Chromosome-length genome assemblies and cytogenomic analyses of pangolins reveal remarkable chromosome counts and plasticity.

We report the first chromosome-length genome assemblies for three species in the mammalian order Pholidota: the white-bellied, Chinese, and Sunda pangolins. Surprisingly, we observe extraordinary karyotypic plasticity within this order and, in female white-bellied pangolins, the largest number of chromosomes reported in a Laurasiatherian mammal: 2n = 114. We perform the first karyotype analysis of an African pangolin and report a Y-autosome fusion in white-bellied pangolins, resulting in 2n = 113 for males. We employ a novel strategy to confirm the fusion and identify the autosome involved by finding the pseudoautosomal region (PAR) in the female genome assembly and analyzing the 3D contact frequency between PAR sequences and the rest of the genome in male and female white-bellied pangolins. Analyses of genetic variability show that white-bellied pangolins have intermediate levels of genome-wide heterozygosity relative to Chinese and Sunda pangolins, consistent with two moderate declines of historical effective population size. Our results reveal a remarkable feature of pangolin genome biology and highlight the need for further studies of these unique and endangered mammals.

Structure and phase transitions in niobium and tantalum derived nanoscale transition metal perovskites, Ba(Ti,MV)O3, M=Nb,Ta.

The prospect of creating ferroelectric or high permittivity nanomaterials provides motivation for investigating complex transition metal oxides of the form Ba(Ti, MV)O3, where M = Nb or Ta. Solid state processing typically produces mixtures of crystalline phases, rarely beyond minimally doped Nb/Ta. Using a modified sol-gel method, we prepared single phase nanocrystals of Ba(Ti, M)O3. Compositional and elemental analysis puts the empirical formulas close to BaTi0.5Nb0.5O3-δ and BaTi0.5Ta0.5O3-δ. For both materials, a reversible temperature dependent phase transition (non-centrosymmetric to symmetric) is observed in the Raman spectrum in the region 533-583 K (260-310 °C); for Ba(Ti, Nb)O3, the onset is at 543 K (270 °C); and for Ba(Ti, Ta)O3, the onset is at 533 K (260 °C), which are comparable with 390-393 K (117-120 °C) for bulk BaTiO3. The crystal structure was resolved by examination of the powder x-ray diffraction and atomic pair distribution function (PDF) analysis of synchrotron total scattering data. It was postulated whether the structure adopted at the nanoscale was single or double perovskite. Double perovskites (A2B'B″O6) are characterized by the type and extent of cation ordering, which gives rise to higher symmetry crystal structures. PDF analysis was used to examine all likely candidate structures and to look for evidence of higher symmetry. The feasible phase space that evolves includes the ordered double perovskite structure Ba2(Ti, MV)O6 (M = Nb, Ta) Fm-3m, a disordered cubic structure, as a suitable high temperature analog, Ba(Ti, MV)O3Pm-3m, and an orthorhombic Ba(Ti, MV)O3Amm2, a room temperature structure that presents an unusually high level of lattice displacement, possibly due to octahedral tilting, and indication of a highly polarized crystal.

Genome-wide association study reveals genetic variants associated with HIV-1C infection in a Botswana study population.

Although there have been many studies of gene variant association with different stages of HIV/AIDS progression in United States and European cohorts, few gene-association studies have assessed genic determinants in sub-Saharan African populations, which have the highest density of HIV infections worldwide. We carried out genome-wide association studies on 766 study participants at risk for HIV-1 subtype C (HIV-1C) infection in Botswana. Three gene associations (AP3B1, PTPRA, and NEO1) were shown to have significant association with HIV-1C acquisition. Each gene association was replicated within Botswana or in the United States-African American or United States-European American AIDS cohorts or in both. Each associated gene has a prior reported influence on HIV/AIDS pathogenesis. Thirteen previously discovered AIDS restriction genes were further replicated in the Botswana cohorts, extending our confidence in these prior AIDS restriction gene reports. This work presents an early step toward the identification of genetic variants associated with and affecting HIV acquisition or AIDS progression in the understudied HIV-1C afflicted Botswana population.

The platypus genome unraveled.

The genome of the platypus has been sequenced, assembled, and annotated by an international genomics team. Like the animal itself the platypus genome contains an amalgam of mammal, reptile, and bird-like features.

The evolutionary history of extinct and living lions.

