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Background Early cancer detection could identify tumors at a time when outcomes are superior and treatment is less morbid. This prospective case-control sub-study (from NCT02889978 and NCT03085888) assessed the performance of targeted methylation analysis of circulating cell-free DNA (cfDNA) to detect and localize multiple cancer types across all stages at high specificity. Participants and methods The 6689 participants [2482 cancer (>50 cancer types), 4207 non-cancer] were divided into training and validation sets. Plasma cfDNA underwent bisulfite sequencing targeting a panel of >100 000 informative methylation regions. A classifier was developed and validated for cancer detection and tissue of origin (TOO) localization. Results Performance was consistent in training and validation sets. In validation, specificity was 99.3% [95% confidence interval (CI): 98.3% to 99.8%; 0.7% false-positive rate (FPR)]. Stage I–III sensitivity was 67.3% (CI: 60.7% to 73.3%) in a pre-specified set of 12 cancer types (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile-duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach), which account for ∼63% of US cancer deaths annually, and was 43.9% (CI: 39.4% to 48.5%) in all cancer types. Detection increased with increasing stage: in the pre-specified cancer types sensitivity was 39% (CI: 27% to 52%) in stage I, 69% (CI: 56% to 80%) in stage II, 83% (CI: 75% to 90%) in stage III, and 92% (CI: 86% to 96%) in stage IV. In all cancer types sensitivity was 18% (CI: 13% to 25%) in stage I, 43% (CI: 35% to 51%) in stage II, 81% (CI: 73% to 87%) in stage III, and 93% (CI: 87% to 96%) in stage IV. TOO was predicted in 96% of samples with cancer-like signal; of those, the TOO localization was accurate in 93%. Conclusions cfDNA sequencing leveraging informative methylation patterns detected more than 50 cancer types across stages. Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies.

Background: This study assessed the checkpoint kinase 1 inhibitor prexasertib in patients with extensive-stage small-cell lung cancer (ED-SCLC). Patients and Methods: This was a parallel-cohort phase II study of 105 mg/m2 prexasertib once every 14 days for patients who progressed after no more than two prior therapies and had platinum-sensitive (Cohort 1) or platinum-resistant/platinum-refractory (Cohort 2) disease. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Exploratory endpoints included biomarker identification and assessment of an alternative regimen (Cohort 3: 40 mg/m2 days 1-3, 14-day cycle). Results: In Cohort 1 (n = 58), ORR was 5.2%; DCR, 31%; median PFS, 1.41 months (95% confidence interval [CI], 1.31-1.64); and median OS, 5.42 months (95% CI, 3.75-8.51). In Cohort 2 (n = 60), ORR was 0%; DCR, 20%; median PFS, 1.36 months (95% CI, 1.25-1.45); and median OS, 3.15 months (95% CI, 2.27-5.52). The most frequent all-grade, related, treatment-emergent adverse events were decreased neutrophil count (Cohort 1, 69.6%; Cohort 2, 73.3%), decreased platelet count (Cohort 1, 51.8%; Cohort 2, 50.0%), decreased white blood cell count (Cohort 1, 28.6%; Cohort 2, 40.0%), and anemia (Cohort 1, 39.3%; Cohort 2, 28.3%). Eleven patients (19.6%) in Cohort 1 and one patient (1.7%) in Cohort 2 experienced grade ?3 febrile neutropenia. Prexasertib pharmacokinetics were consistent with prior studies. Cohort 3 outcomes were similar to those of Cohorts 1 and 2. No actionable biomarkers were identified. Conclusion: Prexasertib did not demonstrate activity to warrant future development as monotherapy in ED-SCLC. © 2021 The Authors Boehringer Ingelheim; Amgen; Bristol-Myers Squibb; Eli Lilly and Company; Pfizer; Astellas Pharma US; AstraZeneca; Merck; Novartis; Roche; AbbVie; University of Michigan; Takeda Pharmaceuticals U.S.A.; Merck Sharp and Dohme; PTC Therapeutics; TG Therapeutics; NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research; Bayer Fund; National Institute for Health Research; European Commission; Daiichi-Sankyo; Oryzon Genomics; Otsuka Pharmaceutical; UCLH Biomedical Research Centre We thank the patients who participated in this trial and the study coordinators, nurses, nurse practitioners, clinical research assistants, and doctors who assisted with the research. The authors also thank Erin Wagner from BioStat Solutions, Inc., for statistical support and Lisa Golden, Rod Decker, and Elizabeth Spoljoric for their input and contributions to the study. MDF is supported by the University College London/University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre and runs early phase studies in the NIHR UCLH Clinical Research Facility supported by the University College London Experimental Cancer Medicine Centre. Eli Lilly and Company contracted with Syneos Health for writing support provided by Andrea D. Humphries, PhD, and editing support provided by Noelle Gasco. L.A. Byers reports receiving research funding and fees as an advisor or consultant from AstraZeneca, GenMab, and Sierra Oncology; research funding from Tolero Pharmaceuticals; and fees as an advisor or consultant from Bristol Myers Squibb, Althia, Merck, Pfizer, PharmaMar, AbbVie, Jazz Pharmaceuticals, Genentech, and Debiopharm Group. A. Navarro reports receiving fees as an advisor or consultant from Pfizer and Boehringer Ingelheim; fees from Roche and AstraZeneca speakers’ bureaus; fees for expert testimony from Oryzon Genomics and MedSIR; and fees or reimbursement for travel, accommodations, or other expenses from Roche, Pfizer, and Boehringer Ingelheim. M. Johnson reports grant funding to her institution from Eli Lilly and Company, Abbvie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, EMD Serono, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Hengrui Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Merck, Mirati Therapeutics, Neovia Onclogy, Novartis, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Regeneron Pharmaceuticals, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, TMUNITY Therapeutics, University of Michigan, and WindMIL; receiving fees for consulting services from Eli Lilly and Company, Abbvie, Amgen, AstraZeneca, Atreca, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Daiichi Sankyo, EMD Serono, Genentech/Roche, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Incyte, Janssen, Loxo Oncology, Merck, Mirati Therapeutics, Novartis, Pfizer, Ribon Therapeutics, Sanofi, WindMIL, Achilles Therapeutics, Bristol Myers Squibb, Eisai, G1 Therapeutics, and Association of Community Cancer Centers; and receiving fees for consulting services performed by her spouse from Astellas and Otsuka Pharmaceuticals. K.H. Dragnev reports funding to the institution for the conduct of the trial from Eli Lilly and Company and support to the institution for conduct of company-sponsored trials from Merck, Roche/Genentech, G1 Therapeutics, Io Therapeutics, and Novartis. S. McNeely reports receiving personal fees and non-financial support from Eli Lilly and Company. A.B. Lin and spouse are both employees and shareholders of Eli Lilly and Company. M. Forster reports receiving educational grants from Merck Sharp & Dohme for the EACH study and the POPPY study, from Boehringer Ingelheim for the DARWIN1 study, and from AstraZeneca for the ORCA2 study, as well as fees for advisory and consultancy work from Achilles, AstraZeneca, Bristol Myers Squibb, Merck, Nanobiotix, Novartis, Pfizer, Pharmamar, Roche, Takeda, Bayer, and Guardant Advisory. The remaining authors have stated that they have no conflicts of interest.

Motivation Cell-free nucleic acid (cfNA) sequencing data require improvements to existing fusion detection methods along multiple axes: high depth of sequencing, low allele fractions, short fragment lengths and specialized barcodes, such as unique molecular identifiers. Results AF4 was developed to address these challenges. It uses a novel alignment-free kmer-based method to detect candidate fusion fragments with high sensitivity and orders of magnitude faster than existing tools. Candidate fragments are then filtered using a max-cover criterion that significantly reduces spurious matches while retaining authentic fusion fragments. This efficient first stage reduces the data sufficiently that commonly used criteria can process the remaining information, or sophisticated filtering policies that may not scale to the raw reads can be used. AF4 provides both targeted and de novo fusion detection modes. We demonstrate both modes in benchmark simulated and real RNA-seq data as well as clinical and cell-line cfNA data. Availability and implementation AF4 is open sourced, licensed under Apache License 2.0, and is available at: https://github.com/grailbio/bio/tree/master/fusion.

