Time-point Data Research Articles

The concept of recovery kinetics: an observational study of continuous post-operative monitoring in spine surgery.

The spine surgeon's understanding of an individual patient's burden of disease and functional disability in daily life is shaped by patient-reported outcome measures (PROMs). Although PROMs are useful in understanding the patient's perception of their disease, the use of PROMs constitutes a "snapshot" approach of single timepoint data capture, omitting day-to-day fluctuations in functional status. We introduce the concept of kinetics when considering continuous and objective postoperative patient monitoring with wearable sensors. A prospective single-centre series was performed using patients either undergoing lumbar decompression for lumbar spinal stenosis (LSS) (n=12), or posterior lumbar fusion for degenerative spondylolisthesis (n=12). The Oswestry Disability Index (PROM) was conducted preoperatively and 12-weeks postoperatively. During this timeframe, continuous measurements of step count and distance travelled were made using a wrist-based wearable accelerometer. Over the 12-week study period, mean daily step count for all participants improved from 4,700 to 7,700 steps per day (P=0.013), following an initial dip in total steps taken. The mean daily distance travelled improved from 3,300 to 5,300 meters per day (P=0.003). Decompression group recovered at a faster rate than the fusion group. Although overall improvement was similar between the decompression and fusion groups, the recovery kinetics varied. The recovery kinetics approach of continuous postoperative monitoring provides additional insight to postoperative patient progress.

The relationship between early weight loss and weight loss maintenance with naltrexone-bupropion therapy.

SummaryBackgroundExtended-release (ER) naltrexone/bupropion (NB) was associated with greater weight loss than placebo in four randomized, 56-week trials. The association of NB with longer-term maintenance of weight loss remains unknown.MethodsWe conducted a post-hoc analysis of four phase III, randomized, double-blind, placebo-controlled, 56-week studies (COR-I, COR-II, COR-BMOD, and COR-DM), the placebo-controlled cardiovascular outcomes trial LIGHT (208 weeks), and the randomized, open-label trial IGNITE (78 weeks). Included subjects were treated with NB 32 mg/360 mg or placebo, with baseline, week 16, and final time point data. The primary outcome was Kaplan-Meier-estimated weight loss maintenance in each study for up to 204 weeks.FindingsOur analysis included data from 10,198 particpants (NB=5412; placebo=4786). Proportions of patients with ≥5% or ≥10% weight loss maintenance were numerically higher for NB vs. placebo in all studies and time points. Differences were statistically significant for ≥5% weight loss maintenance in COR-BMOD and COR-I/-II at weeks 52 and 56 and the LIGHT study at weeks 52, 104, and 208. For ≥10% weight loss maintenance, differences were statistically significant in COR-I/COR-II at weeks 52 and 56.InterpretationThese data suggest that NB could be used as part of long-term, comprehensive weight loss and weight loss maintenance strategies.FundingOrexigen Therapeutics, Inc. and Bausch Health Canada.

Affective Attitudes Toward Robots at Work: A Population-Wide Four-Wave Survey Study

Robotization of work is progressing fast globally, and the process has accelerated during the COVID-19 pandemic. Utilizing integrated threat theory as a theoretical framework, this study investigated affective attitudes toward introducing robots at work using a four timepoint data (n = 830) from a Finnish working population longitudinal study. We used hybrid multilevel linear regression modelling to study within and between participant effects over time. Participants were more positive toward introducing robots at work during the COVID-19 pandemic than before it. Increased cynicism toward individuals’ own work, robot-use self-efficacy, and prior user experiences with robots predicted positivity toward introducing robots at work over time. Workers with higher perceived professional efficacy were less and those with higher perceived technology-use productivity, robot-use self-efficacy, and prior user experiences with robots were more positive toward introducing robots at work. In addition, the affective attitudes of men, introverts, critical personalities, workers in science and technology fields, and high-income earners were more positive. Robotization of work life is influenced by workers’ psychological well-being factors and perceived as a welcomed change in the social distancing reality of the pandemic.

Estimation of plant height and yield based on UAV imagery in faba bean (Vicia faba L.)

BackgroundFaba bean is an important legume crop in the world. Plant height and yield are important traits for crop improvement. The traditional plant height and yield measurement are labor intensive and time consuming. Therefore, it is essential to estimate these two parameters rapidly and efficiently. The purpose of this study was to provide an alternative way to accurately identify and evaluate faba bean germplasm and breeding materials.ResultsThe results showed that 80% of the maximum plant height extracted from two-dimensional red–green–blue (2D-RGB) images had the best fitting degree with the ground measured values, with the coefficient of determination (R2), root-mean-square error (RMSE), and normalized root-mean-square error (NRMSE) were 0.9915, 1.4411 cm and 5.02%, respectively. In terms of yield estimation, support vector machines (SVM) showed the best performance (R2 = 0.7238, RMSE = 823.54 kg ha−1, NRMSE = 18.38%), followed by random forests (RF) and decision trees (DT).ConclusionThe results of this study indicated that it is feasible to monitor the plant height of faba bean during the whole growth period based on UAV imagery. Furthermore, the machine learning algorithms can estimate the yield of faba bean reasonably with the multiple time points data of plant height.

