Search

The development of formulations from plant or animal extracts and polymeric platforms has been well established toward emulsion-based delivery systems, avoiding the use of conventional surfactants. This approach involves the stabilization of poorly water-soluble extracts by polymers, improving their dispersion into food and pharmaceutical products, avoiding premature degradation, and resulting in better bioavailability. According to the literature, extracts are obtained via conventional and novel methods, which exhibit advantages and disadvantages related to using organic solvent, temperature, time, pressure, and equipment cost. Similarly, for polymer-based emulsifiers, there are different methods to obtain them. Also, their chemical composition and morphology (linear, branched, and crosslinked) play relevant roles in their performance as stabilizing agents. On the other hand, oil-in-water emulsions from plant-animal extracts and biocompatible polymers have been prepared using different strategies focused on achieving high stability of the colloidal system. Hence, this review provides current information regarding some protocols used for the extraction/synthesis of materials and the development of promising formulations.

The relationship between new greenspaces and gentrification is an important one for urbanization. Here the authors show a positive relationship for at least one decade between greening in the 1990s–2000s and gentrification that occurred between 2000–2016 in 17 of 28 studied cities in North America and Europe.

Background: Radiomics refers to the acquisition of traces of quantitative features that are usually non-perceptible to human vision and are obtained from different imaging techniques and subsequently transformed into high-dimensional data. Diffuse midline gliomas (DMG) represent approximately 20% of pediatric CNS tumors, with a median survival of less than one year after diagnosis. We aimed to identify which radiomics can discriminate DMG tumor regions (viable tumor and peritumoral edema) from equivalent midline normal tissue (EMNT) in patients with the positive H3.F3K27M mutation, which is associated with a worse prognosis. Patients and methods: This was a retrospective study. From a database of 126 DMG patients (children, adolescents, and young adults), only 12 had H3.3K27M mutation and available brain magnetic resonance DICOM file. The MRI T1 post-gadolinium and T2 sequences were uploaded to LIFEx software to post-process and extract radiomic features. Statistical analysis included normal distribution tests and the Mann–Whitney U test performed using IBM SPSS® (Version 27.0.0.1, International Business Machines Corp., Armonk, NY, USA), considering a significant statistical p-value ≤ 0.05. Results: EMNT vs. Tumor: From the T1 sequence 10 radiomics were identified, and 14 radiomics from the T2 sequence, but only one radiomic identified viable tumors in both sequences (p < 0.05) (DISCRETIZED_Q1). Peritumoral edema vs. EMNT: From the T1 sequence, five radiomics were identified, and four radiomics from the T2 sequence. However, four radiomics could discriminate peritumoral edema in both sequences (p < 0.05) (CONVENTIONAL_Kurtosis, CONVENTIONAL_ExcessKurtosis, DISCRETIZED_Kurtosis, and DISCRETIZED_ExcessKurtosis). There were no radiomics useful for distinguishing tumor tissue from peritumoral edema in both sequences. Conclusions: Less than 5% of the radiomic characteristics identified tumor regions of medical–clinical interest in T1 and T2 sequences of conventional magnetic resonance imaging. The first-order and second-order radiomic features suggest support to investigators and clinicians for careful evaluation for diagnosis, patient classification, and multimodality cancer treatment planning.

The increasing rate of food allergies in children, combined with the role of food as an integral part of the school day has led to the emergence of anaphylaxis as a daily threat to students, regardless of prior allergy diagnosis. Stock epinephrine--non-patient specific epinephrine auto-injectors that may be used during emergencies--is a means for schools to prepare for anaphylactic events and protect children with allergies. The Maricopa County Department of Public Health initiated the School Surveillance and Medication Program (SSMP), a data capture program, to facilitate the process of stocking epinephrine in schools. Spearheaded by the implementation efforts of the Kyah Rayne Foundation, program enrollment increased 146% between the 2020-2021 and 2021-2022 school years. The increased proportion of schools enrolled in the SSMP and the number of school personnel trained to administer epinephrine demonstrates the feasibility of school-centered stock epinephrine programs and validates strategies for increasing program uptake.

