FURIN gene variants (rs6224/rs4702) as potential markers of death and cardiovascular traits in severe COVID-19.

Furin is a protease that plays a key role in the infection cycle of SARS-CoV-2 by cleaving the viral proteins during the virus particle assembly. In addition, Furin regulates several physiological processes related to cardio-metabolic traits. DNA variants in the FURIN gene are candidates to regulate the risk of developing these traits as well as the susceptibility to severe COVID-19. We genotyped two functional FURIN variants (rs6224/rs4702) in 428 COVID-19 patients in the intensive care unit. The association with death (N = 106) and hypertension, diabetes, and hyperlipidaemia was statistically evaluated. The risk of death was associated with age, hypertension, and hypercholesterolemia. The two FURIN alleles linked to higher expression (rs6224 T and rs4702 A) were significantly increased in the death cases (odds ratio= 1.40 and 1.43). Homozygosis for the two high expression genotypes (rs6224 TT and rs4702 AA) and for the T-A haplotype was associated with an increased risk of hypercholesterolemia. In the multiple logistic regression both, hypercholesterolemia and the TT + AA genotype were significantly associated with death. In conclusion, besides its association with hypercholesterolemia, FURIN variants might be independent risk factors for the risk of death among COVID-19 patients.

The APOB polymorphism rs1801701 A/G (p.R3638Q) is an independent risk factor for early-onset coronary artery disease: Data from a Spanish cohort.

BACKGROUND AND AIMS: Apoliprotein B (ApoB) has been associated with hypercholesterolemia and ischemic coronary disease. This study was aimed to determine the effect of two APOB gene variants in the risk of developing early-onset coronary artery disease (EO-CAD) in a Spanish population. The association of these polymorphisms with hypercholesterolemia was also analysed. METHODS AND RESULTS: The study involved a total of 889 healthy population controls (397 male) and 790 EO-CAD cases (636 male; EO-CAD was defined as male <60 years and women <65 years). All the patients had at least one vessel with angiography documented atherosclerotic lesion. Patients and controls were genotyped for the APOB variants rs1801701 A/G (p.R3638Q) and rs1367117 C/T (p.T98I). Allele and genotype frequencies were compared between the groups (patients vs. controls, hyper-vs. normo-cholesterolemia) by logistic regression. The rs1801701 was significantly associated with EO-CAD in male (OR = 1.44, 95%CI = 1.05-1.99) and female (OR = 2.22, 95%CI = 1.58-3.14). This SNP was significantly associated with hypercholesterolemia in female, with a trend in male. The association with EO-CAD was independent of hypercholesterolemia (multiple logistic regression). CONCLUSION: A common APOB polymorphism (rs1801701) was an independent risk factor for EO-CAD in our population. The risk-effect was more significant in female than in male.

An elderly Jervell and Lange-Nielsen patient heterozygous compound for two new KCNQ1 mutations.

We present the case of a 66-year-old female with early onset deafness and seizures, who was diagnosed with epilepsy at the age of 2 years. She received antiepileptic drugs and was free of syncope episodes for 32 years. After a syncope at the age of 34, the ECG was characteristic of long-QT syndrome and was treated with antiarrhythmic drugs. Sequencing of the KCNQ1 gene identified two novel KCNQ1 variants interpreted to be pathogenic, and the patient was finally diagnosed with Jervell and Lange-Nielsen syndrome. © 2016 Wiley Periodicals, Inc.

Does reducing ischemia time justify to catheterize firstly the culprit artery in every primary PCI?