A84 SECURE ELECTRONIC DOCUMENT SIGNING UPTAKE IN BIOLOGIC PRESCRIBING FOR IMMUNE MEDIATED DISEASES

BackgroundThe COVID-19 pandemic drastically impacted workflows in gastroenterology practice. Physicians managing immune-mediated diseases (IMDs) must complete special authorization (SA) and prescription renewal (Rx) forms for patients on biologic therapy. This adds significant administrative burden potentially leading to delays in therapy initiation and care continuity. Historically, document completion has largely been paper-based, with forms faxed between patient support programs (PSPs) and physician offices. Disruption of normal office processes during the pandemic necessitated the movement of existing paper-based workflows online. The use of secure electronic document signing (SEDS) platforms has allowed physicians to receive and complete documents digitally.AimsTo evaluate the impact of SEDS-based biologic documentation on clinical practice. Objectives were 1) to determine if the use of SEDS platforms increased timeliness of document returns compared to traditional workflows 2) assess whether SEDS usage is acceptable and sustainable and 3) assess MD satisfaction with SEDS platforms.MethodsThis was a retrospective audit of SEDS and paper-based biologic document workflows from a single PSP (Abbvie Care). Outcomes of interest were the number of documents completed monthly using SEDS, new monthly users, and the number of active monthly users between April 1, 2020-March 31, 2021. Time (days) to SEDS completion (vs. paper process) was determined by reviewing timepoint data for SA and Rx documents from May 2019-January 2020 (‘pre- SEDS’) and for SEDS documents from May 2020-January 2021(‘SEDS’). The return time (RT) was defined as the time between date sent to a physician’s office by the PSP to the date returned to the PSP. Documents in the pre-SEDS cohort with a RT exceeding 30 days were excludedResultsIn totality, 5573 SA and Rx documents were completed by 383 physicians using the SEDS platform from April 2020-March 2021. A mean of 14.6 (sd 21.8) documents were signed per physician. The number of monthly electronic documents processed increased from 104 in April 2020 to 800 in March 2021. Active monthly users increased from 24 in April 2020 to 213 in March 2021 (31 new users monthly). A total of 19,387 paper documents were processed during the ‘pre-SEDS’ period and 3,317 electronic documents processed in the ‘SEDS’ period. The mean RT in the ‘pre-SEDS’ period was 8.03 days (Sd 8.2) and the ‘SEDS’ period was 1.11 days (sd 2.6).ConclusionsThis data demonstrates acceptability, appropriateness, and improved processing efficiency of a SEDS platform improving timeliness of patient care. Next steps in this research include surveying physicians to understand the work-flow impact of SEDS, functionality, long-term sustainability, satisfaction and impacts on disease related outcomes.Funding AgenciesNone

Hepatitis C Screening and Treatment Program in Hungarian Prisons in the Era of Direct Acting Antiviral Agents.

A hepatitis C virus (HCV) screening and treatment program was conducted in Hungarian prisons on a voluntary basis. After HCV-RNA testing and genotyping for anti-HCV positives, treatments with direct-acting antiviral agents were commenced by hepatologists who visited the institutions monthly. Patients were supervised by the prisons’ medical staff. Data were retrospectively collected from the Hungarian Hepatitis Treatment Registry, from the Health Registry of Prisons, and from participating hepatologists. Eighty-four percent of Hungarian prisons participated, meaning a total of 5779 individuals (28% of the inmate population) underwent screening. HCV-RNA positivity was confirmed in 317/5779 cases (5.49%); 261/317 (82.3%) started treatment. Ninety-nine percent of them admitted previous intravenous drug use. So far, 220 patients received full treatment and 41 patients are still on treatment. Based on the available end of treatment (EOT) + 24 weeks timepoint data, per protocol sustained virologic response rate was 96.8%. In conclusion, the Hungarian prison screening and treatment program, with the active participation of hepatologists and the prisons’ medical staff, is a well-functioning model. Through the Hungarian experience, we emphasize that the “test-and-treat” principle is feasible and effective at micro-eliminating HCV in prisons, where infection rate, as well as history of intravenous drug usage, are high.

