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Background: Small nucleolar RNAs (snoRNAs) are an abundant class of noncoding RNAs present in all eukaryotes and best known for their involvement in ribosome biogenesis. In mammalian genomes, many snoRNAs exist in multiple copies, resulting from recombination and retrotransposition from an ancestral snoRNA. To gain insight into snoRNA copy regulation, we used Rfam classification and normal human tissue expression datasets generated using low structure bias RNA-seq to characterize snoRNA families., Results: We found that although box H/ACA families are on average larger than box C/D families, the number of expressed members is similar for both types. Family members can cover a wide range of average abundance values, but importantly, expression variability of individual members of a family is preferred over the total variability of the family, especially for box H/ACA snoRNAs, suggesting that while members are likely differentially regulated, mechanisms exist to ensure uniformity of the total family abundance across tissues. Box C/D snoRNA family members are mostly embedded in the same host gene while box H/ACA family members tend to be encoded in more than one different host, supporting a model in which box C/D snoRNA duplication occurred mostly by cis recombination while box H/ACA snoRNA families have gained copy members through retrotransposition. And unexpectedly, snoRNAs encoded in the same host gene can be regulated independently, as some snoRNAs within the same family vary in abundance in a divergent way between tissues., Conclusions: SnoRNA copy regulation affects family sizes, genomic location of the members and controls simultaneously member and total family abundance to respond to the needs of individual tissues.

The experience of pain during a severe burn is multifactorial, both in the typology of the burn and in the circumstances of its occurrence. Third-degree burns are painless as the dermis and its nociception sensors are damaged. After a severe burn, from initial management, to home care, to a long hospital stay, pain evolves with its etiology and requires specific management., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

The role of the preferential orientation of clay platelets on the properties of a wide range of natural and engineered clay-rich media is well established. However, a reference function for describing the orientation of clay platelets in these different materials is still lacking. Here, we conducted a systematic study on a large panel of laboratory-made samples, including different clay types or preparation methods. By analyzing the orientation distribution functions obtained by X-ray scattering, we identified a unique signature for the preferred orientation of clay platelets and determined an associated reference orientation function using the maximum-entropy method. This new orientation distribution function is validated for a large set of engineered clay materials and for representative natural clay-rich rocks. This reference function has many potential applications where consideration of preferred orientation is required, including better long-term prediction of water and solute transfer or improved designs for new generations of innovative materials.

Purpose: Direct-acting antiviral agents have demonstrated their efficacy in treating HCV recurrence after liver transplantation and particularly the sofosbuvir/daclatasvir combination. Pharmacokinetic data on both calcineurin inhibitors and direct-acting antiviral exposure in liver transplant recipients remain sparse., Methods: Patients were enrolled from the ANRS CO23 CUPILT cohort. All patients treated with sofosbuvir/daclatasvir with or without ribavirin were included in this study when blood samples were available to estimate the clearance of immunosuppressive therapy before direct-acting antiviral initiation and during follow-up. Apparent tacrolimus and cyclosporine clearances were estimated from trough concentrations measured using validated quality control assays., Results: Sixty-seven mainly male patients (79%) were included, with a mean age of 57 years and mean MELD score of 8.2; 50 were on tacrolimus, 17 on cyclosporine. Ribavirin was combined with sofosbuvir/daclatasvir in 52% of patients. Cyclosporine clearance remained unchanged as well as tacrolimus clearance under the ribavirin-free regimen. Tacrolimus clearance increased 4 weeks after direct-acting antivirals and ribavirin initiation versus baseline (geometric mean ratio 1.81; 90% CI 1.30-2.52). Patients under ribavirin had a significantly higher fibrosis stage (> 2) (p = 0.02) and lower haemoglobin during direct-acting antiviral treatment (p = 0.02) which impacted tacrolimus measurements. Direct-acting antiviral exposure was within the expected range., Conclusion: Our study demonstrated that liver transplant patients with a recurrence of hepatitis C who are initiating ribavirin combined with a sofosbuvir-daclatasvir direct-acting antiviral regimen may be at risk of lower tacrolimus concentrations because of probable ribavirin-induced anaemia and higher fibrosis score, although there are no effects on cyclosporine levels., Trial Registration: NCT01944527.

