Showing papers by "Stephen J. O'Brien published in 2020"
Spanish National Research Council1, University of Copenhagen2, Universiti Malaysia Terengganu3, University of Birmingham4, Norwegian University of Science and Technology5, Chinese Academy of Sciences6, Russian Academy of Sciences7, Pontifícia Universidade Católica do Rio Grande do Sul8, Smithsonian Conservation Biology Institute9, Smithsonian Institution10, Walter Reed Army Institute of Research11, University of Porto12, University of Oxford13, Nova Southeastern University14
TL;DR: It is found that cave and modern lions shared an ancestor ca.
Abstract: 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.
59 citations
TL;DR: A new method is introduced that implements a global search using a genetic algorithm for the automatic and unsupervised inference of demographic history from joint AFS data and is able to infer multiple demographic models at different local optima close to the global one.
Abstract: Background The demographic history of any population is imprinted in the genomes of the individuals that make up the population. One of the most popular and convenient representations of genetic information is the allele frequency spectrum (AFS), the distribution of allele frequencies in populations. The joint AFS is commonly used to reconstruct the demographic history of multiple populations, and several methods based on diffusion approximation (e.g., ∂a∂i) and ordinary differential equations (e.g., moments) have been developed and applied for demographic inference. These methods provide an opportunity to simulate AFS under a variety of researcher-specified demographic models and to estimate the best model and associated parameters using likelihood-based local optimizations. However, there are no known algorithms to perform global searches of demographic models with a given AFS. Results Here, we introduce a new method that implements a global search using a genetic algorithm for the automatic and unsupervised inference of demographic history from joint AFS data. Our method is implemented in the software GADMA (Genetic Algorithm for Demographic Model Analysis, https://github.com/ctlab/GADMA). Conclusions We demonstrate the performance of GADMA by applying it to sequence data from humans and non-model organisms and show that it is able to automatically infer a demographic model close to or even better than the one that was previously obtained manually. Moreover, GADMA is able to infer multiple demographic models at different local optima close to the global one, providing a larger set of possible scenarios to further explore demographic history.
42 citations
University of Copenhagen1, Ulsan National Institute of Science and Technology2, Norwegian University of Science and Technology3, University of Sydney4, Spanish National Research Council5, University of Birmingham6, University of Porto7, University of Oxford8, Saint Petersburg State University of Information Technologies, Mechanics and Optics9, UPRRP College of Natural Sciences10, Pontifícia Universidade Católica do Rio Grande do Sul11, Smithsonian Conservation Biology Institute12, Walter Reed Army Institute of Research13, Smithsonian Institution14, Leibniz Association15, University of Potsdam16, Swedish Museum of Natural History17, Kunming Institute of Zoology18, Universiti Malaysia Terengganu19
TL;DR: It is suggested that Homotherium may have been more abundant than the limited fossil record suggests, and relatively high levels of genetic diversity are uncovered, enhancing understanding of the evolution and ecology of this remarkable lineage.
32 citations
TL;DR: In this article, a systematic review of cancer metastasis development in colon cancer is presented, where Epithelial-mesenchymal transition (EMT) is a major process in tumor metastasis.
Abstract: Colorectal cancer (CRC) is a leading cause of cancer-related death. Epithelial-mesenchymal transition (EMT) is a major process in tumor metastasis development. This systematic review aims to descri...
26 citations
TL;DR: 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.
Abstract: 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. To assess the incidence of PG and identify factors associated with PG in IBD patients. 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. 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. 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.
25 citations
TL;DR: The aim of this review was to discuss the different roles of TAMs in CRC and their phenotype‐specific metabolic pathways to identify potential new targets for CRC treatment.
