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Parkinson's Disease (PD) develops unilaterally, which may be related to brain hemispheric differences in gene expression. Here we measured bulk RNA-seq levels in neuronal nuclei obtained from prefrontal cortex postmortem brain samples from males and females with PD and from healthy controls. Left and right hemispheres from each brain were related the side of symptom onset and compared. We employed two a priori approaches; first we identified genes differentially expressed between PD and controls and between left vs right PD brain hemispheres. Second, we examined the presence of, and correlates to, variable asymmetry seen in candidate PD differentially expressed genes. We found large variation among individuals with PD, and PD stratification by gene expression similarity was required for patterns of genetic asymmetry to emerge. For a subset of PD brains, hemispherical variation of CCT and BEX gene levels correlated with the side of PD symptom onset.
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Genome-wide association studies have identified thousands of single nucleotide polymorphisms that associate with increased risk for Parkinson's disease (PD), but the functions of most of them are unknown. Using assay for transposase-accessible chromatin (ATAC) and H3K27ac chromatin immunoprecipitation (ChIP) sequencing data, we identified 73 regulatory elements in microglia that overlap PD risk SNPs. To determine the target genes of a "risk enhancer" within intron two of SNCA, we used CRISPR-Cas9 to delete the open chromatin region where two PD risk SNPs reside. The loss of the enhancer led to reduced expression of multiple genes including SNCA and the adjacent gene MMRN1. It also led to expression changes of genes involved in glucose metabolism, a process that is known to be altered in PD patients. Our work expands the role of SNCA in PD and provides a connection between PD-associated genetic variants and underlying biology that points to a risk mechanism in microglia.
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CpG methylation generally occurs on both DNA strands and is essential for mammalian development and differentiation. Until recently, hemimethylation, in which only one strand is methylated, was considered to be simply a transitory state generated during DNA synthesis. The discovery that a subset of CCCTC-binding factor (CTCF) binding sites is heritably hemimethylated suggests that hemimethylation might have an unknown biological function. Here we show that the binding of CTCF is profoundly altered by which DNA strand is methylated and by the specific CTCF binding motif. CpG methylation on the motif strand can inhibit CTCF binding by up to 7-fold, whereas methylation on the opposite strand can stimulate binding by up to 4-fold. Thus, hemimethylation can alter binding by up to 28-fold in a strand-specific manner. The mechanism for sensing methylation on the opposite strand requires two critical residues, V454 and S364, within CTCF zinc fingers 7 and 4. Similar to methylation, CpG hydroxymethylation on the motif strand can inhibit CTCF binding by up to 4-fold. However, hydroxymethylation on the opposite strand removes the stimulatory effect. Strand-specific methylation states may therefore provide a mechanism to explain the transient and dynamic nature of CTCF-mediated chromatin interactions.
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Fator de Ligação a CCCTC , Metilação de DNA , Proteínas Repressoras , Animais , Sítios de Ligação , Fator de Ligação a CCCTC/metabolismo , Cromatina , Ilhas de CpG , DNA/metabolismo , Mamíferos/genética , Proteínas Repressoras/metabolismoRESUMO
One of the most significant risk variants for Parkinson's disease (PD), rs356182, is located at the PD-associated locus near the alpha-synuclein (α-syn) encoding gene, SNCA. SNCA-proximal variants, including rs356182, are thought to function in PD risk through enhancers via allele-specific regulatory effects on SNCA expression. However, this interpretation discounts the complex activity of genetic enhancers and possible non-conical functions of α-syn. Here we investigated a novel risk mechanism for rs356182. We use CRISPR-Cas9 in LUHMES cells, a model for dopaminergic midbrain neurons, to generate precise hemizygous lesions at rs356182. The PD-protective (A/-), PD-risk (G/-) and wild-type (A/G) clones were neuronally differentiated and then compared transcriptionally and morphologically. Among the affected genes was SNCA, whose expression was promoted by the PD-protective allele (A) and repressed in its absence. In addition to SNCA, hundreds of genes were differentially expressed and associated with neurogenesis and axonogenesis-an effect not typically ascribed to α-syn. We also found that the transcription factor FOXO3 specifically binds to the rs356182 A-allele in differentiated LUHMES cells. Finally, we compared the results from the rs356182-edited cells to our previously published knockouts of SNCA and found only minimal overlap between the sets of significant differentially expressed genes. Together, the data implicate a risk mechanism for rs356182 in which the risk-allele (G) is associated with abnormal neuron development, independent of SNCA expression. We speculate that these pathological effects manifest as a diminished population of dopaminergic neurons during development leading to the predisposition for PD later in life.
