Cofactor Genomics: A Sequencing Service Company Emerges from the Technology Development Laboratory

Jump Starting Technologies, Patent Issues, and Translational Medicine Poster SessionCofactor Genomics is based in St. Louis, MO and provides sequencing and analysis services to academic and industry clients. We are a small company committed to changing the service sequencing paradigm by offering our customers front-to-back solutions; experimental design, next-generation sequencing, and advanced analytics for their work. Cofactor Genomics was founded by individuals with one-of-a-kind experience in Next-Generation sequencing technology development. The Cofactor Genomics executive team spent a collective 35 years working in the Technology Development Group at The Genome Center at Washington University in St. Louis, Missouri. From early 2004 to late 2008, their primary responsibilities within the group were to investigate, evaluate and develop both wet-lab and computational applications for emerging Next-Generation sequencing technology platforms. Their experience began with beta testing the 454 Life Sciences (now Roche) GS 20, continued with beta testing the first serial numbered instrument from Solexa (now Illumina), and culminated with beta testing the Applied Biosystems (now Life Technologies) SOLiD instrument. Our individual experiences were unique within the realm of next-generation sequencing technology, thus extremely complimentary for a consolidation and commercialization of skill sets; Matt Hickenbotham became a renowned expert in library construction and Next-Gen instrumentation, Jon Armstrong emerged as an expert in targeted and reduced representation genomic sequencing, and Ryan Richt and Dr. Jarret Glasscock were two of the first individuals in the world to characterize the data generated by these instruments. It is this early-access wet-lab and computational experience with these disruptive sequencing technologies that provided the foundation for operations at Cofactor Genomics. Cofactor Genomics has been in operation for 2 years and has already established a proven track record of capability, versatility, remarkably consistent high quality data generation, and delivering custom data analysis solutions. We constructed 268 different sequencing libraries in our first year spanning nearly every sequencing application and multiple Next-Gen instrument platforms. This feat would be impossible for any firm other than Cofactor to complete in such a short time frame, much to the credit of our highly skilled and talented team. We pooled our talents to form a company offering customers end-to-end sequencing solutions that ultimately allow them to concentrate on what they do best, breakthrough research

Analytical performance of an immunoprofiling assay based on RNA models

As immuno-oncology drugs grow more popular in the treatment of cancer, better methods are needed to quantify the tumor immune cell component to determine which patients are most likely to benefit from treatment. Methods such as flow cytometry can accurately assess the composition of infiltrating immune cells; however, they show limited use in formalin-fixed, paraffin-embedded (FFPE) specimens. This article describes a novel hybrid-capture RNA sequencing assay, ImmunoPrism, that estimates the relative percentage abundance of eight immune cell types in FFPE solid tumors. Immune health expression models were generated using machine learning methods and used to uniquely identify each immune cell type using the most discriminatively expressed genes. The analytical performance of the assay was assessed using 101 libraries from 40 FFPE and 32 fresh-frozen samples. With defined samples, ImmunoPrism had a precision of ±2.72%, a total error of 2.75%, and a strong correlation (

Phase I Study Assessing the Pharmacokinetic Profile, Safety, and Tolerability of a Single Dose of Ceftazidime-Avibactam in Hospitalized Pediatric Patients.

This study aimed to investigate the pharmacokinetics (PK), safety, and tolerability of a single dose of ceftazidime-avibactam in pediatric patients. A phase I, multicenter, open-label PK study was conducted in pediatric patients hospitalized with an infection and receiving systemic antibiotic therapy. Patients were enrolled into four age cohorts (cohort 1, ≥12 to <18 years; cohort 2, ≥6 to <12 years; cohort 3, ≥2 to <6 years; cohort 4, ≥3 months to <2 years). Patients received a single 2-h intravenous infusion of ceftazidime-avibactam (cohort 1, 2,000 to 500 mg; cohort 2, 2,000 to 500 mg [≥40 kg] or 50 to 12.5 mg/kg [<40 kg]; cohorts 3 and 4, 50 to 12.5 mg/kg). Blood samples were collected to describe individual PK characteristics for ceftazidime and avibactam. Population PK modeling was used to describe characteristics of ceftazidime and avibactam PK across all age groups. Safety and tolerability were assessed. Thirty-two patients received study drug. Mean plasma concentration-time curves, geometric mean maximum concentration (Cmax), and area under the concentration-time curve from time zero to infinity (AUC0-∞) were similar across all cohorts for both drugs. Six patients (18.8%) reported an adverse event, all mild or moderate in intensity. No deaths or serious adverse events occurred. The single-dose PK of ceftazidime and avibactam were comparable between each of the 4 age cohorts investigated and were broadly similar to those previously observed in adults. No new safety concerns were identified. (This study has been registered at ClinicalTrials.gov under registration no. NCT01893346.)