Lions are one of the world's most iconic megafauna, yet little is known about their temporal and spatial demographic history and population differentiation. We analyzed a genomic dataset of 20 specimens: two ca. 30,000-y-old cave lions (Panthera leo spelaea), 12 historic lions (Panthera leo leo/Panthera leo melanochaita) that lived between the 15th and 20th centuries outside the current geographic distribution of lions, and 6 present-day lions from Africa and India. We found that cave and modern lions shared an ancestor ca. 500,000 y ago and that the 2 lineages likely did not hybridize following their divergence. Within modern lions, we found 2 main lineages that diverged ca. 70,000 y ago, with clear evidence of subsequent gene flow. Our data also reveal a nearly complete absence of genetic diversity within Indian lions, probably due to well-documented extremely low effective population sizes in the recent past. Our results contribute toward the understanding of the evolutionary history of lions and complement conservation efforts to protect the diversity of this vulnerable species.

Validation of a Custom Interface Pressure Measurement System to Improve Fitting of Transtibial Prosthetic Check Sockets.

Achievement of fit between the residual limb and prosthetic socket during socket manufacture is a priority for clinicians and is essential for safety. Clinicians have recognised the potential benefits of having a sensor system that can provide objective socket-limb interface pressure measurements during socket fitting, but the cost of existing systems makes current technology prohibitive. This study will report on the characterisation, validation and preliminary clinical implementation of a low cost, portable, wireless sensor system designed for use during socket manufacture. Characterisation and benchtop testing demonstrated acceptable accuracy, behaviour at variable temperature, and dynamic response for use in prosthetic socket applications. Our sensor system was validated with simultaneous measurement by a commercial sensor system in the sockets of three transtibial prosthesis users during a fitting session in the clinic. There were no statistically significant differences between the sensor system and the commercial sensor for a variety of functional activities. The sensor system was found to be valid in this clinical context. Future work should explore how pressure data relates to ratings of fit and comfort, and how objective pressure data might be used to assist in clinical decision making.

Evolution of gene regulation in ruminants differs between evolutionary breakpoint regions and homologous synteny blocks.

The role of chromosome rearrangements in driving evolution has been a long-standing question of evolutionary biology. Here we focused on ruminants as a model to assess how rearrangements may have contributed to the evolution of gene regulation. Using reconstructed ancestral karyotypes of Cetartiodactyls, Ruminants, Pecorans, and Bovids, we traced patterns of gross chromosome changes. We found that the lineage leading to the ruminant ancestor after the split from other cetartiodactyls was characterized by mostly intrachromosomal changes, whereas the lineage leading to the pecoran ancestor (including all livestock ruminants) included multiple interchromosomal changes. We observed that the liver cell putative enhancers in the ruminant evolutionary breakpoint regions are highly enriched for DNA sequences under selective constraint acting on lineage-specific transposable elements (TEs) and a set of 25 specific transcription factor (TF) binding motifs associated with recently active TEs. Coupled with gene expression data, we found that genes near ruminant breakpoint regions exhibit more divergent expression profiles among species, particularly in cattle, which is consistent with the phylogenetic origin of these breakpoint regions. This divergence was significantly greater in genes with enhancers that contain at least one of the 25 specific TF binding motifs and located near bovidae-to-cattle lineage breakpoint regions. Taken together, by combining ancestral karyotype reconstructions with analysis of cis regulatory element and gene expression evolution, our work demonstrated that lineage-specific regulatory elements colocalized with gross chromosome rearrangements may have provided valuable functional modifications that helped to shape ruminant evolution.

Room Temperature Fabrication of Macroporous Lignin Membranes for the Scalable Production of Black Silicon.

Rising global demand for biodegradable materials and green sources of energy has brought attention to lignin. Herein, we report a method for manufacturing standalone lignin membranes without additives for the first time to date. We demonstrate a scalable method for macroporous (∼100 to 200 nm pores) lignin membrane production using four different organosolv lignin materials under a humid environment (>50% relative humidity) at ambient temperatures (∼20 °C). A range of different thicknesses is reported with densely porous films observed to form if the membrane thickness is below 100 nm. The fabricated membranes were readily used as a template for Ni2+ incorporation to produce a nickel oxide membrane after UV/ozone treatment. The resultant mask was etched via an inductively coupled plasma reactive ion etch process, forming a silicon membrane and as a result yielding black silicon (BSi) with a pore depth of >1 µm after 3 min with reflectance <3% in the visible light region. We anticipate that our lignin membrane methodology can be readily applied to various processes ranging from catalysis to sensing and adapted to large-scale manufacturing.

