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Adolescence is a challenging time of change in voicing, normally and in pathology. An increased focus on voice production in relation to genetics can expand our knowledge of the onset of puberty and voice change. Our aim with this review was to connect research of genetics to voice production in adolescence. We need further understanding of the developmental background of voice in childhood and adolescence, because many genetic multi handicaps include voice production. Genetic development related to voice production was the focus in a search made by the Royal English Society of Medicine, with only a few results. We supplemented with references to genetic studies of adults and animals as well as adjacent areas of voice production. The genetic development of voice production is steered from the hypothalamus probably related to growth hormone. The genetic voice production in adults form the basis for understanding development. Some research results were found related to the pubertal steps. The findings are important in the future, using advanced voice analysis and artificial intelligence methods in patients with Multi handicaps.

Supplementary Figure 5: Histopathology of the HuCCT-1 xenograft tumors from control group and groups treated with gemcitabine and gemcitabine in combination with tocilizumab.

Supplementary Figure 4: Pathway over-representation analysis of differentially expressed miRNAs across cellular compartments (parent cells, EV) and treatment groups (anti-IL6R (tocilizumab), anti-YKL40) in biliary tract cancer cells in vitro.

Supplementary Figure 2: Correlation of circulating biomarkers with CRP.

Purpose:Biliary tract cancer (BTC) is a heterogeneous group of rare gastrointestinal malignancies with dismal prognosis often associated with inflammation. We assessed the prognostic value of IL6 and YKL-40 compared with CA19-9 before and during palliative chemotherapy. We also investigated in mice whether IL6R inhibition in combination with gemcitabine could prolong chemosensitivity.Experimental Design:A total of 452 Danish participants with advanced (locally advanced and metastatic) BTC were included from six clinical trials (February 2004 to March 2017). Serum CA19-9, IL6, and YKL-40 were measured before and during palliative treatment. Associations between candidate biomarkers and progression-free survival (PFS) and overall survival (OS) were analyzed by univariate and multivariate Cox regression. Effects of inhibiting IL6R and YKL-40 were assessed in vitro, and of IL6R inhibition in vivo.Results:High pretreatment levels of CA19-9, IL6, and YKL-40, and increasing levels during treatment, were associated with short PFS and OS in patients with advanced BTC. IL6 provided independent prognostic information, independent of tumor location and in patients with normal serum CA19-9. ROC analyses showed that IL6 and YKL-40 were predictive of very short OS (OS < 6 months), whereas CA19-9 was best to predict OS > 1.5 years. Treatment with anti-IL6R and gemcitabine significantly diminished tumor growth when compared with gemcitabine monotherapy in an in vivo transplant model of BTC.Conclusions:Serum IL6 and YKL-40 are potential new prognostic biomarkers in BTC. IL6 provides independent prognostic information and may be superior to CA19-9 in certain contexts. Moreover, anti-IL6R should be considered as a new treatment option to sustain gemcitabine response in patients with BTC.

Supplementary Figure 1: Kaplan-Meier plots depicting progression free survival (PFS) for patients with advanced biliary tract cancer as a function of pretreatment biomarker levels divided into tertiles

Supplementary Data, Supplementary Figure Legends, Supplementary Tables

Supplementary Figure 3: Effects of gemcitabine treatment on IL6(R) expression in vitro, impact of IL-6R and YKL-40 inhibition in BTC cell lines in vitro, expression of IL6(R) in BTC patient tumors.

Supplementary figure 2. A, ChIP using DCR1 promoter specific primers. Quantitative data show chromatin enrichment of Bcl3 relative to input after controlling for non-specific binding using anti-histone H1 (positive control) and anti-IgG, normalized to vehicle treatment, {plus minus} SD of 3 triplicate samples repeated. Semi-quantitative blot of the PCR product from the p50 and Bcl3 ChIP experiments are shown (right). B, immunoblot with anti-DcR1 or anti-Bcl3 in U87 cells transfected with empty vector (EV) or Bcl3 and treated with 100 μM TMZ for the indicated time. C, qPCR analysis of DCR1 mRNA expression in U87 clones expressing the indicated sh-DcR1 or sh-control construct. Data show mean DCR1 transcript expression relative to GAPDH, {plus minus}SD of triplicate samples. D, trypan blue dye exclusion in sh-cntl and sh-DcR1-3 cells following treatment with vehicle or 100 μM TMZ for the indicated times. Data show mean % cell death, {plus minus} SD of triplicate samples. *, P < 0.05. **, P < 0.01.

