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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

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.

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.

BACKGROUND Chronobiological studies with anticancer drugs have shown that their effectiveness and/or toxicity is significantly influenced by the time of their administration in the circadian cycle. Previous studies also have shown that the myelotoxicity of interferons is similarly influenced. PURPOSE This study was undertaken to evaluate the antitumor activity of interferons as a function of their administration to animals at defined points in the circadian cycle with equal light and dark periods. METHODS A murine tumor model was employed. Following adaptation to alternating cycles of 12 hours of light and 12 hours of dark for a period of 2-3 weeks, C57BL/6 mice were inoculated with B16 melanoma cells intraperitoneally at different hours after light onset. Exactly 24 hours after inoculation, each group received intraperitoneal injections of either recombinant human interferon alpha (rHuIFN-alpha A/D), recombinant murine IFN-gamma (rMuIFN-gamma), or interferon-carrier solution as control (once a day for 5 days) and were monitored for the length of their survival. RESULTS The antitumor activity (calculated as percent increased life span) of both rHuIFN-alpha A/D and rMuIFN-gamma varied with the points at which they were administered in the circadian cycle. However, the points showing minimum and maximum activity for rHuIFN-alpha A/D (12-16 and 0-4 hours after light onset, respectively) did not correspond with the points for the rMuIFN-gamma (0-8 and 16 hours after light onset, respectively). To generate maximum antitumor activity, approximately fivefold higher amounts of rHuIFN-alpha A/D were required at 12 than at 4 hours after light onset (dose range, 3333-90,000 IU/d) (P < .0001). Similarly, for rMuIFN-gamma at least 8.5-fold greater amounts were required at 8 than at 16 hours after light onset (dose range, 667-6000 IU/d) (P < .01). CONCLUSIONS In the murine tumor model, administration of rHuIFN-alpha A/D at 4 hours after light onset and rMuIFN-gamma at 16 hours after light onset may produce maximum antitumor activity.

Superficial doses were measured for static TomoTherapy Hi-Art beams for normal and oblique incidence. Dose was measured at depthsor = 2 cm along the central axis of 40 x 5 cm2 and 40 x 2.5 cm2 beams at normal incidence for source to detector distances (SDDs) of 55, 70, and 85 cm. Measurements were also made at depths normal to the phantom surface for the same beams at oblique angles of 30 degrees, 45 degrees, 60 degrees, 75 degrees, and 83 degrees from the normal. Data were collected with a Gammex/RMI model 449 parallel-plate chamber embedded in a solid water phantom and with LiF thermoluminescent dosimeters (TLDs) in the form of powder. For comparison, measurements were made on a conventional 6 MV beam (Varian Clinac 2100C) at normal incidence and at an oblique angle of 60 degrees from the normal. TomoTherapy surface dose varied with the distance from the source and the angle of incidence. For normal incidence, surface dose increased from 0.16 to 0.43 cGy/MU as the distance from the source decreased from 85 to 55 cm for the 40 x 5 cm2 field and increased from 0.12 to 0.32 cGy/MU for the 40 x 2.5 cm2 field. As the angle of incidence increased from 0 degrees to 83 degrees, surface dose increased from 0.24 to 0.63 cGy/MU for the 40 x 5 cm2 field and from 0.18 to 0.58 cGy/MU for the 40 x 2.5 cm2 field. For normal incidence at 55 cm SDD, the surface dose relative to the dose at d(max) for the 40 x 5 cm2 TomoTherapy Hi-Art beam was 31% less than that from a conventional, flattening filter based linear accelerator. These data should prove useful in accessing the accuracy of the TomoTherapy treatment planning system to predict the dose at superficial depths for a static beam delivery.

The accepted routes of interferon (IFN) administration in clinical applications are intramuscular, subcutaneous, intraperitoneal, intratumor, and intravenous. Recently, oral administration of interferons has been shown to cause a suppression of peripheral white blood cell (WBC) counts. Moreover, orally administered interferons mediate their peripheral WBC suppression via a different mechanism than that of intraperitoneally administered interferons. This study extends the previous studies to show that the peripheral WBC suppression induced by oral interferon treatment reflects an actual bone marrow suppression. The bone marrow-suppressive effects of orally and subcutaneously administered recombinant human IFN-alpha A/D (rHuIFN-alpha A/D) have been partially characterized in kinetics studies and compared with the peripheral WBC-suppressive effects of orally and subcutaneously administered rHuIFN-alpha A/D. Oral and subcutaneous administrations of rHuIFN-alpha A/D cause a significant suppression of peripheral WBC counts with 1 day of rHuIFN-alpha A/D administration. This suppression reaches its maximum level with 3 days of rHuIFN-alpha A/D administration and plateaus over a 12-day treatment time. Similarly, oral and subcutaneous administrations of rHuIFN-alpha A/D cause a significant suppression of bone marrow function with 1 day of rHuIFN-alpha A/D administration. This suppression reaches its maximum level with 3 days of rHuIFN-alpha A/D administration and plateaus over a 12-day treatment time. Thus, the WBC-suppressive and bone marrow-suppressive effects of rHuIFN-alpha A/D administered either orally or subcutaneously parallel each other. The peripheral WBC-suppressive activities of orally and subcutaneously administered rHuIFN-alpha A/D diminish at the same rate, after cessation of rHuIFN-alpha A/D treatment. Peripheral WBC suppression is lost by 5 days after cessation of rHuIFN-alpha A/D treatment. The mechanisms by which orally and subcutaneously administered interferons exert their bone marrow-suppressive effects differ, however. Bone marrow suppression mediated by subcutaneous administration of murine IFN-alpha/beta (MuIFN-alpha/beta) is blocked by the presence of circulating antibodies to MuIFN-alpha/beta. In contrast, the bone marrow suppression mediated by oral administration of MuIFN-alpha/beta occurs even in the presence of circulating antibodies to MuIFN-alpha/beta. These results continue to support a potential clinical role for oral administration of interferons, particularly for the control of diseases of myelogenous origin.

