Benefits and Safety of Periprocedural Heparin During Thrombectomy in Patients Contra-Indicated for Alteplase.

BACKROUND AND PURPOSE: Role of peri-procedural heparin as an adjuvant treatment during mechanical thrombectomy (MT) for patients contra-indicated for alteplase remains a source of debate. METHODS: We included patients from the multicenter French register ETIS that underwent MT without administration of alteplase, and compared patients who received heparin during MT with patients who did not. Heparin impact on outcome were analyzed regarding final TICI score, NIHSS at day one, modified rankin scale (mRS) and intracranial hemorrhagic transformation on imaging at day one. RESULTS: Over 1031 patients, 751 were included between January 2015 and June 2018 in 6 different centers, and 223 (26.69%) received heparin. Heparin administration was associated with a significant deleterious effect on NIHSS at 24h [adjusted OR = 1.2; p = 0.02], mRS at 3 months [adjusted OR 1.58; p = 0.03], and on complete reperfusion [TICI 3 adjusted OR 0.68; p = 0.02]. Heparin administration was associated with a significant reduction of hemorrhagic transformation [adjusted OR 0.48; p = 0.00005]. CONCLUSIONS: Heparin administration during MT seems deleterious for reperfusion and functional outcome. Randomized trials are needed to identify the role of antithrombotic treatments, such as heparin, in the setting of acute ischemic stroke management.

Comparison of a Whole-Brain Contrast-Enhanced 3D TSE T1WI versus Orbits Contrast-Enhanced 2D Coronal T1WI at 3T MRI for the Detection of Optic Nerve Enhancement in Patients with Acute Loss of Visual Acuity.

BACKGROUND AND PURPOSE: MR imaging is the technique of choice for patients presenting with acute loss of visual acuity with no obvious ophthalmologic cause. The goal of our study was to compare orbits contrast-enhanced 2D coronal T1WI with a whole-brain contrast-enhanced 3D (WBCE-3D) TSE T1WI at 3T for the detection of optic nerve enhancement. MATERIALS AND METHODS: This institutional review board-approved retrospective single-center study included patients presenting with acute loss of vision who underwent 3T MR imaging from November 2014 to February 2020. Two radiologists, blinded to all data, individually assessed the presence of enhancement of the optic nerve on orbits contrast-enhanced 2D T1WI and WBCE-3D T1WI separately and in random order. A McNemar test and a Cohen κ method were used for comparing the 2 MR imaging sequences. RESULTS: One thousand twenty-three patients (638 women and 385 men; mean age, 42 [SD, 18.3] years) were included. There was a strong concordance between WBCE-3D T1WI and orbits contrast-enhanced 2D T1WI when detecting enhancement of the optic nerve: κ = 0.87 (95% CI, 0.84-0.90). WBCE-3D T1WI was significantly more likely to detect canalicular enhancement compared with orbits contrast-enhanced 2D T1WI: 178/1023 (17.4%) versus 138/1023 (13.5%) (P < .001) and 108/1023 (10.6%) versus 90/1023 (8.8%) (P = .04), respectively. The WBCE-3D T1WI sequence detected 27/1023 (3%) instances of optic disc enhancement versus 0/1023 (0%) on orbits contrast-enhanced 2D T1WI. There were significantly fewer severe artifacts on WBCE-3D T1WI compared with orbits contrast-enhanced 2D T1WI: 68/1023 (6.6%) versus 101/1023 (9.8%) (P < .001). The median reader-reported confidence was significantly higher with coronal T1WI compared with 3D TSE T1WI: 5 (95% CI, 4-5) versus 3 (95% CI, 1-4; P < .001). CONCLUSIONS: Our study showed that there was a strong concordance between WBCE-3D T1WI and orbits contrast-enhanced 2D T1WI when detecting enhancement of the optic nerve in patients with acute loss of visual acuity with no obvious ophthalmologic cause. WBCE-3D T1WI demonstrated higher sensitivity and specificity in diagnosing optic neuritis, particularly in cases involving the canalicular segments.

Improving the extraction of ancient Yersinia pestis genomes from the dental pulp.

Ancient DNA preserved in the dental pulp offers the opportunity to characterize the genome of some of the deadliest pathogens in human history. However, while DNA capture technologies help, focus sequencing efforts, and therefore, reduce experimental costs, the recovery of ancient pathogen DNA remains challenging. Here, we tracked the kinetics of ancient Yersinia pestis DNA release in solution during a pre-digestion of the dental pulp. We found that most of the ancient Y. pestis DNA is released within 60 min at 37°C in our experimental conditions. We recommend a simple pre-digestion as an economical procedure to obtain extracts enriched in ancient pathogen DNA, as longer digestion times release other types of templates, including host DNA. Combining this procedure with DNA capture, we characterized the genome sequences of 12 ancient Y. pestis bacteria from France dating to the second pandemic outbreaks of the 17th and 18th centuries Common Era.