Supplementary figure 4. A, clonogenic assay in U87 cells treated with Fas ligand (30 ng/ml) and/or FNAb (1 μg/ml). B, clonogenic assay in U87 cells transfected with the indicated siRNA following treatment with vehicle or Fas ligand (30 ng/ml). Data is normalized to vehicle for each si-RNA condition. C, clonogenic assay in U87 cells expressing empty vector (EV) or HA-DcR1 following treatment with Fas ligand (30 ng/ml). *, P < 0.05. D, tumor growth curves of U87 hindlimb xenografts (n = 5 mice per group) treated with the indicated combinations of TMZ and/or NPs carrying the indicated siRNA. Treatments were given as shown. *, P < 0.05, TMZ + NP-si-DcR1 vs. TMZ + NP-si-cntl.

Supplementary figure 1. A, Venn diagram showing overview of genes significantly (FDR < 0.05) altered in response to TMZ in U87 cells stably expressing control or p105 shRNA. DCR1 (TNFRSF10C) was identified as a gene specific to control cells. B, flow cytometric analysis of DcR1 surface expression in U87 cells following treatment with 100 μM TMZ for the indicated time. C, flow cytometric analysis of DcR1 expression in U87-sh-cntl and U87-sh-p105 cells following treatment with TMZ at the indicated concentration. D, immunoblot with anti-p53 and anti-p21 antibodies in U87 cells at indicated time following treatment with 100 μM TMZ.

Supplementary figure 3. A, annexin V binding in U251 cells treated with vehicle or temozolomide (TMZ, 100 μM) following transfection with the indicated siRNA. B, clonogenic assay in A172 cells transfected with the indicated siRNA following treatment with the indicated concentration of TMZ. C, clonogenic assay in U251 cells transfected with si-RNA and treated with TMZ. *, P < 0.05.

Supplementary figure 5. Kaplan-Meier survival curves from the REMBRANDT database stratified based on DCR1 mRNA expression level.

Supplementary Data Legends. Legends for supplementary data presented for publication.

Background Colorectal cancer is the second leading cause of cancer death in Canada. A major risk factor for the development of colorectal cancer is chronic inflammation leading to colitis-associated cancer (CAC). We previously described a CAC mouse model in which tumors arise from DCLK1+ tuft cells following loss of the tumor suppressor adenomatous polyposis coli (APC) and induction of colitis. Interestingly, both colitis and CAC display epigenetic changes that modulate gene expression. However, the impact of DNA methylation changes on colonic tumorigenesis is not known. Thus, we hypothesize that inhibition of DNA methylation in DCLK1+ tuft cells reduces colonic tumorigenesis. Purpose In this study, we aim to investigate the role of DNA methylation in CAC by inhibiting DNA methylation using genetic and pharmacologic means. Method Using a publicly available dataset (GSE75214) of gene expression data analyzed by microarray from colonic biopsies of patients with ulcerative colitis and Crohn’s Disease with active disease, we examined the expression of DNA methyltransferases (DNMTs). Expression of DNMTs in mice with colitis was additionally examined by RT-qPCR and global DNA methylation levels measured by 5-mC ELISA. In separate experiments, Dclk1-CreERT2/Apcf/f mice were crossed to DNMT1f/f mice to knock-out the DNA methyltransferase DNMT1 in DCLK1+ tuft cells. Dclk1/Apcf/f and Dclk1/Apcf/f/DNMT1f/f mice were then administered three doses of tamoxifen followed by 2.5% dextran sodium sulfate (DSS) for five days to induce colitis. Fourteen weeks later, we assessed colonic tumor number and size. In a separate cohort of Dclk1/Apcf/f mice, we induced colitis and treated the mice with six doses of the DNA de-methylating drug 5-AZA-2’-deoxycytidine (5-AZA) or vehicle, and assessed colonic tumor number. To examine DNA methylation changes, we then treated WT mice with 5-AZA and DSS and isolated intestinal epithelial cells. From the intestinal epithelial cell, we isolated DNA and ran the Infinium MouseMethylation BeadChip Array. Result(s) Patients with IBD were found to have increased expression of DNMT1 compared to healthy controls. Mice treated with DSS similarly had increased DNMT1 expression, as well as, global methylation levels compared to controls. Deletion of DNMT1 in DCLK1+ cells significantly inhibited the number and size of colonic tumors. Treatment of mice with 5-AZA decreased global and gene specific DNA methylation levels, and significantly reduced both the number of mice with tumors, and the average colonic tumor number and size per mouse. Conclusion(s) Our findings demonstrate that colitis in both patients and mice is associated with DNA methylation. Furthermore, DNA hypomethylation by 5-AZA treatment or loss of DNMT1 reduces CAC formation suggesting that altered DNA methylation plays a critical role in colonic tumorigenesis. Disclosure of Interest None Declared

