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Summary: EasyVS is a web-based platform built to simplify molecule library selection and virtual screening. With an intuitive interface, the tool allows users to go from selecting a protein target with a known structure and tailoring a purchasable molecule library to performing and visualizing docking in a few clicks. Our system also allows users to filter screening libraries based on molecule properties, cluster molecules by similarity and personalize docking parameters., Availability and Implementation: EasyVS is freely available as an easy-to-use web interface at http://biosig.unimelb.edu.au/easyvs., Contact: douglas.pires@unimelb.edu.au or david.ascher@unimelb.edu.au., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The colonization of Ireland by mammals has been the subject of extensive study using genetic methods and forms a central problem in understanding the phylogeography of European mammals after the Last Glacial Maximum. Ireland exhibits a depauperate mammal fauna relative to Great Britain and continental Europe, and a range of natural and anthropogenic processes have given rise to its modern fauna. Previous Europe-wide surveys of the European badger ( Meles meles ) have found conflicting microsatellite and mitochondrial DNA evidence in Irish populations, suggesting Irish badgers have arisen from admixture between human imported British and Scandinavian animals. The extent and history of contact between British and Irish badger populations remains unclear. We use comprehensive genetic data from Great Britain and Ireland to demonstrate that badgers in Ireland's northeastern and southeastern counties are genetically similar to contemporary British populations. Simulation analyses suggest this admixed population arose in Ireland 600-700 (CI 100-2600) years before present most likely through introduction of British badgers by people. These findings add to our knowledge of the complex colonization history of Ireland by mammals and the central role of humans in facilitating it., Competing Interests: We declare we have no conflict of interest., (© 2020 The Authors.)

High-throughput computational techniques have become invaluable tools to help increase the overall success, process efficiency, and associated costs of drug development. By designing ligands tailored to specific protein structures in a disease of interest, an understanding of molecular interactions and ways to optimize them can be achieved prior to chemical synthesis. This understanding can help direct crucial chemical and biological experiments by maximizing available resources on higher quality leads. Moreover, predicting molecular binding affinity within specific biological contexts, as well as ligand pharmacokinetics and toxicities, can aid in filtering out redundant leads early on within the process. We describe a set of computational tools which can aid in drug discovery at different stages, from hit identification (EasyVS) to lead optimization and candidate selection (CSM-lig, mCSM-lig, Arpeggio, pkCSM). Incorporating these tools along the drug development process can help ensure that candidate leads are chemically and biologically feasible to become successful and tractable drugs.

Invasive plant species threaten native biodiversity, ecosystems, agriculture, industry and human health worldwide, lending urgency to the search for predictors of plant invasiveness outside native ranges. There is much conflicting evidence about which plant characteristics best predict invasiveness. Here we use a global demographic survey for over 500 plant species to show that populations of invasive plants have better potential to recover from disturbance than non-invasives, even when measured in the native range. Invasives have high stable population growth rates in their invaded ranges, but this metric cannot be predicted based on measurements in the native ranges. Recovery from demographic disturbance is a measure of transient population amplification, linked to high levels of reproduction, and shows phylogenetic signal. Our results demonstrate that transient population dynamics and reproductive capacity can help to predict invasiveness across the plant kingdom, and should guide international policy on trade and movement of plants.