Background: Radiomics refers to a recent area of knowledge that studies features extracted from different imaging techniques and subsequently transformed into high-dimensional data that can be associated with biological events. Diffuse midline gliomas (DMG) are one of the most devastating types of cancer, with a median survival of approximately 11 months after diagnosis and 4–5 months after radiological and clinical progression. Methods: A retrospective study. From a database of 91 patients with DMG, only 12 had the H3.3K27M mutation and brain MRI DICOM files available. Radiomic features were extracted from MRI T1 and T2 sequences using LIFEx software. Statistical analysis included normal distribution tests and the Mann–Whitney U test, ROC analysis, and calculation of cut-off values. Results: A total of 5760 radiomic values were included in the analyses. AUROC demonstrated 13 radiomics with statistical significance for progression-free survival (PFS) and overall survival (OS). Diagnostic performance tests showed nine radiomics with specificity for PFS above 90% and one with a sensitivity of 97.2%. For OS, 3 out of 4 radiomics demonstrated between 80 and 90% sensitivity. Conclusions: Several radiomic features demonstrated statistical significance and have the potential to further aid DMG diagnostic assessment non-invasively. The most significant radiomics were first- and second-order features with GLCM texture profile, GLZLM_GLNU, and NGLDM_Contrast.

Abstract Background Democratising the growing body of whole genome sequencing data available for Triticum aestivum (bread wheat) has been impeded by the lack of a genome reference and the large computational requirements for analysing these data sets. Results DAWN (Diversity Among Wheat geNomes) integrates data from the T. aestivum Chinese Spring (CS) IWGSC RefSeq v1.0 genome with public WGS and exome data from 17 and 62 accessions respectively, enabling researchers and breeders alike to investigate genotypic differences between wheat accessions at the level of whole chromosomes down to individual genes. Conclusions Using DAWN we show that it is possible to visualise small and large chromosomal deletions, identify haplotypes at a glance and spot the consequences of selective breeding. DAWN allows us to detect the break points of alien introgression segments brought into an accession when transferring desired genes. Furthermore, we can find possible explanations for reduced recombination in parts of a chromosome, we can predict regions with linkage drag, and also look at diversity in centromeric regions.

Abstract In April 2016, the Population Council, in partnership with the World Health Organization (WHO) and the International Consortium for Emergency Contraception, convened a regional meeting in Lusaka, Zambia, geared toward supporting countries in East and Southern Africa in meeting their obligations under the Maputo Protocol. These obligations include expanding access to women’s reproductive health services – especially women survivors of sexual violence. Government and civil society representatives from six countries participated: Botswana, Ethiopia, Kenya, Malawi, Rwanda, and Zambia. Countries were selected based on to their being priority settings for the projects that sponsored the meeting, coupled with the fact that they were each far enough along in addressing post-rape care to be able to develop concrete policy, programming, and/or legal action plans by the end of the meeting. The meeting was the first activity in a joint project of technical assistance by the conveners, aimed at strengthening access to comprehensive post-rape care for survivors of sexual violence. It aimed to sensitize Member States to their obligations under the Maputo Protocol to expand women’s access to emergency contraception (EC) and safe abortion services, and to inspire them to do so by providing information, research evidence, and a platform for discussion. The meeting deliberations fostered a better understanding of opportunities to broaden access to EC and safe abortion for survivors in the region. Discussions on EC in this regard centered on strengthening EC delivery in the clinical context, decentralizing EC services, increasing community awareness, and overcoming policy barriers. Safe abortion discussions focused primarily on legislation, policy, and integrating these services into existing services for sexual violence survivors. Country-specific action plans were developed to address gaps and weaknesses. The regional technical meeting concluded with a discussion of practical steps that participants could take to facilitate legal, policy, and program reform with respect to pregnancy prevention and safe abortion in their respective countries. The steps revolved around three mainly areas, namely: establishing an evidence base to inform action; creating forums for discussing the issues; and drafting action points to carry the momentum from the meeting forward. This paper details the proceedings from this regional technical meeting – proceedings that are of interest to the field of sexual and gender-based violence (and reproductive health, more broadly) as challenges faced by countries in implementing the Maputo Protocol are outlined, and evidence-informed and practice-based strategies for addressing these challenges are provided.

