Surface perfluoroalkyl chains segregation : a tool for reducing calcium deposits in medical grade poly(methyl methacrylate)

Intraocular lenses can be manufactured from a wide variety of polymers, but due to the lost cost associated with the use of Poly(methyl methacrylate) (PMMA), it is still the preferred material used in the developing countries. However, a major drawback to its use is the build-up of calcium containing deposits that are formed on the intraocular lens over a period of time. In an attempt to hinder this deposition, surface modification of medical grade PMMA has been carried out using perfluoroalkyl chain (1,2,4-trifluoro-3- (C10F21CH2O)-7-(N,N)-dimethylaminoacridine) segregation. The segregation was explored using a 1% 1,2,4-trifluoro-3-(C10F21CH2O)-7-(N,N)-dimethyla- minoacridine in two methods: film casting and spin-coating, a thin film onto preformed PMMA discs. Both methods were compared against control PMMA to determine which method provided the best hindrance against calcium containing deposits when immersed in a simulated aqueous humour solution. Characterisation of the surface using scanning electron microscopy coupled with energy; dispersive x-ray analysis indicated that the surface segregation of perfluoroalkyl chains had hindered calcification in both methods. This pleminary research shows promising results of employing perfluoroalkyl chains in the surface segregation of biomaterials that can be employed in intraocular lenses

Sulfur hexafluoride (SF₆) plasma treatment of medical grade poly(methyl methacrylate)

Medical-grade poly(methyl methacrylate) (PMMA) is widely employed in the fabrication of intraocular lenses (IOLs), but suffers from opacification, a postoperative complication that leads to the failure of the implanted intraocular lenses. The opacification occurs when inorganic-based deposits accumulate on the surface of the IOL and are prevalent in hydrophilic materials. Here, the surface of medical-grade PMMA has been fluorinated by sulphur hexafluoride (SF₆) plasma treatment to increase surface hydrophobicity thus improving the material lifetime in optical applications. Hydrophobic properties of the treated PMMA were investigated by means of contact angle measurements, while chemical modification was assessed by X-ray Photoelectron Spectroscopy (XPS) and Attenuated Total Reflectance Fourier Transform Infrared (ATR/FTIR) spectroscopy. Surface morphological changes due to possible etching effects were investigated by Atomic Force Microscopy (AFM). The transparency of the treated PMMA was assessed by UV/VIS spectroscopy. Finally, the influence of the plasma treatment on the inorganic salts deposition was investigated by immersion in Simulated Aqueous Humour (SAH), followed by XPS analysis. The modified samples showed less deposition on the surface than the unmodified sample, moreover, a decrease of the transmittance in the UV-violet range (300–430 nm) was detected, open the possibility of interesting applications of this treatment for the creation of a UV filter in ophthalmic optical devices

Bypassing the statistical limit of singlet generation in sensitized upconversion using fluorinated conjugated systems

The photon upconversion based on triplet–triplet annihilation (TTA) is a mechanism that converts the absorbed low-energy electromagnetic radiation into higher energy photons also at extremely low excitation intensities, but its use in actual technologies is still hindered by the limited availability of efficient annihilator moieties. We present here the results obtained by the synthesis and application of two new fluorinated chromophores based on phenazine and acridine structures, respectively. Both compounds show upconverted emission demonstrating their ability as TTA annihilator. More interesting, the acridine-based chromophore shows an excellent TTA yield that overcomes the one of some of best model systems. By correlating the experimental data and the quantum mechanical modeling of the investigated compound, we propose an alternative efficient pathway for the generation of the upconverted emissive states involving the peculiar high-energy triplet levels of the dye, thus suggesting a new development strategy for TTA annihilators based on the fine tuning of their high-energy excited states properties

COVID-19 in patients with Myasthenia Gravis: epidemiology and disease course

COVID-19, a disease caused by SARS-CoV-2 infection, has become a global pandemic. Patients with myasthenia gravis (MG), often treated with immunosuppressants, might be at higher risk of developing COVID-19 and of demonstrating a severe disease course. We aimed to study prevalence and describe features of COVID-19 in MG patients

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19

A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death

: The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10-8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10-8). A total of 113 variants were associated with survival at P-value < 1.0 × 10-5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types