Background Cigarette smoking is a major risk factor for cancer and other diseases. While smoking induces chronic inflammation and aberrant immune responses, the effects of smokeless tobacco products (STPs) on immune responses is less clear. Here we evaluated markers related to immune regulation in smokers (SMK), moist snuff consumers (MSC) and non-tobacco consumers (NTC) to better understand the effects of chronic tobacco use. Materials and methods Several markers associated with immune regulation were measured in peripheral blood mononuclear cells (PBMCs) from SMK (n = 40), MSC (n = 40), and NTC (n = 40) by flow cytometry. Results Relative to NTC, seven markers were significantly suppressed in SMK, whereas in MSC, only one marker was significantly suppressed. In a logistic regression model, markers including granzyme B+ lymphocytes, perforin+ lymphocytes, granzyme B+ CD8+T cells, and KLRB1+ CD8+ T cells remained as statistically significant predictors for classifying the three cohorts. Further, cell-surface receptor signaling pathways and cell–cell signaling processes were downregulated in SMK relative to MSC; chemotaxis and LPS-mediated signaling pathways, were upregulated in SMK compared to MSC. A network of the tested markers was constructed to visualize the immunosuppression in SMK relative to MSC. Conclusion Moist snuff consumption is associated with significantly fewer perturbations in inflammation and immune function biomarkers relative to smoking. Impact This work identifies several key immunological biomarkers that differentiate the effects of chronic smoking from the use of moist snuff. Additionally, a molecular basis for aberrant immune responses that could render smokers more susceptible for infections and cancer is provided.

We present a novel algorithm for view synthesis that utilizes a soft 3D reconstruction to improve quality, continuity and robustness. Our main contribution is the formulation of a soft 3D representation that preserves depth uncertainty through each stage of 3D reconstruction and rendering. We show that this representation is beneficial throughout the view synthesis pipeline. During view synthesis, it provides a soft model of scene geometry that provides continuity across synthesized views and robustness to depth uncertainty. During 3D reconstruction, the same robust estimates of scene visibility can be applied iteratively to improve depth estimation around object edges. Our algorithm is based entirely on O(1) filters, making it conducive to acceleration and it works with structured or unstructured sets of input views. We compare with recent classical and learning-based algorithms on plenoptic lightfields, wide baseline captures, and lightfield videos produced from camera arrays.

PurposeImmune checkpoint inhibition (ICI) therapy has improved patient outcomes in advanced non-small cell lung cancer (NSCLC), but better biomarkers are needed. A clinically validated, blood-based proteomic test, or host immune classifier (HIC), was assessed for its ability to predict ICI therapy outcomes in this real-world, prospectively designed, observational study.Materials and methodsThe prospectively designed, observational registry study INSIGHT (Clinical Effectiveness Assessment of VeriStrat® Testing and Validation of Immunotherapy Tests in NSCLC Subjects) (NCT03289780) includes 35 US sites having enrolled over 3570 NSCLC patients at any stage and line of therapy. After enrolment and prior to therapy initiation, all patients are tested and designated HIC-Hot (HIC-H) or HIC-Cold (HIC-C). A prespecified interim analysis was performed after 1-year follow-up with the first 2000 enrolled patients. We report the overall survival (OS) of patients with advanced stage (IIIB and IV) NSCLC treated in the first-line (ICI-containing therapies n=284; all first-line therapies n=877), by treatment type and in HIC-defined subgroups.ResultsOS for HIC-H patients was longer than OS for HIC-C patients across treatment regimens, including ICI. For patients treated with all ICI regimens, median OS was not reached (95% CI 15.4 to undefined months) for HIC-H (n=196) vs 5.0 months (95% CI 2.9 to 6.4) for HIC-C patients (n=88); HR=0.38 (95% CI 0.27 to 0.53), pConclusionBlood-based HIC proteomic testing provides clinically meaningful information for immunotherapy treatment decision in NSCLC independent of PD-L1. The data suggest that HIC-C patients should not be treated with ICI alone regardless of their PD-L1 expression.

Introduction: Central venous catheters (CVC) are often required in critical care settings to provide life-sustaining care. Their usage has improved the quality of care in pediatric patients by providing a secure point of access which minimizes the number of peripheral needle sticks. However, CVC usage is not without risks. Children can experience acute CVC-related complications such as venous thromboembolisms (VTEs) and infections. Over the past 20 years, CVC utilization has increased and its associated complications (VTE, central line associated blood stream infection [CLABSI], catheter dysfunction) result in increased lengths of stay and hospital costs. Clinical studies identify CVCs as the single most important risk for DVT in children. Incidence rates in critically-ill children are widely divergent with historical rates of 2.7-18% and 24.7-32.5 per 1000 catheter days. In addition, other historical rates for another CVC-related complication, CLABSI, are limited but demonstrate a rate of 1.21-6.5% and 14.4 per 1000 catheter days. Prevention of catheter-related thrombosis with prophylactic anticoagulants, such as unfractionated heparin, low molecular weight heparin or warfarin, have been tested in several studies in specific subgroups of patients and the majority of studies in pediatric populations were not able to clearly demonstrate a benefit. Despite this, nearly 50% of surveyed Pediatric Intensive Care Unit (PICUs) utilize various forms and doses of heparin prophylaxis to prevent CVC-associated complications. The Penn State Health Children's Hospital PICU utilizes low dose unfractionated heparin infusions (LDUFHI) at 5-15 units/kg/hr for catheter patency and for the prevention of CVC associated complications. Methods: A retrospective chart review of all CVCs, which include non-tunneled CVC (NT-CVC), tunneled lines (TL) and peripherally inserted central catheters (PICC), utilized in the PICU at The Penn State Health Children's Hospital in 2015 was performed to determine if the usage of LDUFHI in critically ill children to maintain catheter patency results in a lower incidence of VTE and CLABSI without increasing bleeding complications in comparison to historically reported data (Beck et al.,J Pediatr. 1998;133(2):237-241; Faustino et al.,J Pediatr. 2013;162(2):387-391; Krishnaiah et al.,Pediatr Crit Care Med. 2012;13(3):e176-e180.). Results: We identified 178 subjects who had CVC which received LDUFHI in 2015. There were a total of 228 CVCs with the majority being non-tunneled CVCs (54%) followed by tunneled lines (34%) and PICCs (12%). Combined, these catheters resulted in 2086 days of use. There was a total of 5 VTEs events for an overall incidence rate of 2.19% and 2.39 per 1000 catheter days. NT-CVC had the lowest rate (1.63%) followed by TL (2.56%) and PICCs (3.7%). However, PICCs has a slightly lower rate when measuring by catheter days (NT-CVC = 2.2 per 1000 catheter days; TL = 4.01 per 1000 catheter days; PICC = 1.46 per 1000 catheter days). There were 3 CLABSI events for an incidence rate of 1.32% and 1.43 per 1000 catheter days (NT-CVC = 1.63% and 2.2 per 1000 catheter days; TL no events; PICC = 3.7% and 1.46 per 1000 catheter days). There were no episodes of heparin induced thrombocytopenia or major bleeding. Overall, the VTE and CLABSI incidence rates are dramatically lower than historical comparisons (VTE = 2.19% and 2.39 per 1000 catheter days versus 15.8-18% and 24.7-32.5 per 1000 catheter days; CLABSI = 1.32% and 1.43 per 1000 catheter days versus 6.5% and 14.4 per 1000 catheter days). In addition, this study can offer more accurate rates as incidence was also measured as a factor in catheter days. Conclusion: This study used a single tertiary pediatric intensive care site in a non-randomized fashion. These data suggest an overall lower incidence of catheter related VTE and CLABSI in critically-ill children who received LDUFHI when compared to published with comparable pediatric study populations. The incidence of complications such as CLABSI were also lower with LDUFHI usage when compared to published data involving critically ill children. The incidence rates were even lower than recently published data involving non-critically ill children. These findings suggest that a multicenter randomized study should be pursued. Disclosures No relevant conflicts of interest to declare.