Abstract: BACKGROUND The incidence of colorectal cancer (CRC) among patients <50 years of age has increased dramatically over the last decades. At the same time, the growing proportion of obese children and adolescents and the increasing proportion of young and obese patients with CRC suggests an association between metabolic dysfunction and carcinogenesis. Tumor-associated macrophages (TAMs) are able to orchestrate tumor promoting and suppressing mechanisms in CRC. The aim of this review was to discuss the different roles of TAMs in CRC and their phenotype-specific metabolic pathways to identify potential new targets for CRC treatment. METHODS A literature search was performed using PubMed, Cochrane and Embase to identify studies on TAMs and their metabolism in CRC. The following search terms were used in various combinations: (obesity OR adiposity OR obese) AND (macrophage OR polarization OR macrophage metabolism) AND ((colon cancer*) OR (colon carcinoma) OR (colonic tumor*) OR (colonic neoplasm[MeSH]) OR (rectal cancer*) OR (rectal carcinoma) OR (rectal tumor*) OR (rectal neoplasm[MeSH]) OR (colorectal cancer*) OR (colorectal carcinoma) OR (colorectal tumor*) OR (colorectal neoplasm[MeSH])). Studies including data on the phenotype and metabolism of TAMs in CRC were analyzed. RESULTS Evidence for the prognostic utility of macrophage markers in CRC is currently evolving, with a particular role of stage-dependent cellular metabolism profiles of TAMs. Itaconate is one of the metabolites produced by proinflammatory subtypes of TAMs and it is known to have tumor promoting effects. Metabolic pathways that are involved in macrophage activation and reprogramming play a role in a chronic inflammatory setting, consequently affecting the onset and development of CRC. CONCLUSIONS Tumor-promoting metabolites, such as itaconate, are directly regulating these mechanisms, thereby triggering carcinogenesis. Metabolic reprogramming in TAMs can build a bridge between metabolic dysfunction and the onset and progression of CRC through inflammatory pathways, particularly in younger patients with early-onset CRC.
17 citations
Kean University1, Chinese Center for Disease Control and Prevention2, Saint Petersburg State University of Information Technologies, Mechanics and Optics3, UPRRP College of Natural Sciences4, University of Malaya5, Jianghan University6, Smithsonian Conservation Biology Institute7, University of Porto8, Department of Wildlife and National Parks9
TL;DR: It is suggested that pangolins are unlikely the natural reservoir or secondary hosts of COVID‐19 CoV, which seems to be victims infected by CoV carried by a not yet unidentified natural reservoir host species, perhaps due to their weakened immune system.
Abstract: The COVID-19 outbreak has infected over 6 million people across the world. The origin of COVID-19 coronavirus (CoV) remains unknown, although pangolins have been suggested as potential hosts. We investigated two pangolins seized in Guangdong Province, China. Molecular screening revealed CoV in one pangolin (“Dahu”), while another (“Meidong”) was infected by Ehrlichia ruminantium. Dahu exhibited difficulty breathing, infections of lung, intestines, and nostrils, as revealed by computed tomography imaging and necropsy. Previous phylogenetic analyses showed bat coronavirus RaTG13 is closer to COVID-19 CoV compared to pangolin coronavirus. Over 20 caregivers have had close physical contact with CoV-positive Dahu, but none became infected with CoV. Our data suggest that pangolins are unlikely the natural reservoir or secondary hosts of COVID-19 CoV. Pangolins seems to be victims infected by CoV carried by a not yet unidentified natural reservoir host species, perhaps due to their weakened immune system.
16 citations
Saint Petersburg State University1, University Medical Center Groningen2, University of Puerto Rico at Mayagüez3, Smithsonian Conservation Biology Institute4, Saint Petersburg State University of Information Technologies, Mechanics and Optics5, North-Eastern Federal University6, Russian Academy of Sciences7, UPRRP College of Natural Sciences8
TL;DR: 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.
15 citations
TL;DR: BDI is associated with significantly increased hospital costs, length of stay, 30-day readmission, and discharge to an institutional post-acute care facility.
Abstract: Bile duct injury (BDI) is an uncommon but major complication of cholecystectomy that has a poorly defined magnitude of effect on hospital costs. This study sought to calculate the healthcare costs, length of stay, and discharge status associated with bile duct injury in patients undergoing cholecystectomy in the United States. The Premier Healthcare Database, which comprises hospital-billing records from over 700 hospitals in the United States, was queried for all patients undergoing cholecystectomy between January 2010 and March 2018. BDI was defined by ICD-9-CM and ICD-10-CM codes. Patient demographics, clinical characteristics, and operative information were extracted. Hospital costs, length of stay, and discharge status were compared between BDI and non-BDI patients. Propensity score matching was used to minimize confounding factors. Multivariable regression models were used to estimate the association between BDI and the outcomes variables. A total of 1,168,288 cholecystectomies were identified. BDI occurred in 878 patients (0.08%). Laparoscopy was the most common approach (> 95%). The majority of BDI occurred during inpatient admissions (71.0%). BDI patients had higher index admission hospital costs ($18,771 vs. $12,345, p < 0.0001), increased rate of discharge to an institutional post-acute care facility (odds ratio 3.89, 95% CI 2.92–5.19, p < 0.0001), and increased risk of readmission within 30 days after discharge (odds ratio 1.86, 95% CI 1.52–2.28, p < 0.0001), compared to patients without BDI. Among inpatient cholecystectomies, BDI was associated with increased length of stay (8.6 days vs. 4.8 days, p < 0.0001). BDI is associated with significantly increased hospital costs, length of stay, 30-day readmission, and discharge to an institutional post-acute care facility.
