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The current human reference genome, GRCh38, represents over 20 years of effort to generate a high-quality assembly, which has benefitted societysup1,2/sup. However, it still has many gaps and errors, and does not represent a biological genome as it is a blend of multiple individualssup3,4/sup. Recently, a high-quality telomere-to-telomere reference, CHM13, was generated with the latest long-read technologies, but it was derived from a hydatidiform mole cell line with a nearly homozygous genomesup5/sup. To address these limitations, the Human Pangenome Reference Consortium formed with the goal of creating high-quality, cost-effective, diploid genome assemblies for a pangenome reference that represents human genetic diversitysup6/sup. Here, in our first scientific report, we determined which combination of current genome sequencing and assembly approaches yield the most complete and accurate diploid genome assembly with minimal manual curation. Approaches that used highly accurate long reads and parent-child data with graph-based haplotype phasing during assembly outperformed those that did not. Developing a combination of the top-performing methods, we generated our first high-quality diploid reference assembly, containing only approximately four gaps per chromosome on average, with most chromosomes within ±1% of the length of CHM13. Nearly 48% of protein-coding genes have non-synonymous amino acid changes between haplotypes, and centromeric regions showed the highest diversity. Our findings serve as a foundation for assembling near-complete diploid human genomes at scale for a pangenome reference to capture global genetic variation from single nucleotides to structural rearrangements.

Supplementary_Materials_CBCT for Low-Dose Image-Guided Pediatric CNS Radiation Therapy: Final Analysis From a Prospective Low-Dose Cone-Beam CT Protocol From a Multinational Pediatrics Consortium by Sara R. Alcorn, Xian Chiong Zhou, Casey Bojechko, Rodrigo A. Rubo, Michael J. Chen, Karin Dieckmann, Ralph P. Ermoian, Eric C. Ford, Daria Kobyzeva, Shannon M. MacDonald, Todd R. McNutt, Alexey Nechesnyuk, Kristina Nilsson, Hakan Sjostrand, Koren S. Smith, Markus Stock, Erik J. Tryggestad, Rosangela C. Villar, Brian A. Winey and Stephanie A. Terezakis in Technology in Cancer Research & Treatment

Purpose Increased breast density is acknowledged as an independent risk factor for breast cancer and may obscure malignancy on mammography. Approximately half of all mammograms depict dense breasts. Legislation related to mandatory breast density notification was first enacted in Connecticut in 2009. On May 1, 2014, New Jersey joined other states with similar legislation. The New Jersey breast density law (NJBDL) mandates that mammography reports acknowledge the relevance and masking effect of mammographic breast density. The aim of this study was to assess the impact of the NJBDL at one of the state's largest ACR-accredited breast centers. Methods A retrospective chart review was performed to determine changes in imaging and intervention utilization and modality of cancer diagnosis after enactment of the legislation. Data for the present study were extracted from a review of all patients with core biopsy–proven malignancy at a large outpatient breast center between November 1, 2012, and October 31, 2015. Data were divided into the 18-month period before the implementation of the NJBDL (November 1, 2012 to April 30, 2014) and the 18-month period after passage of the law (May 1, 2014 to October 31, 2015). Results Screening ultrasound increased significantly after the implementation of the NJBDL, by 651% (1,530 vs 11,486). MRI utilization increased by 59.3% (2,595 vs 4,134). A total of 1,213 cancers were included in the final analysis, 592 in the first time period and 621 after law implementation. Breast cancer was most commonly detected on screening mammography, followed by diagnostic mammography with ultrasound for palpable concern, in both time periods. Of the 621 cancers analyzed, 26.1% (n = 162) were found in patients 50 years of age or younger. Results demonstrated that with respect to how malignancies were detected, age and average mammographic density were both statistically significant ( P = .002). Conclusions The NJBDL succeeded in publicizing the masking effect of dense breasts. The number of supplemental screening ultrasound and MRI examinations increased after the implementation of this legislation. An efficacy analysis affirmed the high sensitivity of screening MRI compared with other modalities. The use of MRI increased core biopsy efficiency and reduced the number of biopsies needed per cancer diagnosed.

