Respective Time Frames Research Articles

Population-based overall and net survival of childhood leukemia at 1-, 5-, and 10-years of follow-up in three regions of Colombia.

Childhood leukemia (CL) is the most common type of childhood cancer worldwide and in Colombia. Thanks to therapeutic innovations and improved access, the survival of children and adolescents with leukemia has increased considerably worldwide, especially in high-income countries. In Colombia, a middle-income country, survival has also been observed to increase in big cities. However, the survival rate in intermediate cities is still unknown. This study aimed to assess short- and long-term survival rates of children with leukemia coming from three intermediate Colombian cities as well as to compare overall survival (OS) rates versus relative survival (RS) rates of this population of children. Data from population-based cancer registries in three Colombian cities (Bucaramanga metropolitan area, Manizales and Pasto) were analyzed. OS and RS of up to 10 years were estimated for children who were diagnosed with leukemia at ages 0-18 years between 1998 and 2018 and followed up for vital status. RS was calculated using the Pohar-Perme method. We performed a separate survival analysis by gender and by period of diagnosis (before and after 2010). We included data from 507 children and adolescents diagnosed with leukemia. RS at 1, 5 and 10 years after diagnosis were similar between the populations for the respective timeframes (RS Bucaramanga 86.5%, 66.9% and 52.5%; Manizales 81.1%, 62.8% and 61.1%; Pasto 81.7% at 1 year, 66.2% at 5 years and 59.4% at 10 years). OS and RS were very similar for all estimates and periods. There were no clear differences in RS between genders across the three population-based cancer registries and there was an improvement in RS after 2010, particularly in Bucaramanga and Pasto. Our study reports similar 5-year survival rates for CL in these Colombian cities compared to rates documented in other Latin American countries and larger Colombian cities. These are far below what is reported in high-income settings. This highlights opportunities for improvement in the Colombian health system, where numerous barriers persist in terms of suspicion, diagnosis and continuity of treatment for CL.

U–Pb Dating of Fibrous Dolomite in the Hydrothermal Dolostone of the Dengying Formation, Central Sichuan Basin, and Its Response to Supercontinent Breakup

Super-deep drilling in the central Sichuan Basin encountered volcanic rocks of the Suxiong Formation, which are overlain by multiple hydrothermal alterations within the upper section of the Ediacaran Dengying Formation. This provides an excellent research opportunity to understand the pre-Cambrian hydrothermal activity and geological evolution of the western margin of the Yangtze Craton. Observations revealed the development of a series of hydrothermal dolomite aggregates characterized by the presence of brown sphalerite within fractures and pores of the carbonate rock. Microscopically, the dolomite exhibited fibrous columnar crystallization, forming radial bands with a gradual decrease in crystallization intensity from the center to the periphery. Cathodoluminescence analysis revealed the presence of approximately eight dolomite bands within the aggregate. U–Pb dating from the inner to outer bands yielded isotopic ages of 781 ± 12 Ma for the second band, 683 ± 12 Ma for the fifth, 562 ± 12 Ma for the sixth, and 545.4 ± 6.9 Ma for the seventh. The in situ rare earth element (REE) distribution patterns of the 781 and 683 Ma dolomite bands exhibited similarities. They both showed low total REE content (∑REE), with significant fractionation between light and heavy REEs. Additionally, they exhibited negative anomalies in cerium (Ce) and europium (Eu), while heavy REEs were relatively enriched. The dolomite bands at 562 and 545 Ma also exhibited similar REE characteristics, with low ∑REE and weak fractionation between light and heavy REEs. They also displayed distinct negative anomalies in Ce and Eu, indicating similar distribution patterns. These findings suggested that formation of the banded hydrothermal dolostone occurred during different tectonic events, and the presence of heavy REE-enriched hydrothermal fluids suggested a deep-seated origin. This study has provided preliminary evidence that the Dengying Formation, previously considered to be of the Ediacaran age, has undergone multiple episodes of deep-seated fluid infiltration and alteration since the Mesoproterozoic Era. Importantly, these events coincide with the rifting of the Rodinia and Pannotia supercontinents, aligning with their respective timeframes. This finding raises questions regarding the stratigraphic division and correlation of the formations in the deeply buried core area of the basin.

Amharic Speech Search Using Text Word Query Based on Automatic Sentence-like Segmentation

More than 7000 languages are spoken in the world today. Amharic is one of the languages spoken in the East African country Ethiopia. A lot of speech data is being made every day in different languages as machines are getting better at processing and have improved storing capacity. However, searching for a particular word with its respective time frame inside a given audio file is a challenge. Since Amharic has its own distinguishing characteristics, such as glottal, palatal, and labialized consonants, it is not possible to directly use models that are developed for other languages. A popular approach in developing systems for searching particular information in speech involves using an automatic speech recognition (ASR) module that generates the text version of the speech where the word or phrase is searched based on text query. However, it is not possible to transcribe a long audio file without segmentation, which in turn affects the performance of the ASR module. In this paper, we are reporting our investigation on the effects of manual and automatic speech segmentation of Amharic audio files in a spiritual domain. We have used manual segmentation as a baseline for our investigation and found out that sentence-like automatic segmentation resulted in a word error rate (WER) closer to the WER achieved on the manually segmented test speech. Based on the experimental results, we propose Amharic speech search using text word query (ASSTWQ) based on automatic sentence-like segmentation. Since we have achieved lower WER using the previously developed speech corpus, which is in a broadcast news domain, together with the in-domain speech corpus, we recommend using both in- and out-domain speech corpora to develop the Amharic ASR module. The performance of the proposed ASR is a WER of 53% that needs further improvement. Combining two language models (LMs) developed using training text from the two different domains (spiritual and broadcast news) allowed a WER reduction from 53% to 46%. Therefore, we have developed two ASSTWQ systems using the two ASR modules with WERs of 53% and 46%.

