Enantiodivergent Cyclization by Inversion of the Reactivity in Ambiphilic Molecules.

Inverting the reactivity of the functional groups in ambiphilic molecules provides a new synthetic strategy to perform late-stage enantiodivergence. Both enantiomers of the final compound can be obtained from a common chiral precursor. As a proof of concept, the synthesis of substituted five- and six-membered oxacycles is described. The key step is the cyclization of an ambiphilic linear precursor bearing a propargylic alcohol and an epoxide linked through an alkyl chain. Through a slight modification of these linear precursors and employing different reaction conditions, these functional groups can inverse their chemical reactivity, producing one enantiomer or another of the final product. This enantiodivergent cyclization involves three stereogenic centers that can undergo fully controlled retention or inversion of their configuration depending on the cyclization pathway that is activated. The cyclization provides late-stage enantiodivergence, enabling the synthesis of either enantiomers of the oxacycles from a common chiral substrate with total transfer of the enantiomeric purity.

Isosteric Substitution of 4 H-1,2,4-Triazole by 1 H-1,2,3-Triazole in Isophthalic Derivative Enabled Hydrogel Formation for Controlled Drug Delivery.

In this work, we demonstrated that the simple substitution of the 1,2,4-triazole moiety in 5-( 4H-1,2,4-triazol-4-yl)isophthalic acid (5-TIA) by the 1 H-1,2,3-triazol-5-yl unit enables the preparation of a hydrogelator (click-TIA). In sharp contrast to 5-TIA, its isostere click-TIA undergoes self-assembly in water upon sonication, leading to the formation of stable supramolecular viscoelastic hydrogels with a critical gelation concentration of 6 g/L. Hydrogels made of click-TIA as well as hybrid hydrogels made of the mixture click-TIA + 5-TIA (molar ratio 1:0.2) were used to compare different properties of the materials (i.e., rheological properties, thermal properties, mechanical stability, morphology). In terms of toxicity, neither click-TIA nor 5-TIA showed cytotoxic effects on cellular viability of HeLa cells up to 2.3 × 10-3 g/L when compared to untreated cells incubated with DMSO. Furthermore, the hydrogels were used for the encapsulation and in vitro controlled release of oxytetracycline that followed first-order kinetics. For the hydrogel made of click-TIA, a maximum drug release of ∼60% was reached after ∼8 h within a pH range between 6.5 and 10. However, the release rate was reduced to approximately half of its value at pH values between 1.2 and 5.0, whereas the use of hybrid hydrogels made of click-TIA + 5-TIA allowed to reduce the original rate at pH ≤ 6.5.

Identification of putative second genetic hits in schizophrenia carriers of high-risk copy number variants and resequencing in additional samples.

Copy number variants (CNVs) conferring risk of schizophrenia present incomplete penetrance, suggesting the existence of second genetic hits. Identification of second hits may help to find genes with rare variants of susceptibility to schizophrenia. The aim of this work was to search for second hits of moderate/high risk in schizophrenia carriers of risk CNVs and resequencing of the relevant genes in additional samples. To this end, ten patients with risk CNVs at cytobands 15q11.2, 15q11.2-13.1, 16p11.2, or 16p13.11, were subjected to whole-exome sequencing. Rare single nucleotide variants, defined as those absent from main public databases, were classified according to bioinformatic prediction of pathogenicity by CADD scores. The average number of rare predicted pathogenic variants per sample was 13.6 (SD 2.01). Two genes, BFAR and SYNJ1, presented rare predicted pathogenic variants in more than one sample. Follow-up resequencing of these genes in 432 additional cases and 432 controls identified a significant excess of rare predicted pathogenic variants in case samples at SYNJ1. Taking into account its function in clathrin-mediated synaptic vesicle endocytosis at presynaptic terminals, our results suggest an impairment of this process in schizophrenia.

Novel TEVAR technique for thoracic aortic aneurysm repair: A case report.