Coronary artery bypass graft (CABG) operations are associated with all-cause readmission rates of approximately 15%. In attempts to reduce readmission rates, the Hospital Readmission Reduction Program expanded to include CABG operations in 2015. The aim of this study was therefore to develop a predictive readmission scale that would identify patients at higher risk of readmission after CABG using commonly available administrative data.Data of 126,519 patients from California and New York (derivation cohort) and 94,318 patients from Florida and Washington (validation cohort) were abstracted from the State Inpatient Database (2006 to 2011). The readmission after CABG scale was developed to predict 30-day readmission risk and was validated against a separate cohort.Thirty-day CABG readmission rates were 23% in the derivation cohort and 21% in the validation cohort. Predictive factors included older age, female gender (odds ratio [OR], 1.34), African American ethnicity (OR, 1.13), Medicare or Medicaid insurance, and comorbidities, including renal failure (OR, 1.56) and congestive heart failure (OR, 2.82). These were independently predictive of increased readmission rates (p0.01). The readmission scale was then created with these preoperative factors. When applied to the validation cohort, it explained 98% of the readmission variability.The readmission after CABG scale reliably predicts a patient's 30-day CABG readmission risk. By identifying patients at high-risk for readmission before their procedure, risk reduction strategies can be implemented to reduce readmissions and healthcare expenditures.

Fibroadenoma is overwhelmingly the most common pediatric breast lesion. Breast malignancy is quite uncommon in children, most frequently metastatic or hematological malignancy. Core biopsy has largely replaced excision for diagnosis of breast masses in adults. The purpose of this study is two-fold: (1) compare utilization at our institution of interventional procedures vs. surgery for breast mass diagnosis in patients ≤18 years and (2) propose guidelines for breast imaging and biopsy in this population. We extracted data for all patients ≤18 who, between 2004 and 2016, underwent either (a) imaging and/or intervention procedure, or (b) breast surgery, from the Radiology Information System and Pathology Data System, respectively. We recorded age, gender, imaging, procedure, lesion size and histopathology. We found 1,050 pediatric patients ≤18 years who underwent diagnostic breast ultrasound between 2004 and 2016. Of these, 168 patients underwent 199 interventional procedures. One hundred thirty patients underwent 160 core biopsies of solid lesions. Core biopsy pathology diagnosed benign lesions in 99%, of which 84.3% were fibroadenomas (n=135). One malignancy was diagnosed, B cell lymphoma. Two hundred three patients underwent surgical excision for 266 discrete lesions, and 89% were fibroadenomas. Seven benign phyllodes tumors were surgically diagnosed. No malignancies were diagnosed. Core biopsy in patients 18 years and younger is well-tolerated, has few risks, and is preferable to surgery in developing breasts, but the goal is to avoid any breast procedure whenever possible. We propose guidelines for pediatric breast imaging, follow-up, core biopsy and excisions.

Adrenomedullin (AM) is a vasodilatory and chronotropic peptide that has cardioprotective properties in settings of ischemia-reperfusion. Specifically, the 52-amino acid peptide hormone has been shown to reduce infarct size and potentially be protective against malignant arrhythmias. AM reduces L-type calcium currents in rabbit ventricular myocytes, and can possibly be utilized as an antiarrhythmic drug. However, at present it is unclear whether AM has cardiac electrophysiological effects in vivo. In the present study, we investigated whether AM affects sinus and atrioventricular nodal functions, cardiac pacing thresholds, refractory properties and intracardiac conduction intervals in an intact porcine model (Norwegian landrace and Yorkshire hybrids; n=12). Hemodynamic and electrophysiological parameters were recorded at baseline and following 60 min of AM-infusion (100 ng/kg/min). The hemodynamic effects of AM were characterized by a reduced mean arterial pressure (76 ± 9 vs. 57 ± 6; p

Cell surface mucins configure the cell surface by presenting extended protein backbones that are heavily O-glycosylated. The glycopeptide structures establish physicochemical properties at the cell surface that enable and block the formation of biologically important molecular complexes. Some mucins, such as MUC1, associate with receptor tyrosine kinases and other cell surface receptors, and engage in signal transduction in order to communicate information regarding conditions at the cell surface to the nucleus. In that context, the MUC1 cytoplasmic tail (MUC1CT) receives phosphorylation signals from receptor tyrosine kinases and serine/threonine kinases, which enables its association with different signaling complexes that conduct these signals to the nucleus and perhaps other subcellular organelles. We have detected the MUC1CT at promoters of over 500 genes, in association with several different transcription factors, and have shown that promoter occupancy can vary under different growth factor conditions. However, the full biochemical nature of the nuclear forms of MUC1 and its function at these promoter regions remain undefined. I will present evidence that nuclear forms of the MUC1CT include extracellular and cytoplasmic tail domains. In addition, I will discuss evidence for a hypothesis that the MUC1CT possesses a novel catalytic function that enables remodeling of the transcription factor occupancy of promoters, and thereby engages in regulation of gene expression.