Interferons (IFN) have been approved for a number of clinical uses. The accepted routes of administration are intramuscular, subcutaneous, and intravenous. Recently, interferons administered by the oral route have been shown to exert a systemic effect. Oral administrations of IFN-alpha, IFN-beta, and IFN-gamma have been shown to cause a suppression of the peripheral white blood cell (WBC) count in mice. This study investigates the mechanism by which this suppression occurs. The results show that, in contrast to their intraperitoneal administration, oral administration of rHuIFN-alpha A/D or rMuIFN-gamma does not result in the presence of detectable levels of interferons in the blood. In addition, although the presence of circulating specific antibody to interferon blocks the peripheral WBC suppressive effects of intraperitoneally administered MuIFN-beta or rMuIFN-gamma, the presence of those antibodies does not block the peripheral WBC suppressive effects of the orally administered interferons. The peripheral WBC suppressive effect of orally administered rHuIFN-alpha A/D and rMuIFN-gamma can be transferred by injection of blood from oral interferon-treated donor mice to recipient mice. Recipient mice receiving plasma from donor mice showed no peripheral WBC suppression. Recipient mice receiving blood cells from donor mice showed significant peripheral WBC suppression. No effect of orally administered rHuIFN-alpha A/D on the relative percentages of lymphocytes, neutrophils, and monocytes was noted. These results indicate that the mechanism by which orally administered interferons exert their WBC suppressive effect differs from that of intraperitoneally administered interferons. WBC suppression resulting from orally administered interferons may involve cell to cell transfer of the interferons' effects, rather than the systemic distribution of the interferons in the blood. These studies further suggest that there may be a role for oral administration as a new route of interferon administration and provide a glimpse into the mechanism by which the orally administered interferons exert their systemic effects.

We lay out a comprehensive physics case for a future high-energy muon collider, exploring a range of collision energies (from 1 to 100 TeV) and luminosities. We highlight the advantages of such a collider over proposed alternatives. We show how one can leverage both the point-like nature of the muons themselves as well as the cloud of electroweak radiation that surrounds the beam to blur the dichotomy between energy and precision in the search for new physics. The physics case is buttressed by a range of studies with applications to electroweak symmetry breaking, dark matter, and the naturalness of the weak scale. Furthermore, we make sharp connections with complementary experiments that are probing new physics effects using electric dipole moments, flavor violation, and gravitational waves. An extensive appendix provides cross section predictions as a function of the center-of-mass energy for many canonical simplified models., 105 pages, 41 figures, 5 tables

Monoclonal antibodies (mAbs) against prion proteins (PrPs) are indispensable in research and diagnosis of prion diseases, however the majority of these bind both the cellular (PrP(C)) and the disease-associated (PrP(Sc)) isoforms. According to the widely accepted protein-only hypothesis the two isoforms share the same sequence, but differ in their conformation. In the present study we set to determine the critical binding residues of our PrP(Sc)-specific mAbs with the view of discerning which residues play a key role in the conformational transition between PrP(C) and PrP(Sc). Focussing on the V5B2 mAb that provided differential labelling of prion-affected tissue from individuals positive for transmissible spongiform encephalopathies, we performed alanine scanning and phage-display epitope mapping to elucidate the antigenic determinants of this mAb and gain insight into its specificity on a molecular level. We observed that instead of discriminating between the two prion protein isoforms based on conformational differences, V5B2 binds a previously uncharacterized C-terminally truncated form of PrP(Sc) that ends with the residue Y226, which we named PrP226*. The addition of a single C-terminal amino-acid residue completely abolished V5B2 binding, while Western blots using recombinant full-length PrPs and PrPs terminating at Y226 confirmed that the V5B2 mAb discriminates between the two based on their difference in length.