INTRODUCTION AND IMPORTANCE: A thoracic aortic aneurysm (TAA) is a life-threatening condition affecting 5-10 per 100,000 people per year. If not repaired, mortality rates are reported as high as 11.8 %, increasing to 97 %-100 % following a TAA rupture. Thoracic endovascular aortic repairs (TEVAR) are becoming more common, but currently face limitations due to complex vasculature. New techniques may provide a safer alternative. CASE PRESENTATION: 70-year-old male presenting with a history of hypertension, dyslipidemia, and previous replacement of ascending aorta and hemi arch with reimplantation of innominate artery done in 2020. A CT scan done during routine interval monitoring of previous TAA repair demonstrated a new aneurysm, which was confirmed with CT angiogram. A novel TEVAR technique was used for repair. The patient tolerated this procedure well and was discharged from the ICU after six days. CLINICAL DISCUSSION: Open procedures and hybrid techniques for TAA repair are not always suitable for high-risk patients. Alternative parallel grafting techniques have shown promising early results but still lack clinical support and long-term data. Several small-scale studies and case reports have demonstrated the use of in-situ laser fenestrations in various settings, but none have demonstrated the ability to extend the landing zone as far as zone 0 for repair of a Type B TAA. CONCLUSION: The use of this novel technique may be considered suitable in high-risk patients with various subtypes of TAAs not suitable for open repair. More cases and clinical trials are needed to compare risks and long-term results to more commonly performed procedures.

Hybrid repair of thoracic aortic lesions for zone 0 and 1 in high-risk patients.

PURPOSE: Some patients with aortic arch or descending thoracic aorta pathologies are not suited for open repair because of comorbidities that may increase their risk of procedural complications or death. Endovascular approaches may also be difficult when there are inadequate proximal landing zones in the aortic arch. We report our experience using rerouting techniques with bypass, stenting of the branches, or a combination of both to create a landing area in zones 0 and 1 of the aortic arch. METHODS: Since November 2002, thoracic aortic endoluminal grafts were placed in 38 patients in whom the endograft was deployed in zone 0 (n = 27) or zone 1 (n = 11). A retrospective review is included. RESULTS: There were 11 women and 27 men with a mean age of 65.4 years (range 38-88). Aortic pathology included 12 Stanford type A dissections, 10 aortic arch aneurysms, 8 Stanford type B dissections, 3 descending thoracic aortic aneurysms, 2 aortobronchial fistulas, 1 innominate artery aneurysm and 2 aortic arch pseudoaneurysms. In zone 0, 21 had thoracic debranching with an ascending bypass, three patients had a remote-inflow and three patients had a chimney-stent with carotid-carotid bypass. In zone 1, five patients had a carotid-carotid bypass, one patient had an aortic to left common carotid artery (LCCA) bypass and five patients had chimney-stent on the LCCA. Fifty-eight percent of the patients were symptomatic and 26% emergent. Three patients required hemodialysis postoperatively (7.9%), 18 patients (47.4%) required prolonged mechanical ventilation for respiratory insufficiency. Paraplegia occurred in one patient (2.7%), and five patients suffered a cerebrovascular accident (13.1%). There were four early type I and two type II endoleaks. Overall 30-day mortality was 23.7%. CONCLUSIONS: The hybrid approach for repair of the aortic arch pathologies is feasible in patients unfit for open repair. We present the results of performing different techniques to treat the aortic arch with hybrid repair with antegrade or retrograde inflow, stenting of the branches or a combination of both. Long-term results are unknown, and larger series results and comparative studies are needed to determine safety and efficacy.

Institutional differences in endovascular aneurysm repair and aneurysm morphology.

BACKGROUND: Variability exists between institutions in the application of endovascular aneurysm repair (EVAR). This study compares patient-specific variables from a high-volume North American institution with one from the UK. METHODS: One hundred consecutive patients from each institution were studied. All were treated for an intact, infrarenal aortic aneurysm. Patient characteristics and aneurysm-related variables, measured from computed tomography according to Society for Vascular Surgery (USA) reporting standards, were examined. RESULTS: The median (range) age of the American patients was 74 (55-97) years and that of the British patients, 73 (49-89) years. There were 78 men in the American group and 79 men in the British group. All American patients were treated by EVAR compared to 11 % of the British group. Mean (SD) aneurysm diameter for the former was 55 (9) mm and for the latter 64 (11) mm (P < 0.001). While there was no difference in mean diameter of the infrarenal aortic neck (P = 0.918), the aneurysms of British patients (22 %) were more likely to be angulated >60° than those of the American patients (11 %) (P = 0.039). Furthermore, the mean (SD) length of infrarenal aortic neck was shorter in the British patients [21 (11) mm] compared to the American group [25 (12) mm] (P = 0.003). The mean diameter of the common iliac arteries was larger in the British patients than in the American group (P < 0.001). Mean external iliac artery diameter was no different between the groups (P = 0.507). CONCLUSIONS: This group of British patients have a more advanced pattern of aneurysm morphology than American patients of similar age. This difference may, in part, explain variability in the application of EVAR.