SECURE ELECTRONIC DOCUMENT SIGNING UPTAKE IN BIOLOGIC PRESCRIBING FOR IMMUNE MEDIATED DISEASES

BACKGROUNDThe COVID-19 pandemic drastically impacted workflows in gastroenterology practice. Physicians managing immune-mediated diseases (IMDs) must complete special authorization (SA) and prescription renewal (Rx) forms for patients on biologic therapy. This adds significant administrative burden potentially leading to delays in therapy initiation and care continuity. Historically, document completion has largely been paper-based, with forms faxed between patient support programs (PSPs) and physician offices. Disruption of normal office processes during the pandemic necessitated the movement of existing paper-based workflows online. The use of secure electronic document signing (SEDS) platforms has allowed physicians to receive and complete documents digitally.AIMSTo evaluate the impact of SEDS-based biologic documentation on clinical practice. Objectives were 1) to determine if the use of SEDS platforms increased timeliness of document returns compared to traditional workflows 2) assess whether SEDS usage is acceptable and sustainable and 3) assess MD satisfaction with SEDS platforms.METHODSThis was a retrospective audit of SEDS and paper-based biologic document workflows from a single PSP (Abbvie Care). Outcomes of interest were the number of documents completed monthly using SEDS, new monthly users, and the number of active monthly users between April 1, 2020-March 31, 2021. Time (days) to SEDS completion (vs. paper process) was determined by reviewing timepoint data for SA and Rx documents from May 2019-January 2020 (‘pre- SEDS’) and for SEDS documents from May 2020-January 2021(‘SEDS’). The return time (RT) was defined as the time between date sent to a physician’s office by the PSP to the date returned to the PSP. Documents in the pre-SEDS cohort with a RT exceeding 30 days were excludedRESULTSIn totally, 5573 SA and Rx documents were completed by 383 physicians using the SEDS platform from April 2020-March 2021. A mean of 14.6 (sd 21.8) documents were signed per physician. The number of monthly electronic documents processed increased from 104 in April 2020 to 800 in March 2021. Active monthly users increased from 24 in April 2020 to 213 in March 2021 (31 new users monthly). A total of 19,387 paper documents were processed during the ‘pre-SEDS’ period and 3,317 electronic documents processed in the ‘SEDS’ period. The mean RT in the ‘pre-SEDS’ period was 8.03 days (Sd 8.2) and the ‘SEDS’ period was 1.11 days (sd 2.6).CONCLUSIONThis data demonstrates acceptability, appropriateness, and improved processing efficiency of an SEDS platform improving timeliness of patient care. Next steps in this research include surveying physicians to understand the work-flow impact of SEDS, functionality, long-term sustainability, satisfaction and impacts on disease related outcomes.

Assessment of Achilles Tendon Changes After Long-Distance Running Using Ultrashort Echo Time Magnetization Transfer MR Imaging.

Long-distance running is a common cause of Achilles tendinopathy. A reliable magnetic resonance imaging (MRI) technique to track early changes in the tendon caused by running could facilitate more effective interventions to combat progression. To evaluate an ultrashort echo time sequence with magnetization transfer preparation (UTE-MT) in the detection of changes in Achilles tendons of amateur marathon runners before and after long-distance running. Prospective. Thirty-two runners (19 enrolled for full marathons and 13 enrolled for half-marathons) and 5 healthy non-runners. 3.0 T; UTE-MT and dual-echo UTE for T2* assessment (UTE-T2*). MRI was performed 1-week pre-race, 2-days post-race, and 4-weeks post-race. UTE-MT ratio (UTE-MTR) and UTE-T2* of tendon were measured by two independent radiologists who were blinded to the scan time point and participant data. The Achilles tendon was divided into six regions of interest (ROIs) for data analysis, namely the insertion part (INS), middle part (MID), muscle-tendon junction (MTJ), tendon-bone insertion (TBI), tendon-muscle insertion (TMI), and whole tendon (bulk). Analysis of variance and Friedman's rank tests were used to evaluate changes in UTE-MTR and UTE-T2* between time points. Tukey test and Bonferroni method were used for further comparisons. P < 0.05 was considered significant. The UTE-MTR values of most tendon ROIs changed significantly between the measured time points, except for the INS region (P=0.1977). Conversely, the UTE-T2* values only showed significant changes in the MID and TBI regions. Paired comparisons showed that the UTE-MTR decreases in the MTJ, MID, TMI, and bulk regions at 2-days post-race were significant compared to measures taken pre-race and 4-weeks post-race. For UTE-T2* measurements, significant differences were observed only for the MID region between pre-race and 2-days post-race (P=0.0408, 95% CI: 0.0061, 0.1973), and for the TBI region between pre-race and 4-weeks post-race (P=0.0473, 95% CI: 0.0013, 0.1766). The UTE-MT sequence is able to detect biochemical changes in the Achilles tendon after long-distance running. 2 TECHNICAL EFFICACY: Stage 1.

P621 Secure Electronic Document Signing Uptake in Biologic Prescribing for Immune Mediate Diseases