Introduction Acute pulmonary embolism (PE), a common disease with substantial morbidity and mortality. Many previous studies have focused on the short-term consequences after an acute PE, but less attention has been directed to the long-term effects of a PE. The most feared complication is chronic thromboembolic pulmonary hypertension (CTEPH), with reported incidence rates ranging from 0.6 to 4.8%. Even though CTEPH is a rare complication after PE, dyspnea and functional impairment are common complaints, and a syndrome named PPES (post-PE-syndrome) has been suggested. The aim of this study was to follow a large national-wide cohort of post-PE-patients and to gather information regarding long-term symptoms and to determine the prevalence of CTEPH. Patients and methods We identified all patients diagnosed with acute PE in 2005 (ICD-10-SE: I26.0 and I26.9) that were registered in the Swedish National Patient Register (NPR), which has nearly 100% coverage. In 2007, all surviving individuals were invited to participate by letter. They were asked to complete a questionnaire regarding symptoms and risk factors for long-term sequele including CTEPH. Individuals who reported dyspnea or had known risk factors for CTEPH were invited to a follow-up with blood tests (NT-pro-BNP) and pulmonary scintigraphy. If any perfusion defects were detected, an echocardiography was performed. If signs of pulmonary hypertension, a referral was done to the regional PAH-center. Results In 2005, 5793 unique patients were admitted with a PE diagnosis in Sweden. Of those, 3510 were still alive in 2007, and 3226 individuals were contacted and asked to complete the questionnaire. Altogether 2105 (65%) individuals returned the questionnaire, and 53% reported dyspnea and 15% were asymptomatic but had risk factors for CTEPH. Altogether 944 individuals were referred for further follow-up including a recommendation to perform a V/Q-scan. Altogether 530 V/Q-scans were performed and 44% showed perfusion defects, whereof 85% had an echocardiography. Twenty-seven % of them registered a systolic right ventricular pressure of at least 30 mmHg. Referrals resulted in 6 cases with proved CTEPH. In parallel, 10 patients with CTEPH diagnosed before 2005 were detected, and 8 patients were diagnosed after 2005 and outside the study.Altogether 24 patients with CTEPH were thus identified and the cumulative incidence of CTEPH ranged between 0.7 and 1.2%. Conclusion Dyspnea is common after an acute PE and over 40% of them have perfusion defects on a V/Q scan, suggesting the presence of a post PE-syndrome (PPES). The incidence of CTEPH is however low. More research is needed to better define PPES. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Actelion PharamceuticalsSwedish Heart and Lung Foundation

This paper investigates the effect of high school graduation requirements on arrest rates with a specific focus on the number of required courses and the use of exit exams. Identifying variation comes from state-by-cohort changes in the laws governing high school graduation requirements from 1980 to 2010. Combining these law changes with arrest rates of young adults from the Federal Bureau of Investigation's Uniform Crime Reports, I find that the use of exit exams can reduce arrest rates by approximately 7 percent. Although it is difficult to parse out the exact mechanisms, additional exploration into heterogeneity by age and offense, as well as examination of labor market outcomes, suggest that these policies may have increased learning. Given the current debate around the use of exit exams, this paper provides evidence of beneficial effects on nonacademic outcomes. This paper also provides further evidence of the influence of education policy on crime.

The recently-advancing Taku Glacier is excavating subglacial sediments at high rates over multi-decadal timescales. However, sediment redistribution over shorter timescales remains unquantified. We use a variety of methods to study subglacial and proglacial sediment redistribution on decadal, seasonal, and daily timescales to gain insight into sub- and proglacial landscape formation. Both excavation and deposition were observed from 2003 to 2015 (2.8 ± 0.9 m a−1to +2.9 ± 0.9 m a−1). The observed patterns imply that a subglacial conduit has occupied the same site over the past decade. Outwash fans on the subaerial end moraine experience fluvial sediment reworking almost year-round, with net sediment gain in winter and net sediment loss in summer, and an overall mass gain between 2005 and 2015. We estimate that tens of meters of sediment still underlie the glacier terminus, sediments which can be remobilized during future activity. However, imminent retreat from the proglacial moraine will limit its sediment supply, leaving the moraine vulnerable to erosion by bordering rivers. Retreat into an over-deepened basin will leave the glacier vulnerable to increased frontal ablation and accelerating retreat.

