earth nickelates (RENiO_{3-x}). Using a combination of x-ray spectroscopy and resonant soft x-ray magnetic scattering, we find that, while oxygen vacancies rapidly alter the electronic configuration within the Ni and O orbital manifolds, antiferromagnetic order is remarkably robust to substantial levels of carrier doping, only to suddenly collapse beyond 0.21 e^{-}/Ni without an accompanying structural transition. Our work demonstrates that ordered magnetism in RENiO_{3-x} is mostly insensitive to carrier doping up to significant levels unseen in other transition-metal oxides. The sudden collapse of ordered magnetism upon oxygen removal may provide a new mechanism for solid-state magnetoionic switching and new applications in antiferromagnetic spintronics.

18.
Genome Res ; 31(6): 935-946, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33963077

RESUMO

Genomic deletions provide a powerful loss-of-function model in noncoding regions to assess the role of purifying selection on genetic variation. Regulatory element function is characterized by nonuniform tissue and cell type activity, necessarily linking the study of fitness consequences from regulatory variants to their corresponding cellular activity. We generated a callset of deletions from genomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and used deletions from The 1000 Genomes Project Consortium (1000GP) in order to examine whether purifying selection preserves noncoding sites of chromatin accessibility marked by DNase I hypersensitivity (DHS), histone modification (enhancer, transcribed, Polycomb-repressed, heterochromatin), and chromatin loop anchors. To examine this in a cellular activity-aware manner, we developed a statistical method, pleiotropy ratio score (PlyRS), which calculates a correlation-adjusted count of "cellular pleiotropy" for each noncoding base pair by analyzing shared regulatory annotations across tissues and cell types. By comparing real deletion PlyRS values to simulations in a length-matched framework and by using genomic covariates in analyses, we found that purifying selection acts to preserve both DHS and enhancer noncoding sites. However, we did not find evidence of purifying selection for noncoding transcribed, Polycomb-repressed, or heterochromatin sites beyond that of the noncoding background. Additionally, we found evidence that purifying selection is acting on chromatin loop integrity by preserving colocalized CTCF binding sites. At regions of DHS, enhancer, and CTCF within chromatin loop anchors, we found evidence that both sites of activity specific to a particular tissue or cell type and sites of cellularly pleiotropic activity are preserved by selection.

19.
Public Health Genomics ; : 1-13, 2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34058740

RESUMO

BACKGROUND: Genomic testing is increasingly employed in clinical, research, educational, and commercial contexts. Genomic literacy is a prerequisite for the effective application of genomic testing, creating a corresponding need for validated tools to assess genomics knowledge. We sought to develop a reliable measure of genomics knowledge that incorporates modern genomic technologies and is informative for individuals with diverse backgrounds, including those with clinical/life sciences training. METHODS: We developed the GKnowM Genomics Knowledge Scale to assess the knowledge needed to make an informed decision for genomic testing, appropriately apply genomic technologies and participate in civic decision-making. We administered the 30-item draft measure to a calibration cohort (n = 1,234) and subsequent participants to create a combined validation cohort (n = 2,405). We performed a multistage psychometric calibration and validation using classical test theory and item response theory (IRT) and conducted a post-hoc simulation study to evaluate the suitability of a computerized adaptive testing (CAT) implementation. RESULTS: Based on exploratory factor analysis, we removed 4 of the 30 draft items. The resulting 26-item GKnowM measure has a single dominant factor. The scale internal consistency is α = 0.85, and the IRT 3-PL model demonstrated good overall and item fit. Validity is demonstrated with significant correlation (r = 0.61) with an existing genomics knowledge measure and significantly higher scores for individuals with adequate health literacy and healthcare providers (HCPs), including HCPs who work with genomic testing. The item bank is well suited to CAT, achieving high accuracy (r = 0.97 with the full measure) while administering a mean of 13.5 items. CONCLUSION: GKnowM is an updated, broadly relevant, rigorously validated 26-item measure for assessing genomics knowledge that we anticipate will be useful for assessing population genomic literacy and evaluating the effectiveness of genomics educational interventions.

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