No consensus exists about which coronary artery should be firstly catheterized in primary PCIs. Initial catheterization of the "culprit artery" could reduce reperfusion time. However, complete knowledge of coronary anatomy could modify revascularization strategy. The objective of the study was to analyze this issue in ST-elevation myocardial infarction patients undergoing primary PCI. PCIs were performed in 384 consecutive patients. Choice of ipsilateral approach (IA): starting with a guiding catheter for the angiography and PCI of the "culprit artery", or contralateral approach (CA): starting with a diagnostic catheter for the "non-culprit artery" and completing the angiography and PCI of the culprit with a guiding catheter was left to the operator. Differences between two approaches regarding reperfusion time, acute events or revascularization strategies were analyzed. There were no differences between two approaches regarding reperfusion time or clinical events. When the left coronary artery was responsible, IA was more frequent (76.4 vs 22.6 %), but when it was the right coronary artery, CA was preferred (20 vs 80 %); p < 0.0001. With CA, bare metal stents (BMS) were more used than drug eluting (DES) (60.8 vs 39.2 %) inversely than with IA (BMS 41.3 vs DES 59.7 %; p < 0.0001). With CA there were more patients with left main or multivessel disease in which revascularization was completed with non-urgent surgery (4.13 vs 2.4 %, p < 0.0001). Initial CA does not involve higher reperfusion time. Furthermore, overall knowledge of coronary anatomy offers more options in revascularization strategy and may imply a change in management. Despite the need to individualize each case, contralateral approach may be the first option with the exception of unstable patients.

ABCB1 (MDR-1) pharmacogenetics of tacrolimus in renal transplanted patients: a Next Generation Sequencing approach.

BACKGROUND: A CYP3A5 gene polymorphism is the main determinant of Tacrolimus (Tac) dose requirements among renal transplanted patients. In spite of the utility of CYP3A5 genotyping to predict the Tac-dose, many patients exhibit an out of range blood Tac level and it is thus likely that other genes/polymorphisms contribute to define Tac bioavailability. To address this issue we searched for coding sequence variants in the ABCB1/MDR1 gene in renal transplanted patients treated with Tac and who had out of the range blood levels. METHODS: We studied 100 renal transplanted patients treated with Tac, 60 of whom had Tac blood levels below (n=39) and above (n=21) the target range (10-15 ng/mL) at 1 week post-transplant. The DNA was subjected to multiplex amplification followed by massive parallel semiconductor sequencing in the Ion Torrent personal genome machine. RESULTS: We found four missense changes, all reported and present in cases above and below the blood Tac target. In addition, we did not find differences in the allele and genotype frequencies for the common rs1045642 polymorphism (p.I1145I) between the groups. CONCLUSIONS: Our results suggested that the ABCB1 variants had no effect on the risk of showing out of range Tac blood levels among renal transplanted patients.

Next generation sequencing search for uromodulin gene variants related with impaired renal function.

Uromodulin gene (UMOD) mutations have been linked to rare forms of mendelian dominant medullary cystic kidney disease and familial hyperuricemia. In addition, common single nucleotide polymorphisms in the UMOD promoter have been associated with the risk for impaired renal function and chronic kidney disease. Our main purpose was to identify UMOD variants related with impaired renal function in an elderly population. The UMOD gene was next generation sequenced in a total of 100 healthy individuals with normal or reduced renal function [measured as the rate of estimated glomerular filtration (eGFR)]. The identified missense changes and the common promoter rs12917707 polymorphism were determined in individuals with reduced (n = 88) and normal (n = 442) eGFR values. Allele and genotype frequencies were compared between the groups. We only identified a rare UMOD misense change, p.V458L, and the rare leu allele was significantly more frequent in a cohort of individuals with reduced (eGFR < 60) compared to normal eGFR (P = 0.02). The common rs12917707 polymorphism previously linked to renal function and kidney disease was not associated with impaired filtration rate in our cohort. We found a significant effect of the rare p.V458L variant on the value of estimated glomerular filtration. This finding deserves further validation in larger cohorts.

Mutation analysis of the main hypertrophic cardiomyopathy genes using multiplex amplification and semiconductor next-generation sequencing.

