In view of the increasing complexity of both cardiovascular implantable electronic devices (CIEDs) and patients in the current era, practice guidelines, by necessity, have become increasingly specific. This document is an expert consensus statement that has been developed to update and further delineate indications and management of CIEDs in pediatric patients, defined as ≤21 years of age, and is intended to focus primarily on the indications for CIEDs in the setting of specific disease categories. The document also highlights variations between previously published adult and pediatric CIED recommendations and provides rationale for underlying important differences. The document addresses some of the deterrents to CIED access in low- and middle-income countries and strategies to circumvent them. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by class of recommendation and level of evidence. Several questions addressed in this document either do not lend themselves to clinical trials or are rare disease entities, and in these instances recommendations are based on consensus expert opinion. Furthermore, specific recommendations, even when supported by substantial data, do not replace the need for clinical judgment and patient-specific decision-making. The recommendations were opened for public comment to Pediatric and Congenital Electrophysiology Society (PACES) members and underwent external review by the scientific and clinical document committee of the Heart Rhythm Society (HRS), the science advisory and coordinating committee of the American Heart Association (AHA), the American College of Cardiology (ACC), and the Association for European Paediatric and Congenital Cardiology (AEPC). The document received endorsement by all the collaborators and the Asia Pacific Heart Rhythm Society (APHRS), the Indian Heart Rhythm Society (IHRS), and the Latin American Heart Rhythm Society (LAHRS). This document is expected to provide support for clinicians and patients to allow for appropriate CIED use, appropriate CIED management, and appropriate CIED follow-up in pediatric patients.

ABSTRACT IMPACT: We compare the cost-effectiveness of treatments for early prostate cancer, and propose how to maximize the value of care within an increasingly cost-constrained healthcare climate. OBJECTIVES/GOALS: Each year 192,000 men in the United States are diagnosed with prostate cancer. With various treatment options available, there is a growing role for cost-effectiveness analyses which may help maximize the value of care to the patient. In this review we compare the cost-effectiveness of primary treatments for clinically localized prostate cancer. METHODS/STUDY POPULATION: In this systematic review we aim to compare the cost-effectiveness or cost-utility of primary treatment strategies for clinically localized prostate cancer. This review, which adheres to 2009 PRISMA guidelines, included studies of men with clinically localized prostate cancer comparing at least two treatment strategies using the incremental cost-effectiveness ratio (ICER). We included analyses only of the United States healthcare system with at least 10 years of follow-up. These studies were published from 2006 to 2019 and generally included men with low or low to intermediate risk prostate cancer. Most studies reported outcomes for men age 65-70. All studies were prospective simulated trials and used a Markov model to simulate patient outcomes. RESULTS/ANTICIPATED RESULTS: Ten articles were included in the analysis. All studies used a Markov model to simulate a randomized trial. Six studies primarily compared radiation modalities, and four compared observation with immediate treatment. There was substantial heterogeneity in treatment protocols and the patients being simulated. Sensitivity analyses showed these models to be influenced by utility values and length of follow-up. A meta-analysis was not possible as no studies reported the variance of the primary outcome. Heterogeneity in study design limited comparisons of treatments across studies. However, these models were sensitive to patient-specific clinical factors, including life expectancy and the utility during and after each treatment. DISCUSSION/SIGNIFICANCE OF FINDINGS: These studies indicate collectively that the cost-effectiveness of prostate cancer treatment for similarly staged men may be heavily impacted by comorbidities and personal preferences. As the US moves towards value-based care, patient preferences may continue to drive the preferred treatment for newly diagnosed prostate cancer.

ABSTRACT IMPACT: Urine tumor DNA non-invasively detects minimal residual disease and infers tumor mutational burden in locally advanced bladder cancer prior to radical cystectomy, which may potentially enable the selection of patients for bladder-sparing treatment or facilitate personalized adjuvant immunotherapy. OBJECTIVES/GOALS: Standard-of-care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy. The inability to assess minimal residual disease (MRD) non-invasively limits our ability to offer bladder-sparing treatment. We sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. METHODS/STUDY POPULATION: We applied uCAPP-Seq, a targeted sequencing method for detecting utDNA, to urine cell-free DNA samples acquired on the day of radical cystectomy from 42 patients with bladder cancer. utDNA variant-calling was performed non-invasively without prior tumor mutational knowledge. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. Tumor mutational burden (TMB) was inferred from the number of non-silent mutations detected in urine cell-free DNA by applying a linear relationship derived from TCGA whole exome sequencing of 409 MIBC tumors. RESULTS/ANTICIPATED RESULTS: utDNA levels were significantly higher in patients with residual disease detected in their surgical pathology compared to those who achieved a pathologic complete response (P = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD significantly predicted the absence of pathologic complete response with a sensitivity of 81% and specificity of 81%. Positive utDNA MRD also portended significantly worse progression-free survival (HR = 7.4; P = 0.03) compared to negative utDNA MRD. Furthermore, we applied a linear relationship (Pearson r = 0.84; P < 0.0001) to identify patients with high inferred TMB who may have been candidates for early immune checkpoint blockade. DISCUSSION/SIGNIFICANCE OF FINDINGS: utDNA MRD analysis prior to surgery correlated significantly with pathologic response and progression-free survival, which may help select patients for bladder-sparing treatment. utDNA can also non-invasively infer TMB, which could facilitate personalized adjuvant therapy for patients in the future.