10 citations
University of Western Australia1, Edith Cowan University2, University of Queensland3, Saint Petersburg State University of Information Technologies, Mechanics and Optics4, Florida State University College of Arts and Sciences5, Idexx Laboratories6, Shepherd University7, Diabetes Australia8, University of Zurich9
TL;DR: The identification of genetic markers associated with T2D susceptibility in ABB cats will enable preventative health strategies and guide breeding programs to reduce the prevalence of type 2 diabetes in these cats.
Abstract: Genetic variants that are associated with susceptibility to type 2 diabetes (T2D) are important for identification of individuals at risk and can provide insights into the molecular basis of disease. Analysis of T2D in domestic animals provides both the opportunity to improve veterinary management and breeding programs as well as to identify novel T2D risk genes. Australian-bred Burmese (ABB) cats have a 4-fold increased incidence of type 2 diabetes (T2D) compared to Burmese cats bred in the United States. This is likely attributable to a genetic founder effect. We investigated this by performing a genome-wide association scan on ABB cats. Four SNPs were associated with the ABB T2D phenotype with p values <0.005. All exons and splice junctions of candidate genes near significant single-nucleotide polymorphisms (SNPs) were sequenced, including the genes DGKG, IFG2BP2, SLC8A1, E2F6, ETV5, TRA2B and LIPH. Six candidate polymorphisms were followed up in a larger cohort of ABB cats with or without T2D and also in Burmese cats bred in America, which exhibit low T2D incidence. The original SNPs were confirmed in this cohort as associated with the T2D phenotype, although no novel coding SNPs in any of the seven candidate genes showed association with T2D. The identification of genetic markers associated with T2D susceptibility in ABB cats will enable preventative health strategies and guide breeding programs to reduce the prevalence of T2D in these cats.
10 citations
TL;DR: In patients with CC and biliary obstruction, initial ERCP with stent placement and initial PTBD both represent safe and effective methods of biliary decompression.
Abstract: In patients with cholangiocarcinoma (CC), management of biliary obstruction commonly involves either up-front percutaneous transhepatic biliary drainage (PTBD) or initial endoscopic retrograde cholangiopancreatography (ERCP) with stent placement. The objective of the study was to compare the efficacy and of initial ERCP with stent placement with efficacy of initial PTBD in management of biliary obstruction in CC. A single-center database of patients with unresectable CC treated between 2006 and 2017 was queried for patients with biliary obstruction who underwent either PTBD or ERCP. Groups were compared with respect to patient, tumor, procedure, and outcome variables. Of 87 patients with unresectable CC and biliary obstruction, 69 (79%) underwent initial ERCP while 18 (21%) underwent initial PTBD. Groups did not differ significantly with respect to age, gender, or tumor location. Initial procedure success did not differ between the groups (94% ERCP vs 89% PTBD, p = 0.339). Total number of procedures did not differ significantly between the two groups (ERCP median = 2 vs. PTC median = 2.5, p = 0.83). 21% of patients required ERCP after PTBD compared to 25% of patients requiring PTBD after ERCP (p = 1.00). Procedure success rate (97% ERCP vs. 93% PTBD, p = 0.27) and rates of cholangitis (22% ERCP vs. 17% PTBD, p = 0.58) were similar between the groups. Number of hospitalizations since initial intervention did not differ significantly between the two groups (ERCP median = 1 vs. PTC median = 3.5, p = 0.052). In patients with CC and biliary obstruction, initial ERCP with stent placement and initial PTBD both represent safe and effective methods of biliary decompression. Initial ERCP and stenting should be considered for relief of biliary obstruction in such patients in centers with advanced endoscopic capabilities.