BACKGROUND: Mutations in at least 30 genes have been linked to hypertrophic cardiomyopathy (HCM). Due to the large size of the main HCM genes, Sanger sequencing is labor intensive and expensive. The purpose was to develop a next-generation sequencing (NGS) procedure for the main HCM genes. METHODS AND RESULTS: Multiplex amplification of the coding exons of MYH7,MYBPC3,TNNT2,TNNI3,ACTC1,TNNC1,MYL2,MYL3, and TPM1 was designated, followed by NGS with the Ion Torrent PGM (Life Technologies). A total of 8 pools containing DNA from HCM patients were sequenced in a 2-step approach. First, a total of 60 patients (validation cohort) underwent both PGM and Sanger sequencing for the 9 genes. No false-negative variants were found on NGS (100% sensitivity), and a specificity of 97% and 80% was achieved for single-nucleotide and insertion/deletion variants, respectively. Second, the PGM was used to search for mutations in a total of 76 cases not previously studied (discovery cohort). A total of 19 putative mutations were identified in the discovery pools, which were confirmed and assigned to specific patients on Sanger sequencing. CONCLUSIONS: An NGS procedure has been developed for the main sarcomeric genes that would facilitate the screening of large cohorts of patients. In addition, this procedure would facilitate the uncovering of rare gene variants on a population scale.

Griefbots. A New Way of Communicating With The Dead?

There is a growing number of new digital technologies mediating the experiences of grief and the continuing bonds between the bereaved and their loved ones following death. One of the most recent technological developments is the "griefbot". Based on the digital footprint of the deceased, griefbots allow two-way communication between mourners and the digital version of the dead through a conversational interface or chat. This paper explores the mediational role that griefbots might have in the grieving process vis-à-vis that of other digital technologies, such as social media services or digital memorials on the Internet. After briefly reviewing the new possibilities offered by the Internet in the way people relate with the dead, we delve into the particularities of griefbots, focusing on the two-way communication afforded by this technology and the sense of simulation derived from the virtual interaction between the living and the dead. Discussion leads us to emphasize that, while both the Internet and griefbots bring about a significant spatial and temporal expansion to the grief experience -affording a more direct way to communicate with the dead anywhere and at any time- they differ in that, unlike the socially shared virtual space between mourners and loved ones in most digital memorials, griefbots imply a private conversational space between the mourner and the deceased person. The paper concludes by pointing to some ethical issues that griefbots, as a profit-oriented afterlife industry, might raise for both mourners and the dead in our increasingly digital societies.

Design and synthesis of unnatural coordination glycopolymer particles (CGPs): unleashing the potential of catechol-saccharide derivatives.

Our study unveils an innovative methodology that merges catechols with mono- and disaccharides, yielding a diverse array of compounds. This strategic fusion achieves robust yields and introduces ligands with a dual nature: encompassing both the chelating attributes of catechols and the recognition capabilities of carbohydrates. This synergistic design led us to couple one of the novel ligands with an Fe(iii) salt, resulting in the creation of Coordination Glycopolymer Particles (CGPs). These CGPs demonstrate remarkable qualities, boasting outstanding dispersion in both aqueous media and Phosphate Buffered Saline (PBS) solution (pH ∼7.4) at higher concentrations (0.26 mg µL-1). Displaying an average Z-size of approximately 55 nm and favourable polydispersity indices (<0.25), these particles exhibit exceptional stability, maintaining their integrity over prolonged periods and temperature variations. Notably, they retain their superior dispersion and stability even when subjected to freezing or heating to 40 °C, making them exceptionally viable for driving biological assays. In contrast to established methods for synthesizing grafted glycopolymers, where typically a glycopolymer is doped with catechol derivatives to create synergy between chelating properties and those inherent to the saccharide, our approach provides a more efficient and versatile pathway for generating CGPs. This involves combining catechols and carbohydrates within a single molecule, enabling the fine-tuning of organic structure from a monomer design step and subsequently transferring these properties to the polymer.