A meta-analysis of European and Asian cohorts reveals a global role of a functional SNP in the 5' UTR of GDF5 with osteoarthritis susceptibility.

We have performed a meta-analysis combining data for more than 11,000 individuals. It provides compelling evidence for a positive association between a functional single-nucleotide polymorphism (SNP) in the 5'-UTR of GDF5 (+104T/C; rs143383) and osteoarthritis (OA) in European and Asian populations. This SNP has recently been reported to be associated with OA in Japanese and Han Chinese populations. Attempts to replicate this association in European samples have been inconclusive, as no association was found in the case-control cohorts from the UK, Spain and Greece when studied individually. However, the pooled data of UK and Spain found an association of the T-allele with an odds ratio (OR) of 1.10. Although the European studies had adequate power to replicate the original findings from the Japanese cohort (OR = 1.79), these results suggest that the role of the GDF5 polymorphism may not be as strong in Europeans. To clarify whether the European studies were hampered by insufficient power, we combined new data from the UK and the Netherlands with the three published studies of Europe and Asia. The results provide strong evidence of a positive association of the GDF5 SNP with knee OA for Europeans as well as for Asians. The combined association for both ethnic groups is highly significant for the allele frequency model (P = 0.0004, OR = 1.21) and the dominant model (P < 0.0001, OR = 1.48). These findings represent the first highly significant evidence for a risk factor for the development of OA which affects two highly diverse ethnic groups.

Contemporary results of endovascular repair of abdominal aortic aneurysms: effect of anatomical fixation on outcomes.

PURPOSE: To report the contemporary controlled trial experience with the fully supported unibody Powerlink stent-graft for endovascular treatment of abdominal aortic aneurysm (AAA). METHODS: Between 2000 and 2008, 3 prospective multicenter trials of the Powerlink system evaluated 157 AAA patients (141 men; mean age 72.0+/-9.1 years) with mean AAA sac diameter of 5.6+/-0.9 cm who received a bifurcated stent-graft featuring anatomical fixation at the aortoiliac bifurcation and proximal sealing with extension stent-grafts as needed. Challenging infrarenal aortic neck anatomy was present in 83% of patients. Postoperative follow-up occurred at defined intervals to 5 years. RESULTS: Technical success was achieved in 99% of patients. Aneurysm exclusion was achieved in all patients over a mean procedure time of 132+/-58 minutes. No aneurysm-related deaths, ruptures, conversions, or migrations have been observed to current follow-up as these aneurysms have continued to remodel, with > or =92% of patients free from sac growth. CONCLUSION: The implant technique of placing a fully-supported unibody stent-graft at the aortoiliac bifurcation with proximal sealing appears to safely and effectively reline the aorta and exclude aneurysms. Results from controlled clinical trial experience suggest this algorithm can provide stable, secure fixation for patients with challenging infrarenal aortic neck anatomy.

Identification of relevant hub genes for early intervention at gene coexpression modules with altered predicted expression in schizophrenia.

Genetic risk for schizophrenia is due to the joint effect of multiple genes acting mainly at two different processes, prenatal/perinatal neurodevelopment and adolescence/early adulthood synapse maturation. Identification of important genes at the second process is of relevance for early intervention. The aim of this work was to identify gene co-expression modules with altered expression in schizophrenia during adolescence/early adulthood. To this goal, we predicted frontal cortex gene expression in one discovery sample, the largest GWAS of schizophrenia from the Psychiatric Genomics Consortium, using S-prediXcan, and in one target sample, consisting of 625 schizophrenic patients and 819 controls from Spain, using prediXcan. Prediction models were trained on GTEx frontal cortex expression dataset. In parallel, we identified brain co-expression modules from BrainSpan using WGCNA. Then, we estimated polygenic risk scores based on predicted expression (PE-PRS) for each co-expression module in the target sample, based on PE-PRS model from the discovery sample. This analysis led to the identification of a module with mainly adolescence/adulthood expression whose PE-PRS was significantly associated with schizophrenia. The module was significantly enriched in synaptic processes. Several hub genes at this module are drugabble, according to the drug-gene interaction database, and/or involved in synaptic transmission, such as the voltage-gated ion channels SCN2B and KCNAB2, the calcium calmodulin kinases CAMK2A and CAMK1G, or genes involved in synaptic vesicle cycle, such as DNM1, or SYNGR1. Therefore, identification of this module may be the first step in patient stratification based on biology, as well as in drug design and drug repurposing efforts.