Motivation. A blood-based proteomic host immune classifier (HIC) that identifies a patient's disease state as Hot or Cold can aid prognostication and help guide treatment decisions in non-small cell lung cancer (NSCLC). The HIC Hot label is associated with 2-2.5 times longer overall survival (OS) depending on treatment type. While pretreatment HIC labels are informative, label flips over the course of therapy have been observed. We sought to quantify the prevalence of label flips, determine their impact on prognosis, and investigate the utility of longitudinal testing to monitor changes in disease state throughout therapy. Methods. In a real-world observational study (NCT03289780) enrolling over 3,700 patients with NSCLC at any stage and line of therapy to date, 267 of 1464 patients with advanced (Stage 3b/4) NSCLC with at least 1 year follow-up (f/u) had longitudinal testing at first f/u. Patient disease states were designated HH (Hot baseline and f/u), HC (Hot baseline, Cold f/u), CH (Cold baseline, Hot f/u) or CC (Cold baseline and f/u). Results. For patients receiving all therapy lines and regimens, 38 of 209 patients with baseline Hot test result (18%) flipped to Cold (HC), whereas 28 of 58 patients with baseline Cold, (48%) flipped (CH) (table). Patients with a baseline Hot result (HH+HC) had significantly longer OS compared to baseline Cold (CH+CC). Comparing patient groups based on f/u result (HH+CH vs. HC+CC) yielded an even greater separation. Similar trends were observed in the subgroup of patients receiving chemotherapy (n=124), with 18 patients flipping from Hot to Cold (20%), and 12 from Cold to Hot (36%) at f/u. Average time to f/u (TTF) was 6 months and did not vary significantly between groups. Conclusions. For some patients with NSCLC, disease states and prognosis can change in response to therapy. Longitudinal proteomic testing may be a viable method to monitor changes in disease state and host immune response to guide treatment. Survival of study subjectsGroupmOS [95% CI], monthsMean TTF (SD) [95% CI], monthsTotal (N=267)6.12 (3.70) [5.67-6.56]HH (N=171)NR [17.0-und]5.65 (3.50) [4.01-7.29]HC (N=38)11.6 [9.2-und]5.94 (3.31) [4.86-7.03]CH (N=20)NR [11.6-und]6.30 (3.91) [5.71-6.89]CC (N=38)10.2 [7.9-17.4]5.71 (3.19) [4.67-6.76]Total (N=267)HR [95% CI]P valueHH vs. HC1.81 [1.11-2.96]0.018HH vs. CH1.03 [0.47-2.24]0.946HH vs. CC2.56 [1.60-4.10] Citation Format: Eric Schaefer, R. Brian Mitchell, Jason Boyd, James Orsini, Nagaprasad Nagajothi, Savita Bidyasar, Mazen Khalil, Mitchell Haut, Ray Page, Kan Huang, John W. Dubay, Wallace Akerley. Longitudinal blood-based proteomic testing in advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 662.

1526 Background: Remote symptom monitoring of patients receiving cancer treatment has been shown to improve patient outcomes in the research setting. However, there is little evidence that this technology can be implemented and scaled in the real world with the same benefits. Methods: Highlands Oncology Group (HOG) is a 19 physician medical oncology group in Northwest Arkansas. Beginning in June 2020, HOG offered patients receiving parenteral cancer therapy enrollment onto Expain: an EMR-integrated, electronic patient-reported outcomes (ePRO) system which enables remote symptom monitoring during systemic cancer therapy. Patients reported distress and symptoms using the NCCN Distress Thermometer and Problem List instrument. The practice prospectively defined patient reporting intervals based on disease and treatment protocol, as well as thresholds for each symptom that would trigger a nursing notification. Following clinical review, nurses initiated interventions including a telephone call, urgent office visit, or referral to an emergency room when necessary. Results: From June 2020 – January 2021, HOG treated 1261 patients with IV chemotherapy. 769 patients were offered enrollment and 569 (73.9%) were successfully enrolled onto the ePRO system. At the time of enrollment 419 (73.6%) of enrolled patients were in an Oncology Care Model (OCM) episode. Common reasons for declined enrollment were: low symptom burden, non-English speaker, and approaching the end of treatment. Of enrolled patients, the most common tumor types were: gastrointestinal (21.8%), breast (17.5%), and thoracic (16.1%). Patients reported using Expain’s mobile app (89.1%) or Interactive Voice Response interface (IVR, 10.1%) with the following frequency: once a month (12%), twice a month (30%), 3 reports a month (35%), and 4 reports or more (23%); Of patients successfully enrolled 52.72% were still reporting after 3 months. The most common reasons specified for opting-out were: death, hospice admission, and completion of the treatment course. 50% of reports exceeded the practice-defined threshold for a nursing notification. The nurses initiated a follow-up call in response to 78.8% of notifications, and of these calls, 21.2% resulted in an urgent office evaluation. The most common problems triggering an office evaluation were: high NCCN Distress Thermometer score (17.1%), fatigue (16.1%), pain (11.5%), nausea (9.4%), and dyspnea (4.5%). Conclusions: ePRO-based remote monitoring of patients receiving parenteral cancer therapy in routine clinical care is feasible. Patient enrollment and retention are high across all tumor types. Symptoms reported by patients were concordant with previous publications, and a small percent (7% of reports) required an acute office visit. It is expected that office intervention will reduce the use of ER and inpatient services.

TPS3142 Background: Protein tyrosine kinase 7 (PTK7) is a highly conserved receptor tyrosine kinase involved in the Wnt signaling pathway and is overexpressed in multiple cancer types, including non-small cell lung cancer (NSCLC). Cofetuzumab pelidotin (ABBV-647) is an anti-PTK7 antibody-drug conjugate comprising the hu6MO24 monoclonal antibody, a cleavable cysteine-reactive linker, and Aur0101 (an auristatin microtubule inhibitor). It has shown promising preclinical anti-tumor effects (Damelin et al. Sci Transl Med 2017;9[372]:eaag2611) and clinical activity with a manageable safety profile in a Phase 1 study in patients with advanced solid tumors, with promising anti-tumor activity noted in NSCLC (Sachdev et al. DOI: 10.1200/JCO.2018.36.15_suppl.5565). Methods: This open-label, single-arm, multicenter Phase 1b study (NCT04189614) will assess the anti-tumor activity and safety of cofetuzumab pelidotin in approximately 40 patients with PTK7-expressing, recurrent NSCLC. The primary objective is to assess the objective response rate of cofetuzumab pelidotin according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary objectives include the duration of response, progression-free survival, overall survival, and safety and tolerability. Pharmacokinetic and biomarker samples will also be collected throughout for analysis. Patients must be aged ≥18 years with an Eastern Cooperative Oncology Group performance status of 0–1 and have recurrent histologically confirmed NSCLC with PTK7-expressing tumor (using a validated immunohistochemistry assay). Patients must have progressed after treatment with a platinum-based chemotherapy doublet and an immune checkpoint inhibitor (for tumors without targetable genetic alterations), or a platinum-based chemotherapy doublet and targeted agent(s) (for tumors with targetable genetic alterations). Patients must also have received ≤2 prior lines of systemic therapy (≤3 prior lines for tumors treated with targeted agent[s] for genetic alterations), including no more than 1 line of systemic chemotherapy. Cofetuzumab pelidotin (2.8 mg/kg) is administered intravenously every 3 weeks until the patient experiences disease progression, intolerable toxicity, or other study treatment discontinuation criteria are met. The study commenced on February 13, 2020 and enrollment is ongoing. Clinical trial information: NCT04189614.