Objectives To analyze rates, odds ratios (OR), and characteristics of screen-detected and interval cancers after concordant and discordant initial interpretations and consensus in a population-based screening program. Methods Data were extracted from the Cancer Registry of Norway for 487,118 women who participated in BreastScreen Norway, 2006–2017, with 2 years of follow-up. All mammograms were independently interpreted by two radiologists, using a score from 1 (negative) to 5 (high suspicion of cancer). A score of 2+ by one of the two radiologists was defined as discordant and 2+ by both radiologists as concordant positive. Consensus was performed on all discordant and concordant positive, with decisions of recall for further assessment or dismiss. OR was estimated with logistic regression with 95% confidence interval (CI), and histopathological tumor characteristics were analyzed for screen-detected and interval cancer. Results Among screen-detected cancers, 23.0% (697/3024) had discordant scores, while 12.8% (117/911) of the interval cancers were dismissed at index screening. Adjusted OR was 2.4 (95% CI: 1.9–2.9) for interval cancer and 2.8 (95% CI: 2.5–3.2) for subsequent screen-detected cancer for women dismissed at consensus compared to women with concordant negative scores. We found 3.4% (4/117) of the interval cancers diagnosed after being dismissed to be DCIS, compared to 20.3% (12/59) of those with false-positive result after index screening. Conclusion Twenty-three percent of the screen-detected cancers was scored negative by one of the two radiologists. A higher odds of interval and subsequent screen-detected cancer was observed among women dismissed at consensus compared to concordant negative scores. Our findings indicate a benefit of personalized follow-up. Key Points • In this study of 487,118 women participating in a screening program using independent double reading with consensus, 23% screen-detected cancers were detected by only one of the two radiologists. • The adjusted odds ratio for interval cancer was 2.4 (95% confidence interval: 1.9, 2.9) for cases dismissed at consensus using concordant negative interpretations as the reference. • Interval cancers diagnosed after being dismissed at consensus or after concordant negative scores had clinically less favorable prognostic tumor characteristics compared to those diagnosed after false-positive results.

A virtual meteor radar system based on the upper-atmosphere extension of the high-resolution ICOsahedral Non-hydrostatic general circulation model is constructed to validate multistatic specular meteor radar (SMR) analyses. The virtual radar system examines the validity of mean winds and gradients estimation techniques used in multistatic SMRs. The study is motivated by unexpected mean values and tide-like features recently observed in the vertical velocities estimated from multistatic SMRs at different latitudes in the mesosphere and lower thermosphere. The proposed analysis confirms multistatic SMR systems' excellent capability to measure the horizontal mean wind components and gradient terms. It is also found that multistatic SMRs can estimate mean vertical winds if they have an amplitude greater than ±2 m/s. Due to the smoothing inherent to the model results, these results should be treated as lower bounds to the error incurred using real data. Hourly variability in vertical velocity estimates up to ±1–2 m/s in the observed vertical winds are due to contamination by small-scale horizontal structures in the horizontal winds.

Prior research suggests that families prefer schools with higher test scores, shorter distances from home, and certain student demographics. We build on this using data from New Orleans, a context well suited to identification of parent preferences because of its deferred acceptance algorithm and extensive, standardized, and broadly accessible school information. This allows us to study revealed preferences for a richer set of characteristics. We find that families prefer schools with higher school value-added, more extracurricular activities, and after-school childcare. We also find heterogeneity by family income that is more consistent with income constraints than preference heterogeneity. Finally, we show how methodology and data shape the results.