"Cracking and paving": a novel technique to deliver a thoracic endograft despite ilio-femoral occlusive disease.

BACKGROUND: The use of endoluminal grafts to treat thoracic aortic aneurysms has been associated with a decreased morbidity and mortality compared with open thoracic aortic aneurysm repair. High-risk surgical patients with ilio-femoral occlusive disease may not be amenable to general anesthesia and the construction of a retroperitoneal conduit. METHODS AND RESULTS: We report the use of a novel technique consisting of cracking and paving of the ilio-femoral vessels with balloon angioplasty, followed by deployment of an endoconduit to deliver an endoluminal graft under local sedation to treat a high-risk 80-year-old patient with a thoracic aneurysm. CONCLUSION: High-risk surgical patients with iliofemoral disease can undergo endoluminal graft therapy to threat thoracic aortic aneurysms.

Relationships between substance abuse/dependence and psychiatric disorders based on polygenic scores.

Genetic susceptibility to substance use disorders (SUDs) is partially shared between substances. Heritability of any substance dependence, estimated as 54%, is partly explained by additive effects of common variants. Comorbidity between SUDs and other psychiatric disorders is frequent. The present study aims to analyze the additive role of common variants in this comorbidity using polygenic scores (PGSs) based on genome-wide association study discovery samples of schizophrenia (SCZ), bipolar disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, major depressive disorder and anxiety disorders, available from large consortia. PGSs were calculated for 534 patients meeting DSM-IV criteria for dependence of a substance and abuse/dependence of another substance between alcohol, tobacco, cannabis, cocaine, opiates, hypnotics, stimulants, hallucinogens and solvents; and 587 blood donors from the same population, Iberians from Galicia, as controls. Significance of the PGS and percentage of variance explained were calculated by logistic regression. Using discovery samples of similar size, significant associations with SUDs were detected for SCZ PGS. SCZ PGS explained more variance in SUDs than in most psychiatric disorders. Cross-disorder PGS based on five psychiatric disorders was significant after adjustment for the effect of SCZ PGS. SCZ PGS was significantly higher in women than in men abusing alcohol. Our findings indicate that SUDs share genetic susceptibility with SCZ to a greater extent than with other psychiatric disorders, including externalizing disorders such as attention-deficit/hyperactivity disorder. Women have lower probability to develop substance abuse/dependence than men at similar PGS probably because of a higher social pressure against excessive drug use in women.

5-(1H-1,2,3-Triazol-5-yl)isophthalic Acid: A Versatile Ligand for the Synthesis of New Supramolecular Metallogels.

The gelation ability of 5-(1H-1,2,3-triazol-5-yl)isophthalic acid (click-TIA) in the presence of different metal acetates has been studied in different solvents and ligand/metal ratios. This manuscript is focused on the metallogel obtained from the combination of click-TIA and copper(II) acetate, which has been used as a model system in terms of characterization and gelation studies. Sonication treatment of the initial mixture of compounds and the nature of the counter anion were found to be critical factors for the supramolecular assembly of the metal/click-TIA complexes and, hence, for the formation of stable and homogeneous metallogels. The gel materials have been characterized with a variety of techniques including infrared, rheology, UV-vis spectroscopy, powder X-ray diffraction, and scanning electron microscopy.

Endoluminal graft therapy for the treatment of an aorto-bronchial fistula: mid-term follow-up.

Open surgical repair of aorto bronchial fistulas is associated with a high morbidity and mortality. Endovascular stent graft as an alternative therapy, though limited, has produced acceptable initial results, but few reports of mid-term follow-up are available. We report the mid-term results with the use of an endograft to treat a patient with both an aorto bronchial fistula and a contained rupture of the thoracic aorta.

Genome wide analysis of rare copy number variations in alcohol abuse or dependence.