BackgroundThe COVID-19 pandemic drastically impacted workflows in gastroenterology practice. Physicians managing immune-mediated diseases (IMDs) must complete special authorization (SA) and prescription renewal (Rx) forms for patients on biologic therapy. This adds significant administrative burden potentially leading to delays in therapy initiation and care continuity. Historically, document completion has largely been paper-based, with forms faxed between patient support programs (PSPs) and physician offices. The use of secure electronic document signing (SEDS) platforms during the pandemic has allowed physicians to receive and complete documents digitally. The aim of the project was to evaluate the impact of SEDS-based biologic documentation on clinical practice in order to 1) Determine if the use of SEDS platforms increased timeliness of document returns compared to traditional workflows 2) Assess whether SEDS usage is acceptable and sustainable and 3) Assess MD satisfaction with SEDS platforms.MethodsThis was a retrospective audit of SEDS and paper-based biologic document workflows from a single PSP (Abbvie Care). Outcomes of interest were the number of documents completed monthly using SEDS, new monthly users, and the number of active monthly users between April 1, 2020-March 31, 2021. Time (days) to SEDS completion (vs. paper process) was determined by reviewing timepoint data for SA and Rx documents from May 2019-January 2020 (‘pre- SEDS’) and for SEDS documents from May 2020-January 2021(‘SEDS’). The return time (RT) was defined as the time between date sent to a physician’s office by the PSP to the date returned to the PSP. Documents in the pre-SEDS cohort with a RT exceeding 30 days were excluded.ResultsIn total, 5573 SA and Rx documents were completed by 383 physicians using the SEDS platform from April 2020-March 2021. A mean of 14.6 (sd 21.8) documents were signed per physician. The number of monthly electronic documents processed increased from 104 in April 2020 to 800 in March 2021. Active monthly users increased from 24 in April 2020 to 213 in March 2021 (31 new users monthly). A total of 19,387 paper documents were processed during the ‘pre-SEDS’ period and 3,317 electronic documents processed in the ‘SEDS’ period. The mean RT in the ‘pre-SEDS’ period was 8.03 days (sd 8.2) and the ‘SEDS’ period was 1.11 days (sd 2.6).ConclusionThis data demonstrates acceptability, appropriateness, and improved processing efficiency of an SEDS platform improving timeliness of patient care. Next steps in this research include surveying physicians to understand the work-flow impact of SEDS, functionality, long-term sustainability, satisfaction and impacts on disease related outcomes.

THE YOUNG ADULTS’ ADAPTATION STRATEGIES TO THE PANDEMIC WORLD

SARS-CoV-2 pandemic changed lives of almost all humans worldwide. The growing number of restrictions and uncertainty of the future connected with growing isolation took its toll on persons of all ages. The current research investigates the situation and the adaptation strategies of young adults facing the pandemic. The on-line study was conducted in order to observe the changing emotions, behaviours and attitudes of Polish young adults. Herein the results of two time points (April and November/December 2020) data collection results are presented, showing the changes in health protecting behaviours of 1386 students. The differences between gender and working status have been investigated showing the unified attitude towards potential threat which is SARS-CoV-2.

Clonal Hematopoiesis Is Driven By Aberrant Activation of TCL1A

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) may occur when a hematopoietic stem cell (HSC) acquires a fitness-increasing mutation resulting in its clonal expansion. A diverse set of driver genes, such as regulators of DNA methylation, splicing, and chromatin remodeling, have been associated with CHIP, but it remains largely unknown why HSCs bearing these mutations are positively selected. It has been challenging to identify the genetic and environmental factors mediating clonal expansion in humans, partially due to a lack of large cohorts with longitudinal blood sampling of participants. To circumvent this limitation, we developed a method to infer clonal expansion rate from single timepoint data called PACER (passenger-approximated clonal expansion rate).Methods: PACER is based on the principle that genomic passenger mutations can be used to infer the birth date of pre-malignant clones because these mutations accumulate fairly linearly over time. Thus, an individual with CHIP with a greater number of passenger mutations in the mutant clone is expected to have acquired the clone at a later age than someone with fewer passenger mutations. For two individuals of the same age and with clones of the same size, we expect the clone with more passengers to be more fit, as it expanded to the same size in less time. Typically, one would need to isolate single-cell colonies derived from HSCs in order to calculate the total passenger mutation burden. However, we hypothesized that this measure could also be approximated from whole genome sequencing of blood cell DNA, such as that used in large biobank projects. The expansion rate (PACER) is then estimated by adjusting the total passenger count for age and variant allele fraction in each individual. The ability of passengers to predict future clonal expansion was validated using longitudinal blood samples from 51 CHIP carriers in the Women's Health Initiative taken ~10 years apart (Figure 1). It also accurately predicted the known fitness effects due to different driver mutations in 5,551 CHIP carriers from the Trans-Omics for Precision Medicine (TOPMed) program (Figure 2).Results: Having validated the approach, we next hypothesized that we could identify germline variants influencing PACER, thus revealing genes and pathways mediating clonal expansion. The lead hit in a genome-wide association study (GWAS) of PACER was a common single nucleotide polymorphism (SNP) in the TCL1A promoter that was associated with slower clonal expansion in CHIP overall (Figure 3). TCL1A is an oncogene that is activated via translocation in T-cell prolymphocytic leukemia, but has no known role in CHIP or myeloid malignancies. A gene-level analysis indicated that the TCL1A SNP was associated with slower growth of clones bearing TET2 mutations, but had no effect on DNMT3A-mutant clone growth. We further found that those carrying two copies of the protective SNP had 40-80% reduced odds of having clones with driver mutations in TET2, ASXL1, SF3B1, SRSF2, and JAK2, but not DNMT3A. A concomitant decrease in incident myeloid malignancies was also seen in carriers of this protective SNP.Next, we interrogated how the protective SNP influenced TCL1A activity in HSCs. Normal human HSCs lacked open chromatin at the TCL1A promoter and TCL1A expression, but inducing frameshift mutations in TET2 via CRISPR editing led to accessibility of the promoter and gene/protein expression in HSCs (Figure 4). This effect was abrogated in HSCs from donors of the protective TCL1A SNP in a dose-dependent manner. Finally, we found that HSCs from donors homozygous for the protective SNP had markedly less expansion of phenotypic stem and progenitor cells in vitro after the introduction of TET2 mutations than TET2-edited HSCs from donors with two copies of the reference allele.Conclusions: In summary, we developed a novel method to infer the expansion rate of pre-malignant clones and performed the first ever GWAS for this trait. Our results indicate that the fitness advantage of several common driver genes in CHIP and hematological cancers is mediated through TCL1A activation, which may be a therapeutic target to treat these conditions. PACER is an approach that can be widely adopted to uncover genetic and environmental determinants of pre-malignant clonal expansion in blood and other tissues. [Display omitted] DisclosuresDesai: Bristol Myers Squibb: Consultancy; Kura Oncology: Consultancy; Agios: Consultancy; Astex: Research Funding; Takeda: Consultancy; Janssen R&D: Research Funding. Natarajan: Blackstone Life Sciences: Consultancy; Boston Scientific: Research Funding; Novartis: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Apple: Consultancy, Research Funding; Amgen: Research Funding; Genentech: Consultancy; Foresite Labs: Consultancy. Jaiswal: Novartis: Consultancy, Honoraria; AVRO Bio: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Foresite Labs: Consultancy; Caylo: Current holder of stock options in a privately-held company.