Since its inauguration in 1966, the ACM A. M. Turing Award has recognized major contributions of lasting importance in computing. Through the years, it has become the most prestigious technical award in the field, often referred to as the "Nobel Prize of computing." During 2017, ACM celebrated 50 years of the Turing Award and the visionaries who have received it. The aim was to highlight the significant impact of the contributions of the Turing Laureates on computing and society, to look ahead to the future of technology and innovation, and to help inspire the next generation of computer scientists to invent and dream.

While Hail, Caesar! written, directed, and produced by Ethan and Joel Coen initially appears to be merely a light satire of classic Hollywood of the 40s and 50s, it also comments upon several kinds...

Room temperature optical illumination of NV- imbibed single crystal diamonds with a 532 nm laser produces (13)C polarization enhancements up to 200 times greater than that of the thermal equilibrium value at 7.05 T. We report high field NV- mediated (13)C polarization as a function of the number and type (NV- and P1) of defects in commercially available diamonds. Surprisingly, both positive and negative (13)C polarizations are observed depending on the orientation of the crystal with respect to the external magnetic field and the electric field vector of the optical illumination. The data reported herein cannot be explained by a previously proposed mechanism.

9545 Background: Immune checkpoint inhibition (ICI) has improved outcomes for many treatment-naïve advanced non-small cell lung cancer (NSCLC) patients. However, better biomarkers are needed to predict patient response and guide treatment decisions considering added toxicity and higher cost of combination treatments. A prospectively designed, observational study assessed the ability of a clinically validated, blood-based, host immune classifier (HIC) to predict ICI therapy outcomes. Methods: The study (NCT03289780) includes 33 US sites having enrolled over 3,000 NSCLC patients at any stage and line of therapy. All enrolled patients are tested and designated HIC-Hot (HIC-H) or HIC-Cold (HIC-C) prior to therapy initiation. An interim analysis of secondary and exploratory endpoints was performed after 12- 18 months (mo) follow-up with the first 2,000 enrolled patients. We report the overall survival (OS) of HIC-defined subgroups comprising advanced stage (IIIB and higher) NSCLC patients treated with first-line regimens (284 ICI containing treatments, 877 total first-line patients). Results: In a real-world clinical setting, OS of advanced stage NSCLC treatment-naïve patients receiving platinum-based chemotherapy (n = 392) did not differ significantly from patients receiving any type of ICI containing regimen (n = 284); 11.7 mo vs. 14.4 mo; hazard ratio (HR) = 0.94 [95% confidence interval (CI): 0.76–1.17], p = 0.59. HIC-H patients experienced longer survival than HIC-C across multiple regimens, including ICI. For all ICI, median OS (mOS) was not reached for HIC-H (n = 196, CI: 15.4 mo–undefined) vs. 5.0 mo (n = 88, CI: 2.9 mo–6.4 mo) for HIC-C patients (HR = 0.38 [CI: 0.27–0.53], p < 0.0001). Similar results were seen in the ICI only (16.8 mo vs. 2.8 mo; n = 117, HR = 0.36 [CI: 0.22–0.58], p < 0.0001) and ICI/chemotherapy combination subgroups (unreached vs. 6.4 mo; n = 161, HR = 0.41 [CI: 0.26–0.67], p = 0.0003). In the PD-L1 high cohort (PD-L1 ≥50%), mOS for HIC-H was not reached (n = 81, CI: 13.9 mo–undefined) vs. 3.9 mo (n = 41, CI: 2.1 mo–7.8 mo) for HIC-C (HR: 0.39 [CI: 0.24-0.66], p = 0.0003). HIC results were independent of PD-L1 score (p = 0.81) and remained predictive of OS in first-line ICI-treated patients when adjusted for PD-L1 and other covariates by multivariate analysis (HR = 0.40 [CI: 0.28-0.58], p < 0.0001). Conclusions: Blood-based host immune profiling may provide clinically meaningful information for selecting NSCLC patients for two common ICI containing regimens independent of and complementary to PD-L1 score.

Purpose: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non–small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC. Patients and Methods: An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules. Results: The three study parts enrolled 86 patients; all received ≥1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1 and 8 ramucirumab (8 mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combination agents did not affect abemaciclib exposure. The disease control rate was 57% for patients treated with abemaciclib–pemetrexed, 25% for abemaciclib–gemcitabine, and 54% for abemaciclib–ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively. Conclusions: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies. Clin Cancer Res; 24(22); 5543–51. ©2018 AACR.

