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.

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.

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.

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.

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.

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.

Genetic Variation in the H19-IGF2 Cluster Might Confer Risk of Developing Impaired Renal Function.

The H19-IGF2 imprinted gene region could be implicated in the risk of developing impaired renal function (IRF). Our aim was to determine the association of several common H19-IGF2 variants and IRF in a cohort of elderly healthy individuals. The study involved 675 individuals >65 years of age, 184 with type 2 diabetes mellitus (T2DM), and 105 with IRF (estimated glomerular filtration rate [eGFR] <60). They were genotyped for two common H19 single nucleotide polymorphisms (SNPs) (rs2839698 and rs10732516), one H19-IGF2 intergenic indel (rs201858505), and one indel in the 3'UTR of the IGF2. For the H19 SNPs, we also determined the allele present in the methylated chromosome through genotyping the DNA digested with a methylation-sensitive endonuclease. None of the four H19-IGF2 variants was associated with IRF in our cohort. We found a significantly higher frequency of the 3'UTR IGF2 deletion (D) in the eGFR <60 group (p = 0.01; odds ratio = 1.16, 95% confidence interval = 1.10-2.51). This association was independent of age and T2DM, two strong predictors of IRF. In conclusion, a common indel variant in the 3'UTR of the IGF2 gene was associated with the risk of IRF. This association could be explained by the role of IGF2 in podocyte survival, through regulation of IGF2 expression by differential binding of miRNAs to the indel sequences. Functional studies should be necessary to clarify this issue.

Gene variants in the NF-KB pathway (NFKB1, NFKBIA, NFKBIZ) and their association with type 2 diabetes and impaired renal function.

The NF-kappaB pathway might play a role in the pathogenesis of renal disease and type 2 diabetes (T2DM). Our aim was to determine whether common polymorphisms in NF-kappaB genes were associated with impaired renal function and T2DM in a cohort of healthy elderly individuals. We studied 487 individuals, all Caucasian and aged 65-85 years. A total of 104 (21%) had impaired renal function (estimated glomerular filtration rate, eGFR < 60) and 146 (30%) were classified as diabetics. The genotypes of 4 common variants were determined through PCR-RFLP or fluorescent capillary electrophoresis. The NFKB1 variants were significantly associated with T2DM: rs7667496 p = 0.01, OR = 1.68; and rs28362491 p = 0.02, OR = 1.67. They remained significantly associated in a multiple logistic regression with age, gender, hypertension, body mass index, and cholesterol. There was a trend toward the association of these variants with eGFR < 60. The two NFKB1 variants were in linkage disequilibrium (D' = -0.86), and homozygous for the two non-risk alleles (rs7667496 CC + rs28362491 II), were significantly more common in the non-diabetics (p = 0.02). In our cohort the NFKB1 variation was an independent risk factor for developing T2DM. Additional studies to confirm this association are of special interest, as well as studies to give a functional explanation to the genetic association.

Systematic isolated post-dilatation of the side branch as part of the provisional stent technique in the percutaneous treatment of coronary bifurcations. CR12 Registry.

AIMS: To analyse systematic isolated post-dilatation of the side branch as a part of provisional stent technique. METHODS: 1960 angioplasties performed in two centres were prospectively registered, of which 382 were coronary bifurcations with a side branch>2mm. In centre A, isolated post-dilatation of the side branch was performed regardless its impairment after main vessel stenting. In centre B, side branch post-dilatation was performed only if it was severely affected after stent implantation. RESULTS: There was no difference between the two centres in the rate of side branch affection after stent implantation (A: 44.6 vs B: 49.3%, p=0.48) nor in the procedural success rate (A: 98.6% vs B: 96.7%, p=0.45). After one-year follow-up, a reduction of cardiovascular events was observed in centre A (A: 4.4% vs B: 10.4%, p=0.043) with a trend towards lower cardiac mortality (A: 2.2% vs B: 6.5%, p=0.093) and stent thrombosis (A: 0% vs B: 2.6%, p=0.077). There were no differences in the rate of myocardial infarction related to the treated artery (A: 1.4% vs B: 3.9%, p=0.29), or target lesion revascularization (A: 1.4% vs. B: 3.2%, p=0.45). CONCLUSIONS: Systematic isolated post-dilatation of the side branch in the provisional stent technique was associated with a high angiographic success rate, and a low rate of cardiovascular events during follow-up. Although the study design does not allow definitive conclusions, this strategy could be considered a valid option in some cases or even as part of the provisional stent technique.