Has Third-Party Monitoring Improved Water Pollution Data Quality? Evidence from National Surface Water Assessment Sections in China

In China, the central government assesses local governments based on data monitored and reported by local agencies, and the accuracy of local statistics has been controversial. In order to further guarantee the authenticity and reliability of surface water monitoring data, the central government will gradually withdraw the local monitoring powers of the national surface water assessment section and implement third-party monitoring to achieve “national assessment and national monitoring.” This paper is based on the time-point water data of important national water quality automatic monitoring stations from 2015 to 2020, using the McCrary (2008) density test to infer possible data manipulation phenomena, and analyze whether third-party monitoring has improved the accuracy of China’s environmental data. The results of the study show that between 2015 and 2020, the observed 81 monitoring sites had varying degrees of data discontinuity. The discontinuity of the data after third-party monitoring was reduced in dissolved oxygen (DO) measurement, an important indicator in the assessment, implying that third-party monitoring has improved the quality of water environment data and the accuracy of the data. The research in this article provides a reference for third-party participation in environmental governance and proves that the participation of these organizations can reduce data manipulation behaviors of local governments and ensure the effectiveness of environmental data.

661P Conditional survival and 5-year follow-up in CheckMate 214: First-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in advanced renal cell carcinoma (aRCC)

Conditional survival, used to predict sustained treatment benefit, accounts for time since treatment initiation and provides improved prognostic information at landmark time points. Conditional survival in aRCC patients (pts) was estimated in CheckMate 214 with a minimum 5-y follow-up (median follow-up, 67.7 mo). Pts with clear cell aRCC were randomized to N 3 mg/kg + I 1 mg/kg Q3W×4 then N 3 mg/kg Q2W vs S 50 mg QD for 4 wk on, 2 wk off. Trial endpoints included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR; both per independent radiology review using RECIST v1.1) in IMDC intermediate/poor risk (IP; primary), intent-to-treat (ITT; secondary), and favorable risk (FAV; exploratory) pts. Conditional survival—the probability of remaining alive (cOS), progression-free (cPFS), or in response (cDOR) 2 y beyond landmark time points of 2 y and 3 y—was analyzed. Superior OS, PFS, ORR and complete response (CR) benefits with N+I vs S were maintained in ITT and IP pts and are summarized together with outcomes in FAV pts (Table). Consistently higher cOS, cPFS, and cDOR rates were observed with N+I vs S in ITT and IP pts at all time points (Table). In the N+I arm, the probability of remaining alive 2 y beyond the 3-y landmark (cOS) was 81% (ITT), 79% (IP), and 85% (FAV). The probability of remaining progression-free (cPFS) for an additional 2 y beyond the 3-y landmark was 89% (ITT), 90% (IP), and 85% (FAV). For N+I pts who were in response at 3 y, the probability of remaining in response (cDOR) for an additional 2 y was 89% (ITT), 90% (IP), and 85% (FAV). No new safety signals emerged with longer follow-up.Table: 661PITTIPFAVN+I n = 550S n = 546N+I n = 425S n = 422N+I n = 125S n = 124OS HR (95% CI)0.72 (0.62-0.85)0.68 (0.58-0.81)0.94 (0.65-1.37)mOS, mo563847277468PFS HR (95% CI)0.86 (0.73-1.01)0.73 (0.61-0.87)1.60 (1.1-2.3)mPFS, mo12121281229ORR (95% CI), % CR, %39 1232 342 1127 230 1352 6DOR HR (95% CI)0.49 (0.35-0.68)0.46 (0.31-0.66)0.62 (0.32-1.21)mDOR, moNR25NR2061332-y conditional OS from landmark, %a 2 y 3 y76 8172 7275 7968 7277 8578 722-y conditional PFS from landmark, %a 2 y 3 y87 8953 5791 9050 6273 8556 502-y conditional DOR from landmark, %a 2 y 3 y91 8957 6392 9064 8889 8553 45an = pts alive, progression free, or in response at each time point (data not shown). DOR, duration of response; NR, not reached. Open table in a new tab an = pts alive, progression free, or in response at each time point (data not shown). DOR, duration of response; NR, not reached. Long-term follow-up in this 5-y analysis demonstrated durable efficacy benefits with N+I vs S. Conditional survival results predict increased probability of durable OS, PFS, and response with N+I at 2-y and 3-y landmarks, and highlight the long-term clinical benefit with N+I in pts with aRCC.