DNA methylation-based profiling of horse archaeological remains for age-at-death and castration.

Age profiling of archaeological bone assemblages can inform on past animal management practices, but is limited by the fragmentary nature of the fossil record and the lack of universal skeletal markers for age. DNA methylation clocks offer new, albeit challenging, alternatives for estimating the age-at-death of ancient individuals. Here, we take advantage of the availability of a DNA methylation clock based on 31,836 CpG sites and dental age markers in horses to assess age predictions in 84 ancient remains. We evaluate our approach using whole-genome sequencing data and develop a capture assay providing reliable estimates for only a fraction of the cost. We also leverage DNA methylation patterns to assess castration practice in the past. Our work opens for a deeper characterization of past husbandry and ritual practices and holds the potential to reveal age mortality profiles in ancient societies, once extended to human remains.

Assessing the impact of USER-treatment on hyRAD capture applied to ancient DNA.

Ancient DNA preservation in subfossil specimens provides a unique opportunity to retrieve genetic information from the past. As ancient DNA extracts are generally dominated by molecules originating from environmental microbes, capture techniques are often used to economically retrieve orthologous sequence data at the population scale. Post-mortem DNA damage, especially the deamination of cytosine residues into uracils, also considerably inflates sequence error rates unless ancient DNA extracts are treated with the USER enzymatic mix prior to library construction. While both approaches have recently gained popularity in ancient DNA research, the impact of USER-treatment on capture efficacy still remains untested. In this study, we applied hyRAD capture to eight ancient equine subfossil specimens from France (1st-17th century CE), including horses, donkeys and their first-generation mule hybrids. We found that USER-treatment could reduce capture efficacy and introduce significant experimental bias. It differentially affected the size distribution of on-target templates following capture with two distinct hyRAD probe sets in a manner that was not driven by differences in probe sizes and DNA methylation levels. Finally, we recovered unbalanced proportions of donkey-specific and horse-specific alleles in mule capture sequence data, due to the combined effects of USER-treatment, probe sets and reference bias. Our work demonstrates that while USER-treatment can improve the quality of ancient DNA sequence data, it can also significantly affect hyRAD capture outcomes, introducing bias in the sequence data that is difficult to predict based on simple molecular probe features. Such technical batch effects may prove easier to model and correct for using capture with synthetic probes of controlled sizes and diversity content.

The genomic history and global expansion of domestic donkeys.

Donkeys transformed human history as essential beasts of burden for long-distance movement, especially across semi-arid and upland environments. They remain insufficiently studied despite globally expanding and providing key support to low- to middle-income communities. To elucidate their domestication history, we constructed a comprehensive genome panel of 207 modern and 31 ancient donkeys, as well as 15 wild equids. We found a strong phylogeographic structure in modern donkeys that supports a single domestication in Africa ~5000 BCE, followed by further expansions in this continent and Eurasia and ultimately returning to Africa. We uncover a previously unknown genetic lineage in the Levant ~200 BCE, which contributed increasing ancestry toward Asia. Donkey management involved inbreeding and the production of giant bloodlines at a time when mules were essential to the Roman economy and military.

Cumulative incidence of restenosis in the endovascular treatment of extracranial carotid artery stenosis: a meta-analysis.

OBJECTIVE: To assess the cumulative incidence of restenosis and stroke after stenting for cervical carotid artery stenosis. METHODS: We reviewed PubMed, ScienceDirect, and Scopus and included all studies reporting restenosis after stenting. The cumulative incidence of restenosis at 6 and 12 months was calculated. We also estimated the cumulative incidence of ipsilateral stroke within 30 days after stenting. Random effect meta-analysis and meta-regression were performed using relevant study level covariates. Sources of heterogeneity were investigated. RESULTS: Among 7765 records, 40 studies were selected. 15 943 patients and 16 337 carotid arteries were considered. The overall pooled cumulative incidence of restenosis >50% at 12 months was 5.7% (95% CI 3.8% to 8.6%), >70% at 12 months was 5.2% (95% CI 3.3% to 8.2%), >50% at 6 months was 3.9% (95% CI 2.2% to 6.8%), and ipsilateral stroke within 30 days after stenting was 1.6% (95% CI 1.0% to 2.5%) without association with the use of an embolic protection device. We did not identify any relevant source of heterogeneity of the cumulative incidence of restenosis >50% at 12 months. Mean age explained 80.9% (R2=80.9%, p=0.01) of heterogeneities of restenosis >70% at 12 months. The presence of hostile neck explained 53.9% (R2=53.9%, p=0.03) of heterogeneities of restenosis >50% at 6 months. CONCLUSION: This meta-analysis showed a low cumulative rate of restenosis at 12 months and ipsilateral stroke within 30 days after stenting. Older patients and those with hostile neck present a lower risk of in-stent restenosis. The use of an embolic protection device was not associated with a lower risk of stroke.