Genetics plays an important role in alcohol abuse/dependence. Its heritability has been estimated as 45-65%. Rare copy number variations (CNVs) have been confirmed as relevant genetic factors in other neuropsychiatric disorders, such as autism spectrum disorders, schizophrenia, epilepsy, or Tourette syndrome. In the present study, we analyzed the role of rare CNVs affecting exons of coding genes in a sample from Northwest Spain genotyped using the Illumina Infinium PsychArray Beadchip. After rigorous genotyping quality control procedure, 712 patients with alcohol abuse or dependence and 804 controls were used for CNV detection. CNV calling was performed using PennCNV and cnvPartition, and analyses were restricted to CNVs of at least 100 kb and including at least 10 single nucleotide polymorphisms. Logistic regression was used to test for the effect of CNV as well as number of genes affected by CNVs on case/control status, after adjustment for demographic and experimental covariates. We have found an excess of deletions (p = 0.008) and genes affected by deletions (p = 0.017) in cases. This effect was restricted to the 14.8% of affected genes that are intolerant to loss-of-function mutations (gene count p = 0.009). The importance of this subset of genes is emerging in other psychiatric disorders of neurodevelopmental origin, suggesting that disturbance in neurodevelopment mediated by genetic alterations may be a risk factor for alcohol use disorder.

Infected Groin (Graft/Patch): Managed with Sartorious Muscle Flap.

PURPOSE: The purpose of this study was to review the natural history, clinical outcome and safety in patients undergoing sartorius muscle flap (SMF) for groin infection, including lymphocele. MATERIALS AND METHODS: We retrospectively reviewed the records of patients who underwent SMF in a single center between 2000 and 2009. RESULTS: Thirty patients (17 male, 13 female) underwent SMF for groin infection, which included infections of 22 artificial femoral bypass grafts (including 2 cryoveins) and 5 common femoral patch grafts, and 3 lymphocele infections (2 cardiac catheterizations and 1 penile cancer lymph node dissection). Wound isolates were most commonly Gram-positive organisms (n=22) with Gram-negative isolates and mixed infections accounting for 4 and 3 cases, respectively. In 9 patients there was no growth of organisms. Adjunctive wound vacuum-asssisted wound closure therapy was performed in 18 patients. Follow-up duration ranged from 8 days to 56 months (mean 14.1 months) after SMF. Reoperation was performed in 3 patients due to wound bleeding (n=1) and reinfection (n=1). One patient underwent graft excision with external bypass operation. There was 1 mortality case due to sepsis during the study period. CONCLUSION: We found that muscle flap surgery provides successful single-intervention therapy for groin infections including lymphocele. Graft ligation or aggressive excision with bypass surgery should be reserved for patients requiring rapid control of sepsis for lifesaving.

An efficient screening method for simultaneous detection of recurrent copy number variants associated with psychiatric disorders.

Several recurrent copy number variants (CNVs) increasing risk to neuropsychiatric diseases have been identified in recent years. They show variable clinical expressivity, being associated with different disorders, and incomplete penetrance. However, due to its very low frequency, the full variety of clinical outcomes associated with each one of these CNVs is unknown. Current methods for detection of CNVs are labor intensive, expensive or not suitable for high throughput analysis. Quantitative interspecies competitive PCR linked to variant minisequencing and detection by mass-spectrometry may overcome these limitations. Here, we present two multiplex assays based on this method to screen for eleven psychiatric risk CNVs, such as 1q21, 16p11.2, 3q29, or 16p13.11 regions, among others. The assays were tested in our collection of 514 schizophrenia patients. Results were compared with MLPA at two CNVs. Additional positive results were confirmed by exome sequencing. A total of fourteen patients were CNV carriers. The method presents high sensitivity and specificity, showing its utility as a cheap, accurate, high throughput screening tool for recurrent CNVs. The method may be very useful for management of psychiatric patients as well as screening of different collections of samples to better identify the full spectrum of clinical variability.

ß-Hydroxy-γ-lactones as nucleophiles in the Nicholas reaction for the synthesis of oxepene rings. Enantioselective formal synthesis of (-)-isolaurepinnacin and (+)-rogioloxepane A.

The enantioselective formal synthesis of (-)-isolaurepinnacin and (+)-rogioloxepane A has been achieved. The key steps are an intermolecular Nicholas reaction with a ß-hydroxy-γ-lactone as the nucleophile, to form branched linear ethers, and an olefin ring-closing metathesis to obtain the oxepene core.