Within-host evolutionary dynamics of seasonal and pandemic human influenza A viruses in young children.

The evolution of influenza viruses is fundamentally shaped by within-host processes. However, the within-host evolutionary dynamics of influenza viruses remain incompletely understood, in part because most studies have focused on infections in healthy adults based on single timepoint data. Here, we analyzed the within-host evolution of 82 longitudinally sampled individuals, mostly young children, infected with A/H1N1pdm09 or A/H3N2 viruses between 2007 and 2009. For A/H1N1pdm09 infections during the 2009 pandemic, nonsynonymous minority variants were more prevalent than synonymous ones. For A/H3N2 viruses in young children, early infection was dominated by purifying selection. As these infections progressed, nonsynonymous variants typically increased in frequency even when within-host virus titers decreased. Unlike the short-lived infections of adults where de novo within-host variants are rare, longer infections in young children allow for the maintenance of virus diversity via mutation-selection balance creating potentially important opportunities for within-host virus evolution.

Neighbourhood change and spatial inequalities in Cape Town

AbstractCapturing the dynamics of population change in urban areas necessitates access to geographically fine‐grained and temporally consistent data for several time points. Such data are generally not available and they must be created using standard population data which cannot usually be compared across time periods. In this paper, the focus is on changing spatial inequalities in Cape Town, South Africa. This paper details an approach to generation of gridded population counts (250 m by 250 m) for two census years – 2001 and 2011. Census data for Small Area Layers (SALs), Spot Building Count (SBC) data, and Open Street Map (OSM) landuse data were used to construct a grid of populated cells to which population counts are then reallocated. The reallocation of population counts from SALs to grid cells was undertaken using area‐to‐point kriging – an approach which is informed by the spatial variation in the population groups of interest as measured using the variogram. A case study based on population grids of unemployment rates shows how the grids can be used to chart changes and also to measure spatial inequalities across the city at two time points. The advantages of grids for capturing fine‐scale complexities and correctly accounting for physical separation between communities are demonstrated and the results show, while the broad patterns of inequality are consistent across time, there are pronounced increases in inequalities in some neighbourhoods. These areas – and what leads some areas to fall further behind – should be the subject of attention by policy‐makers.

Clonal Evolution in Newly Diagnosed Multiple Myeloma Patients: A Follow-up Study from the Mmrf Commpass Genomics Project