TL;DR: It is postulate that the order of evolutionarily conserved segments in the analyzed pinnipeds is the same as the order proposed for the ancestral Carnivora karyotype (2n = 38).
Abstract: Pinnipedia karyotype evolution was studied here using human, domestic dog, and stone marten whole-chromosome painting probes to obtain comparative chromosome maps among species of Odobenidae (Odobenus rosmarus), Phocidae (Phoca vitulina, Phoca largha, Phoca hispida, Pusa sibirica, Erignathus barbatus), and Otariidae (Eumetopias jubatus, Callorhinus ursinus, Phocarctos hookeri, and Arctocephalus forsteri). Structural and functional chromosomal features were assessed with telomere repeat and ribosomal-DNA probes and by CBG (C-bands revealed by barium hydroxide treatment followed by Giemsa staining) and CDAG (Chromomycin A3-DAPI after G-banding) methods. We demonstrated diversity of heterochromatin among pinniped karyotypes in terms of localization, size, and nucleotide composition. For the first time, an intrachromosomal rearrangement common for Otariidae and Odobenidae was revealed. We postulate that the order of evolutionarily conserved segments in the analyzed pinnipeds is the same as the order proposed for the ancestral Carnivora karyotype (2n = 38). The evolution of conserved genomes of pinnipeds has been accompanied by few fusion events (less than one rearrangement per 10 million years) and by novel intrachromosomal changes including the emergence of new centromeres and pericentric inversion/centromere repositioning. The observed interspecific diversity of pinniped karyotypes driven by constitutive heterochromatin variation likely has played an important role in karyotype evolution of pinnipeds, thereby contributing to the differences of pinnipeds' chromosome sets.
TL;DR: Preoperative opioid prescription was a significant risk factor for adverse outcomes in patients with Crohn’s disease undergoing elective ileocolic resection, and could not assess nonprescribed opioid use.
Abstract: 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 PRESCRIPCION PREOPERATORIA DE OPIOIDES SE ASOCIA CON COMPLICACIONES MAYORES EN PACIENTES CON ENFERMEDAD DE CROHN SOMETIDOS A RESECCION ILEOCOLICA ELECTIVA: El uso de opioides ha crecido exponencialmente en la ultima decada. Se desconoce el efecto de la prescripcion preoperatoria de opioides en pacientes con enfermedad de Crohn sometidos a cirugia.Identificar si la prescripcion preoperatoria de opioides esta asociada con resultados postoperatorios adversos en la enfermedad de Crohn.Este es un estudio observacional retrospectivo de una sola institucion.Este estudio se realizo en un centro academico de atencion terciaria. Los detalles de la prescripcion preoperatoria de opiaceos se recopilaron de la base de datos de "Kentucky All-Schedule Prescription Electronic Reporting" y de las bases de datos electronicas de los estados fronterizos.Pacientes consecutivos sometidos a reseccion ileocolica por enfermedad de Crohn entre 2014-2018.Los resultados examinados fueron complicaciones mayores (Clavien-Dindo ≥3a), duracion de la estancia y el reingreso hospitalario de 30 dias.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 prescripcion preoperatoria de opioides en comparacion con ninguna prescripcion preoperatoria de opioides requirieron mas opioides diarios durante el ingreso hospitalario (p = 0,024). Diecinueve pacientes tuvieron una complicacion postoperatoria importante (prescripcion preoperatoria de opioides: 26% [13/51] frente a ninguna prescripcion preoperatoria de opioides: 9% [6/67]). En el analisis multivariable, la prescripcion de opioides preoperatorios (OR = 2.994, IC 95%: 1.024-8.751, p = 0.045) fueron factores de riesgo significativos para una complicacion mayor. La prescripcion preoperatoria de opioides se asocio con un aumento de la duracion de la estadia (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 limite para una mayor prescripcion de opioides de 300 miligramos equivalentes de morfina dentro de los 6 meses previos a la operacion (p. Ej., 60 tabletas de hidrocodona / acetaminofen 5/325), la prescripcion preoperatoria de opioides siguio 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 prescripcion preoperatoria de opioides fue un factor de riesgo significativo para los resultados adversos en pacientes con enfermedad de Crohn sometidos a reseccion ileocolica electiva. Consulte Video Resumen en http://links.lww.com/DCR/B113.