Advances in Genome Biology & Technology

This year's meeting focused on the latest advances in new DNA sequencing technologies and the applications of genomics to disease areas in biology and biomedicine. Daytime plenary sessions highlighted cutting-edge research in areas such as complex genetic diseases, comparative genomics, medical sequencing, massively parallel DNA sequencing, and synthetic biology. Technical approaches being developed and utilized in contemporary genomics research were presented during evening concurrent sessions. Also, as in previous years, poster sessions bridged the morning and afternoon plenary sessions. In addition, for the third year in a row, the Advances in Genome Biology and Technology (AGBT) meeting was preceded by a pre-meeting workshop that aimed to provide an introductory overview for trainees and other meeting attendees. This year, speakers at the workshop focused on next-generation sequencing technologies, including their experiences, findings, and helpful advise for others contemplating using these platforms in their research. Speakers from genome centers and core sequencing facilities were featured and the workshop ended with a roundtable discussion, during which speakers fielded questions from the audience

Mapping our Universe in 3D with MITEoR

Mapping our universe in 3D by imaging the redshifted 21 cm line from neutral hydrogen has the potential to overtake the cosmic microwave background as our most powerful cosmological probe, because it can map a much larger volume of our Universe, shedding new light on the epoch of reionization, inflation, dark matter, dark energy, and neutrino masses. We report on MITEoR, a pathfinder low-frequency radio interferometer whose goal is to test technologies that greatly reduce the cost of such 3D mapping for a given sensitivity. MITEoR accomplishes this by using massive baseline redundancy both to enable automated precision calibration and to cut the correlator cost scaling from N^2 to NlogN, where N is the number of antennas. The success of MITEoR with its 64 dual-polarization elements bodes well for the more ambitious HERA project, which would incorporate many identical or similar technologies using an order of magnitude more antennas, each with dramatically larger collecting area.Comment: To be published in proceedings of 2013 IEEE International Symposium on Phased Array Systems & Technolog

The Impact of the COVID-19 Pandemic on Racial Disparities in Patients Undergoing Total Shoulder Arthroplasty in the United States

INTRODUCTION: The purpose of this study was to assess racial disparities in total shoulder arthroplasty (TSA) in the US and to determine whether these disparities were affected by the COVID-19 pandemic. METHODS: Centers for Medicare and Medicaid Services (CMS) 100% sample was used to examine primary TSA volume from April-December from 2019-2020. Utilization was assessed for White/Black/Hispanic/Asian populations to determine if COVID-19 affected these groups differently. A regression model adjusted for age/sex/CMS-Hierarchical Condition Categories (HCC) score, dual enrollment (proxy for socioeconomic status), time fixed effects, and Core-based Statistical Area (CBSA) fixed effects was used to study difference across groups. RESULTS: In 2019, TSA volume/1000 beneficiaries was 1.51 for White and 0.57 for non-White, a 2.6-fold difference. In 2020, the rate of TSA in White patients (1.30/1000) was 2.9 times higher than non-White (0.45/1000) during the COVID-19 pandemic (P\u3c0.01). There was an overall 14% decrease in TSA volume/1000 Medicare beneficiaries in 2020; non-White patients had a larger percentage decrease in TSA volume than White (21% vs. 14%, estimated difference;8.7%,p = 0.02). Black patients experienced the most pronounced disparity with estimated difference of 10.1%,p = 0.05, compared with White patients. Similar disparities were observed when categorizing procedures into anatomic and reverse TSA, but not proximal humerus fracture. CONCLUSIONS: During the COVID-19 pandemic, overall TSA utilization decreased by 14% with White patients experiencing a decrease of 14%, and non-White patients experiencing a decrease of 21%. This trend was observed for elective TSA while disparities were less apparent for proximal humerus fracture

Cognitive behavioural therapy for adults with dissociative seizures (CODES): a pragmatic, multicentre, randomised controlled trial.