Automation of pharmaceutical safety case processing represents a significant opportunity to affect the strongest cost driver for a company's overall pharmacovigilance budget. A pilot was undertaken to test the feasibility of using artificial intelligence and robotic process automation to automate processing of adverse event reports. The pilot paradigm was used to simultaneously test proposed solutions of three commercial vendors. The result confirmed the feasibility of using artificial intelligence-based technology to support extraction from adverse event source documents and evaluation of case validity. In addition, the pilot demonstrated viability of the use of safety database data fields as a surrogate for otherwise time-consuming and costly direct annotation of source documents. Finally, the evaluation and scoring method used in the pilot was able to differentiate vendor capabilities and identify the best candidate to move into the discovery phase., (© 2018 Pfizer Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Evidence for macroscopic life in the Paleoproterozoic Era comes from 1.8 billion-year-old (Ga) compression fossils [Han TM, Runnegar B (1992) Science 257:232-235; Knoll et al. (2006) Philos Trans R Soc Lond B 361:1023-1038], Stirling biota [Bengtson S et al. (2007) Paleobiology 33:351-381], and large colonial organisms exhibiting signs of coordinated growth from the 2.1-Ga Francevillian series, Gabon. Here we report on pyritized string-shaped structures from the Francevillian Basin. Combined microscopic, microtomographic, geochemical, and sedimentologic analyses provide evidence for biogenicity, and syngenicity and suggest that the structures underwent fossilization during early diagenesis close to the sediment-water interface. The string-shaped structures are up to 6 mm across and extend up to 170 mm through the strata. Morphological and 3D tomographic reconstructions suggest that the producer may have been a multicellular or syncytial organism able to migrate laterally and vertically to reach food resources. A possible modern analog is the aggregation of amoeboid cells into a migratory slug phase in cellular slime molds at times of starvation. This unique ecologic window established in an oxygenated, shallow-marine environment represents an exceptional record of the biosphere following the crucial changes that occurred in the atmosphere and ocean in the aftermath of the great oxidation event (GOE)., Competing Interests: The authors declare no conflict of interest.

Beyond the application of legal requirements, clinical trials must have a permanent approach of quality control. The clinical investigation centers (CICs) are academic structures of clinical research certified by the French National institute of health and medical research (Inserm) and whose functioning relies on recommendations of good practice. It is important to accompany this standardization of practices by the implementation of a quality management system. This article presents the process that enabled the CIC of Rennes to become certified ISO 9001 by French standards association (Afnor) certification in May, 2016. The application of the fundamental principles of the standard ISO 9001 in the domain of clinical research is approached. The problem of the perimeter for the certification and the related process mapping are exposed. The activities of methodology, management and analysis of clinical studies were chosen for the initial certification of the CIC of Rennes. The perspectives for the extension of the perimeter of certification are also approached at the end of article., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

The 2.1-billion-year-old (Ga) Francevillian series in Gabon hosts some of the oldest reported macroscopic fossils of various sizes and shapes, stimulating new debates on the origin, evolution and organization of early complex life. Here, we document ten representative types of exceptionally well-preserved mat-related structures, comprising "elephant-skin" textures, putative macro-tufted microbial mats, domal buildups, flat pyritized structures, discoidal microbial colonies, horizontal mat growth patterns, wrinkle structures, "kinneyia" structures, linear patterns and nodule-like structures. A combination of petrographic analyses, scanning electron microscopy, Raman spectroscopy and organic elemental analyses of carbon-rich laminae and microtexture, indicate a biological origin for these structures. The observed microtextures encompass oriented grains, floating silt-sized quartz grains, concentrated heavy minerals, randomly oriented clays, wavy-crinkly laminae and pyritized structures. Based on comparisons with modern analogues, as well as an average δ 13 C organic matter (C org ) composition of -32.94 ± 1.17‰ (1 standard deviation, SD) with an outlier of -41.26‰, we argue that the mat-related structures contain relicts of multiple carbon pathways including heterotrophic recycling of photosynthetically derived C org . Moreover, the relatively close association of the macroscopic fossil assemblages to the microbial mats may imply that microbial communities acted as potential benthic O 2 oases linked to oxyphototrophic cyanobacterial mats and grazing grounds. In addition, the mat's presence likely improved the preservation of the oldest large colonial organisms, as they are known to strongly biostabilize sediments. Our findings highlight the oldest community assemblage of microscopic and macroscopic biota in the aftermath of the "Great Oxidation Event," widening our understanding of biological organization during Earth's middle age., (© 2018 John Wiley & Sons Ltd.)