The possible detonation of a radiological dispersal device or improvised nuclear device in a metropolitan city, or the accidental exposures to a radiation source, nuclear accidents, or the all-to-often threats of radiological/nuclear terrorism have led to the urgent need to develop essential analytic tools to assess such radiation exposures, especially radiation doses to exposed individuals. This exposure-assessing work using biological samples, and discipline, is known as biodosimetry. As of late, this field has progressed significantly as it has made use of the advances within newer areas of biologic analytics, namely omics (genomics, proteomics, metabolomics, and transcriptomics), lymphocyte kinetics, optically stimulated luminescence, and electron paramagnetic resonance technology in addition to conventional cytogenetic techniques. The use of automated high throughput platforms and the planning for laboratory surge capacity during the time of need are the latest developments in the field of biomarkers for biodosimetry. Such biomarkers are also needed for radiation exposure/dose conversion estimates that are essential for the development and application of radiation countermeasures, from animals to humans and that are currently being developed following the US Food and Drug Administration Animal Rule. Here, we present and discuss the current status of various biomarkers for assessing radiation dose after radiation exposure. It is anticipated that with the advent of improved biomarkers and associated biomarker platforms for the acute radiation syndrome, exposed victims can be more efficiently triaged and appropriately treated than is currently allowable. The latest advances in the field, and identify the areas where improvement is needed are also listed and discussed.

The availability of safe and effective radiation countermeasures for the military and civilian population represents a significant unmet medical need. To expedite the development of countermeasures for life-threating situations, the United States Food and Drug Administration (US FDA) has implemented the “Animal Rule” which applies to the development and evaluation of drugs and biologics to reduce or prevent life-threatening conditions caused by exposure to lethal or permanently disabling agents where human efficacy trials are neither feasible nor ethical. In addition, the FDA has introduced several incentives (fast track, orphan drug status, and emergency use authorization [EUA]) to attract drug sponsors to develop such agents for human use. Repurposing is vital to make drugs available for life-threatening conditions. Drugs are commonly repurposed for new indications not originally envisioned. By repurposing a drug, it can be made available for human use much quicker, but this pathway also involves issues such as intellectual property rights as corporations are reluctant to expose their blockbuster pharmaceuticals to additional scientific scrutiny. Two radiomitigators for hematopoietic acute radiation syndrome (H-ARS) (Neupogen and Neulasta) have been approved by the FDA through repurposing. The EUA is a legal means for the FDA to approve new drugs or new indications for the previously approved drugs for use during a declared emergency and is a valid way to expedite drug development. Several promising agents with and without FDA investigational new drug (IND) status for ARS are under advanced development. In the next few years, we expect that the FDA will approve a few radioprotectors for H-ARS as well as gastrointestinal ARS via Animal Rule.

A correction to this article has been published and is linked from the HTML version of this article.

Heterosis can rapidly boost yield in crop species but development of hybrid-breeding systems for bread wheat remains a challenge. Here, Tucker et al. describe the molecular identification of the wheat Ms1 gene and discuss its potential for large-scale hybrid seed production in wheat.

Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

Drought and heat waves commonly co-occur in many wheat-growing regions causing significant crop losses. The identification of stress associated quantitative trait loci, particularly those for yield, is problematic due to their association with plant phenology and the high genetic × environment interaction. Here we studied a panel of 315 diverse, spring type accessions of bread wheat (Triticum aestivum) in pots in a semi-controlled environment under combined drought and heat stress over 2 years. Importantly, we treated individual plants according to their flowering time. We found 134 out of the 145 identified loci for grain weight that were not associated with either plant phenology or plant height. The majority of loci uncovered here were novel, with favorable alleles widespread in Asian and African landraces providing opportunities for their incorporation into modern varieties through breeding. Using residual heterozygosity in lines from a nested association mapping population, we were able to rapidly develop near-isogenic lines for important target loci. One target locus on chromosome 6A contributed to higher grain weight, harvest index, thousand kernel weight, and grain number under drought and heat stress in field conditions consistent with allelic effects demonstrated in the genome-wide association study.

Drought and heat stress constrain wheat (Triticum aestivum L.) yields globally. To identify putative mechanisms and candidate genes associated with combined drought and heat stress tolerance, we developed bread wheat near-isogenic lines (NILs) targeting a quantitative trait locus (QTL) on chromosome 6B which was previously associated with combined drought and heat stress tolerance in a diverse panel of wheats. Genotyping-by-sequencing was used to identify additional regions that segregated in allelic pairs between the recurrent and the introduced exotic parent, genome-wide. NILs were phenotyped in a gravimetric platform with precision irrigation and exposed to either drought or to combined drought and heat stress from three days after anthesis. An increase in grain weight in NILs carrying the exotic allele at 6B locus was associated with thicker, greener leaves, higher photosynthetic capacity and increased water use index after re-watering. RNA sequencing of developing grains at early and later stages of treatment revealed 75 genes that were differentially expressed between NILs across both treatments and timepoints. Differentially expressed genes coincided with the targeted QTL on chromosome 6B and regions of genetic segregation on chromosomes 1B and 7A. Pathway enrichment analysis showed the involvement of these genes in cell and gene regulation, metabolism of amino acids and transport of carbohydrates. The majority of these genes have not been characterized previously under drought or heat stress and they might serve as candidate genes for improved abiotic stress tolerance.

Background: Osteoporosis is a major public health problem associated with excess disability and mortality. It is estimated that 50–70% of the variation in osteoporotic fracture risk is attributable to genetic factors. The purpose of this hypothesis-generating study was to identify possible genetic determinants of fracture among African American (AA) women in a GWAS meta-analysis. Methods: Data on clinical fractures (all fractures except fingers, toes, face, skull or sternum) were analyzed among AA female participants in the Women's Health Initiative (WHI) (N = 8155), Cardiovascular Health Study (CHS) (N = 504), BioVU (N = 704), Health ABC (N = 651), and the Johnston County Osteoarthritis Project (JoCoOA) (N = 291). Affymetrix (WHI) and Illumina (Health ABC, JoCoOA, BioVU, CHS) GWAS panels were used for genotyping, and a 1:1 ratio of YRI:CEU HapMap haplotypes was used as an imputation reference panel. We used Cox proportional hazard models or logistic regression to evaluate the association of ~2.5 million SNPs with fracture risk, adjusting for ancestry, age, and geographic region where applicable. We conducted a fixed-effects, inverse variance-weighted meta-analysis. Genome-wide significance was set at P

Wheat landraces, wild relatives and other 'exotic' accessions are important sources of new favorable alleles. The use of those exotic alleles is facilitated by having access to information on the association of specific genomic regions with desirable traits. Here, we conducted a genome-wide association study (GWAS) using a wheat panel that includes landraces, synthetic hexaploids and other exotic wheat accessions to identify loci that contribute to increases in grain yield in southern Australia. The 568 accessions were grown in the field during the 2014 and 2015 seasons and measured for plant height, maturity, spike length, spike number, grain yield, plant biomass, HI and TGW. We used the 90K SNP array and two GWAS approaches (GAPIT and QTCAT) to identify loci associated with the different traits. We identified 17 loci with GAPIT and 25 with QTCAT. Ten of these loci were associated with known genes that are routinely employed in marker assisted selection such as Ppd-D1 for maturity and Rht-D1 for plant height and seven of those were detected with both methods. We identified one locus for yield per se in 2014 on chromosome 6B with QTCAT and three in 2015, on chromosomes 4B and 5A with GAPIT and 6B with QTCAT. The 6B loci corresponded to the same region in both years. The favorable haplotypes for yield at the 5A and 6B loci are widespread in Australian accessions with 112 out of 153 carrying the favorable haplotype at the 5A locus and 136 out of 146 carrying the favorable haplotype at the 6A locus, while the favorable haplotype at 4B is only present in 65 out of 149 Australian accessions. The low number of yield QTL in our study corroborate with other GWAS for yield in wheat, where most of the identified loci have very small effects.

