Mexican Biobank advances population and medical genomics of diverse ancestries.

Latin America continues to be severely underrepresented in genomics research, and fine-scale genetic histories and complex trait architectures remain hidden owing to insufficient data1. To fill this gap, the Mexican Biobank project genotyped 6,057 individuals from 898 rural and urban localities across all 32 states in Mexico at a resolution of 1.8 million genome-wide markers with linked complex trait and disease information creating a valuable nationwide genotype-phenotype database. Here, using ancestry deconvolution and inference of identity-by-descent segments, we inferred ancestral population sizes across Mesoamerican regions over time, unravelling Indigenous, colonial and postcolonial demographic dynamics2-6. We observed variation in runs of homozygosity among genomic regions with different ancestries reflecting distinct demographic histories and, in turn, different distributions of rare deleterious variants. We conducted genome-wide association studies (GWAS) for 22 complex traits and found that several traits are better predicted using the Mexican Biobank GWAS compared to the UK Biobank GWAS7,8. We identified genetic and environmental factors associating with trait variation, such as the length of the genome in runs of homozygosity as a predictor for body mass index, triglycerides, glucose and height. This study provides insights into the genetic histories of individuals in Mexico and dissects their complex trait architectures, both crucial for making precision and preventive medicine initiatives accessible worldwide.

Demographic modeling of admixed Latin American populations from whole genomes.

Demographic models of Latin American populations often fail to fully capture their complex evolutionary history, which has been shaped by both recent admixture and deeper-in-time demographic events. To address this gap, we used high-coverage whole-genome data from Indigenous American ancestries in present-day Mexico and existing genomes from across Latin America to infer multiple demographic models that capture the impact of different timescales on genetic diversity. Our approach, which combines analyses of allele frequencies and ancestry tract length distributions, represents a significant improvement over current models in predicting patterns of genetic variation in admixed Latin American populations. We jointly modeled the contribution of European, African, East Asian, and Indigenous American ancestries into present-day Latin American populations. We infer that the ancestors of Indigenous Americans and East Asians diverged ∼30 thousand years ago, and we characterize genetic contributions of recent migrations from East and Southeast Asia to Peru and Mexico. Our inferred demographic histories are consistent across different genomic regions and annotations, suggesting that our inferences are robust to the potential effects of linked selection. In conjunction with published distributions of fitness effects for new nonsynonymous mutations in humans, we show in large-scale simulations that our models recover important features of both neutral and deleterious variation. By providing a more realistic framework for understanding the evolutionary history of Latin American populations, our models can help address the historical under-representation of admixed groups in genomics research and can be a valuable resource for future studies of populations with complex admixture and demographic histories.

Lack of Association between Common LAG3/CD4 Variants and Risk of Migraine.

Several papers have been published suggesting a probable role of inflammatory factors in the etiopathogenesis of migraine. In this study, we investigated the possible association between common variants in the LAG3/CD4 genes (both genes, which are closely related, encode proteins involved in inflammatory and autoimmune responses) in the risk of migraine in a cohort of Caucasian Spanish participants. For this purpose, the frequencies of CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 genotypes and allelic variants, using a specific TaqMan-based qPCR assay, were assessed in 290 patients diagnosed with migraine and in 300 healthy controls. The relationship of these variables with several clinical features of migraine was also analyzed. The frequencies of the analyzed LAG3/CD4 genotypes did not differ significantly between the two study groups and were not related to the sex, age at onset of migraine, family history of migraine, presence or absence of aura, or the triggering effect of ethanol on migraine episodes. These results suggest a lack of association between common variants in the LAG3/CD4 genes and the risk of developing migraine in the Caucasian Spanish population.

Increased serum diamine oxidase activity in nonallergic patients with migraine.