Incident learning systems are important tools to improve patient safety in radiation oncology, but physician participation in these systems is poor. To understand reporting practices and attitudes, a survey was sent to staff members of four large academic radiation oncology centers, all of which have in-house reporting systems.Institutional review board approval was obtained to send a survey to employees including physicians, dosimetrists, nurses, physicists, and radiation therapists. The survey evaluated barriers to reporting, perceptions of errors, and reporting practices. The responses of physicians were compared with those of other professional groups.There were 274 respondents to the survey, with a response rate of 81.3%. Physicians and other staff agreed that errors and near-misses were happening in their clinics (93.8% v 88.7%, respectively) and that they have a responsibility to report (97% overall). Physicians were significantly less likely to report minor near-misses (P = .001) and minor errors (P = .024) than other groups. Physicians were significantly more concerned about getting colleagues in trouble (P = .015), liability (P = .009), effect on departmental reputation (P = .006), and embarrassment (P.001) than their colleagues. Regression analysis identified embarrassment among physicians as a critical barrier. If not embarrassed, participants were 2.5 and 4.5 times more likely to report minor errors and major near-miss events, respectively.All members of the radiation oncology team observe errors and near-misses. Physicians, however, are significantly less likely to report events than other colleagues. There are important, specific barriers to physician reporting that need to be addressed to encourage reporting and create a fair culture around reporting.

Single Molecule, Real-Time (SMRT) Sequencing holds promise for addressing new frontiers in large genome complexities, such as long, highly repetitive, low-complexity regions and duplication events, and differentiating between transcript isoforms that are difficult to resolve with short-read technologies. We present solutions available for both reference genome improvement (100 MB) and transcriptome research to best leverage long reads that have exceeded 20 Kb in length. Benefits for these applications are further realized with consistent use of size-selection of input sample using the BluePippin™ device from Sage Science. Highlights from our genome improvement projects using the latest P5-C3 chemistry on model organisms with contig N50 exceeding 6 Mb and longest contig exceeding 12.5 Mb with an average base quality of QV50 will be shared. Additionally, the value of long, intact reads to provide a no-assembly approach to investigate transcript isoforms using our Iso-Seq protocol will be presented.

Leukocyte subsets, total leukocyte isolates or full blood samples were subjected to medium-strength square-wave electric impulses (100 V/cm field force, 5 ms duration). On the surface of the leukocytes, the expressions of several markers (CD3, CD4, CD8, CD11a, CD11b and ICAM-1) were determined in order to study the influence of pulsed ionic currents on different aspects of the cellular immune response. Large individual differences were observed among randomly chosen healthy donors, both in the initial expression rate and in the response patterns of different antigens. As a general conclusion, it can be stated that electric impulses with the above parameters activate the state of immune response alertness of human leukocytes. Changes in the activities of several enzymes in the serum in response to electric impulses were also tested in order to examine the feasibility of ex vivo electric treatment of human blood for the establishment of an antiviral and immune activated condition. Slightly elevated lactate dehydrogenase (LDH) levels point to a possibility of enhanced haemolysis, while the lack of an elevation in the membrane-bound peroxidase activity indicates the absence of haemolysis. Significant rises were detected in the serum superoxide dismutase (SOD) activities. Since most ex vivo blood manipulations are characterised by the appearance of superoxide radicals in the serum, a SOD activity enhancement is considered beneficial in these cases. A mild, but significant reduction in the blood clotting time indicates that electric treatment of human blood should be performed with special attention to thrombosis-prone conditions, and adequate precautions and countermeasures should be introduced. Although wider examinations are required before this method can be fully recommended, ex vivo blood treatment with medium-strength electric impulses seems to be a promising adjuvant course for the establishment of acute immune potentiation and an antiviral state in patients undergoing dialysis treatment.

Historically the training of teams has been implemented using a face-to-face approach. In the past decade, on-line multiuser virtual environments have offered a solution for training teams whose members are geographically dispersed. In order to develop on effective team training activity, a high sense of presence among the participant needs to be reached. Previous research studies reported being able to reach a high level of presence even when using inexpensive technology such as laptop and headset. This study evaluates the level of presence of ten subjects who have to perform a team-building activity in a multi-user virtual environment using a laptop computer and a headset. The authors are interested in determining which user characterizes, such as gender, age and knowledge of computers, have a strong correlation with the level of sense of presence. The results of this study showed that female participants were more likely to engage in the activity and perceived fewer negative effects. Participants who reported less negative effects such as feeling tired, dizzy, or experiencing eye strain during the team-building activity reached a higher level of sense of presence., Comment: 10 pages, 1 figure, 5 tables; The International Journal of Multimedia & Its Applications (IJMA) Vol.3, No.2, May 2011