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (

Microsatellite (SSR) markers were developed for the following tropical forage species, using accessions available from the plant genetic resources (PGR) collections held by EMBRAPA (Brazilian Agricultural Research Corporation): Brachiaria brizantha, B. humidicola, Panicum maximum, Paspalum spp., Stylosanthes capitata, S. guianensis, S. macrocephala, Calopogonium mucunoides and Centrosema spp. The markers were used to analyze population structure and genetic diversity, evolution and origin of the genetic variability in the center of origin, mating systems and genetic resources in EMBRAPA’s germplasm bank. The results shed light on the amount of genetic variation within and between populations, revealed the need in some cases for further plant collection to adequately represent the species in PGR collections, allowed us to assemble core collections (subsets of the total collections) that should contain most of the available diversity and (in the case of the legumes) showed the need to avoid unwanted outcrossing when regenerating conserved material. The data will allow plant breeders to better select accessions for hybrid production, discriminate between genotypes and use marker-assisted selection in breeding programs. Our results will also underpin the construction of genetic maps, mapping of genes of agronomic interest and numerous other studies on genetic variability, population structure, gene flow and reproductive systems for the tropical forage species studied in this work.

Phenomenological Psychopathology understands delusion as the result of changes in the aprioristic structure of consciousness. In this article, we will review the main contributions that classical and contemporary phenomenological authors have made to the theme. Departing from these psychopathological syntheses, we will discuss the structural genesis of this phenomenon, the possible evolutionary consequences of the delusional state, and its general meaning within the ontological framework of consciousness. At the same time that the analytical depth of the contributions restated here comprises the best of what has been done within the phenomenological approach, the reality is that extensive areas remain uncharted, especially when regarding the clinical consequence of these insights for clinical practice. Thus, as notes of a preliminary nature, we will make observations about the therapeutic implications of previous phenomenological findings. Among them, we shall emphasize the importance of the aprioristic sphere of consciousness in the design of a pharmacological and psychotherapeutic approach to schizophrenia worthy of the psychopathological tradition to which this contribution is affiliated.

A “Psicopatologia Geral” (PG) de Karl Jaspers é uma das mais célebres contribuições ao campo da psicopatologia. A obra situa-se em um período de transição de paradigmas, alocada entre a visão das patologias mentais, enquanto enfermidades médicas e enquanto modificação estrutural da consciência. Por ocasião de seu lançamento, em 1913, apresentou ideias que eram, então, consideradas caducas, além de apontamentos inovadores. Este artigo pretendeu revisitar o conceito de compreensão psicológica (ou empática) (Verstehen) em Jaspers (PG), as suas leis fundamentais, bem como as suas limitações, através da ótica fenomenológica. Para tanto, partiu de uma concisa apresentação do legado da PG e de algumas diferenças epistemológicas significativas entre a psicopatologia jasperiana e a psicopatologia fenomenológica. Por fim, dada a distinção entre as duas vertentes psicopatológicas, o construto de compreensão apresentado por Karl Jaspers foi colocado em discussão, sob a perspectiva fenomenológica.