TL;DR: HalSynteny enables an accurate and rapid identification of synteny in multiple full-genome alignments and performs efficient processing of pairwise alignment blocks for any pair of genomes in the alignment.
Abstract: Background Large-scale sequencing projects provide high-quality full-genome data that can be used for reconstruction of chromosomal exchanges and rearrangements that disrupt conserved syntenic blocks. The highest resolution of cross-species homology can be obtained on the basis of whole-genome, reference-free alignments. Very large multiple alignments of full-genome sequence stored in a binary format demand an accurate and efficient computational approach for synteny block production. Findings halSynteny performs efficient processing of pairwise alignment blocks for any pair of genomes in the alignment. The tool is part of the HAL comparative genomics suite and is targeted to build synteny blocks for multi-hundred-way, reference-free vertebrate alignments built with the Cactus system. Conclusions halSynteny enables an accurate and rapid identification of synteny in multiple full-genome alignments. The method is implemented in C++11 as a component of the halTools software and released under MIT license. The package is available at https://github.com/ComparativeGenomicsToolkit/hal/.
TL;DR: Pre-infusion AFP independently predicted survival after Y-90 treatment for HCC, but not radiographic response, and can help guide treatment decisions.
Abstract: Background Few studies have assessed the relationship between serum alpha-fetoprotein (AFP) and yttrium-90 (Y-90) radioembolization response in hepatocellular carcinoma (HCC). The objective of the study was to evaluate whether peri-procedural serum AFP was correlated with Y-90 therapy response in HCC. Methods Patients undergoing Y-90 radioembolization with glass microspheres (TheraSphere™) for HCC between 2006 and 2013 at a single center were evaluated. The relationship between AFP and 6-month radiographic improvement (complete or partial response by modified RECIST criteria), overall (OS), and disease-specific survival (DSS) were analyzed. Results Seventy-four patients underwent a total of 124 Y-90 infusions. Median age was 65 years, median AFP was 37 ng/mL (range: 2–112,593 ng/mL) and median model for end-stage liver disease score was 6.2 (range:1.8–11.2). Increased AFP was not associated with radiographic improvement (odds ratio (OR) = 0.99, 95% confidence interval (CI) = 0.75–1.30, p = 0.92). Median OS was 15.2 months and was increased in patients with low AFP compared to high AFP (30.8 months vs. 7.8 months, p Conclusion Pre-infusion AFP independently predicted survival after Y-90 treatment for HCC, but not radiographic response, and can help guide treatment decisions.
TL;DR: A two stage genome wide association study in a cohort of Chinese patients designed to discover single nucleotide variants that associate with HBV infection and clearance of HBV found two significant gene associations that suggest the influence of DOCK8 and CA9 as potential risk genetic factors in the persistence ofHBV infection.
TL;DR: Evaluating the normal excursion of LHBT that occurs through a glenohumeral range of motion found that shoulder positioning is an important consideration in establishing a normal length-tension relationship during biceps tenodesis and elbow position does not significantly affect LHBT excursion.
Abstract: Background:Restoration of the long head of the biceps tendon (LHBT) length-tension relationship is critical in preserving muscle strength and efficiency when performing biceps tenodesis. While stat...
TL;DR: A 24-year-old woman with an 8-year history of Crohn’s disease (CD) presented as a referral for management of peristomal pyoderma gangrenosum (PG), with 3-months status postproctocolectomy with end ileostomy for medically refractory pancolonic CD.