BACKGROUND: Dissociative seizures are paroxysmal events resembling epilepsy or syncope with characteristic features that allow them to be distinguished from other medical conditions. We aimed to compare the effectiveness of cognitive behavioural therapy (CBT) plus standardised medical care with standardised medical care alone for the reduction of dissociative seizure frequency. METHODS: In this pragmatic, parallel-arm, multicentre randomised controlled trial, we initially recruited participants at 27 neurology or epilepsy services in England, Scotland, and Wales. Adults (≥18 years) who had dissociative seizures in the previous 8 weeks and no epileptic seizures in the previous 12 months were subsequently randomly assigned (1:1) from 17 liaison or neuropsychiatry services following psychiatric assessment, to receive standardised medical care or CBT plus standardised medical care, using a web-based system. Randomisation was stratified by neuropsychiatry or liaison psychiatry recruitment site. The trial manager, chief investigator, all treating clinicians, and patients were aware of treatment allocation, but outcome data collectors and trial statisticians were unaware of treatment allocation. Patients were followed up 6 months and 12 months after randomisation. The primary outcome was monthly dissociative seizure frequency (ie, frequency in the previous 4 weeks) assessed at 12 months. Secondary outcomes assessed at 12 months were: seizure severity (intensity) and bothersomeness; longest period of seizure freedom in the previous 6 months; complete seizure freedom in the previous 3 months; a greater than 50% reduction in seizure frequency relative to baseline; changes in dissociative seizures (rated by others); health-related quality of life; psychosocial functioning; psychiatric symptoms, psychological distress, and somatic symptom burden; and clinical impression of improvement and satisfaction. p values and statistical significance for outcomes were reported without correction for multiple comparisons as per our protocol. Primary and secondary outcomes were assessed in the intention-to-treat population with multiple imputation for missing observations. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN05681227, and ClinicalTrials.gov, NCT02325544. FINDINGS: Between Jan 16, 2015, and May 31, 2017, we randomly assigned 368 patients to receive CBT plus standardised medical care (n=186) or standardised medical care alone (n=182); of whom 313 had primary outcome data at 12 months (156 [84%] of 186 patients in the CBT plus standardised medical care group and 157 [86%] of 182 patients in the standardised medical care group). At 12 months, no significant difference in monthly dissociative seizure frequency was identified between the groups (median 4 seizures [IQR 0-20] in the CBT plus standardised medical care group vs 7 seizures [1-35] in the standardised medical care group; estimated incidence rate ratio [IRR] 0·78 [95% CI 0·56-1·09]; p=0·144). Dissociative seizures were rated as less bothersome in the CBT plus standardised medical care group than the standardised medical care group (estimated mean difference -0·53 [95% CI -0·97 to -0·08]; p=0·020). The CBT plus standardised medical care group had a longer period of dissociative seizure freedom in the previous 6 months (estimated IRR 1·64 [95% CI 1·22 to 2·20]; p=0·001), reported better health-related quality of life on the EuroQoL-5 Dimensions-5 Level Health Today visual analogue scale (estimated mean difference 6·16 [95% CI 1·48 to 10·84]; p=0·010), less impairment in psychosocial functioning on the Work and Social Adjustment Scale (estimated mean difference -4·12 [95% CI -6·35 to -1·89]; p<0·001), less overall psychological distress than the standardised medical care group on the Clinical Outcomes in Routine Evaluation-10 scale (estimated mean difference -1·65 [95% CI -2·96 to -0·35]; p=0·013), and fewer somatic symptoms on the modified Patient Health Questionnaire-15 scale (estimated mean difference -1·67 [95% CI -2·90 to -0·44]; p=0·008). Clinical improvement at 12 months was greater in the CBT plus standardised medical care group than the standardised medical care alone group as reported by patients (estimated mean difference 0·66 [95% CI 0·26 to 1·04]; p=0·001) and by clinicians (estimated mean difference 0·47 [95% CI 0·21 to 0·73]; p<0·001), and the CBT plus standardised medical care group had greater satisfaction with treatment than did the standardised medical care group (estimated mean difference 0·90 [95% CI 0·48 to 1·31]; p<0·001). No significant differences in patient-reported seizure severity (estimated mean difference -0·11 [95% CI -0·50 to 0·29]; p=0·593) or seizure freedom in the last 3 months of the study (estimated odds ratio [OR] 1·77 [95% CI 0·93 to 3·37]; p=0·083) were identified between the groups. Furthermore, no significant differences were identified in the proportion of patients who had a more than 50% reduction in dissociative seizure frequency compared with baseline (OR 1·27 [95% CI 0·80 to 2·02]; p=0·313). Additionally, the 12-item Short Form survey-version 2 scores (estimated mean difference for the Physical Component Summary score 1·78 [95% CI -0·37 to 3·92]; p=0·105; estimated mean difference for the Mental Component Summary score 2·22 [95% CI -0·30 to 4·75]; p=0·084), the Generalised Anxiety Disorder-7 scale score (estimated mean difference -1·09 [95% CI -2·27 to 0·09]; p=0·069), and the Patient Health Questionnaire-9 scale depression score (estimated mean difference -1·10 [95% CI -2·41 to 0·21]; p=0·099) did not differ significantly between groups. Changes in dissociative seizures (rated by others) could not be assessed due to insufficient data. During the 12-month period, the number of adverse events was similar between the groups: 57 (31%) of 186 participants in the CBT plus standardised medical care group reported 97 adverse events and 53 (29%) of 182 participants in the standardised medical care group reported 79 adverse events. INTERPRETATION: CBT plus standardised medical care had no statistically significant advantage compared with standardised medical care alone for the reduction of monthly seizures. However, improvements were observed in a number of clinically relevant secondary outcomes following CBT plus standardised medical care when compared with standardised medical care alone. Thus, adults with dissociative seizures might benefit from the addition of dissociative seizure-specific CBT to specialist care from neurologists and psychiatrists. Future work is needed to identify patients who would benefit most from a dissociative seizure-specific CBT approach. FUNDING: National Institute for Health Research, Health Technology Assessment programme

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13