BACKGROUND/OBJECTIVES: Histamine has shown a possible role in the etiopathogenesis of migraine. It has been reported an association between some polymorphisms in the diamine oxidase (DAO) gene and migraine, especially in women. Two studies addressing DAO activity in migraine patients showed conflicting results. We investigated the possible relationship of serum DAO activity and histamine levels and 3 polymorphisms in the DAO gene with the risk for migraine. METHODS: We studied the frequencies of DAO rs10156191, rs1049742 and rs1049793 genotypes and allelic variants in 298 migraine patients and 360 healthy controls (using a TaqMan-based qPCR assay), and serum DAO activity and histamine levels in a subset of 99 migraine patients and 115 controls with strict exclusion criteria, and analysed the relationship of these variables with several clinical features of migraine. RESULTS: The frequencies of the DAO genotypes and allelic variants analysed were similar in migraine patients and controls. Serum DAO activity was significantly higher in migraine patients (Vmax/Km 4.24 ± 2.93 vs. 3.60 ± 7.64, p < 0.001), especially in females (Vmax/Km 4.63 ± 2.96 vs. 3.18 ± 2.32, p < 0.0001), while serum histamine was similar in both study groups. CONCLUSION: Serum DAO activity was increased in patients with migraine, especially in females, while serum histamine levels were normal. None of the studied polymorphisms was associated with the risk for migraine.

Impact of weekday and weekend mobility and public policies on COVID-19 incidence and deaths across 76 large municipalities in Colombia: statistical analysis and simulation.

BACKGROUND: Despite widespread restrictions on residents' mobility to limit the COVID-19 pandemic, controlled impact evaluations on such restrictions are rare. While Colombia imposed a National Lockdown, exceptions and additions created variations across municipalities and over time.  METHODS: We analyzed how weekend and weekday mobility affected COVID-19 cases and deaths. Using GRANDATA from the United Nations Development Program (UNDP) we examined movement in 76 Colombian municipalities, representing 60% of Colombia's population, from March 2, 2020 through October 31, 2020. We combined the mobility data with Colombia's National Epidemiological Surveillance System (SIVIGILA) and other databases and simulated impacts on COVID-19 burden.  RESULTS: During the study period, Colombians stayed at home more on weekends compared to weekdays. In highly dense municipalities, people moved less than in less dense municipalities. Overall, decreased movement was associated with significant reductions in COVID-19 cases and deaths two weeks later. If mobility had been reduced from the median to the threshold of the best quartile, we estimate that Colombia would have averted 17,145 cases and 1,209 deaths over 34.9 weeks, reductions of 1.63% and 3.91%, respectively. The effects of weekend mobility reductions (with 95% confidence intervals) were 6.40 (1.99-9.97) and 4.94 (1.33-19.72) times those of overall reductions for cases and deaths, respectively. CONCLUSIONS: We believe this is the first evaluation of day-of-the week mobility on COVID-19. Weekend behavior was likely riskier than weekday behavior due to larger gatherings and less social distancing or protective measures. Reducing or shifting such activities outdoors would reduce COVID-19 cases and deaths.

LAG3/CD4 Genes Variants and the Risk for Restless Legs Syndrome.

According to several studies, inflammatory factors could be related to the pathogenesis of idiopathic restless legs syndrome (RLS). In addition, RLS and Parkinson's disease (PD) have shown a possible relationship, and recent studies have shown an association between CD4 rs1922452 and CD4 rs951818 single nucleotide variants (SNVs) and the risk for PD. For these reasons, we investigated the possible association between common variants in the LAG3/CD4 genes (which encoded proteins involved in inflammatory and autoimmune responses) and the risk for RLS in a Caucasian Spanish population. We assessed the frequencies of CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 genotypes and allelic variants in 285 patients with idiopathic RLS and 350 healthy controls using a specific TaqMan-based qPCR assay. We also analyzed the possible influence of the genotypes' frequencies on several variables, including age at onset of RLS, gender, family history of RLS, and response to drugs commonly used in the treatment of RLS. We found a lack of association between the frequencies of genotypes and allelic variants of the 3 SNVs studied and the risk of RLS, and a weak though significant association between the CD4 rs1922452 GG genotype and an older age at onset of RLS. With the exception of this association, our findings suggest that common SNVs in the CD4/LAG3 genes are not associated with the risk of developing idiopathic RLS in Caucasian Spanish people.

Lung cancer mortality attributable to residential radon exposure in Spain and its regions.