Increased Expression of Long Non-coding RNA H19 is Associated With Colon Cancer Recurrence.

BACKGROUND: Colon cancer is a leading cause of cancer-related death. Long non-coding (Lnc) RNAs are critical mediators of tumor biology. H19 is a well-characterized lncRNA involved in p53 regulation and cancer progression. A specific colon cancer data set was utilized to determine if tumor H19 expression is associated with recurrence-free and overall survival. METHODS: Clinical patient data from The Cancer Genome Atlas colon adenocarcinoma data set was downloaded using FirebrowseR and normalized H19 expression from the associated RNA-seq data set downloaded using cBioportal. Univariable and multivariable Cox proportional regression analyses were used to identify an association between H19 expression in colon cancer tissue and recurrence-free, and overall survival. RESULTS: Three hundred eight patients were studied. Median age was 68 years (interquartile range: 58-77 years) and 156 patients (51%) were men. Increased H19 expression was associated with KRAS mutation status (P= 0.016). There was no difference in overall survival between the low and high H19 expression groups (log rank = 0.481); however, increased H19 expression was associated with reduced recurrence-free survival (Log-Rank = 0.012). On multivariable regression analysis, increased H19 expression (Hazard ratio  = 1.83, 95%CI: 1.02-3.27, P= 0.042), and stage III or IV disease (Hazard ratio  = 2.39, 95%CI: 1.34-4.27, P= 0.003) were risk factors for reduced recurrence-free survival. CONCLUSIONS: Colon cancer H19 expression is associated with advanced stage of tumor disease and is a significant risk factor for reduced recurrence-free survival. Tumor expression of H19 may have potential for both prognostic and therapeutic uses in the future.

White shark genome reveals ancient elasmobranch adaptations associated with wound healing and the maintenance of genome stability.

The white shark (Carcharodon carcharias; Chondrichthyes, Elasmobranchii) is one of the most publicly recognized marine animals. Here we report the genome sequence of the white shark and comparative evolutionary genomic analyses to the chondrichthyans, whale shark (Elasmobranchii) and elephant shark (Holocephali), as well as various vertebrates. The 4.63-Gbp white shark genome contains 24,520 predicted genes, and has a repeat content of 58.5%. We provide evidence for a history of positive selection and gene-content enrichments regarding important genome stability-related genes and functional categories, particularly so for the two elasmobranchs. We hypothesize that the molecular adaptive emphasis on genome stability in white and whale sharks may reflect the combined selective pressure of large genome sizes, high repeat content, high long-interspersed element retrotransposon representation, large body size, and long lifespans, represented across these two species. Molecular adaptation for wound healing was also evident, with positive selection in key genes involved in the wound-healing process, as well as Gene Ontology enrichments in fundamental wound-healing pathways. Sharks, particularly apex predators such as the white shark, are believed to have an acute sense of smell. However, we found very few olfactory receptor genes, very few trace amine-associated receptors, and extremely low numbers of G protein-coupled receptors. We did however, identify 13 copies of vomeronasal type 2 (V2R) genes in white shark and 10 in whale shark; this, combined with the over 30 V2Rs reported previously for elephant shark, suggests this gene family may underlie the keen odorant reception of chondrichthyans.

Ultrasmall Downconverting Nanoparticle for Enhanced Cerenkov Imaging.

Cerenkov imaging provides an opportunity to expand the application of approved radiotracers and therapeutic agents by utilizing them for optical approaches, which opens new avenues for nuclear imaging. The dominating Cerenkov radiation is in the UV/blue region, where it is readily absorbed by human tissue, reducing its utility in vivo. To solve this problem, we propose a strategy to shift Cerenkov light to the more penetrative red-light region through the use of a fluorescent down-conversion technique, based upon europium oxide nanoparticles. We synthesized square-shape ultrasmall Eu2O3 nanoparticles, functionalized with polyethylene glycol and chelate-free radiolabeled for intravenous injection into mice to visualize the lymph node and tumor. By adding trimethylamine N-oxide during the synthesis, we significantly increased the brightness of the particle and synthesized the (to-date) smallest radiolabeled europium-based nanoparticle. These features allow for the exploration of Eu2O3 nanoparticles as a preclinical cancer diagnosis platform with multimodal imaging capability.

Design and Development of a Bimodal Optical Instrument for Simultaneous Vibrational Spectroscopy Measurements.