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Doença de Parkinson , alfa-Sinucleína , Humanos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Diferenciação Celular/genética , Neurônios Dopaminérgicos/metabolismo , Expressão Gênica , Doença de Parkinson/genética , Doença de Parkinson/metabolismoRESUMO
As researchers grapple with the mechanisms and implications of alpha-synuclein (α-syn) in neuropathology, it is often forgotten that the function(s) of α-syn in healthy cells remain largely elusive. Previous work has relied on observing α-syn localization in the cell or using knockout mouse models. Here, we address the specific role of α-syn in human dopaminergic neurons by disrupting its gene (SNCA) in the human dopaminergic neuron cell line, LUHMES. SNCA-null cells were able to differentiate grossly normally and showed modest effects on gene expression. The effects on gene expression were monodirectional, resulting primarily in the significant decrease of expression for 401 genes, implicating them as direct, or indirect positive targets of α-syn. Gene ontological analysis of these genes showed enrichment in terms associated with proliferation, differentiation, and synapse activity. These results add to the tapestry of α-syn biological functions. SIGNIFICANCE STATEMENT: The normal functions of α-syn have remained controversial, despite its clear importance in Parkinson's Disease pathology, where it accumulates in Lewy bodies and contributes to neurodegeneration. Its name implies synaptic and nuclear functions, but how it participates at these locations has not been resolved. Via knock-out experiments in dopaminergic neurons, we implicate α-syn as a functional participant in synapse activity and in proliferation/differentiation, the latter being novel and provide insight into α-syn's role in neuronal development.
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Neurônios Dopaminérgicos , Doença de Parkinson , alfa-Sinucleína , Animais , Proliferação de Células , Neurônios Dopaminérgicos/metabolismo , Expressão Gênica , Humanos , Camundongos , Doença de Parkinson/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
In jurisdictions throughout the United States, thousands of sexual assault kits (SAKs; also known as a "rape kits") have not been submitted by the police for forensic DNA testing. DNA evidence may be helpful to sexual assault investigations and prosecutions by identifying perpetrators, revealing serial offenders through DNA matches across cases, and exonerating those who have been wrongly accused. This paper describes a longitudinal action research project conducted in Detroit, Michigan after that city discovered approximately 11,000 untested sexual assault kits in a police department storage facility. We conducted a root cause analysis to examine individual, organizational, community, and societal factors that contributed to the development of the rape kit backlog in Detroit. Based on those findings, we implemented and evaluated structural changes to increase staffing, promote kit testing, and retrain police and prosecutors so that cases could be reopened for investigation and prosecution. As we conducted this work, we also studied how this action research project impacted the Detroit criminal justice system. Participating in this project changed stakeholders' attitudes about the utility of research to address community problems, the usefulness of DNA evidence in sexual assault cases, and the impact of trauma on survivors. The results led to new protocols for SAK testing and police investigations, and new state legislation mandating SAK forensic DNA testing.
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Vítimas de Crime , Estupro , Delitos Sexuais , Direito Penal , Pesquisa sobre Serviços de Saúde , Humanos , Aplicação da Lei , Estados UnidosRESUMO
Genetic risk for complex diseases very rarely reflects only Mendelian-inherited phenotypes where single-gene mutations can be followed in families by linkage analysis. More commonly, a large set of low-penetrance, small effect-size variants combine to confer risk; they are normally revealed in genome-wide association studies (GWAS), which compare large population groups. Whereas Mendelian inheritance points toward disease mechanisms arising from the mutated genes, in the case of GWAS signals, the effector proteins and even general risk mechanism are mostly unknown. Instead, the utility of GWAS currently lies primarily in predictive and diagnostic information. Although an amazing body of GWAS-based knowledge now exists, we advocate for more funding towards the exploration of the fundamental biology in post-GWAS studies; this research will bring us closer to causality and risk gene identification. Using Parkinson's Disease as an example, we ask, how, where, and when do risk loci contribute to disease?