Multiple Myeloma (MM) is an incurable malignancy of bone marrow plasma cells characterized by wide molecular diversity and complex clonal and subclonal architecture. Intra-tumor heterogeneity reflects the evolution of the disease. Clonal structure may affect response to treatment, which, in turn, may shape tumor evolution and, consequently, contribute to drug resistance. Thus, analysis of tumor clonality has profound implications for personalized medicine.Using our recently developed network model of newly diagnosed MM from the MMRF CoMMpass study (Lagana et al, Leukemia 2017) , MMNet, we have identified patterns of gene co-expression significantly associated with tumor clonality and showed that clonality is correlated with mutational burden and relapse.In order to characterize the evolution of clonal structure from diagnosis to relapse, we analyzed Whole-Exome data (WES) from 19 patients enrolled in CoMMpass for whom sequencing data for multiple time points was available. The cohort included both male (12; 63%) and female (7; 37%) patients of white/caucasian (14; 73%) and black/african-american (5; 27%) origin. Patients were distributed among five of the ten classes defined by MMNet: CCND1 (4; 21%), MAF (1; 5%), MMSET (2; 10%), HY/NRAS (4; 21%), and IMM (4; 21%) (4 were unassigned). Also, six patients had the t(11;14) and two had the t(4;14) chromosomal translocations. All patients had received induction therapy, consisting of combinations of proteasome inhibitors (PI) (Bortezomib: 19, 100%; Carfilzomib: 3, 16%), immunomodulatory drugs (IMiDs) (Lenalidomide: 13, 68%; Pomalidomide: 2, 10%; Thalidomide: 1, 5%), steroids (18, 95%) and monoclonal antibodies (Daratumumab: 1, 5%). Best responses to therapy were CR/sCR (3; 16%), VGPR (7; 37%) and PR (9; 47%). Fourteen (68%) patients had SD or PD at the second sequencing time point, with a median PFS of 456 days.Our analysis inferred subclonal tumor composition and evolution based on somatic mutations and copy number alterations (CNA) using PhyloWGS (Deshwar et al, Genome Biol 2015). Patients had one (14; 74%), two (4; 21%) or three (1; 5%) founding clones at baseline, and numerous subclones. Trajectories of cancer cell populations revealed dramatic changes in most patients in terms of clonal and subclonal cell fractions between baseline and relapse. In most patients we observed emergence of new competing clones at relapse, where one or more subclones decreasing in size were replaced by other subclones, indicating selective pressure introduced by therapy (Fig. 1).Subclones were characterized in terms of mutations and CNA and were labeled as stable/resistant or sensitive based on their trajectories from baseline to relapse. Our analysis revealed significant inter-patient heterogeneity in terms of mutations and clonal composition, with few overlaps. We identified subclonal drivers by screening the observed mutations and CNA against a database of known cancer drivers and analysis of co-occurrence and mutual exclusivity. Our analysis revealed that stable/resistant clones were characterized by concurrent deletion of 17p and 13q, and/or mutations in NRAS. In particular, 7 out of 19 patients had at least one mutation in NRAS, observed at baseline in 5 cases, and with two patients carrying two different mutations in two different clones. Our findings support earlier adoption of targeted therapy against RAS (e.g. Trametinib). Other drivers found exclusively in resistant clones included DIS3, FAM46C, ROBO1 and CCND1.Overall, our analysis provides genomics characterization of relapsed patients in CoMMpass following induction therapy, reveals heterogeneous clonal and subclonal composition and trajectories from baseline to relapse, and defines specific somatic mutations (e.g. NRAS) and CNA as drivers of resistance to induction therapy. [Display omitted] DisclosuresMadduri:Foundation Medicine, Inc.: Consultancy. Chari:Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Amgen: Honoraria, Research Funding; Celgene Corporation: Consultancy, Research Funding. Cho:Bristol Myers-Squibb: Other: advisory board, Research Funding; Agenus, Inc.: Research Funding; Genentech: Other: advisory board, Research Funding; Ludwig Institute for Cancer Research: Research Funding; Multiple Myeloma Research Foundation: Research Funding. Barlogie:Millenium Pharmaceuticals: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding. Jagannath:Celgene: Consultancy; Bristol-Meyers Squibb: Consultancy; Merck: Consultancy; Medicom: Speakers Bureau; MMRF: Speakers Bureau; Novartis: Consultancy. Dudley:GlaxoSmithKline: Consultancy; Janssen Pharmaceuticals, Inc.: Consultancy; Ayasdi, Inc.: Equity Ownership; Ecoeos, Inc.: Equity Ownership; NuMedii, Inc.: Equity Ownership, Patents & Royalties; Ontomics, Inc.: Equity Ownership; Personalis: Patents & Royalties; AstraZeneca: Consultancy.

In Non-Selected Patients Treated for Influenza, Oseltamivir, a Glycosialidase Inhibitor, Demonstrates Improvement in Platelet Counts Compared to Time of Dosing, but Not over Baseline Levels

Background:Severe thrombocytopenia can cause morbidity or mortality in many patients, especially those with hematologic cancers or who are treated with chemotherapy. Safer and more rational treatment options are critically needed. Platelet aging and clearance, and therefore the quantity of circulating platelets, is intimately tied to the loss of sialic acid on the platelet surface. Platelets lose surface sialic acid gradually as they circulate and age through cleavage by sialidases. In vitro desialylation of the platelet could be circumvented with a sialidase inhibitor. Oseltamivir phosphate (Tamiflu) is an FDA-approved antiviral sialidase inhibitor and has been prescribed worldwide for the treatment of patients with influenza. Multiple case reports have shown a significant improvement in platelet quantity in patients with thrombocytopenia who were treated with oseltamivir. We here investigated the in vivo effect of oseltamivir treatment on platelet counts in a historical cohort.Methods:We performed a retrospective observational study in 52 patients treated at the Medical College of Wisconsin. All patients received one treatment course of 75 mg oseltamivir phosphate between October 2004 and February 2017 due to suspicion of influenza. Excluded patients included those who received a different dose of oseltamivir and those who received multiple treatment courses during this time. Constraints in patient platelet count availability at various time-points around dosing led us to divide our two time-point comparison analysis into four groups: (1) baseline (defined as 30 days prior to dosing) vs. 30 days post-treatment, (2) baseline vs. 100 days post-treatment, (3) first day of treatment vs. 30 days post-treatment and (4) first day of treatment vs. 100 days post-treatment. Data were analyzed using paired t-testing after normalizing with a logarithmic scale. Statistical analyses were done with significance level of p<0.05.Results:The mean patient age was 61 years old (range 25-88 years old) and 59.6% were male. Treatment courses ranged from 1 to 15 doses over 1 to 14 days with an average treatment course of 4.3 doses over 3.9 days (median of 4 doses over 3 days). There were a total of 26 patients in Group 1, 24 patients in Group 2, 32 patients in Group 3, and 32 patients in Group 4. Some patients had data for multiple time-points and are therefore represented in more than one group.In Groups 3 and 4, the difference in platelet count was statistically significant (p<0.05) between the first day of oseltamivir administration and 30 days or 100 days after the last dose. About 72% of patients (23 out of 32) in Group 3 experienced a 2-fold increase in platelet count at 30 days following termination of treatment and 84% of patients (27 out of 32) in Group 4 experienced a 2.1-fold increase in platelet count at 100 days following termination of treatment.In Groups 1 and 2, where end-points were compared to 30 days prior to oseltamivir administration (baseline), platelet counts were also increased, but were not found to be statistically significant. About 65% of patients (17 out of 26) in Group 1 experienced a 1.1-fold increase in platelet count 30 days following termination of treatment. About 63% of patients (15 out of 24) in Group 2 experienced a 2.5-fold increase in platelet count 100 days following termination of treatment.Conclusions:Multiple published case reports have pointed to improvements in thromobocytopenia following dosing of oseltamivir for the treatment of influenza. Our data also shows significant increases in platelet counts when 30 day and 100 day post-treatment levels are compared to levels on the first day of treatment. However, our analysis does not indicate that treatment with oseltamivir significantly increases a patient's platelet count over baseline (defined as 30 days prior to dosing). To our knowledge, this is the only data to look at platelet counts both at the time of drug administration as well as at baseline to assess effect. Platelet counts may be decreased at the time of drug dosing due to concomitant illness, in particular, influenza. Whether there is an independent effect of oseltamivir on platelet clearance will require a controlled study. We plan further research to clarify potential therapeutic application of this commonly available sialidase inhibitor in patients with chronically low platelets. DisclosuresMichaelis:Incyte: Other: consultation for product; Celgene: Speakers Bureau; Novartis: Other: Consultation for New Product.