Lung cancer has the highest cancer mortality rate in developed countries. The principal risk factor for lung cancer is tobacco use, with residential radon being the leading risk factor among never smokers and the second among ever smokers. We sought to estimate mortality attributable to residential radon exposure in Spain and its Autonomous Regions, with correction for dwelling height and differentiation by tobacco use. We applied a prevalence-based method for estimating attributable mortality. For estimations, we considered exposure to radon in the different Autonomous Regions corrected for dwelling height, using the National Statistics Institute Housing Census and prevalence of tobacco use (never smokers, smokers and ex-smokers). The results showed that 3.8% (838 deaths) of lung cancer mortality was attributable to radon exposure of over 100 Bq/m3, a figure that rises to 6.9% (1,533 deaths) when correction for dwelling height is not performed. By Autonomous Region, the highest population attributable fractions, corrected for dwelling height, were obtained for Galicia, Extremadura, and the Canary Islands, where 7.0, 6.9, and 5.5% of lung cancer mortality was respectively attributable to radon exposure. The greatest part of the attributable mortality occurred in men and among smokers and ex-smokers. Residential radon exposure is a major contributor to lung cancer mortality, though this contribution is highly variable among the different territories, indicating the need for targeted prevention policies. Correction of estimates for dwelling height is fundamental for providing reliable estimates of radon-attributable mortality.

Active commuting to school among 36,781 Spanish children and adolescents: A temporal trend study.

This study examines trends in the rates of active commuting to school (ACS) in Spanish children (n = 18 343; 8.93 ± 1.68) and adolescents (n = 18 438; 14.11 ± 1.58) aged 6-18 years from 2010 to 2017. Given the study period included the economic crisis in Spain (2008-2013), the second aim of this study was to compare ACS rates during and after the economic crisis. Data were obtained from 28 studies conducted across Spain. The overall trends in ACS were evaluated using multilevel logistic regression analysis. Among Spanish children and adolescents, the rates of ACS to school ranged around 60% between 2010 and 2017. The rates of ACS in Spanish youth did not change significantly during the 2010-2017 period, except a sporadic increase in the rate of ACS in adolescents in 2012-2013. No significant association between the ACS and the economic crisis time period in youth was found. As conclusion, the ACS remains stable in Spain during the last decade, which is a promising result regarding the evidenced decreasing trend in many countries. Further educational and policy strategies are important to continue promoting this behavior in children and adolescents in the long term.

Intentional mind-wandering as intentional omission: the surrealist method.

Mind-wandering seems to be paradigmatically unintentional. However, experimental findings have yielded the paradoxical result that mind-wandering can also be intentional. In this paper, we first present the paradox of intentional mind-wandering and then explain intentional mind-wandering as the intentional omission to control one's own thoughts. Finally, we present the surrealist method for artistic production to illustrate how intentional omission of control over thoughts can be deployed towards creative endeavors.

Association between endothelial nitric oxide synthase (NOS3) rs2070744 and the risk for migraine.

Because nitric oxide could play an important role in the pathogenesis of migraine (suggested by experimental, neuropathological, biochemical, and pharmacological data), and a recent meta-analysis showed an association between the single-nucleotide polymorphism (SNP) rs2070744 in the endothelial nitric oxide synthase (eNOS or NOS3) gene (chromosome 7q36.1) and the risk for migraine in Caucasians, we attempted to replicate the possible association between this SNP and the and the risk for migraine in the Caucasian Spanish population. The frequencies for the NOS3 rs2070744 genotypes and allelic variants were assessed in 283 migraine patients and 287 healthy controls with a TaqMan-based qPCR Assay. The putative influence on genotype frequency of age at onset of migraine attacks, gender, family history of migraine, absence or presence of aura, and triggering of migraine attacks by ethanol, were also analyzed. The frequencies of NOS3 rs2070744 genotypes and allelic variants were not associated with the risk for migraine (OR [95%] CI for the minor allele = 0.91 [0.72-1.15]) and were not influenced by age at onset of migraine, gender, presence of aura, or triggering of migraine attacks by ethanol. NOS3 rs2070744CC genotypes were significantly more frequent in patients with a family history of migraine. NOS3 rs2070744 SNP is not associated with the risk for migraine in Caucasian Spanish people although it might be related to family history.

Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial.

Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. Hepatoblastoma-derived C3A cells express anti-inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin ≥8 mg/dL, Maddrey's discriminant function ≥ 32, and Model for End-Stage Liver Disease (MELD) score ≤ 35 were randomized to receive standard of care (SOC) only or 3-5 days of continuous ELAD treatment plus SOC. After a minimum follow-up of 91 days, overall survival (OS) was assessed by using a Kaplan-Meier survival analysis. A total of 203 subjects were enrolled (96 ELAD and 107 SOC) at 40 sites worldwide. Comparison of baseline characteristics showed no significant differences between groups and within subgroups. There was no significant difference in serious adverse events between the 2 groups. In an analysis of the intent-to-treat population, there was no difference in OS (51.0% versus 49.5%). The study failed its primary and secondary end point in a population with sAH and with a MELD ranging from 18 to 35 and no upper age limit. In the prespecified analysis of subjects with MELD < 28 (n = 120), ELAD was associated with a trend toward higher OS at 91 days (68.6% versus 53.6%; P = .08). Regression analysis identified high creatinine and international normalized ratio, but not bilirubin, as the MELD components predicting negative outcomes with ELAD. A new trial investigating a potential benefit of ELAD in younger subjects with sufficient renal function and less severe coagulopathy has been initiated. Liver Transplantation 24 380-393 2018 AASLD.

Response to Symptoms and Prehospital Delay in Stroke Patients. Is It Time to Reconsider Stroke Awareness Campaigns?

BACKGROUND: Despite recent advances in acute stroke care, reperfusion therapies are given to only 1%-8% of patients. Previous studies have focused on prehospital or decision delay. We aim to give a more comprehensive view by addressing different time delays and decisions. METHODS: A total of 382 patients with either acute stroke or transient ischemic attack were prospectively included. Sociodemographic and clinical parameters and data on decision delay, prehospital delay, and first medical contact were recorded. Multivariate logistic regression analyses were conducted to identify factors related to decision delay of 15 minutes or shorter, calling the Extrahospital Emergency Services, and prehospital delay of 60 minutes or shorter and 180 minutes or shorter. RESULTS: Prehospital delay was 60 minutes or shorter in 11.3% of our patients and 180 minutes or shorter in 48.7%. Major vascular risk factors were present in 89.8% of patients. Severity was associated with decision delay of 15 minutes or shorter (odds ratio [OR] 1.08; confidence interval [CI] 1.04-1.13), calling the Extrahospital Emergency Services (OR 1.17; CI 1.12-1.23), and prehospital delay of 180 minutes or shorter (OR 1.08; CI 1.01-1.15). Adult children as witnesses favored a decision delay of 15 minutes or shorter (OR 3.44; CI 95% 1.88-6.27; P < .001) and calling the Extrahospital Emergency Services (OR 2.24; IC 95% 1.20-4.22; P = .012). Calling the Extrahospital Emergency Services favored prehospital delay of 60 minutes or shorter (OR 5.69; CI 95% 2.41-13.45; P < .001) and prehospital delay of 180 minutes or shorter (OR 3.86; CI 95% 1.47-10.11; P = .006). CONCLUSIONS: Severity and the bystander play a critical role in the response to stroke. Calling the Extrahospital Emergency Services promotes shorter delays. Future interventions should encourage immediately calling the Extrahospital Emergency Services, but the target should be redirected to those with known risk factors and their caregivers.

Outcomes in Adults With Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study.