Quantitative voice analysis for clinical use has been focused upon for many years. The aim was to test if Glottal Analysis Tools (GAT) could be used, based on High-Speed Video (HSV) to quantify distances between the vocal folds at any place on the vocal folds. The software includes a reproduced computed film of the vocal fold movements online. 20 normal HSV and 30 with insufficient closure in the rear part of the vocal folds (rear glottal gap) were compared in a case-control study. The distance of trajectories was chosen at 50% and 10% from the rear part of the glottis and maximum and minimum distances between the vocal folds were defined during phonation in the 2 groups. It was possible to calculate the absolute data of insufficiency of closure of the vocal folds compared to normal HSV with a statistical difference of p

Tree heights are important input for many inventory and ecosystem models. While optical and infrared sensors such as LiDAR are widely used in forest surveys, microwave radar has the unique advantage of being able to operate in bad weather or poor visibility conditions. In this work, we employed a LiDAR combined with a compact ultra-wideband frequency modulated continuous wave (FMCW) radar onboard a Single Otter aircraft to collect data over forested areas in Alaska. While the primary focus of the mission was to map the surface elevation and snow thickness of Alaskan glaciers as a part of NASA Operation IceBridge (OIB), we recorded LiDAR and radar returns during the transit flights to analyze backscattering signatures from tree-covered areas, thereby assessing the potential application of our radar to forest and vegetation remote sensing. We analyzed these measurements and estimated the tree heights along the flight trajectory. The very good agreement between the tree height profiles from the two instruments shows promising results for wide area forestry studies using microwave radar.

Author(s): MacGregor, JA; Boisvert, LN; Medley, B; Petty, AA; Harbeck, JP; Bell, RE; Blair, JB; Blanchard-Wrigglesworth, E; Buckley, EM; Christoffersen, MS; Cochran, JR; Csatho, BM; De Marco, EL; Dominguez, RAT; Fahnestock, MA; Farrell, SL; Gogineni, SP; Greenbaum, JS; Hansen, CM; Hofton, MA; Holt, JW; Jezek, KC; Koenig, LS; Kurtz, NT; Kwok, R; Larsen, CF; Leuschen, CJ; Locke, CD; Manizade, SS; Martin, S; Neumann, TA; Nowicki, SMJ; Paden, JD; Richter-Menge, JA; Rignot, EJ; Rodriguez-Morales, F; Siegfried, MR; Smith, BE; Sonntag, JG; Studinger, M; Tinto, KJ; Truffer, M; Wagner, TP; Woods, JE; Young, DA; Yungel, JK | Abstract: The National Aeronautics and Space Administration (NASA)’s Operation IceBridge (OIB) was a 13-year (2009–2021) airborne mission to survey land and sea ice across the Arctic, Antarctic, and Alaska. Here, we review OIB’s goals, instruments, campaigns, key scientific results, and implications for future investigations of the cryosphere. OIB’s primary goal was to use airborne laser altimetry to bridge the gap in fine-resolution elevation measurements of ice from space between the conclusion of NASA’s Ice, Cloud, and land Elevation Satellite (ICESat; 2003–2009) and its follow-on, ICESat-2 (launched 2018). Additional scientific requirements were intended to contextualize observed elevation changes using a multisensor suite of radar sounders, gravimeters, magnetometers, and cameras. Using 15 different aircraft, OIB conducted 968 science flights, of which 42% were repeat surveys of land ice, 42% were surveys of previously unmapped terrain across the Greenland and Antarctic ice sheets, Arctic ice caps, and Alaskan glaciers, and 16% were surveys of sea ice. The combination of an expansive instrument suite and breadth of surveys enabled numerous fundamental advances in our understanding of the Earth’s cryosphere. For land ice, OIB dramatically improved knowledge of interannual outlet-glacier variability, ice-sheet, and outlet-glacier thicknesses, snowfall rates on ice sheets, fjord and sub-ice-shelf bathymetry, and ice-sheet hydrology. Unanticipated discoveries included a reliable method for constraining the thickness within difficult-to-sound incised troughs beneath ice sheets, the extent of the firn aquifer within the Greenland Ice Sheet, the vulnerability of many Greenland and Antarctic outlet glaciers to ocean-driven melting at their grounding zones, and the dominance of surface-melt-driven mass loss of Alaskan glaciers. For sea ice, OIB significantly advanced our understanding of spatiotemporal variability in sea ice freeboard and its snow cover, especially through combined analysis of fine-resolution altimetry, visible imagery, and snow radar measurements of the overlying snow thickness. Such analyses led to the unanticipated discovery of an interdecadal decrease in snow thickness on Arctic sea ice and numerous opportunities to validate sea ice freeboards from satellite radar altimetry. While many of its data sets have yet to be fully explored, OIB’s scientific legacy has already demonstrated the value of sustained investment in reliable airborne platforms, airborne instrument development, interagency and international collaboration, and open and rapid data access to advance our understanding of Earth’s remote polar regions and their role in the Earth system.