Advances in genomic sequencing have enormous potential to revolutionize personalized medicine, however distinguishing disease-causing from benign variants remains a challenge. The increasing number of human genome and exome sequences available has revealed areas where unfavourable variation is removed through purifying selection. Here, we present the MTR-Viewer, a web-server enabling easy visualization at the gene or variant level of the Missense Tolerance Ratio (MTR), a measure of regional intolerance to missense variation calculated using variation from 240 000 exome and genome sequences. The MTR-Viewer enables exploration of MTR calculations, using different sliding windows, for over 18 000 human protein-coding genes and 85 000 alternative transcripts. Users can also view MTR scores calculated for specific ethnicities, to enable easy exploration of regions that may be under different selective pressure. The spatial distribution of population and known disease variants is also displayed on the protein's domain structure. Intolerant regions were found to be highly enriched for ClinVar pathogenic and COSMIC somatic missense variants (Mann-Whitney U test P < 2.2 × 10-16). As the MTR is not biased by known domains and protein features, it can highlight functionally important regions within genes overlooked or inaccessible by traditional methods. MTR-Viewer is freely available via a user friendly web-server at http://biosig.unimelb.edu.au/mtr-viewer/., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease., Methods: Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed., Results: Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia., Conclusion: Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment., Trial Registration: ClinicalTrials.gov NCT01724580 and NCT02974595., Funding: This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Objective: The SLE Responder Index (SRI) is a composite endpoint used in SLE trials. This investigation examined the clinical trial elements that drive response measured by the SRI., Methods: Analyses are based on data from two phase 3 trials (n = 2262) that evaluated the impact of an anti-B-cell activating factor antibody on disease activity using SRI-5 as the primary endpoint (ClinicalTrials.gov NCT01196091 and NCT01205438)., Results: The SRI-5 response rate at week 52 for all patients was 32.8%. Non-response due to a lack of SLEDAI improvement, concomitant medication non-compliance or dropout was 31, 16.5 and 19.1%, respectively. Non-response due to deterioration in BILAG or Physician's Global Assessment after SLEDAI improvement, concomitant medication compliance and trial completion was 0.5%. Disease activity in three SLEDAI organ systems was highly prevalent at baseline: mucocutaneous, 90.6%; musculoskeletal, 82.9%; and immunologic, 71.6%. Disease activity in each of the other organ systems was <11% of patients. Four clinical manifestations were highly prevalent at baseline: arthritis, 82.6%; rash, 69.2%; alopecia, 58.2%; and mucosal ulcer, 32.5%. The combined prevalence of renal, vascular and CNS disease at baseline was 17.6%; these patients had high SRI-5 response rates. Adjustments to corticosteroids were allowed during the first 24 weeks. Increases in corticosteroids above 2.5 mg/day were observed in 16.2% of placebo patients over the first 24 weeks after randomization., Conclusion: The primary drivers of SRI-5 response were SLEDAI improvement, concomitant medication adherence and trial completion. Arthritis, rash, alopecia and mucosal ulcer were the most prevalent clinical manifestations at baseline. Corticosteroid increases and rare, highly weighted disease manifestations in SLEDAI can confound the SRI signal., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Gene panel and exome sequencing have revealed a high rate of molecular diagnoses among diseases where the genetic architecture has proven suitable for sequencing approaches, with a large number of distinct and highly penetrant causal variants identified among a growing list of disease genes. The challenge is, given the DNA sequence of a new patient, to distinguish disease-causing from benign variants. Large samples of human standing variation data highlight regional variation in the tolerance to missense variation within the protein-coding sequence of genes. This information is not well captured by existing bioinformatic tools, but is effective in improving variant interpretation. To address this limitation in existing tools, we introduce the missense tolerance ratio (MTR), which summarizes available human standing variation data within genes to encapsulate population level genetic variation. We find that patient-ascertained pathogenic variants preferentially cluster in low MTR regions ( P < 0.005) of well-informed genes. By evaluating 20 publicly available predictive tools across genes linked to epilepsy, we also highlight the importance of understanding the empirical null distribution of existing prediction tools, as these vary across genes. Subsequently integrating the MTR with the empirically selected bioinformatic tools in a gene-specific approach demonstrates a clear improvement in the ability to predict pathogenic missense variants from background missense variation in disease genes. Among an independent test sample of case and control missense variants, case variants (0.83 median score) consistently achieve higher pathogenicity prediction probabilities than control variants (0.02 median score; Mann-Whitney U test, P < 1 × 10 -16 ). We focus on the application to epilepsy genes; however, the framework is applicable to disease genes beyond epilepsy., (© 2017 Traynelis et al.; Published by Cold Spring Harbor Laboratory Press.)

Objectives: To test the feasibility of modified biopsy needles as probes for irreversible electroporation ablation and periprocedural biopsy., Methods: Core biopsy needles of 16-G/9-cm were customized to serve as experimental ablation probes. Computed tomography-guided percutaneous irreversible electroporation was performed in in vivo porcine kidneys with pairs of experimental (n = 10) or standard probes (n = 10) using a single parameter set (1667 V/cm, ninety 100 µs pulses). Two biopsy samples were taken immediately following ablation using the experimental probes (n = 20). Ablation outcomes were compared using computed tomography, simulation, and histology. Biopsy and necropsy histology were compared., Results: Simulation-suggested ablations with experimental probes were smaller than that with standard electrodes (455.23 vs 543.16 mm 2 ), although both exhibited similar shape. Computed tomography (standard: 556 ± 61 mm 2 , experimental: 515 ± 67 mm 2 ; P = .25) and histology (standard: 313 ± 77 mm 2 , experimental: 275 ± 75 mm 2 ; P = .29) indicated ablations with experimental probes were not significantly different from the standard. Histopathology indicated similar morphological changes in both groups. Biopsies from the ablation zone yielded at least 1 core with sufficient tissue for analysis (11 of the 20)., Conclusions: A combined probe for irreversible electroporation ablation and periprocedural tissue sampling from the ablation zone is feasible. Ablation outcomes are comparable to those of standard electrodes., (© The Author(s) 2015.)