Association of the Genetic Variation in the Long Non-Coding RNA FENDRR with the Risk of Developing Hypertrophic Cardiomyopathy.

Background: In around 40−60% of Hypertrophic Cardiomyopathy (HCM) cases pathogenic variants are not identified. Our aim was to evaluate the possible association of lncRNAs with the risk of developing HCM. Methods: We sequenced 10 lncRNAs coding genes that have been associated with cardiovascular disease in a discovery cohort (238 HCM patients and 212 controls) by NGS, and genotyped rs74035787 G>A and rs1424019 A>G polymorphism in a validation cohort (962 HCM patients and 923 controls). Finally, we sequenced the FENDRR promoter by Sanger sequencing. Results: We observed by NGS that FENDRR rs39527, rs39529 and rs40384 polymorphisms were significantly associated with HCM in our cohort (p = 0.0284; OR: 0.24, 95%CI: 0.07−0.86). NGS results were confirmed by genotyping rs74035787 polymorphism (p = 0.001; OR:0.38, 95%CI: 0.21−0.66). Moreover, it is also associated when stratification by sex (p = 0.003; OR:0.20, 95%CI: 0.06−0.53), and age (≥50 years old p = 0.001, OR:0.33, 95%CI: 0.16−0.63) Moreover, the risk of HCM in the carriers of the GG genotype of the rs1424019 polymorphism was significantly higher than that of the AA/AG genotypes carriers in the elderly subjects (p = 0.045, OR:1.24, 95%CI: 1.01−1.53). On the other hand, we observed significant differences in the rs74035787 A/rs1424019 G haplotype frequency (p = 0.0035; OR: 0.20, 95%CI: 0.07−0.59). Conclusions: Our study suggested a significant association between FENDRR gene variants and HCM.

Functional polymorphisms in the CYP3A4, CYP3A5, and CYP21A2 genes in the risk for hypertension in pregnancy.

An intronic single nucleotide polymorphism (SNP) in the CYP3A5 gene (CYP3A5*3; SNP rs776746) affects RNA splicing and enzymatic activity. The CYP3A5*3 frequency increased with distance from the equator and natural selection has been proposed to explain the worldwide distribution of this allele. CYP3A activity has been related with the risk for hypertension in pregnancy, a major cause of morbidity and mortality among women, and CYP3A5*3 could reduce the risk for this disease in populations from regions with high sodium and water availability. The CYP3A5 genotype was related with blood pressure in the general population, but the effect on the risk for hypertension in pregnancy has not been evaluated.We compared the allele and genotype frequencies of three functional SNPs in the CYP3A5 (rs776746), CYP3A4 (rs2740574), and CYP21A2 (rs6471) genes between pregnant women who developed hypertension (n = 250) or who remained normotensive (control group, n = 250). In addition, we sequenced the full CYP3A5 coding sequence in 40 women from the two groups to determine whether some gene variants could explain the risk for hypertensive pregnancies in our population.Allele and genotype frequencies did not differ between hypertensive and normotensive women for the three CYP variants. We did not find CYP3A5 nucleotide changes that could explain a higher risk for hypertension in pregnancy. Our data suggests that the variation in CYP3A5, CYP3A4, and CYP21A2 did not contribute to the risk for hypertension in pregnancy in our population.

Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia.