BACKGROUND: Acute liver failure (ALF) is a rare syndrome of severe, rapid-onset hepatic dysfunction-without prior advanced liver disease-that is associated with high morbidity and mortality. Intensive care and liver transplantation provide support and rescue, respectively. OBJECTIVE: To determine whether changes in causes, disease severity, treatment, or 21-day outcomes have occurred in recent years among adult patients with ALF referred to U.S. tertiary care centers. DESIGN: Prospective observational cohort study. (ClinicalTrials .gov: NCT00518440). SETTING: 31 liver disease and transplant centers in the United States. PATIENTS: Consecutively enrolled patients-without prior advanced liver disease-with ALF (n = 2070). MEASUREMENTS: Clinical features, treatment, and 21-day outcomes were compared over time annually for trends and were also stratified into two 8-year periods (1998 to 2005 and 2006 to 2013). RESULTS: Overall clinical characteristics, disease severity, and distribution of causes remained similar throughout the study period. The 21-day survival rates increased between the two 8-year periods (overall, 67.1% vs. 75.3%; transplant-free survival [TFS], 45.1% vs. 56.2%; posttransplantation survival, 88.3% vs. 96.3% [P < 0.010 for each]). Reductions in red blood cell infusions (44.3% vs. 27.6%), plasma infusions (65.2% vs. 47.1%), mechanical ventilation (65.7% vs. 56.1%), and vasopressors (34.9% vs. 27.8%) were observed, as well as increased use of N-acetylcysteine (48.9% vs. 69.3% overall; 15.8% vs. 49.4% [P < 0.001] in patients with ALF not due to acetaminophen toxicity). When examined longitudinally, overall survival and TFS increased throughout the 16-year period. LIMITATIONS: The duration of enrollment, the number of patients enrolled, and possibly the approaches to care varied among participating sites. The results may not be generalizable beyond such specialized centers. CONCLUSION: Although characteristics and severity of ALF changed little over 16 years, overall survival and TFS improved significantly. The effects of specific changes in intensive care practice on survival warrant further study. PRIMARY FUNDING SOURCE: National Institutes of Health.

Development of a material sparing bulk density test comparable to a standard USP method for use in early development of API's.

Bulk density can be a key indicator of performance, and may influence choice of formulation route of materials in pharmaceutical development. During early development, the cost of API's can be expensive and the availability of material for powder property analysis is limited. The aim of this work was to investigate a suitable small-scale, low material requirement, bulk density test which would provide comparable data to the recommended large volume USP test. Materials with a range of morphological characteristics typically seen in the pharmaceutical industry were assessed to ensure that methods were suitably robust. It was found that the USP II "low volume" test does not give equivalent results to other tests in the USP, across the range of materials. An alternative test based on the FT4 powder rheometer at a scale of 25 mL gave results equivalent to the large volume USP I standard test. The use of smaller 10-mL methods was also found to give acceptable results for materials that were considered well-behaved but were more variable with difficult to handle materials with low bulk density.

[SSRI AND BONE METABOLISM IN HIV + PATIENTS WITH ANTIRETROVIRAL THERAPY]. / Inhibidores de captación de serotonina y metabolismo óseo en pacientes VIH+ con tratamiento antirretroviral.

We report a series of 9 male HIV + patients, average age of 41.2 years, viral load negative (<50 copies RNA/ml), treated with antiretroviral (nucleoside and non-nucleoside inhibitors of reverse transcriptase) without systemic infections, the CNS diseases or marker or corticoidoterapia in progress. Were evaluated and supported by their infectologists interconsultation during the period October 2008-October 2013 by depressive syndrome. Psychotherapeutic and psychiatric treatment was initiated with SSRIs and clonazepam; Neuroimaging control and biochemical laboratory studies at baseline and 2 months of treatment were conducted. In the course of psychopharmacological treatment not suffer fractures due to falls and alterations were detected in bone metabolism markers and images. He studied with endocrinology and interdisciplinary medical clinic, decided to withdraw the SSRIs with normalization of biochemical values and psychotherapeutic treatment was continued. We will raise the associations between the use of SSRIs, disturbances of bone metabolism with clinical correlation and possible drug interactions between antidepressants and antiretroviral.

Minimal Hepatic Encephalopathy.

Minimal hepatic encephalopathy (MHE) is a pervasive frequent complication of cirrhosis of any etiology. The diagnosis of MHE is difficult as the standard neurologic examination is essentially within normal limits. None of the symptoms and signs of overt HE is present in a patient with MHE, such as confusion, disorientation, or asterixis. Progress has been made in diagnostic tools for detection of attention and cognitive deficits at the point of care of MHE. The development of MHE significantly impacts quality of life and activities of daily life in affected patients including driving motor vehicles and machine operation.

Sexual dimorphism of Dyschiriini (Coleoptera, Carabidae): Comparative morphological SEM study of palpi sensilla and its possible role in intraspecific chemical communication.