Vibrational spectroscopy techniques are widely used in analytical chemistry, physics and biology. The most prominent techniques are Raman and Fourier-transform infrared spectroscopy (FTIR). Combining both techniques delivers complementary information of the test sample. We present the design, construction, and calibration of a novel bimodal spectroscopy system featuring both Raman and infrared measurements simultaneously on the same sample without mutual interference. The optomechanical design provides a modular flexible system for solid and liquid samples and different configurations for Raman. As a novel feature, the Raman module can be operated off-axis for optical sectioning. The calibrated system demonstrates high sensitivity, precision, and resolution for simultaneous operation of both techniques and shows excellent calibration curves with coefficients of determination greater than 0.96. We demonstrate the ability to simultaneously measure Raman and infrared spectra of complex biological material using bovine serum albumin. The performance competes with commercial systems; moreover, it presents the additional advantage of simultaneously operating Raman and infrared techniques. To the best of our knowledge, it is the first demonstration of a combined Raman-infrared system that can analyze the same sample volume and obtain optically sectioned Raman signals. Additionally, quantitative comparison of confocality of backscattering micro-Raman and off-axis Raman was performed for the first time.

Outcomes of the novel Odon Device in indicated operative vaginal birth.

BACKGROUND: No new method of assisting vaginal birth has been introduced into clinical practice since the development of the vacuum extractor in the 1950s. The Odon Device is a new device that employs a circumferential air cuff over the fetal head to assist birth. In this study, the Odon Device has been used to assist vaginal birth for standard clinical indications. OBJECTIVE: This study aimed to investigate the clinical impact, safety, and acceptability of the Odon Device to women, their babies, and clinicians and to assess the feasibility of recruiting women to an interventional intrapartum research study. STUDY DESIGN: This is a nonrandomized, single-arm interventional feasibility study of the Odon Device for operative vaginal birth undertaken in a single maternity unit: Southmead Hospital, Bristol, United Kingdom. The Odon Device was used to assist birth in 40 women who required the birth to be assisted for suspected fetal compromise and/or prolonged second stage of labor. The primary clinical outcome was the proportion of births successfully assisted with the Odon Device, and the primary feasibility outcome was the proportion of eligible women who were approached and who agreed to participate. Neonatal outcome data were reviewed at day 28, and maternal outcomes were investigated up to day 90. RESULTS: Between October 2018 and January 2019, 298 of 384 approached, eligible women (77.6%) consented to participate. Of these women, 40 received the intervention-the use of the Odon Device. Birth was assisted in all cephalic (occiput anterior, occiput transverse, and occiput posterior) fetal positions, at all stations at or below the ischial spine and with or without regional analgesia. The Odon Device was effective in 19 of 40 cases (48%). Of the 40 births, 21 (52.5%) required additional assistance: 18 of 40 births (45%) were completed using nonrotational forceps, 1 of 40 births (3%) required rotational forceps, and 2 of 40 births (5%) required an emergency cesarean delivery. There was no serious maternal or neonatal adverse event related to the use of the device, and there was no serious adverse device effect. There were 4 devices (10%) that were ineffective because of a manufacturing fault. Furthermore, 39 of 40 women (98%) reported a high birth perception score. All practitioners were able to use the device as intended, although some steps in using the device were reported to be easier to perform (setup and deflation of air chamber) than others (application of the device and withdrawal of the applicator). CONCLUSION: Recruitment to an interventional study of a new device for operative vaginal birth was feasible; 78% of eligible women were willing to participate, often expressing an aspiration for an alternative to forceps and vacuum. The success rate of the Odon Device was lower than reported success rates of vacuum and forceps; however, in this study, the device had been used to assist birth for standard clinical indications. There was no significant maternal or neonatal safety concern associated with the use of the device, although the number of births studied was small. Further feasibility study to establish iterative changes to the device, technique, and clinical indications is necessary.

Decreased Tumoral Expression of Colon-Specific Water Channel Aquaporin 8 Is Associated With Reduced Overall Survival in Colon Adenocarcinoma.