BACKGROUND: Hereditary Spastic Paraplegias (HSP) are characterized by progressive spasticity and weakness of the lower limbs. At least 45 loci have been identified in families with autosomal dominant (AD), autosomal recessive (AR), or X-linked hereditary patterns. Mutations in the SPAST (SPG4) and ATL1 (SPG3A) genes would account for about 50% of the ADHSP cases. METHODS: We defined the SPAST and ATL1 mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype). RESULTS: We found 50 SPAST mutations (including two large deletions) in 54 patients and 7 ATL1 mutations in 11 patients. A total of 33 of the SPAST and 3 of the ATL1 were new mutations. A total of 141 (31%) were familial cases, and we found a higher frequency of mutation carriers among these compared to apparently sporadic cases (38% vs. 5%). Five of the SPAST mutations were predicted to affect the pre-mRNA splicing, and in 4 of them we demonstrated this effect at the cDNA level. In addition to large deletions, splicing, frameshifting, and missense mutations, we also found a nucleotide change in the stop codon that would result in a larger ORF. CONCLUSIONS: In a large cohort of Spanish patients with spastic paraplegia, SPAST and ATL1 mutations were found in 15% of the cases. These mutations were more frequent in familial cases (compared to sporadic), and were associated with heterogeneous clinical manifestations.

Gene Variant in the NF-κB Pathway Inhibitor NFKBIA Distinguishes Patients with Psoriatic Arthritis within the Spectrum of Psoriatic Disease.

BACKGROUND AND AIMS: The NF-κB pathway has been implicated in the genetic aetiology of psoriatic disease. However, since most patients with arthritis have psoriasis, discerning the genetic contributions to both aspects of psoriatic disease is not easy. Our aim was to study the association of common polymorphisms in genes of the NF-κB pathway in patients with psoriatic disease in order to dissect the contribution of this pathway in the appearance of each component (skin and joint) of the disease. PATIENTS AND METHODS: We investigated the association between three common variants in NFKB1 (rs230526), NFKBIA (rs7152376), and NFKBIZ (rs3217713 indel) and the risk of developing psoriatic disease. We genotyped a total of 690 psoriatic disease patients and 550 controls. Patients with cutaneous psoriasis of at least 10 years of evolution without associated arthritis were defined to have pure cutaneous psoriasis (PCP). RESULTS: The rare NFKBIA rs7152376 C was significantly more frequent in the PsA group vs. controls (OR = 2.03 (1.3-3.1), p < 0.01). The difference was even higher between PsA and PCP patients (OR = 3.2 (2.1-5.1), p < 0.001). Neither NFKB1 rs230526 nor NFKBIZ rs3217713 indel was associated with the risk of developing psoriatic disease as a whole compared to controls. CONCLUSIONS: Our study supports a significant effect of the NFKBIA gene on the risk of developing PsA, thus contributing to better discerning of the polymorphisms of this pathway that explain this risk within the spectrum of psoriatic disease. Additional studies with larger cohorts and from different populations are necessary to validate these results.

Gene variants in the NF-KB pathway (NFKB1, NFKBIA, NFKBIZ) and risk for early-onset coronary artery disease.

The nuclear-factor kappa-beta (NF-KB) is a driver of inflammation, and plays an important role in the pathogenesis of atherosclerosis and coronary artery disease (CAD). Early-onset CAD is defined as a coronary ischaemic episode at an age ≤55 years, and in our population was strongly associated with male sex and smoking. Our aim was to determine whether common variants in three NF-KB genes were associated with early-onset CAD. We studied 609 patients with early-onset CAD and 423 healthy controls, all male. Allele and genotype frequencies for the NFKB1 rs28362491 (-94 delATTG) and NFKBIA rs8904 were not significantly different between the two groups. For the NFKBIZ rs3217713, the deletion allele was significantly more frequent in the patients than in controls (0.27 vs. 0.22; p = 0.004). Deletion-carriers were more frequent in the patients (p < 0.001), with an OR = 1.48 (95%CI = 1.15-1.90). We performed a multiple logistic regression (linear generalized model) with smoking, hypercholesterolemia, type 2 diabetes, hypertension, and the rs3217713 deletion carriers remained significantly associated with early-onset CAD (p = 0.01). In our population, the NFKBIZ variant was an independent risk factor for developing early-onset CAD.

Superiority of wall motion score index over left ventricle ejection fraction in predicting cardiovascular events after an acute myocardial infarction.