Background: Failure to achieve sustained virological response (SVR) with hepatitis C virus (HCV) direct-acting antiviral (DAA)-based regimens is commonly associated with emergence of resistance-associated substitutions (RASs). Retreatment of patients who failed prior DAAs remains challenging. The aim of this prospective and randomized study was to evaluate the efficacy (primary endpoint: SVR 12 weeks after end of treatment [SVR12]) and safety of sofosbuvir + grazoprevir/elbasvir + ribavirin for 16 or 24 weeks in patients who had failed to achieve SVR on previous NS5A- or NS3-based therapy and with evidence of RASs at failure., Methods: Patients were chronically infected with HCV genotype 1 or 4. Most of them had advanced fibrosis or compensated cirrhosis (liver stiffness 5.8-48.8 kPa)., Results: All patients achieved HCV RNA below the lower limit of quantification (either target detected [unquantifiable] or target not detected) during treatment. SVR12 was achieved by 25 of 26 patients. The only patient who did not reach SVR was a patient who died, but HCV RNA was negative at this time (5 weeks after stopping treatment). No patient discontinued treatment because of adverse events or virological failure. Globally, treatment was well tolerated., Conclusions: Our findings support the concept of retreating with sofosbuvir + grazoprevir/elbasvir + ribavirin, for 16 weeks, genotype 1 or 4 DAA-experienced patients with proven NS5A or NS3 RASs., Clinical Trials Registration: NCT02647632.

Background: A few direct antiviral agents have been studied in difficult-to-treat patients infected by hepatitis C virus (HCV) genotype 4 (GT4). The efficacy of daclatasvir (DCV), asunaprevir (ASV), pegylated interferon and ribavirin (Peg-IFN/RBV) association was investigated in these patients., Patients and Methods: This open-label, single-arm, phase 2 study was conducted in HCV GT4 patients who were null or partial responders to Peg-IFN/RBV. Patients received 24 weeks of DCV (60 mg, once daily), ASV (100 mg, twice daily) and Peg-IFN/RBV. The primary endpoint was sustained virologic response at post-treatment week 12 [sustained virologic response (SVR)12]., Results: Sixty patients were included; 45 (75%) were previous null responders and 27 (45%) had cirrhosis. The most frequent subtypes were GT4a (48%) and GT4d (27%) with 25% of the patients being infected with other subtypes such as 4c, 4r, 4f, 4k, 4j and 4q. The global SVR12 was 95% (90% confidence interval: 90.4-99.6) and 96.3% (90% confidence interval: 87.5-99.5) in cirrhotic patients. All patients achieving SVR12 also achieved SVR24. Previous Peg-IFN/RBV response, IL28b genotype, cirrhosis status or GT4 subtypes did not influence SVR12 rates. Serious adverse events occurred in 13% of the patients, four being cirrhotic and four noncirrhotic. Three (5%) patients stopped HCV therapy prematurely: one because of virologic breakthrough and two because of serious adverse events. Grade 3/4 laboratory abnormalities included leukopenia (33%), neutropenia (27%), thrombocytopenia (4%) and transaminases increase (2%)., Conclusion: Association of DCV plus ASV and peg-IFN/RBV for 24 weeks demonstrated a high rate of SVR12 in HCV GT4-infected prior nonresponders, independently of the cirrhotic status or the GT4 subtype. The safety profile was acceptable, even in cirrhotic patients.

Metformin associated lactic acidosis (MALA) is a serious complication occurring especially in elderly patients given high doses of the drug. We report a non-fatal case of MALA with pronounced acidosis (pH 6.76, lactate 30.81 mmol/l) and high metformin concentrations (127 mg/l) in a patient who had developed acute renal failure after undergoing an operation. Multiple measurements of biological parameters and metformin blood concentrations showed the effectiveness of repeated hemodialysis sessions on metformin elimination. Cases previously reported with such a severe MALA were associated with a high mortality rate. We show that close monitoring in an intensive care unit together with prompt and repeated dialysis sessions can lead to a favorable outcome.

We describe a male patient with ocular colobomata, cleft palate, polydactyly, panhypopituitarism and possible craniosynostosis, whom we have followed for 30 years. Although there are some similarities to other documented syndromes, this previously unreported combination of features appears to constitute a new syndrome.