Background Spartalizumab (PDR001) is an anti-PD-1 monoclonal antibody that is been explored in different tumor types. Preliminary safety and efficacy results from Groups B (B) and C (C) of a phase Ib study investigating spartalizumab with platinum-based chemotherapy in PD-L1 unselected advanced NSCLC (NCT03064854) are reported here. Methods Treatment-naive, stage IIIB/IV NSCLC, EGFR/ALK/ROS-1(-) pts, PS 0-1, were assigned to B (non-squamous NSCLC) or C (squamous/non-squamous NSCLC) for 4 cycles (21 day/cycle) of spartalizumab (initial dose – 300 mg Q3W) + pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 followed by maintenance spartalizumab + pemetrexed (in B), or 4 cycles of spartalizumab (initial dose – 300 mg Q3W) + paclitaxel 200 mg/m2 + carboplatin AUC 6 followed by maintenance with spartalizumab (in C). Primary endpoints are recommended dose for expansion (RDE) and ORR by investigator assessment. Results At data cutoff of 15 May 2019, 38 pts in B and 33 pts in C were treated; 14 pts (36.8%) in B and 4 pts (12.1%) in C are still receiving treatment. Primary reason for discontinuation was progressive disease: 13 of 38 pts (34.2%) in B and 25 of 33 pts (75.8%) in C. DLTs were grade 4 hyponatremia and grade 2 posterior reversible encephalopathy syndrome in B (2 pts) and grade 4 neutropenic colitis in C (1 pt). RDE of spartalizumab in combination with platinum-based chemotherapy for both groups was 300 mg Q3W. Most common AEs (≥50%, any grade) were nausea (73.7%) and neutropenia (50%) in B; neutropenia (57.6%) and anemia (54.5%) in C. ORR and complete response rate were 50% and 5.3% in B, and 51.5% and 3% in C. Median DOR (months; 95% CI) by investigator assessment was 13.8 (4.9, NE) in B and 8.2 (5.1, 15.4) in C. Median PFS (months; 95% CI) by investigator assessment was 10.4 (5.4, 15.0) in B and 6.3 (4.1, 10.1) in C. Responses were observed at different PD-L1 expression levels with higher rate in PD-L1 tumor proportion score (TPS) ≥ 50%. Assessment of additional immune biomarkers is ongoing. Conclusions RDE of spartalizumab in combination with platinum-based chemotherapy is 300 mg Q3W. Safety profile and preliminary clinical activity are consistent with prior experience with spartalizumab, other immune checkpoint inhibitors and chemotherapy treatments administered. Clinical trial identification NCT03064854. Editorial acknowledgement Shiva Krishna Rachamadugu, Novartis Healthcare Pvt Ltd, Hyderabad, India. Legal entity responsible for the study Novartis Pharmaceuticals Corporation. Funding Novartis Pharmaceuticals Corporation. Disclosure A. Santoro: Advisory / Consultancy: BMS, Servier, Gilead, Pfizer, Eisai, Bayer, Msd, Arqule; Speaker Bureau / Expert Testimony: Takeda, BMS, Roche, AbbVie, Amgen, Celgene, Servier, Gilead, Astrazeneca, Pfizer, Arqule, Lilly, Sandoz, Eisai, Novartis, Bayer, MSD. P. Garrido Lopez: Advisory / Consultancy: Roche, MSD, BMS, Boerhinger Ingelheim, Pfizer, AbbVie, Guardant Health, Novartis, Lilly, AstraZeneca, Janssen, Sysmex, Blueprint Medicines, Takeda; Speaker Bureau / Expert testimony: Roche, MSD, BMS, Pfizer, Novartis, Boerhinger Ingelheim, Rovi; Research grant / Funding (institution), For Clinical Trails: Roche, MSD, BMS, Takeda, Lilly, Pfizer, Novartis, PharmaMar, Celgene, Sanofi, GSK, Theradex Oncology, BluePrint Medicines; Research grant / Funding (institution), For Contracted Research: Guardant Health, Sysmex. D.S.W. Tan: Honoraria (self): Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, Takeda ; Advisory / Consultancy: Novartis, Bayer, Boehringer Ingelheim, Celgene, AstraZeneca, Eli-lily, Loxo; Research grant / Funding (self): Novartis, AstraZeneca, GlaxoSmithKline, Bayer, Pfizer ; Travel / Accommodation / Expenses: Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche,Takeda . L. Paz-Ares: Honoraria (self): Roche, Novartis, Pfizer, Lilly, BMS, MSD, Merck, Boehringer Ing., AstraZeneca, Amgen, Sanofi, PharmaMar, Takeda; Leadership role: Genomica. F. Shepherd: Honoraria (self): Novartis, AstraZeneca, Roche, BMS, Merck, EMD Serono; Advisory / Consultancy: Novartis, AstraZeneca, Roche, BMS, Merck, EMD Serono; Shareholder / Stockholder / Stock options: AstraZeneca. A. Bearz: Advisory / Consultancy: Takeda; Boehringer Ingelheim, Roche , MSD, Novartis; Speaker Bureau / Expert testimony: Takeda; Boehringer Ingelheim, Roche , MSD; Pfizer; Research grant / Funding (institution): AstraZeneca. F. Barlesi: Honoraria (self): AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda; Research grant / Funding (institution): AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, MedImmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis; Non-remunerated activity/ies: Principal Investigator for AstraZeneca, BMS, Merck, Pierre Fabre and F. Hoffmann-La Roche, Ltd, sponsored trials (or ISR). J.F. Vansteenkiste: Honoraria (self), Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Roche, Apotex; Research grant / Funding (institution): MSD. T.M. Kim: Research grant / Funding (institution): Alpha Biopharma, AstraZeneca/MedImmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, and Yuhan ; Research grant / Funding (self): AstraZeneca ; Non-remunerated activity/ies, Advisory / Consultancy: AstraZeneca, Novartis, Sanofi, and Bayer . T.R. Overbeck: Advisory / Consultancy, Consulting fees: AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Medac, MSD, Novartis, Roche/Genentech; Research grant / Funding (institution), sponsored research agreements: AstraZeneca, Eli Lilly, Roche/Genentech, Sanofi-Aventis; Travel / Accommodation / Expenses, Travel Support: AstraZeneca, Boehringer Ingelheim, Eli Lilly and Roche/Genentech. I.I. Rybkin: Research grant / Funding (institution): Merck, AbbVie, ARMO Biosciences, Beyond Spring Pharmaceutical, Bristol-Myers Squibb, Novartis, Mirati Therapeutical Inc., Nilogen, Inc., Pfizer, Polaris Group, Syndax Inc., Xcovery Inc., BerGenBio AS, Incyte Corporation, AstraZeneca, Amgen; Advisory / Consultancy: AstraZeneca. E. Felip: Advisory / Consultancy: AbbVie, AstraZeneca, Blue Print Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Helath, Janssen, Medscape, Merck Kgaa, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Touchtime; Speaker Bureau / Expert Testimony: AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Kgaa, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda; Research Grant / Funding (Self): Fundacion Merck Salud Grant For Oncology Innovation Emd Serono. W. Zhou: Full / Part-time employment: Novartis. L. Santarpia: Full / Part-time employment: Novartis. S. Eddy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. All other authors have declared no conflicts of interest.

In this study, placing parallel-connected baffles in the vicinity of the inlet was proposed to improve hydraulic conditions for enhancing TSS (total suspended solids) removal. The purpose of the retrofit baffle design is to divide the large and fast inflow into smaller and slower flows to increase flow uniformity. This avoids short-circuiting and increases residence time in the sedimentation basin. The newly proposed parallel-connected baffle configuration was assessed in the laboratory by comparing its TSS removal performance and the optimal flow residence time with those from the widely used series-connected baffles. The experimental results showed that the parallel-connected baffles outperformed the series-connected baffles because it could disperse flow faster and in less space by splitting the large inflow into many small branches instead of solely depending on flow internal friction over a longer flow path, as was the case under the series-connected baffles. Being able to dampen faster flow before entering the sedimentation basin is critical to reducing the possibility of disturbing any settled particles, especially under high inflow conditions. Also, for a large sedimentation basin, it may be more economically feasible to deploy the proposed parallel retrofit baffle in the vicinity of the inlet than series-connected baffles throughout the entire settling basin.

In 1969, Robert E. Gregg collected five species of ants (Hymenoptera: Formicidae) in three Subarctic localities near the town of Churchill, Manitoba, Canada, which he documented in a 1972 publication in The Canadian Entomologist. To determine whether there have been any additions to the local fauna – as might be predicted to occur in response to a warming climate and increased traffic to the Port of Churchill in the intervening 40 years – we re-collected ants from the same localities in 2012. We identified the ants we collected from Gregg’s sampling sites using both traditional morphological preparations and DNA barcoding. In addition, we examined specimens from Gregg’s initial collection that are accessioned at the Field Museum of Natural History (Chicago, Illinois, United States of America). Using this integrative approach we report seven species present at the same sites Gregg sampled 40 years earlier. We conclude that the apparent increase is likely not due to any arrivals from more southerly distributed ants, but to the increased resolution provided by DNA barcodes to resident species complexes with a complicated history. We provide a brief synopsis of these results and their taxonomic context.

Spiking Neural Networks offer low precision communication, robustness, and low power consumption and are attractive for autonomous applications. One of the well accepted learning rules for these networks is spike time dependent plasticity which is governed by the pre- and postsynaptic spike timings. To stabilize the plasticity and avoid saturation in these learning rules, synaptic normalization is used. In this work, we propose a circuit to efficiently realize synaptic normalization in a neuromemristive system and show how it improves the plasticity for unsupervised on-device learning. High-level modeling shows the efficacy of synaptic normalization in pattern recognition and feature extraction.

The purpose of this study was to investigate the highest bottom shear stress, induced by wind in an area of Hamilton Harbour, Ontario, Canada known as Randle Reef. The study was conducted in support of a component of a contaminated sediment remediation plan utilizing a thin layer of sand to manage contaminated sediments. Toward this end, four acoustic Doppler current profilers (ADCPs) were deployed at two locations in the study region to measure velocity profiles for the purpose of indirectly measuring bottom shear stress (BSS) and model verification. There is no easy way to directly measure BSS in the field. As a result, the use of the logarithmic-profile method from the ADCP measured high resolution velocity profiles in the bottom layer was explored. This approach, according to our best knowledge, has not been published for a wind driven flow in a small open water body. To use the indirectly measured BSS to estimate the highest BSS in the study area, a three-dimensional hydrodynamic model was adopted to provide the spatial and temporal information of the bottom flow. The results showed that the modeled and measured flow velocity components agreed reasonably well at most of the water depths with the correlation coefficients being greater than 0.6. However, agreements between the modeled and measured bottom flow speeds were worse than expected due to the error contributions from both the modeled velocity components. Therefore, the modeled flow speed required rescaling based on ADCP velocity measurements before it could be deemed reliable. This is especially important in estimation of the BSS with a quadratic formula because the calculated BSS is proportional to the square of the speed.