Purpose: To report incidence of acute versus delayed presentations of bleeding requiring embolization after focal liver biopsy, in correlation with angiographic findings and treatment success rates. The available literature will be reviewed as well., Materials and Methods: Health Insurance Portability and Accountability Act-compliant institutional review board approved retrospective review of 2180 consecutive patients undergoing 2335 targeted liver biopsies at a tertiary-care cancer center. Hepatic arterial embolization episodes within 30days from biopsy were identified via radiology PACS. Electronic medical record review was performed for indication of embolization and postembolization clinical course., Results: The incidence of postbiopsy bleeding requiring embolization was 0.5% (12/2335 biopsies). In those with bleeding, 1/12 (8%) had no hepatic arterial findings at angiography. Angiographic hepatic arterial findings resolved after embolization in 11/11 patients (100% technical success). Bleeding ceased after embolization in 10/12 patients (83% clinical success). Complications were seen in 2/12 (17%) patients: cholecystitis and hepatic infarct, respectively. Delayed presentation of bleeding (defined as >24h postbiopsy) occurred in 5/12 (42%) patients; the longest latency was 12days., Conclusion: The overall incidence of bleeding requiring embolization in our population was 0.5%. This complication rate compares favorably to the 0-4.2% (median: 0.29%) rate quoted in the available, heterogeneous, literature on this topic. Delayed presentation occurred in almost half of patients. Arterial embolization carries excellent technical and clinical success rates., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Context: Touch preparations (TP) of core needle biopsies (CNBs) are used at some institutions for on-site assessment of CNB adequacy. In our clinical practice, we have encountered instances in which TPs resulted in substantial depletion of CNB cellularity., Objective: To examine the effect of increasingly vigorous TPs on cellularity and DNA content of CNBs., Design: Ex vivo CNBs (n = 56) were performed on resected lung and kidney tumor specimens. For each specimen, CNBs were performed in quadruplicate on tumor and nontumor tissue and subjected to 1 of 4 TP methods: imprint, 1-cm drag, 2-cm drag, or full-slide drag. Overall cellularity in TPs relative to corresponding CNBs was estimated semiquantitatively. DNA was extracted and quantified from 12 TPs and corresponding CNBs. Two cytopathologists performed a blinded diagnostic assessment of Diff-Quik-stained TPs., Results: Cellularity of imprint, 1-cm, 2-cm, and full-slide TPs represented, on average, 19%, 33%, 41%, and 46% of total CNB cellularity, respectively (p = .003). Average DNA content in imprint, 1-cm, and 2-cm TPs was 0.3 μg (range, 0.1-0.8 μg), 0.4 μg (range, 0.1-1 μg), and 0.6 μg (range, 0.2-1.3 μg), respectively, which represented on average 15%, 36%, and 50%, respectively, of total CNB DNA content. Diagnostic accuracy was not inferior for less-extensive TPs, compared with more-extensive TPs., Conclusions: Vigorous TPs may contain a substantial fraction of CNB cellularity and DNA content, whereas more-limited TPs are less disruptive to CNBs but remain suitable for cytologic assessment. We suggest avoiding excessively forceful TPs and, whenever clinically feasible, obtaining additional samples to ensure sufficient cellularity for potential ancillary studies.