BACKGROUND: Colon cancer survival is dependent on metastatic potential and treatment. Large RNA-sequencing data sets may assist in identifying colon cancer-specific biomarkers to improve patient outcomes. OBJECTIVE: This study aimed to identify a highly specific biomarker for overall survival in colon adenocarcinoma by using an RNA-sequencing data set. DESIGN: Raw RNA-sequencing and clinical data for patients with colon adenocarcinoma (n = 271) were downloaded from The Cancer Genome Atlas. A binomial regression model was used to calculate differential RNA expression between paired colon cancer and normal epithelium samples (n = 40). Highly differentially expressed RNAs were examined. SETTINGS: This study was conducted at the University of Louisville using data acquired by The Cancer Genome Atlas. PATIENTS: Patients from US accredited cancer centers between 1998 and 2013 were analyzed. MAIN OUTCOME MEASURES: The primary outcome measures were recurrence-free and overall survival. RESULTS: The median age was 66 years (147/271 men, 180/271 White patients). Thirty RNAs were differentially expressed in colon adenocarcinoma compared with paired normal epithelium, using a log-fold change cutoff of ±6. Using median expression as a cutoff, 4 RNAs were associated with worse overall survival: decreased ZG16 (log-rank = 0.023), aquaporin 8 (log-rank = 0.023), and SLC26A3 (log-rank = 0.098), and increased COL1A1 (log-rank = 0.105). On multivariable analysis, low aquaporin 8 expression (HR, 1.748; 95% CI, 1.016-3.008; p = 0.044) was a risk factor for worse overall survival. Our final aquaporin 8 model had an area under the curve of 0.85 for overall survival. On subgroup analysis, low aquaporin 8 was associated with worse overall survival in patients with high microsatellite instability and in patients with stage II disease. Low aquaporin 8 expression was associated with KRAS and BRAF mutations. Aquaporin 8 immunohistochemistry was optimized for clinical application. LIMITATIONS: This was a retrospective study. CONCLUSION: Aquaporin 8 is a water channel selectively expressed in normal colon tissue. Low aquaporin 8 expression is a risk factor for worse overall survival in patients who have colon cancer. Aquaporin 8 measurement may have a role as a colon-specific prognostic biomarker and help in patient risk stratification for increased surveillance. See Video Abstract at http://links.lww.com/DCR/B603. LA DISMINUCIN DE LA EXPRESIN TUMORAL DE LA ACUAPORINA DEL CANAL DE AGUA ESPECFICO DEL COLON SE ASOCIA CON UNA REDUCCIN DE LA SUPERVIVENCIA GENERAL EN EL ADENOCARCINOMA DE COLON: ANTECEDENTES:La supervivencia del cáncer de colon depende del potencial metastásico y del tratamiento. Grandes conjuntos de datos de secuenciación de ARN pueden ayudar a identificar biomarcadores específicos del cáncer de colon para mejorar los resultados de los pacientes.OBJETIVO:Identificar un biomarcador altamente específico para la supervivencia general en el adenocarcinoma de colon utilizando un conjunto de datos de secuenciación de ARN.DISEÑO:La secuenciación de ARN sin procesar y los datos clínicos para pacientes con adenocarcinoma de colon (n = 271) se descargaron de The Cancer Genome Atlas. Se utilizó un modelo de regresión binomial para calcular la expresión diferencial de ARN entre muestras de cáncer de colon emparejadas y muestras de epitelio normal (n = 40). Se examinaron los ARN expresados de forma altamente diferencial.ENTORNO CLINICO:Este estudio se realizó en la Universidad de Louisville utilizando datos adquiridos por The Cancer Genome Atlas.PACIENTES:Se analizaron pacientes de centros oncológicos acreditados en Estados Unidos entre 1998-2013.PRINCIPALES MEDIDAS DE VALORACION:Las principales medidas de valoración fueron la supervivencia general y libre de recurrencia.RESULTADOS:La mediana de edad fue de 66 años (147/271 hombres, 180/271 caucásicos). Treinta ARN se expresaron diferencialmente en el adenocarcinoma de colon en comparación con el epitelio normal emparejado, utilizando un límite de cambio logarítmico de ± 6. Utilizando la expresión mediana como punto de corte, cuatro ARN se asociaron con una peor supervivencia general: disminución de ZG16 (rango logarítmico = 0,023), acuaporina8 (rango logarítmico = 0,023) y SLC26A3 (rango logarítmico = 0,098) y aumento de COL1A1 (log -rango = 0,105). En el análisis multivariable, la baja expresión de acuaporina8 (HR = 1,748, IC del 95%: 1,016-3,008, p = 0,044) fue un factor de riesgo para una peor supervivencia global. Nuestro modelo de aquaporin8 final tuvo un AUC de 0,85 para la supervivencia global. En el análisis de subgrupos, la acuaporina8 baja se asoció con una peor supervivencia general en pacientes con MSI-H y en pacientes en estadio II. La baja expresión de acuaporina8 se asoció con mutaciones de KRAS y BRAF. La inmunohistoquímica de aquaporina8 se optimizó para su aplicación clínica.LIMITACIONES:Este fue un estudio retrospectivo.CONCLUSIÓN:La acuaporina8 es un canal de agua expresado selectivamente en el tejido normal del colon. La baja expresión de AQP8 es un factor de riesgo de peor supervivencia global en pacientes con cáncer de colon. La medición de aquaporina8 puede tener un papel como un biomarcador de pronóstico específico del colon y ayudar en la estratificación del riesgo del paciente para una mayor vigilancia. Consulte Video Resumen en http://links.lww.com/DCR/B603.