Study Design: A prospective, observational case series of eighteen children with early onset scoliosis undergo spine manipulation and casting. Objective: Determine if respiratory system compliance decreases during casting warrants tracheal intubation in all Derotational casting procedures. Background: Children with early onset scoliosis with a Cobb angle greater than 25 degrees will have significant progression of their scoliosis. Surgical techniques cannot result in spine fusion as growth retardation will ensue. Serial thoracolumbar casting may correct the scoliosis or delay the need for surgery. The cast, however, is highly restrictive until the cast is appropriately cut. Does respiratory system compliance decrease a significant degree to require tracheal intubation in all Derotational casting procedures? Methods: Eighteen children (mean age: 4.5 years, mean weight: 16.9 kg) undergoing initial scoliosis casting were enrolled. Anesthesia was induced with sevoflurane in oxygen, an intravenous catheter was inserted, intravenous propofol administered and tracheal intubation performed. Baseline measurements of heart rate, blood pressure, SpO2, peak inspiratory pressure (PIP), and pulmonary compliance were made before casting, immediately after casting, and after cast cut-out. Results: PIP increased from 15.8 cm H2O to 42.6 after cast application and decreased to 20.2 after cast cut-out. Compliance decreased from 1.08 ml/cm H2O/kg to 0.21 after cast application and increased to 0.61 after cast cut-out. There were no clinically significant changes in heart rate, blood pressure, or SpO2. Conclusion: The thoracolumbar cast applied for scoliosis treatment causes severe restriction of chest wall movement and subsequent deterioration of pulmonary function. The time of severe restriction of chest wall motion is short and is relieved once cast cut-outs are performed. The marked increase in PIP and decrease in compliance that occurs during the casting process necessitates tracheal intubation.

Subperiosteal orbital hematoma is a rare occurrence, typically developing as a result of orbital trauma. The spontaneous formation of a subperiosteal orbital hematoma (sSOH) may also occur but is less frequent. To date there has been no documented cases of sSOH as the initial presentation of an unknown metastatic neoplasm to the skull. We provide a case of a woman with unknown lung adenocarcinoma that metastasized to the skull which caused the formation of a sSOH resulting in orbital compression syndrome.A 57-year-old female presented with double vision, retro-orbital right eye pain, and vision loss in the right eye. A magnetic resonance imaging revealed a right orbital compressive lesion with an adjacent supraorbital skull lesion and separate left frontal skull lesion. Intra-operative findings along with post-operative immunohistochemistry staining revealed sSOH resulting from a metastatic lung adenocarcinoma to the skull. Further metastatic work up also revealed an occult lung mass and multiple spinal lesions.Differential diagnosis of etiologies causing the formation of sSOH in an adult without history of trauma should include metastatic neoplasm to the skull and warrants metastatic workup. Treatment options of sSOH have included observation with spontaneous resolution; however, we opted for surgical decompression of the eye and biopsy of the skull mass.

Objective: To measure Irish opinion on a range of assisted human reproduction (AHR) treatments. Methods: A nationally representative sample of Irish adults (n = 1,003) were anonymously sampled by telephone survey. Results: Most participants (77%) agreed that any fertility services offered internationally should also be available in Ireland, although only a small minority of the general Irish population had personal familiarity with AHR or infertility. This sample finds substantial agreement (63%) that the Government of Ireland should introduce legislation covering AHR. The range of support for gamete donation in Ireland ranged from 53% to 83%, depending on how donor privacy and disclosure policies are presented. For example, donation where the donor agrees to be contacted by the child born following donation, and anonymous donation where donor privacy is completely protected by law were supported by 68% and 66%, respectively. The least popular (53%) donor gamete treatment type appeared to be donation where the donor consents to be involved in the future life of any child born as a result of donor fertility treatment. Respondents in social class ABC1 (58%), age 18 to 24 (62%), age 25 to 34 (60%), or without children (61%) were more likely to favour this donor treatment policy in our sample. Conclusion: This is the first nationwide assessment of Irish public opinion on the advanced reproductive technologies since 2005. Access to a wide range of AHR treatment was supported by all subgroups studied. Public opinion concerning specific types of AHR treatment varied, yet general support for the need for national AHR legislation was reported by 63% of this national sample. Contemporary views on AHR remain largely consistent with the Commission for Assisted Human Reproduction recommendations from 2005, although further research is needed to clarify exactly how popular opinion on these issues has changed. It appears that legislation allowing for the full range of donation options (and not mandating disclosure of donor identity at a stipulated age) would better align with current Irish public opinion.

This paper presents a sub-1 V CMOS bandgap voltage reference that accounts for the presence of direct tunneling-induced gate current. This current increases exponentially with decreasing oxide thickness and is especially prevalent in traditional non-high-i¾?/metal gate ultra-thin oxide CMOS technologies tox

Objective To compare serum anti-Müllerian hormone (AMH) and other endocrine parameters between patients diagnosed with polycystic ovary syndrome (PCOS) and age-matched ovulatory women. Materials and methods AMH, DHEAS, FSH, LH, PRL, TSH and total testosterone (TT) were prospectively measured in oligo-ovulatory PCOS patients (n = 595) and in ovulatory non-PCOS women (n = 157) referred to a tertiary infertility center. Mean BMI was similar across the two study populations and there were no smokers in the sample. Patients in both groups were further classified into three categories by age: < 25 yrs, 25-34 yrs, and ≥ 35 yrs. Selected clinical and demographic characteristics were tabulated for each group. Results Serum AMH was significantly higher among PCOS patients compared to non-PCOS controls in the non-stratified sample (7.54 ± 5.8 vs. 2.49 ± 2.0 ng/mL, respectively; p < 0.0001), while serum FSH, DHEAS, TSH and prolactin were similar for both groups (p > 0.05). As expected, mean (total) testosterone levels were notably different between PCOS vs. non-PCOS controls (0.84 ± 0.76 vs. 0.43 ± 0.38 ng/mL, respectively; p < 0.001), and mean AMH level was significantly lower in the oldest age category (> 35 yrs) compared to both younger control groups (p < 0.0001). Both DHEAS and total testosterone decreased with age among PCOS patients, although mean serum DHEAS for women age > 35 yrs was significantly lower than DHEAS measured in younger women with PCOS (p < 0.02). For PCOS patients, AMH remained relatively stable irrespective of age. Conclusion Although AMH can serve as a satisfactory marker of ovarian reserve, for PCOS patients the expected decline in AMH associated with reproductive aging appears attenuated despite ovarian senescence. In contrast, mean DHEAS levels were markedly lower among older PCOS women (> 35 yrs) compared to younger PCOS patients.

The unacceptable multiple gestation rate currently associated with in vitro fertilization (IVF) would be substantially alleviated if the routine practice of transferring more than one embryo were reconsidered. While transferring a single embryo is an effective method to reduce the clinical problem of multiple gestation, rigid adherence to this approach has been criticized for negatively impacting clinical pregnancy success in IVF. In general, single embryo transfer is viewed cautiously by IVF patients although greater acceptance would result from a more effective embryo selection method. Selection of one embryo for fresh transfer on the basis of chromosomal normalcy should achieve the dual objective of maintaining satisfactory clinical pregnancy rates and minimizing the multiple gestation problem, because embryo aneuploidy is a major contributing factor in implantation failure and miscarriage in IVF. The initial techniques for preimplantation genetic screening unfortunately lacked sufficient sensitivity and did not yield the expected results in IVF. However, newer molecular genetic methods could be incorporated with standard IVF to bring the goal of single embryo transfer within reach. Aiming to make multiple embryo transfers obsolete and unnecessary, and recognizing that array comparative genomic hybridization (aCGH) will typically require an additional 12 h of laboratory time to complete, we propose adopting aCGH for mainstream use in clinical IVF practice. As aCGH technology continues to develop and becomes increasingly available at lower cost, it may soon be considered unusual for IVF laboratories to select a single embryo for fresh transfer without regard to its chromosomal competency. In this report, we provide a rationale supporting aCGH as the preferred methodology to provide a comprehensive genetic assessment of the single embryo before fresh transfer in IVF. The logistics and cost of integrating aCGH with IVF to enable fresh embryo transfer are also discussed.