Whether monozygotic (MZ) and dizygotic (DZ) twins differ from each other in a variety of phenotypes is important for genetic twin modeling and for inferences made from twin studies in general. We analyzed whether there were differences in individual, maternal and paternal education between MZ and DZ twins in a large pooled dataset. Information was gathered on individual education for 218,362 adult twins from 27 twin cohorts (53% females; 39% MZ twins), and on maternal and paternal education for 147,315 and 143,056 twins respectively, from 28 twin cohorts (52% females; 38% MZ twins). Together, we had information on individual or parental education from 42 twin cohorts representing 19 countries. The original education classifications were transformed to education years and analyzed using linear regression models. Overall, MZ males had 0.26 (95% CI [0.21, 0.31]) years and MZ females 0.17 (95% CI [0.12, 0.21]) years longer education than DZ twins. The zygosity difference became smaller in more recent birth cohorts for both males and females. Parental education was somewhat longer for fathers of DZ twins in cohorts born in 1990–1999 (0.16 years, 95% CI [0.08, 0.25]) and 2000 or later (0.11 years, 95% CI [0.00, 0.22]), compared with fathers of MZ twins. The results show that the years of both individual and parental education are largely similar in MZ and DZ twins. We suggest that the socio-economic differences between MZ and DZ twins are so small that inferences based upon genetic modeling of twin data are not affected.

The recently developed three-dimensional electron microscopic (EM) method of serial block-face scanning electron microscopy (SBEM) has rapidly established itself as a powerful imaging approach. Volume EM imaging with this scanning electron microscopy (SEM) method requires intense staining of biological specimens with heavy metals to allow sufficient back-scatter electron signal and also to render specimens sufficiently conductive to control charging artifacts. These more extreme heavy metal staining protocols render specimens light opaque and make it much more difficult to track and identify regions of interest (ROIs) for the SBEM imaging process than for a typical thin section transmission electron microscopy correlative light and electron microscopy study. We present a strategy employing X-ray microscopy (XRM) both for tracking ROIs and for increasing the efficiency of the workflow used for typical projects undertaken with SBEM. XRM was found to reveal an impressive level of detail in tissue heavily stained for SBEM imaging, allowing for the identification of tissue landmarks that can be subsequently used to guide data collection in the SEM. Furthermore, specific labeling of individual cells using diaminobenzidine is detectable in XRM volumes. We demonstrate that tungsten carbide particles or upconverting nanophosphor particles can be used as fiducial markers to further increase the precision and efficiency of SBEM imaging.

In the lead-up to the Square Kilometre Array (SKA) project, several next-generation radio telescopes and upgrades are already being built around the world. These include APERTIF (The Netherlands), ASKAP (Australia), e-MERLIN (UK), VLA (USA), e-EVN (based in Europe), LOFAR (The Netherlands), MeerKAT (South Africa), and the Murchison Widefield Array. Each of these new instruments has different strengths, and coordination of surveys between them can help maximise the science from each of them. A radio continuum survey is being planned on each of them with the primary science objective of understanding the formation and evolution of galaxies over cosmic time, and the cosmological parameters and large-scale structures which drive it. In pursuit of this objective, the different teams are developing a variety of new techniques, and refining existing ones. To achieve these exciting scientific goals, many technical challenges must be addressed by the survey instruments. Given the limited resources of the global radio-astronomical community, it is essential that we pool our skills and knowledge. We do not have sufficient resources to enjoy the luxury of re-inventing wheels. We face significant challenges in calibration, imaging, source extraction and measurement, classification and cross-identification, redshift determination, stacking, and data-intensive research. As these instruments extend the observational parameters, we will face further unexpected challenges in calibration, imaging, and interpretation. If we are to realise the full scientific potential of these expensive instruments, it is essential that we devote enough resources and careful study to understanding the instrumental effects and how they will affect the data. We have established an SKA Radio Continuum Survey working group, whose prime role is to maximise science from these instruments by ensuring we share resources and expertise across the projects. Here we describe these projects, their science goals, and the technical challenges which are being addressed to maximise the science return.

The challenges associated with meeting 20nm technology requirements for better Cu CMP process uniformity and lower defectivity have been studied. Required improvements in uniformity were obtained through platen process optimization along with evaluation & selection of specific Cu slurries and pads and their performance reported. The principal factors influencing defect formation, including Cu barrier metallurgy, interconnect pattern density and process queue times were studied. Specific new post CMP clean chemistries were evaluated to assess their capability to suppress defect formation and their performance reported. The trade off between uniformity and defect suppression as a function slurry, pad and post Cu CMP clean chemistry is described.

Detailed understanding of growth termination in vertically aligned single-walled carbon nanotubes (SWNTs) made via supergrowth, or water-assisted growth, remains critical to achieving the ultralong SWNTs necessary for next-generation applications. We describe the irreversible catalyst morphology evolution that occurs during growth, and which limits the lifetime of surface supported catalysts. Growth termination is strongly dependent on growth temperature, but not sensitive to C2H2:H2O ratio. In addition to both planar Ostwald ripening of small (sub-5 nm) Fe catalyst particles and diffusion of metal atoms into the alumina support, other features that contribute to growth termination or deceleration are described, including center-of-mass particle motions and coalescence of smaller species of surface supported Fe nanoparticles. Additionally, a temperature-induced structural transition in the alumina catalyst support is found to be coincident with abrupt growth termination at temperatures of 800 °C and higher. In situ electron microscopy observations are used to directly support these observations.