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BACKGROUND: Cell-to-cell propagation of α-synuclein (α-syn) aggregates is thought to contribute to the pathogenesis of Parkinson's disease (PD) and underlie the spread of α-syn neuropathology. Increased pro-inflammatory cytokine levels and activated microglia are present in PD and activated microglia can promote α-syn aggregation. However, it is unclear how microglia influence α-syn cell-to-cell transfer. METHODS: We developed a clinically relevant mouse model to monitor α-syn prion-like propagation between cells; we transplanted wild-type mouse embryonic midbrain neurons into a mouse striatum overexpressing human α-syn (huα-syn) following adeno-associated viral injection into the substantia nigra. In this system, we depleted or activated microglial cells and determined the effects on the transfer of huα-syn from host nigrostriatal neurons into the implanted dopaminergic neurons, using the presence of huα-syn within the grafted cells as a readout. RESULTS: First, we compared α-syn cell-to-cell transfer between host mice with a normal number of microglia to mice in which we had pharmacologically ablated 80% of the microglia from the grafted striatum. With fewer host microglia, we observed increased accumulation of huα-syn in grafted dopaminergic neurons. Second, we assessed the transfer of α-syn into grafted neurons in the context of microglia activated by one of two stimuli, lipopolysaccharide (LPS) or interleukin-4 (IL-4). LPS exposure led to a strong activation of microglial cells (as determined by microglia morphology, cytokine production and an upregulation in genes involved in the inflammatory response in the LPS-injected mice by RNA sequencing analysis). LPS-injected mice had significantly higher amounts of huα-syn in grafted neurons. In contrast, injection of IL-4 did not change the proportion of grafted dopamine neurons that contained huα-syn relative to controls. As expected, RNA sequencing analysis on striatal tissue revealed differential gene expression between LPS and IL-4-injected mice; with the genes upregulated in tissue from mice injected with LPS including several of those involved in an inflammatory response. CONCLUSIONS: The absence or the hyperstimulation of microglia affected α-syn transfer in the brain. Our results suggest that under resting, non-inflammatory conditions, microglia modulate the transfer of α-syn. Pharmacological regulation of neuroinflammation could represent a future avenue for limiting the spread of PD neuropathology.
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Encéfalo/metabolismo , Microglia/metabolismo , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Feminino , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Degeneração Neural/induzido quimicamente , Degeneração Neural/patologia , Doença de Parkinson/tratamento farmacológicoRESUMO
BACKGROUND: Breast cancer genetic predisposition is governed by more than 142 loci as revealed by genome-wide association studies (GWAS). The functional contribution of these risk loci to breast cancer remains unclear, and additional post-GWAS analyses are required. METHODS: We identified active regulatory elements (enhancers, promoters, and chromatin organizing elements) by histone H3K27 acetylation and CTCF occupancy and determined the enrichment of risk variants at these sites. We compared these results with previously published data and for other cell lines, including human mammary epithelial cells, and related these data to gene expression. RESULTS: In terms of mapping accuracy and resolution, our data augment previous annotations of the MCF-7 epigenome. After intersection with GWAS risk variants, we found 39 enhancers and 15 CTCF occupancy sites that, between them, overlapped 96 breast cancer credible risk variants at 42 loci. These risk enhancers likely regulate the expression of dozens of genes, which are enriched for GO categories, including estrogen and prolactin signaling. CONCLUSIONS: Ten (of 142) breast cancer risk loci likely function via enhancers that are active in MCF-7 and are well suited to targeted manipulation in this system. In contrast, risk loci cannot be mapped to specific CTCF-binding sites, and the genes linked to risk CTCF sites did not show functional enrichment. The identity of risk enhancers and their associated genes suggests that some risk may function during later processes in cancer progression. IMPACT: Here, we report how the ER+ cell line MCF-7 can be used to dissect risk mechanisms for breast cancer.