Background: The purpose of the study is to compare characteristics of Aboriginal patient hospital admissions with non-Aboriginal admissions to the Ophthalmology Unit of the Royal Adelaide Hospital., Methods: A retrospective review of separation data was undertaken of hospital inpatient and day surgery admissions to the Royal Adelaide Hospital Ophthalmology Unit for the period July 1997 to January 2005., Results: There were 11 944 admissions to the Ophthalmology Unit (including inpatients and day surgery cases), of which 273 (2.29%) were Aboriginal patients. Of the total, 2779 (23.3%) patients were admitted for at least 24 h (inpatients), and 9165 (76.7%) stayed less than 24 h (mostly day surgery cases). Aboriginal patients comprised 6.8% of inpatient admissions, and 0.9% of admissions less than 24 h. The average age of Aboriginal patients (52.9 years) was significantly less than non-Aboriginal patients (62.6 years; P < 0.0001). The median length of stay for Aboriginal patients was 5 days compared with 3 days in non-Aboriginal patients. Aboriginal patients were more likely to be from interstate (RR 10.3 P < 0.0001), more likely to have diabetes mellitus (RR 2.7 P < 0.0001), and more likely to be admitted for cataract surgery (RR 4.18 P < 0.0001) and lid disorders (RR 6.04 P < 0.0001) than non-Aboriginal patients., Conclusion: Aboriginal patients admitted to the Ophthalmology Unit were younger in age, more frequently from interstate, and had longer admissions than non-Aboriginal patients. These results have important implications for ophthalmic health-care planning.

Objectives: To report a patient with ischemic orbital compartment syndrome as a complication of spinal surgery in the prone position., Design: Interventional case report., Methods: An 80-year-old man underwent a prolonged lumbar decompression laminectomy for spinal stenosis, under general anesthesia in the prone position. Several hours later, the patient complained of left periocular pain and reduced vision. Examination revealed significant facial edema, left proptosis, and a tight orbit, as well as no light perception and elevated intraocular pressure in the left eye, with complete internal and external ophthalmoplegia., Main Outcome Measures: Clinical course, imaging findings, management, and final outcome., Results: Magnetic resonance imaging confirmed the clinical diagnosis of a compartment syndrome with elevated intraorbital tension. A lateral canthotomy and cantholysis were performed, and high-dose IV steroids were started. The proptosis and facial swelling subsided gradually, but no improvement was noted in left visual acuity or left ocular movements., Conclusion: It is important to be familiar with this rare complication after prolonged surgery in the prone position. Although the prognosis seems to be poor, it is essential to monitor these patients perioperatively and to intervene surgically and medically once the diagnosis of orbital compartment syndrome is established.

Purpose: Esthesioneuroblastoma is a rare malignancy arising from the olfactory mucosa in the nasal fossa, which can invade the orbit producing ophthalmic symptoms and signs. The purpose of this study was to present a case series and review the literature to assess the characteristics of orbital involvement by esthesioneuroblastoma., Methods: Retrospective case series of all patients treated for biopsy-proven esthesioneuroblastoma at the Royal Adelaide Hospital between 1992 and 2004., Results: Nine patients (5 male, 4 female) with a mean age of 50 years (range, 20 to 66 years) were reviewed. One case was classified as Kadish stage A, 1 as Kadish stage B, and 7 as Kadish stage C. Mean time from onset of symptoms to diagnosis was 17 months (range, 2 to 24 months). Radiologic orbital invasion was present in 4 cases and was associated with ophthalmic symptoms or signs in 3 of these cases. These included proptosis (2 cases), periorbital pain (1 case), decreased visual acuity (1 case), extraocular muscle restriction (1 case), and chemosis (1 case). One patient with symptoms secondary to orbital invasion was initially referred to and assessed by an ophthalmologist. All patients who had or went on to have development of orbital invasion had advanced disease at diagnosis. Treatment was surgical (9/9), with the addition of radiotherapy (6/9) and chemotherapy (2/9). Mean follow-up was 3.6 years (range, 0.5 to 8.5 years). Six of 9 patients had tumor recurrence. Two had metastasis. Five of 9 patients remained alive., Conclusions: Orbital invasion by esthesioneuroblastoma is not uncommon. It is important to be aware of this malignancy because a significant proportion of patients will present with ophthalmic signs and symptoms.