Outcomes of patients at estimated low surgical risk undergoing transcatheter aortic valve implantation with balloon-expandable prostheses.

INTRODUCTION AND OBJECTIVES: Transcatheter aortic-valve implantation (TAVI) is an accepted treatment for patients with severe aortic stenosis and high surgical risk. However, there is lack in data about TAVI in low-risk patients that are already being treated with this therapy in some clinical contexts. METHODS: A retrospective analysis of patients treated with transfemoral TAVI using Edwards Sapien prosthesis in one center was performed, classifying the patients into three groups according to the surgical risk (high/intermediate/low risk for STS score>8/4-8/<4). Clinical characteristics, procedure and follow-up outcomes were collected, comparing the results between low and high surgical risk groups. RESULTS: 89 TAVIs using Edwards balloon expandable prosthesis were performed (9 Sapien XT and 80 Sapien 3 valves were implanted). 40 patients (45%) presented a STS score<4, while 33 (37%) had a STS>8. Low-risk patients were significantly younger and had lower rates of coronary artery disease, peripheral vascular disease, pulmonary lung disease and atrial fibrillation. There were no significant differences in most of the technical variables of the procedure, apart from vascular complications and complete left bundle branch block after valve implant, which were higher in the group with STS>8. Patients of low risk presented shorter hospital stay (2,91±1,6, vs 4,8±3,9 days), with lower rates of mortality at mid- and long follow-up (death from any cause 15,2% vs 0%, p 0,04). CONCLUSIONS: TAVI in low-risk patients is safe and associated with better outcome at mid and long-term follow-up compared to high-risk patients.

NFKBIZ in Psoriasis: Assessing the association with gene polymorphisms and report of a new transcript variant.

The IκBζ protein (NFKBIZ gene) is a nuclear inhibitor of NF-κB and plays an important role in the pathogenesis of Psoriasis (Psor). We sought to determine whether common NFKBIZ variants were associated with the risk of developing Psor. A total of 392 patients and 336 controls were genotyped for a common intron 10 indel that could affect pre-mRNA splicing. We found a significantly higher frequency of the insertion among the cw6-positive patients (p=0.01). Cw6-positive+intron 10 ins/ins were significantly more frequent in the patients (OR=3.61). The analysis of the cDNA from leukocytes showed a NFKBIZ transcript lacking exon 10, present in all the tested samples. This new alternative transcript lacks a domain predicted to interact with the NFKB1/p50 protein. Functional studies to define the effect of this alternative transcript on the regulation of the NF-κB pathway are necessary.

Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients.

BACKGROUND: Recent exome sequencing studies identified filamin C (FLNC) as a candidate gene for hypertrophic cardiomyopathy (HCM). Our aim was to determine the rate of FLNC candidate variants in a large cohort of HCM patients who were also sequenced for the main sarcomere genes. METHODS AND RESULTS: A total of 448 HCM patients were next generation-sequenced (semiconductor chip technology) for the MYH7, MYBPC3, TNNT2, TNNI3, ACTC1, TNNC1, MYL2, MYL3, TPM1, and FLNC genes. We also sequenced 450 healthy controls from the same population. Based on the reported population frequencies, bioinformatic criteria, and familial segregation, we identified 20 FLNC candidate variants (13 new; 1 nonsense; and 19 missense) in 22 patients. Compared with the patients, only 1 of the control's missense variants was nonreported (P=0.007; Fisher exact probability test). Based on the familial segregation and the reported functional studies, 6 of the candidate variants (in 7 patients) were finally classified as likely pathogenic, 10 as variants of uncertain significance, and 4 as likely benign. CONCLUSIONS: We provide a compelling evidence of the involvement of FLNC in the development of HCM. Most of the FLNC variants were associated with mild forms of HCM and a reduced penetrance, with few affected in the families to confirm the segregation. Our work, together with others who found FLNC variants among patients with dilated and restrictive cardiomyopathies, pointed to this gene as an important cause of structural cardiomyopathies.