BACKGROUND:: There are few data on the prognostic significance of the wall motion score index compared with left ventricle ejection fraction after an acute myocardial infarction. Our objective was to compare them after the hyperacute phase. METHODS:: Transthoracic echocardiograms were performed in 352 consecutive patients with myocardial infarction, after the first 48 hours of admission and before hospital discharge (median 56.3 hours (48.2-83.1)). We evaluated the ability of the wall motion score index and left ventricular ejection fraction to predict the combined endpoint (mortality and rehospitalization for heart failure) as a primary objective and the independent events of the combined endpoint as a secondary objective. RESULTS:: In 80.7% of patients, the wall motion score index was high despite having an ejection fraction >40%. No patient had an ejection fraction <55% with a normal index. After a follow-up of 30.5 months (24.2-49.5), both variables were predictors of the composite endpoint and all-cause mortality ( p<0.0001), although only the wall motion score index was a predictor of readmission for heart failure ( p=0.007). By multivariate analysis, a wall motion score index >1.8 proved to be the most powerful predictor of the composite endpoint (hazard ratio: 8.5; 95% confidence interval 3.7-18.8; p<0.0001). The superiority of the wall motion score index over ejection fraction was especially significant in patients with less myocardial damage (non-ST elevation myocardial infarction, or left ventricle ejection fraction >40%). CONCLUSIONS:: Both variables provide important prognostic information after a myocardial infarction. Beyond the hyperacute phase, wall motion score index is a more powerful prognostic predictor, especially in subgroups with less myocardial damage.

Eugenics, sexual pedagogy and social change: constructing the responsible subject of governmentality in the Spanish Second Republic.

This study focuses on eugenics in Spain, and more specifically on the 'official' eugenics whose platform was the Primeras Jornadas Eugénicas Españolas (First Spanish Eugenic Days, FSED). The aim of this paper is to relate eugenics to 'governmentality' rather than to State politics alone and to 'Latin eugenics' rather than to 'mainline eugenics'. On the one hand, the FSED were largely centred on the development of a new sexual code which would set Catholic sexual morality aside. For this reason, sexual pedagogy was one of the most relevant topics during the FSED, personal responsibility becoming the first step to social change. The concern about making people play an active role in their own self-regulation is typical of governmentality. The latter refers to societies where power is decentered and where the objective is to structure the field of action of others (the conduct of conduct). On the other hand, the FSED emphasised preventive eugenics such as welfare programmes and health campaigns rather than negative eugenics such as the sterilisation of the unfit. The situation in Spain was mirrored in countries such as Brazil, Argentina and Mexico, which allows us to think about them in terms of 'Latin eugenics' rather than 'mainline eugenics' from countries such as Great Britain, Germany and the USA.

Percutaneous Closure of a Femoral Arteriovenous Fistula During Transfemoral TAVI.

Percutaneous AVF closure was performed post TAVI in a patient with severe aortic stenosis and an AVF between the right SFA and femoral vein.

Genetic variation at the long noncoding RNA H19 gene is associated with the risk of hypertrophic cardiomyopathy.

AIM: The long noncoding RNA H19 and its host micro RNA miR-675 have been found deregulated in cardiac hypertrophy and heart failure tissues. Our aim was to investigate whether the H19 gene variants were associated with the risk of hypertrophic cardiomyopathy (HCM). PATIENTS & METHODS: We genotyped two H19 tag single nucleotide polymorphisms in 405 HCM patients and 550 controls, and sequenced this gene in 100 patients. RESULTS: The rs2107425 C was significantly increased in sarcomere no-mutation patients (n = 225; p = 0.01): CC versus CT + TT, p = 0.017; odd ratios: 1.51. Sequencing of the H19 coding transcript identified two patients heterozygous carriers for a rare variant, rs945977096 G/A, that was absent among the controls. CONCLUSION: Our study suggested a significant association between H19 variants and the risk of developing HCM.