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Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Fator de Ligação a CCCTC/genética , Células MCF-7 , Modelos Genéticos , Neoplasias da Mama/patologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Haplótipos , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Fatores de RiscoRESUMO
The purpose of this study was to test hypothesized relationships of the health promotion model (HPM) as a means of predicting moderate-to-vigorous physical activity (MVPA) among urban, adolescent girls. A secondary analysis of baseline data from a group randomized controlled trial was conducted. The study involved eight urban schools in the Midwestern United States. The sample included girls (N = 517) in the 5th-8th grades. Data were collected on age, body mass index, pubertal status, enjoyment, self-efficacy, social support, options for physical activity (PA), and commitment to PA. MVPA was measured via accelerometers worn by the girls for 7 days. Structural equation modeling was used to analyze study aims. Mean age of the sample was 11.8 years (standard deviation [SD] = 1.0). Girls attained an average of 3.0 (SD = 1.2) minutes per hour of MVPA. Self-efficacy had a positive direct (ß = .337; p < .001) and total effect (ß = .310; p < .001) on MVPA. Social support and options for PA were not significant predictors of commitment to PA or MVPA. Commitment to PA had a negative but nonsignificant effect (ß = -.056; p = .357) on MVPA. The model predicted 10.1% of the variance in MVPA with 9.6% of the variance predicted by self-efficacy. Limitations include lack of longitudinal analysis and inability to generalize the results to other populations such as boys. PA self-efficacy continues to emerge as a significant predictor of MVPA in the HPM. Continued theory testing is needed to better understand the correlates and determinants of PA among adolescent girls before designing theory-based interventions to promote PA.
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Comportamento do Adolescente/psicologia , Atitude Frente a Saúde , Exercício Físico/psicologia , Estilo de Vida Saudável , População Urbana/estatística & dados numéricos , Adolescente , Criança , Feminino , Promoção da Saúde , Humanos , Meio-Oeste dos Estados UnidosRESUMO
Hundreds of thousands of previously untested sexual assault kits (SAKs) have been uncovered in police property storage facilities across the United States, representing a national failure in institutional response to sexual assault. Faced with this discovery, jurisdictions must now decide if and how they should test these kits. Some stakeholders have suggested prioritizing kits for testing by victim, offender, or assault characteristics, based on the belief that these characteristics can predict the likely utility of DNA testing. However, little research has examined the empirical merits of such prioritization. To address this gap in the literature and inform SAK testing policies, we randomly sampled 900 previously untested SAKs from Detroit, MI. The sampled SAKs were submitted for DNA testing, and eligible DNA profiles were entered into Combined DNA Index System (CODIS), the federal DNA database. Police records associated with each SAK were coded for victim, offender, and assault characteristics, and logistic regression analyses were conducted to test whether these characteristics predict which SAKs yield DNA profiles that match ("hit") to other criminal offenses in CODIS. Testing this sample of previously-untested SAKs produced a substantial number of CODIS hits, but few of the tested variables were significant predictors of CODIS hit rate. These findings suggest that testing all previously-unsubmitted kits may generate information that is useful to the criminal justice system, while also potentially addressing the institutional betrayal victims experienced when their kits were ignored.
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Vítimas de Crime , Criminosos , Ciências Forenses/estatística & dados numéricos , Estupro , Manejo de Espécimes/estatística & dados numéricos , Direito Penal , Bases de Dados de Ácidos Nucleicos , Feminino , Humanos , Aplicação da Lei , Michigan , Alocação de Recursos , Estados UnidosRESUMO
Transition cow diseases can negatively impact animal welfare and reduce dairy herd profitability. Transition cow disease incidence has remained relatively stable over time despite monitoring and management efforts aimed to reduce the risk of developing diseases. Dairy cattle disease risk is monitored by assessing multiple factors, including certain biomarker test results, health records, feed intake, body condition score, and milk production. However, these factors, which are used to make herd management decisions, are often reviewed separately without considering the correlation between them. In addition, the biomarkers that are currently used for monitoring may not be representative of the complex physiological changes that occur during the transition period. Predictive modeling, which uses data to predict future or current outcomes, is a method that can be used to combine the most predictive variables and their interactions efficiently. The use of an effective predictive model with relevant predictors for transition cow diseases will result in better targeted interventions, and therefore lower disease incidence. This review will discuss predictive modeling methods and candidate variables in the context of transition cow diseases. The next step is to investigate novel biomarkers and statistical methods that are best suited for the prediction of transition cow diseases.