Ultracontinuous Single Haplotype Genome Assemblies for the Domestic Cat (Felis catus) and Asian Leopard Cat (Prionailurus bengalensis).

In addition to including one of the most popular companion animals, species from the cat family Felidae serve as a powerful system for genetic analysis of inherited and infectious disease, as well as for the study of phenotypic evolution and speciation. Previous diploid-based genome assemblies for the domestic cat have served as the primary reference for genomic studies within the cat family. However, these versions suffered from poor resolution of complex and highly repetitive regions, with substantial amounts of unplaced sequence that is polymorphic or copy number variable. We sequenced the genome of a female F1 Bengal hybrid cat, the offspring of a domestic cat (Felis catus) x Asian leopard cat (Prionailurus bengalensis) cross, with PacBio long sequence reads and used Illumina sequence reads from the parents to phase >99.9% of the reads into the 2 species' haplotypes. De novo assembly of the phased reads produced highly continuous haploid genome assemblies for the domestic cat and Asian leopard cat, with contig N50 statistics exceeding 83 Mb for both genomes. Whole-genome alignments reveal the Felis and Prionailurus genomes are colinear, and the cytogenetic differences between the homologous F1 and E4 chromosomes represent a case of centromere repositioning in the absence of a chromosomal inversion. Both assemblies offer significant improvements over the previous domestic cat reference genome, with a 100% increase in contiguity and the capture of the vast majority of chromosome arms in 1 or 2 large contigs. We further demonstrated that comparably accurate F1 haplotype phasing can be achieved with members of the same species when one or both parents of the trio are not available. These novel genome resources will empower studies of feline precision medicine, adaptation, and speciation.

Draft de novo Genome Assembly of the Elusive Jaguarundi, Puma yagouaroundi.

The Puma lineage within the family Felidae consists of 3 species that last shared a common ancestor around 4.9 million years ago. Whole-genome sequences of 2 species from the lineage were previously reported: the cheetah (Acinonyx jubatus) and the mountain lion (Puma concolor). The present report describes a whole-genome assembly of the remaining species, the jaguarundi (Puma yagouaroundi). We sequenced the genome of a male jaguarundi with 10X Genomics linked reads and assembled the whole-genome sequence. The assembled genome contains a series of scaffolds that reach the length of chromosome arms and is similar in scaffold contiguity to the genome assemblies of cheetah and puma, with a contig N50 = 100.2 kbp and a scaffold N50 = 49.27 Mbp. We assessed the assembled sequence of the jaguarundi genome using BUSCO, aligned reads of the sequenced individual and another published female jaguarundi to the assembled genome, annotated protein-coding genes, repeats, genomic variants and their effects with respect to the protein-coding genes, and analyzed differences of the 2 jaguarundis from the reference mitochondrial genome. The jaguarundi genome assembly and its annotation were compared in quality, variants, and features to the previously reported genome assemblies of puma and cheetah. Computational analyzes used in the study were implemented in transparent and reproducible way to allow their further reuse and modification.

Genome-wide sequence analyses of ethnic populations across Russia.

The Russian Federation is the largest and one of the most ethnically diverse countries in the world, however no centralized reference database of genetic variation exists to date. Such data are crucial for medical genetics and essential for studying population history. The Genome Russia Project aims at filling this gap by performing whole genome sequencing and analysis of peoples of the Russian Federation. Here we report the characterization of genome-wide variation of 264 healthy adults, including 60 newly sequenced samples. People of Russia carry known and novel genetic variants of adaptive, clinical and functional consequence that in many cases show allele frequency divergence from neighboring populations. Population genetics analyses revealed six phylogeographic partitions among indigenous ethnicities corresponding to their geographic locales. This study presents a characterization of population-specific genomic variation in Russia with results important for medical genetics and for understanding the dynamic population history of the world's largest country.

Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia.

BACKGROUND: Imatinib, a selective BCR-ABL1 kinase inhibitor, improved the prognosis for patients with chronic myeloid leukemia (CML). We conducted efficacy and safety analyses on the basis of more than 10 years of follow-up in patients with CML who were treated with imatinib as initial therapy. METHODS: In this open-label, multicenter trial with crossover design, we randomly assigned patients with newly diagnosed CML in the chronic phase to receive either imatinib or interferon alfa plus cytarabine. Long-term analyses included overall survival, response to treatment, and serious adverse events. RESULTS: The median follow-up was 10.9 years. Given the high rate of crossover among patients who had been randomly assigned to receive interferon alfa plus cytarabine (65.6%) and the short duration of therapy before crossover in these patients (median, 0.8 years), the current analyses focused on patients who had been randomly assigned to receive imatinib. Among the patients in the imatinib group, the estimated overall survival rate at 10 years was 83.3%. Approximately half the patients (48.3%) who had been randomly assigned to imatinib completed study treatment with imatinib, and 82.8% had a complete cytogenetic response. Serious adverse events that were considered by the investigators to be related to imatinib were uncommon and most frequently occurred during the first year of treatment. CONCLUSIONS: Almost 11 years of follow-up showed that the efficacy of imatinib persisted over time and that long-term administration of imatinib was not associated with unacceptable cumulative or late toxic effects. (Funded by Novartis Pharmaceuticals; IRIS ClinicalTrials.gov numbers, NCT00006343 and NCT00333840 .).

Preoperative Opioid Prescription Is Associated With Major Complications in Patients With Crohn's Disease Undergoing Elective Ileocolic Resection.