Sexual dimorphism in Dyschiriini (Coleoptera, Carabidae) consists of the presence of an autapomorphic sensory area in apical palpomeres of males, here named as Male Palpi Sensory Area (MPSA). In this work, microstructure of palpi, with focus on MPSA, is characterized and formally described using Scanning Electron Microscopy (SEM). Interspecific variability among 13 species and three subgenera of Dyschirius Bonelli, 1810 and one species of Reicheiodes Ganglbauer, 1891 is assessed. Palpi of studied Dyschiriini presented up to 4 sensilla classes (coeloconica, basiconica, digitiformia, trichodea) in both sexes, while males had one more class (sensilla placodea) found grouped in MPSA. Measurements of sensilla and MPSA are provided. Differences among taxa corresponded to development grade of MPSA and its number of sensilla placodea. The MPSA of Dyschirius (Dyschirius) thoracicus Rossi, 1790 were clearly different to the rest of the studied subgenera and species of Dyschirius and Reicheiodes, whose MPSA were similar and had slight intraspecific variability. We suggest that function of MPSA is likely detection of female pheromones, which would evidence chemical communication between sexes. We hypothesize that evolution of MPSA could be related to burrowing habits of Dyschiriini and its possible sexual behavior in soil tunnels. Study of MPSA may help to elucidate phylogenetic relationships among members of the tribe.

Sequence-based epitope mapping of high pathogenicity avian influenza H5 clade 2.3.4.4b in Latin America.

High Pathogenicity Avian Influenza (HPAI) poses a significant threat to public and animal health. Clade 2.3.4.4b recently emerged from the Eastern hemisphere and disseminated globally, reaching the Latin American (LATAM) region in late 2022 for the first time. HPAI in LATAM has resulted in massive mortalities and culling of poultry and wild birds, causing infection in mammals and humans. Despite its meaningful impact in the region, only occasional evidence about the genetic and epitope characteristics of the introduced HPAI is reported. Hence, this study seeks to phylogenetically characterize the molecular features and the source of HPAI in LATAM by evaluating potential antigenic variations. For such a purpose, we analyzed 302 whole genome sequences. All Latin American viruses are descendants of the 2.3.4.4b clade of the European H5N1 subtype. According to genomic constellations deriving from European and American reassortments, the identification of three major subtypes and eight sub-genotypes was achievable. Based on the variation of antigenic motifs at the HA protein in LATAM, we detected three potential antigenic variants, indicating the HA-C group as the dominant variant. This study decidedly contributes to unraveling the origin of the 2.3.4.4b clade in LATAM, its geographic dissemination, and evolutionary dynamics within Latin American countries. These findings offer useful information for public health interventions and surveillance initiatives planned to prevent and manage the transmission of avian influenza viruses.

Vitamin D receptor and binding protein genes variants in patients with migraine.

BACKGROUND/OBJECTIVES: Several studies have shown a relationship between vitamin D and migraine, including the association between decreased serum 25-hydroxyvitamin D in patients with migraine and the positive effects of vitamin D supplementations in the therapy of this disease. Two single-nucleotide variants (SNVs) vitamin D receptor (VDR) gene, VDR rs2228570, and VDR rs731236 have shown an association with migraine risk in a previous case-control association study, while an exome sequencing study identified a rare variant in GC vitamin D binding protein gene. This study aims to look for the association between several common variants in these two genes and the risk for migraine. METHODS: We genotyped 290 patients diagnosed with migraine and 300 age-matched controls using specific TaqMan assays for VDR rs2228570, VDR rs731236, VDR rs7975232, VDR rs739837, VDR rs78783628, GC rs7041, and GC rs4588 SNVs. RESULTS: We did not find an association between these SNVs and the risk for migraine. None of these SNVs were related to the positivity of a family history of migraine or with the presence of aura. The VDR rs731236A allele showed a significant association with the triggering of migraine attacks by ethanol (Pc = 0.007). CONCLUSIONS: In summary, the results of the current study suggest a lack of association between common SNVs in the VDR and GC gene and the risk of developing migraine. The possible relationship between VDR rs731236 and the triggering of migraine episodes with ethanol deserves future studies.