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Doenças dos Bovinos/patologia , Modelos Biológicos , Animais , Biomarcadores/sangue , Bovinos , Feminino , Lactação , Valor Preditivo dos Testes , Fatores de RiscoRESUMO
In genome-wide association studies of complex diseases, many risk polymorphisms are found to lie in non-coding DNA and likely confer risk through allele-dependent differences in gene regulatory elements. However, because distal regulatory elements can alter gene expression at various distances on linear DNA, the identity of relevant genes is unknown for most risk loci. In Parkinson's disease, at least some genetic risk is likely intrinsic to a neuronal subpopulation of cells in the brain regions affected. In order to compare neuron-relevant methods of pairing risk polymorphisms to target genes as well as to further characterize a single-cell model of a neurodegenerative disease, we used the portionally-dopaminergic, neuronal, mesencephalic-derived cell line LUHMES to dissect differentiation-specific mechanisms of gene expression. We compared genome-wide gene expression in undifferentiated and differentiated cells with genome-wide histone H3K27ac and CTCF-bound regions. Whereas promoters and CTCF binding were largely consistent between differentiated and undifferentiated cells, enhancers were mostly unique. We matched the differentiation-specific appearance or disappearance of enhancers with changes in gene expression and identified 22,057 enhancers paired with 6388 differentially expressed genes by proximity. These enhancers are enriched with at least 13 transcription factor response elements, driving a cluster of genes involved in neurogenesis. We show that differentiated LUHMES cells, but not undifferentiated cells, show enrichment for PD-risk SNPs. Candidate genes for these loci are largely unrelated, though a subset is linked to synaptic vesicle cycling and transport, implying that PD-related disruption of these pathways is intrinsic to dopaminergic neurons.
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Predisposição Genética para Doença/genética , Mesencéfalo/patologia , Neurônios/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Sequência de Aminoácidos/genética , Linhagem Celular , HumanosRESUMO
Genome-wide association studies of Parkinson's disease have revealed polymorphic variants associated with closely mapped genes of interest. We propose here that those genes may only represent the tip of an iceberg of regulatory effects and do not necessary reflect disease relevance. To usefully interpret a risk locus, one needs to consider 5 dimensions of information, which represent the three-dimensional structure of chromatin (dimensions #1- 3), which is locally variable across time (dimension #4), and, most importantly, dependent on cell type and context (dimension #5).
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Cromatina/genética , Doença de Parkinson/genética , Cromatina/ultraestrutura , Elementos Facilitadores Genéticos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Locos de Características Quantitativas , Fatores de Risco , Fatores de TempoRESUMO
Despite high prevalence rates of elder abuse and neglect (EA/N), compliance with mandatory reporting remains low. A lack of practical training on EA/N has been identified as a barrier. This article describes the development, implementation, and evaluation of an innovative virtual-reality-based educational intervention intended to improve EA/N recognition and reporting among nurses and social workers providing in-home services. The educational intervention consisted of two parts, including an introductory course and advanced assessment training in virtual reality. The advanced assessment training was focused on learning to use the QualCare Scale, an instrument used to assess quality of family caregiving. Data was evaluated in terms of user satisfaction, changes in knowledge, and changes in practice. Results indicate that participants were satisfied with the content and format of the training program. Participants made gains in knowledge in identification and had 99% accuracy in their mandatory reporting decisions. Importantly, professionals reported making changes in their daily practice based on knowledge and skills learnt. Evaluation data indicate that this interdisciplinary training program was a satisfactory way to learn that produced changes in knowledge and impacted clinical practice. Few implementation barriers were encountered during this project suggesting it would be replicable.
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Abuso de Idosos , Geriatria/educação , Notificação de Abuso , Realidade Virtual , Idoso , Educação , Educação em Enfermagem/métodos , Escolaridade , Abuso de Idosos/prevenção & controle , Abuso de Idosos/psicologia , Humanos , Práticas Interdisciplinares , Ensino , Materiais de EnsinoRESUMO
An increasing number of U.S. law enforcement agencies have disclosed that they have large numbers of untested sexual assault kits (SAKs; also called "rape kits") in police property storage. Whether previously untested SAKs should be tested for DNA evidence has been the subject of considerable public debate. To inform policy and practice regarding rape kit testing, the current study tested a sample of 900 previously unsubmitted SAKs from Detroit, Michigan, and documented the DNA forensic testing outcomes associated with those kits. We assessed how many SAKs yielded DNA profiles eligible for upload into CODIS (Combined DNA Index System), the federal DNA criminal database; how many resulted in a DNA match (termed a "CODIS hit"); and how many of those hits were associated to other sexual assault crimes (i.e., serial sexual assault hits). Overall, there were 259 CODIS hits, 69 of which had DNA matches to another sexual assault case. The potential utility of a DNA profile and CODIS hit may vary depending on whether offender was known or unknown to the victim, so we examined these outcomes separately for SAKs associated with stranger- and non-stranger-perpetrated sexual assaults. We also present six case study examples of how DNA testing and CODIS hits helped identify serial sexual assaults in both stranger and non-stranger sexual assault cases. Implications for rape kit testing policies are discussed.