BackgroundAssociations of atherosclerosis risk factors with unrecognized myocardial infarction (UMI) are unclear. We investigated associations of midlife risk factors with UMI and recognized MI (RMI) detected 31 years later by cardiac magnetic resonance. Methods and ResultsThe Reykjavik Study (1967–1991) collected serial risk factors in subjects, mean (SD) age 48 (7) years. In ICELAND‐MI (2004–2007), 936 survivors (76 (5) years) were evaluated by cardiac magnetic resonance. Analysis included logistic regression and random effects modeling. Comparisons are relative to subjects without MI. At baseline midlife evaluation, a modified Framingham risk score was significantly higher in RMI and in UMI versus no MI (7.4 (6.3)%; 7.1 (6.2)% versus 5.4 (5.8)%, P

After publication of the original article [1], it was noticed one of the author’s Given Names was misspelled. Sarah Rich’s name was misspelled as Sara Rich. The author’s name is correctly presented in the author list of this correction.

O presente artigo discute a validade do conceito de endogeneidade, tal como apresentado previamente por Hubertus Tellenbach, na esquizofrenia. Inicialmente, as características inerentes ao fenômeno endógeno, tais como perda de ritmos, alteração da cinese vital e reversibilidade, serão revistas e analisadas dentro de uma perspectiva essencialista, cara à proposta fenomenológica. Em um segundo momento, tal essência endógena será colocada a prova no curso da esquizofrenia, em diálogo estreito com o conceito de estrutura psíquica. Finalmente, serão tecidas algumas considerações preliminares sobre a importância da incorporação de tal noção de endogeneidade nos estudos psicopatológicos da esquizofrenia.

Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of published variants in CHD loci with incident CHD, attempted to fine map these loci, and characterize novel variants influencing CHD risk in African Americans.Up to 8,201 African Americans (including 546 first CHD events) were genotyped using the MetaboChip array in the Atherosclerosis Risk in Communities (ARIC) study and Women's Health Initiative (WHI). We tested associations using Cox proportional hazard models in sex- and study-stratified analyses and combined results using meta-analysis. Among 44 validated CHD loci available in the array, we replicated and fine-mapped the SORT1 locus, and showed same direction of effects as reported in studies of individuals of European ancestry for SNPs in 22 additional published loci. We also identified a SNP achieving array wide significance (MYC: rs2070583, allele frequency 0.02, P = 8.1 × 10(-8)), but the association did not replicate in an additional 8,059 African Americans (577 events) from the WHI, HealthABC and GeneSTAR studies, and in a meta-analysis of 5 cohort studies of European ancestry (24,024 individuals including 1,570 cases of MI and 2,406 cases of CHD) from the CHARGE Consortium.Our findings suggest that some CHD loci previously identified in individuals of European ancestry may be relevant to incident CHD in African Americans.

O artigo propõe uma interpretação da categoria biográfica processo, conceito clássico desenvolvido por Karl Jaspers, sob a ótica da Psicopatologia Fenomenológica. Inicialmente, faz uma breve apresentação de proposições chaves da centenária obra Psicopatologia Geral, que confluirão para a definição de processo psíquico. Em um segundo momento, o artigo localiza os distintos planos de observação das duas abordagens psicopatológicas, a de Karl Jaspers e a Fenomenológica, contrastando suas metodologias. Finalmente, propõe uma leitura fenomenológica, temporoespacial por excelência, de processo, buscando apontar microscopicamente, no locus estrutural, o seu estatuto.

O presente artigo discorre a respeito da mobilidade da estrutura psíquica, especificamente na esquizofrenia. Inicialmente, parte de uma breve revisão das categorias de entendimento dessa patologia dentro da tradição da Psicopatologia Fenômeno-Estrutural. A seguir, faz algumas considerações a respeito do campo endógeno, correlacionando-o com os conceitos apresentados. E, por fim, o artigo foca na questão da cinética estrutural, diferenciando tipos ideais de movimentação e suas possíveis implicações prognósticas e terapêuticas.

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of ∼2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom ∼50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8×10(-7) and p = 1.5×10(-6) respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5×10(-12)). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report.