Influence of Anatomic Changes on the Outcomes of Carotid Siphon Aneurysms After Deployment of Flow-Diverter Stents.

BACKGROUND: Flow-diverter stent (FDS) deployment can cause morphological and hemodynamic changes in the carotid siphon (CS), influencing the occlusion rate of aneurysms in this location. OBJECTIVE: To evaluate morphological changes to the CS after FDS deployment and their relationship with the rate of occlusion of intracranial aneurysms. METHODS: A cohort of 183 patients with CS aneurysms were treated by deployment of Pipeline® FDS (Medtronic Inc, Dublin, Ireland). Their CSs were classified as type U, V, C, or S, depending on morphology. The posterior and anterior bend angles were measured on strict lateral cerebral angiogram with digital subtraction before FDS deployment, immediately after deployment, and at 6 mo. Differences between angles were analyzed to identify any correlations with rates of aneurysm occlusion, using the O'Kelly-Marotta classification. RESULTS: FDS deployment was associated with immediate changes in CS morphology. The mean anterior angle increased from 3.97 ± 25.06° to 22.05 ± 25.18° (P < .001) and the mean posterior angle increased from 71.98 ± 31.27° to 79.43 ± 31.80° (P < .001). Multivariate analysis revealed a progressive, statistically significant increase in frequency of complete (grade D) occlusion at 6-mo follow-up with increasing anterior bend angle (prevalence ratios (PR) = 1.42 for increases between 5.3° and 12°, P = .017; PR = 1.56 for increases between 12.1° and 27.6°, P = .002; PR = 1.83 for increases >27.6°, P < .001, all vs increases <5.3°). CONCLUSION: FDS deployment induces changes in CS morphology. Specifically, increases in mean anterior angle are associated with better radiological results on 6-mo follow-up digital subtraction angiography.

A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors.

Angiotensin I-converting enzyme inhibitors (ACEi), which are used to treat common cardiovascular diseases, are associated with a potentially life-threatening adverse reaction known as angioedema (AE-ACEi). We have previously documented a significant association between AE-ACEi and low plasma aminopeptidase P (APP) activity. With eight large pedigrees, we hereby demonstrate that this quantitative trait is partially regulated by genetic factors. We tested APP activity using a variance-component QTL analysis of a 10-cM genomewide microsatellite scan enriched with seven markers over two candidate regions. We found significant linkage (LOD = 3.75) to a locus that includes the XPNPEP2 candidate gene encoding membrane-bound APP. Mutation screening of this QTL identified a large coding deletion segregating in one pedigree and an upstream single-nucleotide polymorphism (C-2399A SNP), which segregates in the remaining seven pedigrees. Measured genotype analysis strongly suggests that the linkage signal for APP activity at this locus is accounted for predominantly by the SNP association. In a separate case-control study (20 cases and 60 controls), we found significant association of this SNP to ACEi-induced AE (P=.0364). In conclusion, our findings provide supporting evidence that the C-2399A variant in XPNPEP2 is associated with reduced APP activity and a higher incidence of AE-ACEi.

The spectrum of systemic involvement in adults presenting with renal lesion and mitochondrial tRNA(Leu) gene mutation.

The A3243G mutation of the mitochondrial tRNA(Leu) gene has been recently reported in rare patients with focal and segmental glomerulosclerosis (FSGS). However, the full spectrum of systemic and kidney manifestations in adults presenting with this mutation remains poorly defined. Assessment of renal and nonrenal manifestations was performed in nine patients with A3243G mutation and prominent kidney disease diagnosed in adulthood. At first renal evaluation, median age was 35 years. Renal lesions consisted of FSGS (n = 2), tubulointerstitial nephropathy (n = 3), or bilateral enlarged cystic kidneys (n = 1). All but one patient exhibited extrarenal manifestations: deafness (8 of 9) requiring hearing aid in half the cases, diabetes mellitus (3 of 9), neuromuscular involvement (2 of 9), hypertrophic cardiomyopathy (1 of 9), and macular dystrophy (1 of 9). After a median follow-up of 5 yr, five patients progressed to end-stage renal disease between the ages of 15 and 51 years, four being successfully transplanted. Similarly, extrarenal manifestations progressed since all patients had deafness and diabetes (including three posttransplants), while half had neuromuscular, cardiac, or retinal involvement. In the adult patients with A3243G mutation and renal involvement, preexisting deafness is almost consistently found. While FSGS remains the most typical lesion, tubulointerstitial nephropathy or bilateral, enlarged cystic kidneys may also be encountered. In most cases, diabetes mellitus, macular dystrophy, hypertrophic cardiomyopathy, or neuromuscular features occur later in the course of the disease. The severity of the clinical course is heterogeneous, with end-stage renal failure being reached between the second and sixth decades. Renal transplantation may be offered to these patients, despite a high incidence of steroid-induced diabetes mellitus.