Abstract: A 24-year-old woman with an 8-year history of Crohn’s disease (CD) presented as a referral for management of peristomal pyoderma gangrenosum (PG), with 3-months status postproctocolectomy with end ileostomy for medically refractory pancolonic CD. Her past medical history included a jejunal resection but no previous extraintestinal manifestations of CD. She was otherwise healthy and a nonmoker. At presentation, she was being treated with oral 6-mercaptopurine (125 mg once per day). On examination, a painful 4-cm ulcer to the right of her ileostomy was present and causing pouching difficulties (Fig. 1A). A punch biopsy on the border of the ulcer was obtained in the office. Her initial treatment consisted of an intralesional injection of both 1% lidocaine with epinephrine (3 mL) and methyprednisone 40 mg/mL (1 mL). Subsequently, the biopsy was read as an inflammatory cell infiltrate, consistent with PG. Despite multiple rounds of intralesional injections every other week, the ulcer progressively enlarged (Fig. 1B). Concurrently, she developed PG at her surgical incision (Fig. 1C). Because of her disease progression, her treatment was changed to topical 0.1% tacrolimus ointment once daily and oral mycophenolate mofetil 1000 mg twice daily. On this therapy regimen, the lesions progressively decreased in size (Figs. 1D–I) and healed after 7 months (Fig. 1I). She transitioned later to maintenance therapy with adalimumab 40 mg every 2 weeks and has shown no signs of PG for 3 years. CLINICAL QUESTIONS
TL;DR: The results emphasize that impaired monocyte function is, at least in part, related to dysregulated IκKα/β activation, and that IκF/β is likely involved in mounting a sufficient monocyte inflammatory response.
Abstract: Following major trauma, sepsis or surgery, some patients exhibit an impaired monocyte inflammatory response that is characterized by a decreased response to a subsequent bacterial challenge. To investigate this poorly understood phenomenon, we adopted an in-vitro model of endotoxin tolerance utilising primary human CD14 + monocytes to focus on the effect of impairment on IκKα/β, a critical part of the NFκB pathway. Impaired monocytes had decreased IκKα mRNA and protein expression and decreased phosphorylation of the IκKα/β complex. The impaired monocyte secretome demonstrated a distinct cytokine/chemokine footprint from the naive monocyte, and that TNF-α was the most sensitive cytokine or chemokine in this setting of impairment. Inhibition of IκKα/β with a novel selective inhibitor reproduced the impaired monocyte phenotype with decreased production of TNF-α, IL-6, IL-12p70, IL-10, GM-CSF, VEGF, MIP-1β, TNF-β, IFN-α2 and IL-7 in response to an LPS challenge. Surgical patients with infection also exhibited an impaired monocyte phenotype and had decreased SITPEC, TAK1 and MEKK gene expression, which are important for IκKα/β activation. Our results emphasize that impaired monocyte function is, at least in part, related to dysregulated IκKα/β activation, and that IκKα/β is likely involved in mounting a sufficient monocyte inflammatory response. Future studies may wish to focus on adjuvant therapies that augment IκKα/β function to restore monocyte function in this clinically important problem.
TL;DR: In this article, the authors analyzed the incidence of point mutations widely used for drug resistance detection in laboratory practice and conduct comparative analysis of whole-genome sequence (WGS) for clinical M. tuberculosis strains collected from patients with pulmonary tuberculosis and extra-pulmonary tuberculosis (XPTB) localization.
Abstract: Mycobacterium tuberculosis is a highly studied pathogen due to public health importance. Despite this, problems like early drug resistance, diagnostics and treatment success prediction are still not fully resolved. Here, we analyze the incidence of point mutations widely used for drug resistance detection in laboratory practice and conduct comparative analysis of whole-genome sequence (WGS) for clinical M. tuberculosis strains collected from patients with pulmonary tuberculosis (PTB) and extra-pulmonary tuberculosis (XPTB) localization. A total of 72 pulmonary and 73 extrapulmonary microbiologically characterized M. tuberculosis isolates were collected from patients from 2007 to 2014 in Russia. Genomic DNA was used for WGS and obtained data allowed identifying major mutations known to be associated with drug resistance to first-line and second-line antituberculous drugs. In some cases previously described mutations were not identified. Using genome-based phylogenetic analysis we identified M. tuberculosis substrains associated with distinctions in the occurrence in PTB vs. XPTB cases. Phylogenetic analyses did reveal M. tuberculosis genetic substrains associated with TB localization. XPTB was associated with Beijing sublineages Central Asia (Beijing CAO), Central Asia Clade A (Beijing A) and 4.8 groups, while PTB localization was associated with group LAM (4.3). Further, the XPTB strain in some cases showed elevated drug resistance patterns relative to PTB isolates. HIV was significantly associated with the development of XPTB in the Beijing B0/W148 group and among unclustered Beijing isolates.
TL;DR: This narrative is a personal view of adventures in genetic science and society that have blessed my life and career across five decades, and illustrates how genetic individualization in human and animals has improved forensic evidence in capital crimes.