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Vítimas de Crime/legislação & jurisprudência , Delitos Sexuais/legislação & jurisprudência , Manejo de Espécimes/estatística & dados numéricos , Esfregaço Vaginal/estatística & dados numéricos , Criminosos , Feminino , Humanos , Aplicação da Lei/métodos , Masculino , Polícia , Estupro/legislação & jurisprudênciaRESUMO
BACKGROUND: Infant feeding practices are a focus of early obesity prevention. We tested whether infant growth velocity increased after breastfeeding termination and complementary food introduction. METHODS: Our secondary analysis included a sample of 547 mother-infant dyads from a longitudinal randomized controlled trial conducted in Michigan and Colorado. Infant anthropometrics at birth, baseline, and 6- and 12-month follow-up were standardized to BMI-for-age z-score (ZBMI) according to World Health Organization (WHO) growth charts. We used growth curve models with time-varying predictors to quantify effects of breastfeeding termination and timing of complementary food introduction on growth velocity. RESULTS: Median breastfeeding duration was 2.0 months [confidence interval (CI) = 2.0-2.5]; median introduction of complementary foods occurred at 3.0 months (CI = 2.8-3.2). Breastfed infants not yet introduced to complementary foods had an average ZBMI growth velocity of 0.050 (CI = -0.013 to 0.113) z-score units per month [zpm], not significantly faster than WHO growth trajectory (p = 0.118) defined as 0 zpm. Breastfeeding termination had negligible effect on ZBMI growth velocity (γ11 = 0.001, CI = -0.027 to 0.030, p = 0.927). Introduction of complementary foods increased ZBMI growth velocity relative to an average child in the sample, but not significantly (γ12 = 0.033, CI = -0.034 to 0.100, p = 0.334). Growth velocities for infants receiving complementary foods both before and after breastfeeding termination were significantly faster than the WHO growth trajectory (0.083 zpm, CI = 0.052-0.114, and 0.084 zpm, CI = 0.064-0.105, respectively, p's < 0.001). CONCLUSIONS: Average postcomplementary food introduction growth velocity was significantly higher than WHO growth trajectory, but did not differ from the sample's initial average trajectory. Growth curve models can accurately estimate effects of feeding practices on infant growth to direct obesity prevention efforts.
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Aleitamento Materno , Desenvolvimento Infantil , Comportamento Alimentar , Fórmulas Infantis , Índice de Massa Corporal , Desenvolvimento Infantil/fisiologia , Colorado/epidemiologia , Feminino , Humanos , Lactente , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Michigan/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Padrões de Referência , Fatores de Tempo , DesmameRESUMO
Aims: This study compared the psychometric properties of two self-efficacy instruments related to physical activity. Factorial validity, cross-group and longitudinal invariance, and composite reliability were examined. Methods: Secondary analysis was conducted on data from a group randomized controlled trial investigating the effect of a 17-week intervention on increasing moderate to vigorous physical activity among 5th-8th grade girls (N = 1,012). Participants completed a 6-item Physical Activity Self-Efficacy Scale (PASE) and a 7-item Self-Efficacy for Exercise Behaviors Scale (SEEB) at baseline and post-intervention. Confirmatory factor analyses for intervention and control groups were conducted with Mplus Version 7.4 using robust weighted least squares estimation. Model fit was evaluated with the chi-square index, comparative fit index, and root mean square error of approximation. Composite reliability for latent factors with ordinal indicators was computed from Mplus output using SAS 9.3. Results: Mean age of the girls was 12.2 years (SD = 0.96). One-third of the girls were obese. Girls represented a diverse sample with over 50% indicating black race and an additional 19% identifying as mixed or other race. Both instruments demonstrated configural invariance for simultaneous analysis of cross-group and longitudinal invariance based on alternative fit indices. However, simultaneous metric invariance was not met for the PASE or the SEEB instruments. Partial metric invariance for the simultaneous analysis was achieved for the PASE with one factor loading identified as non-invariant. Partial metric invariance was not met for the SEEB. Longitudinal scalar invariance was achieved for both instruments in the control group but not the intervention group. Composite reliability for the PASE ranged from 0.772 to 0.842. Reliability for the SEEB ranged from 0.719 to 0.800 indicating higher reliability for the PASE. Reliability was more stable over time in the control group for both instruments. Conclusions: Results suggest that the intervention influenced how girls responded to indicator items. Neither of the instruments achieved simultaneous metric invariance making it difficult to assess mean differences in PA self-efficacy between groups.