Nested R-groups are fundamental to patent Markush structure’s complexity, yet there have not been many recent publications in this field. We have developed a web application, called iMarVis, which provides chemists with the ability to navigate nested R-groups and study selected subsets of chemical space. In order to accurately capture R-group hierarchy, a new underlying numbering system was created. This numbering system also facilitates additional Markush structure analysis, including chemical space size calculation and enumeration. This article describes the new numbering system in detail and highlights the importance of understanding and depicting the R-group hierarchy.

We present a quantitative, systematic study of the polarization of the Zeeman magnetic sublevels of the NV-defect in diamond as a function of magnetic field alignment relative to the NV-defect axis. The orientation dependence of NV-polarization in the lab frame is accounted for by a Wigner rotation of a constant defect frame polarization. We also find that the NV-defect level polarizations vary with the P1 defect concentration, and that the polarization of the m s = 0 state with optical pumping decreases from 46% to 36% in samples as P1 concentrations vary from 20 ppm to 100 ppm, respectively.

Objective To evaluate effects of simvastatin on selected biochemical parameters and reproductive outcome among patients with polycystic ovary syndrome (PCOS) who undergo in vitro fertilization (IVF). Methods Patients with PCOS were randomized to receive either oral simvastatin, 20 mg/d (n = 32), or placebo (n = 32) in a prospective, double-blind, randomized clinical trial (NCT 005-75601) in parallel with controlled ovarian hyperstimulation for IVF. All patients were determined to be at average risk for cardiovascular disease, based on high-sensitivity C-reactive protein (hsCRP) measurement at entry. After an 8-week treatment interval concluding at periovulatory human chorionic gonadotropin administration, selected clinical and laboratory parameters were measured. Results Mean serum total testosterone level decreased by 25% in the simvastatin group, compared to a 10% reduction in the placebo group ( P < 0.001). A trend of lower serum luteinizing hormone levels was noted in experimental and control groups (29% vs 22%, respectively), although this difference was not significant ( P > 0.05). Neither fasting insulin nor quantitative insulin sensitivity check index were significantly impacted by simvastatin ( P > 0.05). As expected, total cholesterol was not modified among placebo patients but was significantly reduced after simvastatin ( P = 0.001). In addition, hsCRP and vascular cell adhesion protein-1 were both significantly lower after simvastatin therapy compared to controls ( P ≤ 0.005 for both). At study completion, no important change in body mass index was observed in either group ( P ≥ 0.60). Although oocyte maturation, fertilization, and clinical pregnancy rates were all higher after simvastatin, none of these improvements were statistically significant. Conclusions This report presents data from the first prospective, randomized, placebo-controlled clinical investigation of simvastatin in the setting of PCOS and IVF. Simvastatin seems to be compatible with gonadotropin therapy for IVF and can offer beneficial endocrine and cardiovascular effects for patients with PCOS who undergo embryo transfer. Although the observed improvements in reproductive function were mild, the reductions in hsCRP and vascular cell adhesion protein-1 after simvastatin treatment were significant, suggesting the need for further clinical trials to clarify simvastatin's impact on reproductive physiology.

Recent studies have shown that manufacturing costs and design complexities may delay the widespread use of high-κ/metal gate nanoscale CMOS technologies. This implies that traditional (non-high-κ/non-metal gate) ultra-thin oxide technologies will remain active due to economic factors for longer periods of time. Direct tunneling is a significant source of MOSFET gate current in these technologies. Its presence fundamentally alters MOSFET functionality by invalidating the simplifying design assumption of infinite gate resistance. Analog circuit solutions to its problems do not exist in the literature. This paper proposes design solutions that attempt to minimize, balance, and cancel the negative effects of direct tunneling on analog design in traditional ultra-thin oxide CMOS technologies. The proposed solutions re quire only ultra-thin oxide devices and are investigated in a 65-nm CMOS technology with a nominal VDD of 1 V and a physical oxide thickness of 1.25 nm.

Signal integrity has become a major problem in digital IC design. One cause is device scaling that results in a sharp reduction of supply voltage, creating stringent noise margin requirements to ensure functionality. This paper introduces both a novel on-chip decoupling capacitance methodology and active noise cancellation (ANC) structure. The decoupling methodology focuses on quantification and location. The ANC structure, with an area of 50 ?m × 55 ?m, uses decoupling capacitance to sense noise and inject a proportional current into VSS as a method of reduction. A chip has been designed and fabricated using TSMC's 90-nm technology. Measurements show that the decoupling methodology improved the average voltage headroom loss by 17% while the ANC structure improved the average voltage headroom loss by 18%.

The concept of ovarian reserve describes the natural oocyte endowment and is closely associated with female age, which is the single most important factor influencing reproductive outcome. Fertility potential first declines after the age of 30 and moves downward rapidly thereafter, essentially reaching zero by the mid-40s. Conceptions beyond this age are exceedingly rare, unless oocytes obtained from a younger donor are utilised. How best to estimate ovarian reserve clinically remains controversial. Passive assessments of ovarian reserve include measurement of serum follicle stimulating hormone (FSH), oestradiol (E(2)), anti-Müllerian hormone (AMH), and inhibin-B. Ultrasound determination of antral follicle count (AFC), ovarian vascularity and ovarian volume also can have a role. The clomiphene citrate challenge test (CCCT), exogenous FSH ovarian reserve test (EFORT), and GnRH-agonist stimulation test (GAST) are provocative methods that have been used to assess ovarian reserve. Importantly, a patient's prior response to gonadotropins also provides highly valuable information about ovarian function. Regarding prediction of reproductive outcome, in vitro fertilisation (IVF) experience at our centres and elsewhere has shown that some assessments of ovarian reserve perform better than others. In this report, these tests are discussed and compared; we also present practical strategies to organise screening as presently used at our institutions. Experimental challenges to the long-held tenet of irreversible ovarian ageing are also introduced and explored. While pregnancy rates after IVF are influenced by multiple (non-ovarian) factors including in vitro laboratory conditions, semen parameters, psychological stress and technique of embryo transfer, predicting response to gonadotropin treatment nevertheless remains an important aim in the evaluation of the couple struggling with infertility.

The purpose of this study was to evaluate the serum estradiol (E2) per oocyte ratio (EOR) as a function of selected embryology events and reproductive outcomes with IVF.This retrospective analysis included all IVF cycles where oocyte collection and fresh transfer occurred between January 2001 and November 2012 at a single institution. Patients were divided by three age groups (35, 35-39, and ≥40 years) and further stratified into nine groups based on EOR (measured in pmol/L/oocyte). Terminal serum E2 (pmol/mL) was recorded on day of hCG trigger administration, and fertilization rate, cleavage rate, number of good quality embryos, and reproductive outcomes were recorded for each IVF cycle.During the study interval, 9109 oocyte retrievals were performed for 5499 IVF patients (mean = 1.7 cycles/patient). A total of 63.4 % of transfers were performed on day 3 (n = 4926), while 36.6 % were carried out on day 5 (n = 2843). Clinical pregnancy rates were highest in patients with EOR of 250-750 and declined as this ratio increased, independent of patient age. While the odds ratio (OR) for clinical pregnancy where EOR = 250-750 vs. EOR 1500 was 3.4 (p 0.001; 95 % CI 2.67-4.34), no statistically significant correlation was seen in fertilization, cleavage rates or number of good quality embryos as a function of EOR.Predicting reproductive outcomes with IVF has great utility both for patients and providers. The former have the opportunity to build realistic expectations, and the latter are better able to counsel according to measured clinical parameters. A better understanding of follicular dynamics and ovarian response to gonadotropin stimulation could optimize IVF treatments going forward.