Abstract: This narrative is a personal view of adventures in genetic science and society that have blessed my life and career across five decades. The advances I enjoyed and the lessons I learned derive from...
TL;DR: This dataset fills in one gap in the genome knowledge of animal phyla with a draft genome of Bugula neritina (phylum Bryozoa), as well as genes and proteins predicted de novo and verified using transcriptome data, along with the functional annotation.
Abstract: Many animal phyla have no representatives within the catalog of whole metazoan genome sequences. This dataset fills in one gap in the genome knowledge of animal phyla with a draft genome of Bugula neritina (phylum Bryozoa). Interest in this species spans ecology and biomedical sciences because B. neritina is the natural source of bioactive compounds called bryostatins. Here we present a draft assembly of the B. neritina genome obtained from PacBio and Illumina HiSeq data, as well as genes and proteins predicted de novo and verified using transcriptome data, along with the functional annotation. These sequences will permit a better understanding of host-symbiont interactions at the genomic level, and also contribute additional phylogenomic markers to evaluate Lophophorate or Lophotrochozoa phylogenetic relationships. The effort also fits well with plans to ultimately sequence all orders of the Metazoa.
TL;DR: This exploration of whole genome sequences presents a comprehensive characterisation of human genomic variations in the population of Botswana and their potential in contributing to a deeper understanding of population diversity and health in Africa and the African diaspora.
Abstract: The study of human genome variations can contribute towards understanding population diversity and the genetic aetiology of health-related traits. We sought to characterise human genomic variations of Botswana in order to assess diversity and elucidate mutation burden in the population using whole genome sequencing. Whole genome sequences of 390 unrelated individuals from Botswana were available for computational analysis. The sequences were mapped to the human reference genome GRCh38. Population joint variant calling was performed using Genome Analysis Tool Kit (GATK) and BCFTools. Variant characterisation was achieved by annotating the variants with a suite of databases in ANNOVAR and snpEFF. The genomic architecture of Botswana was delineated through principal component analysis, structure analysis and FST. We identified a total of 27.7 million unique variants. Variant prioritisation revealed 24 damaging variants with the most damaging variants being ACTRT2 rs3795263, HOXD12 rs200302685, ABCB5 rs111647033, ATP8B4 rs77004004 and ABCC12 rs113496237. We observed admixture of the Khoe-San, Niger-Congo and European ancestries in the population of Botswana, however population substructure was not observed. This exploration of whole genome sequences presents a comprehensive characterisation of human genomic variations in the population of Botswana and their potential in contributing to a deeper understanding of population diversity and health in Africa and the African diaspora.
TL;DR: Functional analysis revealed that novel rare-variants within the ANKRD39, LOC105378523 and GTF3C3 genes were significantly associated with HIV-1 progression and highlighted the significance of whole genome sequencing in pinpointing rare-Variants of clinical relevance.
Abstract: Despite the high burden of HIV-1 in Botswana, the population of Botswana is significantly underrepresentation in host genetics studies of HIV-1. Furthermore, the bulk of previous genomics studies evaluated common human genetic variations, however, there is increasing evidence of the influence of rare variants in the outcome of diseases which may be uncovered by comprehensive complete and deep genome sequencing. This research aimed to evaluate the role of rare-variants in susceptibility to HIV-1 and progression through whole genome sequencing. Whole genome sequences (WGS) of 265 HIV-1 positive and 125 were HIV-1 negative unrelated individuals from Botswana were mapped to the human reference genome GRCh38. Population joint variant calling was performed using Genome Analysis Tool Kit (GATK) and BCFTools. Cumulative effects of rare variant sets on susceptibility to HIV-1 and progression (CD4+ T-cell decline) were determined with optimized Sequence Kernel Association Test (SKAT-O). In silico functional analysis of the prioritized variants was performed through gene-set enrichment using databases in GeneMANIA and Enrichr. Novel rare-variants within the ANKRD39 (8.48 × 10−8), LOC105378523 (7.45 × 10−7) and GTF3C3 (1.36 × 10−6) genes were significantly associated with HIV-1 progression. Functional analysis revealed that these genes are involved in viral translation and transcription. These findings highlight the significance of whole genome sequencing in pinpointing rare-variants of clinical relevance. The research contributes towards a deeper understanding of the host genetics HIV-1 and offers promise of population specific interventions against HIV-1.