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Genome-wide association studies (GWAS) have linked dozens of single nucleotide polymorphisms (SNPs) with Parkinson's disease (PD) risk. Ascertaining the functional and eventual causal mechanisms underlying these relationships has proven difficult. The majority of risk SNPs, and nearby SNPs in linkage disequilibrium (LD), are found in intergenic or intronic regions and confer risk through allele-dependent expression of multiple unknown target genes. Combining GWAS results with publicly available GTEx data, generated through eQTL (expression quantitative trait loci) identification studies, enables a direct association of SNPs to gene expression levels and aids in narrowing the large population of potential genetic targets for hypothesis-driven experimental cell biology. Separately, overlapping of SNPs with putative enhancer segmentations can strengthen target filtering. We report here the results of analyzing 7,607 PD risk SNPs along with an additional 23,759 high linkage disequilibrium-associated variants paired with eQTL gene expression. We found that enrichment analysis on the set of genes following target filtering pointed to a single large LD block at 6p21 that contained multiple HLA-MHC-II genes. These MHC-II genes remain associated with PD when the genes were filtered for correlation between GWAS significance and eQTL levels, strongly indicating a direct effect on PD etiology.
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Antígenos de Histocompatibilidade Classe II/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Locos de Características QuantitativasRESUMO
BACKGROUND/OBJECTIVES: Universal screening for elder abuse and neglect is a current controversy in geriatrics, fueled by the lack of evidence on valid and reliable instruments. Since each U.S. State and many other countries have their own legal definitions of what constitutes elder abuse and neglect, this further complicates instrument development and clinical assessment. The purpose of this paper is to present data on the sensitivity and specificity of the QualCare Scale, an instrument with utility in detecting clinically significant elder abuse and neglect among older adults receiving care at home. DESIGN: Data used in this analysis were collected during a training program in which trainees completed assessments (N=80) of standardized case scenarios of caregiving dyads. Trainees completed the QualCare Scale during each assessment. SETTING: This training program, including the assessments of the standardized case scenarios, was completed using a custom designed virtual-reality platform. Trainees were able to interact with the environment, older adult and caregiver within the case scenario. PARTICIPANTS: Thirty-six nurses and social workers from two Michigan Medicaid Waiver Sites participated in the training program. Each participant assessed between one and five scenarios, yielding the sample of 80 assessments used in this analysis. MEASUREMENTS: The research team designed each standardized case scenario to reflect whether or not the QualCare Scale subscale score should indicate reportable elder abuse and neglect per the State statute. Accordingly, the research team's QualCare Scale scores for each scenario were used as the gold standard criterion of clinical significance for comparison against the participant's assessment scores. RESULTS: Sensitivity and specificity for each of the six QualCare subscales was determined. Overall, the subscales had high sensitivity (≥0.811) but a wide range for specificity (0.167-1.000). CONCLUSION: The QualCare Scale can be an effective tool in detecting clinically significant elder abuse and neglect among older adults receiving care at home. This tool is suitable and feasible for use by practitioners working in home care. The QualCare Scale score indicating clinically significant or reportable elder abuse and neglect can be raised or lowered to be consistent with State or Country statutes, or simply used to create appropriate care plans to support caregiving. Findings from the QualCare Scale can support the multidisciplinary team in planning for and evaluating preventative interventions.