The Effect of Transit Signal Priority on Bus Rapid Transit Headway Adherence

We report the results of an experiment to evaluate the impact of transit signal priority (TSP) on headway adherence for a bus rapid transit (BRT) system in Provo / Orem, Utah. The bus requests TSP based on its unpublished schedule, but users perceive only a headway. Quantile regression models estimated on raw timepoint data from the BRT system reveal that TSP significantly improves headway adherence, after controlling for peak times, direction, and cumulative trip dwell time. We also find that requiring the bus to be 2 minutes late before requesting TSP improves headway adherence more than allowing all buses to request TSP.

Multivariate Meta-Analysis of the Mortality Effect of Prone Positioning in the Acute Respiratory Distress Syndrome.

The efficacy of prone positioning (PP) as therapy of the acute respiratory distress syndrome (ARDS) has varied in recent meta-analyses. The efficacy question was reviewed using a cohesive multivariate meta-analysis model incorporating all available common time-point data. Data from a core group of 8 randomized controlled trials (2001-2013) utilized in 8 current meta-analyses (2014-2017) was extracted for common time points. Multivariate meta-analysis and meta-regression models for prone-hours per day, mechanical ventilation tidal-volume and baseline patient PaO2/FiO2, considered as continuous and categorical predictors, determined the pooled relative risk (RR) of mortality for prone versus supine positioning. Mortality RR at 28-30 days, 2-3 months and 6-months was not significant overall (P > 0.05). Meta-regression of categorical predictors indicated significant mortality reduction (P ≤ 0.001) for ≥ 12 prone-hours (versus < 12), lung protective ventilation (versus none) and moderate-severe ARDS (versus all ARDS). Meta-regressions of continuous predictors were also significant (P ≤ 0.021) and yielded treatment inflection points of efficacious therapy for ≥ 12 prone-hours per day, ≤ 8.5 mL/kg tidal volume and ≤ PaO2/FiO2 ratio of 130. The mortality treatment effect of PP in ARDS, was not demonstrated in the unadjusted meta-analysis model. Moderator effects indicated consistent significant benefit of prone positioning. In the absence of individual patient data, multivariate models provide more decisive conclusions than individual time point analyses.

Online disease risk monitoring using DEWMA control chart

Early detection of a disease risk plays a vital role in successful treatment of the disease. Many chronic diseases, e.g., stroke, can be treated satisfactorily if they can be detected early. Traditionally, people evaluate their health conditions by comparing the current readings of their medical risk factors with some threshold values, and if irregular readings are triggered out, further medical tests are conducted to find the causes of the disease. A limitation of the traditional disease detection methods is the usage of only current time point data while ignoring the historical data. To use the history of the process for early detection of the disease using statistical process control, we suggest the use of a double exponential weighted moving average control chart to monitor risk factors sequentially. For the estimation of disease risk factors, different kernel functions are used. In particular, we use Epanechnikov, triangular, tricube, biweight, Gaussian, triweight, and cosine kernels. To evaluate the performance of different kernel functions, we conducted simulations as well as a real data set is used. The real data set is about 1055 stroke patients, out of which 27 individuals have suffered from a stroke attack at least once during the study time and the remaining 1028 people did not experience stroke. Numerical results show that the suggested method performs well in detection of early disease risk. Furthermore, it is observed that the biweight kernel function performs better than the other kernel functions for online disease risk monitoring. It is also noticed that for small smoothing parameters of the DEWMA chart, the Epanechinkov and cosine kernels perform better whereas tricube and biweight for the large smoothing parameters.