Smoking tobacco reduces lung function. African Americans have both lower lung function and decreased metabolism of tobacco smoke compared to European Americans. African ancestry is also associated with lower pulmonary function in African Americans. We aimed to determine whether African ancestry modifies the association between smoking and lung function and its rate of decline in African Americans.We evaluated a prospective ongoing cohort of 1,281 African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study initiated in 1997. We also examined an ongoing prospective cohort initiated in 1985 of 1,223 African Americans in the Coronary Artery Disease in Young Adults (CARDIA) Study. Pulmonary function and tobacco smoking exposure were measured at baseline and repeatedly over the follow-up period. Individual genetic ancestry proportions were estimated using ancestry informative markers selected to distinguish European and West African ancestry. African Americans with a high proportion of African ancestry had lower baseline forced expiratory volume in one second (FEV₁) per pack-year of smoking (-5.7 ml FEV₁/ smoking pack-year) compared with smokers with lower African ancestry (-4.6 ml in FEV₁/ smoking pack-year) (interaction P value = 0.17). Longitudinal analyses revealed a suggestive interaction between smoking, and African ancestry on the rate of FEV(1) decline in Health ABC and independently replicated in CARDIA.African American individuals with a high proportion of African ancestry are at greater risk for losing lung function while smoking.

Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.

A major goal of personalized medicine is to pre-symptomatically identify individuals at high risk for disease using knowledge of each individual's particular genetic profile and constellation of environmental risk factors. With the identification of several well-replicated risk factors for age-related macular degeneration (AMD), the leading cause of legal blindness in older adults, this previously unreachable goal is beginning to seem less elusive. However, recently developed algorithms have either been much less accurate than expected, given the strong effects of the identified risk factors, or have not been applied to independent datasets, leaving unknown how well they would perform in the population at large. We sought to increase accuracy by using novel modeling strategies, including multifactor dimensionality reduction (MDR) and grammatical evolution of neural networks (GENN), in addition to the traditional logistic regression approach. Furthermore, we rigorously designed and tested our models in three distinct datasets: a Vanderbilt-Miami (VM) clinic-based case-control dataset, a VM family dataset, and the population-based Age-related Maculopathy Ancillary (ARMA) Study cohort. Using a consensus approach to combine the results from logistic regression and GENN models, our algorithm was successful in differentiating between high- and low-risk groups (sensitivity 77.0%, specificity 74.1%). In the ARMA cohort, the positive and negative predictive values were 63.3% and 70.7%, respectively. We expect that future efforts to refine this algorithm by increasing the sample size available for model building, including novel susceptibility factors as they are discovered, and by calibrating the model for diverse populations will improve accuracy.

Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.

Este estudio se centró en validar el modelo de Solidaridad en el contexto del terremoto de México de 2017. Se analizaron respuestas de 604 participantes afectados por el sismo del 19 de septiembre de 2017 en la Ciudad de México y zonas conurbadas. El modelo demostró un buen ajuste, con valores significativos en diversas métricas estadísticas como Chi-cuadrado, CFI, TLI, SRMR y RMSEA. Los hallazgos principales del estudio incluyen una fuerte correlación entre la observación de apoyo social emocional y su provisión (β = 0,69), mientras que la observación de apoyo social coordinado no predijo de forma significativa su provisión (β = 0,06). La Identificación Social emergió como un predictor clave de la Eficacia Colectiva y del Apoyo Esperado, destacando su rol en la solidaridad. Además, se encontró que la eficacia colectiva y el apoyo esperado son predictores significativos para brindar apoyo social coordinado, más que la observación de este tipo de ayuda. Este resultado es crucial para comprender los mecanismos detrás de la solidaridad en situaciones de emergencia. El estudio también reveló un efecto de moderación significativo de la Identidad Social en la relación entre Eficacia Colectiva y la provisión de Apoyo Social, evidenciando que la Identidad Social no solo motiva a ofrecer apoyo social, sino que también influye en cómo se percibe y actúa sobre la eficacia colectiva. Estos resultados resaltan la importancia de la observación y la identificación social en la solidaridad, fundamentales para las políticas públicas en México.