BACKGROUND: Opioid use has grown exponentially over the last decade. The effect of preoperative opioid prescription in patients with Crohn's disease undergoing surgery is unknown. OBJECTIVE: The purpose of this study was to identify whether preoperative opioid prescription is associated with adverse postoperative outcomes in Crohn's disease. DESIGN: This is a single-institution retrospective observational study. SETTINGS: This study was performed at an academic tertiary care center. Details of preoperative opioid prescription were collected from the Kentucky All-Schedule Prescription Electronic Reporting database and the electronic databases of bordering states. PATIENTS: Consecutive patients undergoing ileocolic resection for Crohn's disease from 2014 to 2018 were included. MAIN OUTCOME MEASURES: The outcomes examined were major complications (Clavien-Dindo ≥3a), length of stay, and 30-day hospital readmission. RESULTS: Fifty one of 118 patients were prescribed opioids within 6 months preoperatively (range, 0-33,760 morphine milligram equivalents). Patients with preoperative opioid prescription compared with no preoperative opioid prescription required more daily opioids during hospital admission (p = 0.024). Nineteen patients had a major postoperative complication (preoperative opioid prescription: 26% (13/51) vs no preoperative opioid prescription: 9% (6/67)). On multivariable analysis, preoperative opioid prescription (OR = 2.994 (95% CI, 1.024-8.751); p = 0.045) was a significant risk factor for a major complication. Preoperative opioid prescription was associated with increased length of stay (p < 0.001) and was a risk factor for readmission (OR = 2.978 (95% CI, 1.075-8.246); p = 0.036). Twenty-four patients were readmitted. Using a cutoff for higher opioid prescription of 300 morphine milligram equivalents within 6 months preoperation (eg, 60 tablets of hydrocodone/acetaminophen 5/325), preoperative opioid prescription remained a risk factor for major postoperative complications (OR = 3.148 (95% CI, 1.110-8.928); p = 0.031). LIMITATIONS: This was a retrospective study and could not assess nonprescribed opioid use. CONCLUSIONS: Preoperative opioid prescription was a significant risk factor for adverse outcomes in patients with Crohn's disease undergoing elective ileocolic resection. See Video Abstract at http://links.lww.com/DCR/B113. LA PRESCRIPCIÓN PREOPERATORIA DE OPIOIDES SE ASOCIA CON COMPLICACIONES MAYORES EN PACIENTES CON ENFERMEDAD DE CROHN SOMETIDOS A RESECCIÓN ILEOCÓLICA ELECTIVA: El uso de opioides ha crecido exponencialmente en la última década. Se desconoce el efecto de la prescripción preoperatoria de opioides en pacientes con enfermedad de Crohn sometidos a cirugía.Identificar si la prescripción preoperatoria de opioides está asociada con resultados postoperatorios adversos en la enfermedad de Crohn.Este es un estudio observacional retrospectivo de una sola institución.Este estudio se realizó en un centro académico de atención terciaria. Los detalles de la prescripción preoperatoria de opiáceos se recopilaron de la base de datos de "Kentucky All-Schedule Prescription Electronic Reporting" y de las bases de datos electrónicas de los estados fronterizos.Pacientes consecutivos sometidos a resección ileocólica por enfermedad de Crohn entre 2014-2018.Los resultados examinados fueron complicaciones mayores (Clavien-Dindo ≥3a), duración de la estancia y el reingreso hospitalario de 30 días.A cincuenta y uno de 118 pacientes se le recetaron opioides dentro de los 6 meses preoperatorios (rango, 0 a 33,760 equivalentes de miligramos de morfina). Los pacientes con prescripción preoperatoria de opioides en comparación con ninguna prescripción preoperatoria de opioides requirieron más opioides diarios durante el ingreso hospitalario (p = 0,024). Diecinueve pacientes tuvieron una complicación postoperatoria importante (prescripción preoperatoria de opioides: 26% [13/51] frente a ninguna prescripción preoperatoria de opioides: 9% [6/67]). En el análisis multivariable, la prescripción de opioides preoperatorios (OR = 2.994, IC 95%: 1.024-8.751, p = 0.045) fueron factores de riesgo significativos para una complicación mayor. La prescripción preoperatoria de opioides se asoció con un aumento de la duración de la estadía (p <0.001) y fue un factor de riesgo para el reingreso (OR = 2.978, IC 95%: 1.075-8.246, p = 0.036). Veinticuatro pacientes fueron readmitidos. Utilizando un límite para una mayor prescripción de opioides de 300 miligramos equivalentes de morfina dentro de los 6 meses previos a la operación (p. Ej., 60 tabletas de hidrocodona / acetaminofén 5/325), la prescripción preoperatoria de opioides siguió siendo un factor de riesgo para complicaciones postoperatorias mayores (OR = 3.148 IC 95%: 1.110-8.928, p = 0.031).Este fue un estudio retrospectivo y no pudo evaluar el uso de opioides no prescritos.La prescripción preoperatoria de opioides fue un factor de riesgo significativo para los resultados adversos en pacientes con enfermedad de Crohn sometidos a resección ileocólica electiva. Consulte Video Resumen en http://links.lww.com/DCR/B113.

Pyoderma Gangrenosum in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Pyoderma gangrenosum (PG) is an uncommon but severe extra-intestinal manifestation (EIM) of inflammatory bowel disease (IBD). The incidence and risk factors for PG are disputed. AIMS: To assess the incidence of PG and identify factors associated with PG in IBD patients. METHODS: A search of electronic databases (Ovid and PubMed) was conducted between 1966 and 2019. Studies that calculated the incidence of PG in IBD patient cohorts were included. Patient demographics, IBD subtype, and EIM presence were recorded. A review of our institutional database of 1057 IBD patients was conducted. A multivariate regression model and meta-analysis were conducted to identify risk factors for PG. A random effects model was used to combine the data of included studies. RESULTS: Fourteen studies were included in addition to 1057 IBD patients and 26 PG cases from the Louisville cohort. In total, there were 379 cases of PG in the cumulative cohort of 61,695 IBD patients. The PG incidence in individual studies ranged from 0.4 to 2.6%. In the institutional cohort, ocular EIMs and a permanent stoma were significant risk factors for PG. In the meta-analysis, PG was associated with female gender (RR = 1.328, 95% CI 1.161-1.520), Crohn's disease (RR = 1.193, 95% CI 1.001-1.422), erythema nodosum (RR = 9.281, 95% CI 6.081-14.164), and ocular EIM (RR = 4.55, 95% CI 3.04-6.81). There was study heterogeneity when assessing IBD subtype, ocular, and joint EIMs. CONCLUSIONS: There are conflicting data on the incidence and risk factors for PG. This meta-analysis confirms an association between PG and female gender, Crohn's disease, erythema nodosum, and ocular EIM that have been described in smaller studies.