Purpose: To evaluate the feasibility of focal intraluminal irreversible electroporation (IRE) in the ureter with a novel electrode catheter and to study the treatment effects in response to increasing pulse strength., Materials and Methods: Five IRE treatment settings were each evaluated twice for the ablation of normal ureter in 5 Yorkshire pigs (n = 1-4 ablations per animal; total of 10 ablations) with the use of a prototype device under ultrasound and fluoroscopic guidance. Animals received unilateral or bilateral treatment, limited to a maximum of 2 ablations in any 1 ureter. Treatment was delivered with increasing pulse strength (from 1,000 V to 3,000 V in increments of 500 V) while keeping the pulse duration (100 μs) and number of pulses (n = 90) constant. Ureter patency was assessed with antegrade ureteropyelography immediately following treatment. Animals were euthanized within 4 hours after treatment, and treated urinary tract was harvested for histopathologic analysis with hematoxylin and eosin and Masson trichrome stains., Results: IRE was successfully performed in all animals, without evidence of ureteral perforation. Hematoxylin and eosin analysis of IRE treatments demonstrated full-thickness ablation at higher field strengths (mucosa to the adventitia). Masson trichrome stains showed preservation of connective tissue at all field strengths., Conclusions: Intraluminal catheter-directed IRE ablation is feasible and produces full-thickness ablation of normal ureters. There was no evidence of lumen perforation even at the maximum voltages evaluated., (Copyright © 2015 SIR. Published by Elsevier Inc. All rights reserved.)

Purpose: To report and compare outcomes after radiofrequency ablation for treatment-naïve first primary, metachronous, and synchronous T1 lung tumors., Materials and Methods: This institutional review board-approved retrospective study reviewed 29 patients (12 men and 17 women; median age, 73 y; age range, 55-86 y) with treatment-naïve T1 lung tumors treated with radiofrequency ablation. Tumors in the 29 patients included 21 T1a and 8 T1b first primary (n = 11), metachronous (n = 14), or synchronous (n = 4) tumors (adenocarcinoma, n = 25; squamous cell carcinoma, n = 3; unspecified, n = 1). Median tumor diameter was 14 mm (range, 10-26 mm). Surveillance computed tomography or positron emission tomography-computed tomography was performed over a median period of 28 months (range, 12-83 mo). Technical success and effectiveness rates and overall and progression-free 1-year, 3-year, and 5-year survivals were calculated according to stage, first primary, metachronous, and synchronous tumor status., Results: Technical success and effectiveness was 97%. Local control occurred in 17 of 21 T1a tumors (81%) and 5 of 8 T1b tumors (62.5%). The local progression rate of first primary tumors (5 of 11; 45%) was higher than that of metachronous (2 of 14; 14%; P = .07) and synchronous (0 of 4; P = .01) tumors. Estimated 1-year, 3-year, and 5-year local tumor progression-free survival was 79%, 75%, and 75%. Estimated 1-year, 3-year, and 5-year overall survival was 100%, 60%, and 14%. Survival outcomes were similar for patients with first primary, metachronous, or synchronous tumors., Conclusions: Radiofrequency ablation results in good local control and progression-free survival in patients with treatment-naïve T1 lung tumors, including patients with metachronous and synchronous tumors., (Copyright © 2014 SIR. Published by Elsevier Inc. All rights reserved.)

A new ablation modality, irreversible electroporation (IRE), has been of increasing interest in interventional radiology. Its nonthermal mechanism of action of killing tumor cells allows physicians the ability to ablate tumors in areas previously contraindicated for thermal ablation. This article reviews the current published clinical outcomes, imaging follow-up, and the current knowledge gaps in the procedure for patients treated with IRE.

Aims: The aim of this study was to evaluate the impact of systemic lupus erythematosus (SLE) on the lives of patients in order to inform the development of a conceptual model., Methods: Twenty-two participants with SLE (defined as meeting four of the 11 ACR criteria) were recruited for this study. Semi-structured, in-person interviews were conducted with each participant, exploring the symptoms experienced and the impact on the patient's life. Thematic analysis of interview transcripts was conducted in ATLAS.ti software to identify areas of impact and explore the interrelationships between concepts to inform the development of a conceptual model., Results: Almost all participants were female (95%); the sample was diverse in terms of age (mean age of 45.5 years; age range of 20-60 years), ethnicity (59% black/African American) and disease duration. Commonly reported symptoms were pain, fatigue/tiredness and skin problems. Qualitative analysis revealed seven themes relating to the impact of SLE symptoms on patient's Health Related Quality of Life (HRQL): emotions, social, family and leisure activities, daily activities, cognition, appearance, employment activities and independence. The interrelationships between symptoms, impacts and symptom triggers are illustrated in a conceptual model., Conclusions: The conceptual model illustrates the wide-reaching impact of SLE symptoms on a patient's HRQL, and the potential broad impact of a treatment that improves SLE symptoms.

The successful use of Silastic sheeting for the prevention of recurrent ureteral fibrosis following ureteral lysis in 3 patients with retroperitoneal fibrosis is reported.