The immunopathological events in the kidneys of lupus nephritis (LN) patients are poorly understood due in part to the difficulty in acquiring serial biopsies and the inherent limitations in their analysis. To identify a means to circumvent these limitations, we investigated whether immune cells of kidney origin are present in patient urine and whether they correlate with kidney pathology. Flow cytometry analysis was performed on peripheral blood and urine cells of 69 SLE patients, of whom 41 were LN patients. In addition, type I IFN (IFNα/β) levels were determined in plasma and urine by bioassay. Approximately 60% of non-LN patients had urine lymphocytes. In these patients, T cells were always present and predominantly CD8(+), while B cells were either absent or a mixture of naive and memory B cells. In contrast, >90% of LN patients had urine lymphocytes. In half, the B and T cells resembled those in non-LN patient urine; however, in the remaining patients, the B cells were exclusively Ig-secreting plasmablasts or plasma cells (PB/PCs) and the T cells were predominantly CD4(+). In addition, pDCs and IFNα/β frequently accompanied PB/PCs. The majority of patients with urine PB/PCs presented with proliferative nephritis and a significant loss of kidney function, which in some cases had progressed to end stage renal disease (ESRD). In conclusion, urine can provide access to cells of kidney resident populations for phenotypic and functional characterization. Analysis of these cells provides insight into the kidney immunopathology and may serve as biomarkers to identify patients at risk for developing LN and progressing to ESRD.

Almost all systemic agents used in cancer therapy can cause infusion-related reactions. Hypersensitivity or infusion reactions to platinum compounds are acquired, whereas reactions to taxanes and monoclonal antibodies usually occur during the first few minutes of the first infusion. By understanding the symptoms and treatment of infusion reactions, healthcare team members can provide timely and appropriate treatment and positively impact patient care.

A 39 year-old woman with previous salpingectomy developed a symptomatic heterotopic right cornual pregnancy identified by transvaginal ultrasonography at six weeks' gestation. The patient had previously undergone an ipsilateral partial salpingectomy, and the conception was established four months later after one cycle of controlled ovarian hyperstimulation, in vitro fertilization (IVF) and embryo transfer. We performed immediate surgical excision of the ectopic implantation with conservation of the intrauterine pregnancy. Progesterone was administered as 200 mg/d lozenge (troche) plus 200 mg/d rectal suppository, maintained from day of embryo transfer through the perioperative period and until 11th gestational week. Following an uneventful obstetrical course, a healthy male infant was delivered by cesarean at term. In this report, we review the incidence and significance of heterotopic gestation in the context of IVF/embryo transfer. Risk factors for complex intra- and extra-uterine pregnancies are also outlined. Additionally, the clinical management of heterotopic pregnancy, including a novel approach to progesterone supplementation, is discussed.

Objective: The Patient Protection & Affordable Care Act (ACA), or “Obamacare”, represents the most substantial reform of the U.S. healthcare system since the 1965 creation of Medicare and Medicaid. This investigation sought to ascertain knowledge and opinion among physicians providing women’s healthcare services about how this national health program will impact access to fertility treatments.Methods: Between May-July 2014, doctor’s perceptions of ACA were registered by anonymous questionnaire submitted to program directors and house staff at 50 accredited obstetrics & gynecology training centers in USA. Self-reported political preferences were also tabulated for each respondent.Results: Overall, 53.3% of participants (n = 114) claimed familiarity with ACA although this varied significantly by seniority (68.8% of faculty vs. 40% of trainees; p = .003). Among respondents 54.9% identified as liberal, 23% as moderate, and 19.5% as conservative. Most physicians in this sample (51.8%) anticipated a positive impact on assisted fertility care from ACA, 17.9% predicted an adverse effect, and just under one third (30.3%) either had no opinion or were unable to make a prediction.Conclusions: This study offers the first analysis of women’s healthcare physicians’ opinion about the impact of ACA on assisted fertility services. Our report finds low general familiarity of ACA among doctors. Moreover, marked divisions of opinion exist among physicians concerning the ACA in general, as well as what role the ACA should play in the provision of assisted fertility care specifically. If U.S. physicians are to provide leadership on women’s healthcare policy initiatives with a view to reach consensus (especially with respect to assisted fertility services), improved awareness of the ACA and its sequela will be crucial.

This Open Access Master's Thesis is brought to you for free and open access by the CGU Student Scholarship at Scholarship @ Claremont. It has been accepted for inclusion in CGU Theses & Dissertations by an authorized administrator of Scholarship @ Claremont. For more information, please contact scholarship@cuc.claremont.edu. Recommended Citation Elliott, Eric Scott, "Historical Accuracy and the IRA Over 70 Years of Cinema" (2012). CGU Theses & Dissertations. Paper 23. http://scholarship.claremont.edu/cgu_etd/23

Purpose: Our purpose was to determine if the presence of a hydrosalpinx effects the outcome of in vitro fertilization (IVF)–embryo transfer. Methods: We performed a retrospective analysis of IVF cycle stimulation sheets. Results: A total of 1000 patients with tubal factor infertility was analyzed. There were 60 hydrosalpinx patients who underwent 116 initiated cycles with 106 embryo transfers, compared to 940 control patients undergoing 1428 initiated cycles with 1150 embryo transfers. Both groups had a similar response to ovarian stimulation, number of oocytes retrieved, and number of embryos transferred. The hydrosalpinx group had a significantly higher preclinical loss rate (22/59 = 37% vs 80/566 = 14%; P = 0.001), a significantly lower implantation rate (55/352 = 16% vs 795/3795 = 21%; P = 0.013), a trend toward a reduced delivery rate per transfer (28/106 = 26% vs 387/1150 = 34%; P = 0.066), a significantly higher ectopic pregnancy rate (5/59 = 8% vs 16/566 = 3%; P = 0.04), and a similar spontaneous abortion rate (9/37 = 24% vs 99/486 = 20%; P = 0.28) compared to the control tubal factor group. Conclusions: This study demonstrates a decrease in implantation rates and an increase in preclinical miscarriages and ectopic pregnancies in patients with hydrosalpinges compared to tubal-factor patients without sonographic evidence of dilated fallopian tubes.

We present a proposal for a further intercomparison exercise following discussions at the 16th International Radiocarbon Conference in Groningen in 1997. This new intercomparison will build on previous exercises by making use of both reference materials already characterized and additional known-age material. For this comparison, we describe two separate but essentially related protocols that are meant to satisfy the different priorities of radiometric and AMS laboratories. The new intercomparison is planned to begin in mid-1998.

Interlaboratory comparisons have been widely used in analytical chemistry and radiochemistry as an important part of ongoing quality assurance programs. The 14C community has been no exception in this respect, and in just under 20 years, there have been a number of significant and very extensive interlaboratory trials organized by individual laboratories and the International Atomic Energy Agency (IAEA) to the benefit of the 14C community (both labs and users) (Otlet et al. 1980; ISG 1982; Scott et al. 1990; Rozanski et al. 1992; Scott et al. 1992; Gulliksen and Scott 1995). The comparisons have varied widely in terms of sample type and preparation, but all have had as their primary goal the investigation of the comparability of results produced under possibly quite different laboratory protocols. As techniques have been developed and new labs formed, the reference materials created as a result of the intercomparisons have presented an opportunity for checking procedures and results. Users have been reassured by the existence of regular comparisons as one sign of the concern that laboratories have to ensure highest quality results, but also confused about how to make use of the results from past exercises in the interpretation of sets of dates from many laboratories. The laboratories have also learned valuable lessons from participation in such studies. These have included identification of systematic offsets and additional sources of variation and in studies which have used realistic samples requiring pretreatment, chemical synthesis and counting, it has been possible to identify the stage at which such problems have arisen and to quantify the relative contributions to the overall variation. In this paper, we will briefly review the comparisons so far, draw some conclusions from their findings, and make proposals for the future organization of intercomparisons.