Impact of an augmented intelligence-based tool upon the timeliness of referrals to palliative care and hospice in patients with advanced cancer in the real-world setting.

12127 Background: Timely integration of palliative care (PC) and hospice management for patients with advanced cancer requires informed clinical decision-making and expectation-setting to help patients realize their end-of-life (EOL) goals. Longer stay with hospice is a quality indicator in oncology care that requires earlier referral to PC and hospice. We have previously demonstrated that an augmented intelligence (AI) tool used to predict 30-day mortality can assist with an increase in referrals to PC and hospice. In this secondary analysis, we report on the impact of the AI tool on the timeliness of referral to PC and hospice prior to death. However, calculating days with hospice across multiple hospice providers and geographies can be challenging. Thus, we used a real-world (RW) measure of 14 to 90 days prior to death as a surrogate for timeliness for hospice and 90 to 180 days prior to death for a PC referral. Methods: Medical records of patients at a large community-based hematology/oncology practice in the Pacific Northwest who experienced a mortality event pre-deployment (January 2017 to April 2018) or post-deployment (May 2018 to June 2021) of the AI tool were electronically reviewed for evidence of a PC or hospice referral. Patients were included if the referral was between 14 to 90 days of the mortality event for hospice care or between 90 to 180 days prior to death for PC. Outcomes for additional timepoints (1-3 days and 4-13 days and >90 days) will be provided at the final presentation. Data were analyzed using a statistical process control chart. Results: Of the patients who experienced a mortality event, the following percentages had been referred pre- and post-deployment of the AI tool: PC 7.1% pre- and 15.0% post-deployment; hospice 11.5% pre- and 32.1% post-deployment. A system shift (≥6 points in a row steadily increasing or decreasing) occurred early after deployment, in June 2018. The overall improvements were 111.0% in PC referrals and 179.1% in hospice referrals within the respective timeframes. Conclusions: Deployment of an AI tool at a hematology/oncology practice substantially increased the proportions of patients referred to PC 90-180 days prior to death and hospice between 14 -90 days prior to death, suggesting a favorable impact on timeliness of referrals. If confirmed in additional studies, the AI-based tool can be utilized to integrate PC early in the management of patients with advanced cancer.[Table: see text]

The Role of Soluble Urokinase Plasminogen Activator Receptor (suPAR) in the Context of Aneurysmal Subarachnoid Hemorrhage (aSAH)-A Prospective Observational Study.

ObjectiveOutcome after aneurysmal subarachnoid hemorrhage (aSAH) is highly variable and largely determined by early brain injury and delayed cerebral ischemia (DCI). Soluble urokinase plasminogen activator receptor (suPAR) represents a promising inflammatory marker which has previously been associated with outcome in traumatic brain injury and stroke patients. However, its relevance in the context of inflammatory changes after aSAH is unclear. Here, we aimed to characterize the role of circulating suPAR in both serum and cerebrospinal fluid (CSF) as a novel biomarker for aSAH patients.MethodsA total of 36 aSAH patients, 10 control patients with unruptured abdominal aneurysm and 32 healthy volunteers were included for analysis. suPAR was analyzed on the day of admission in all patients. In aSAH patients, suPAR was also determined on the day of DCI and the respective time frame in asymptomatic patients. One- and two-sample t-tests were used for simple difference comparisons within and between groups. Regression analysis was used to assess the influence of suPAR levels on outcome in terms of modified Rankin score.ResultsSignificantly elevated suPAR serum levels (suPAR-SL) on admission were found for aSAH patients compared to healthy controls, but not compared to vascular control patients. Disease severity as documented according to Hunt and Hess grade and modified Fisher grade was associated with higher suPAR CSF levels (suPAR-CSFL). In aSAH patients, suPAR-SL increased daily by 4%, while suPAR-CSFL showed a significantly faster daily increase by an average of 22.5% per day. Each increase of the suPAR-SL by 1 ng/ml more than tripled the odds of developing DCI (OR = 3.06). While admission suPAR-CSFL was not predictive of DCI, we observed a significant correlation with modified Rankin's degree of disability at discharge.ConclusionElevated suPAR serum level on admission as a biomarker for early inflammation after aSAH is associated with an increased risk of DCI. Elevated suPAR-CSFL levels correlate with a higher degree of disability at discharge. These distinct relations and the observation of a continuous increase over time affirm the role of inflammation in aSAH and require further study.

Football coach replacement – short-term effect on performance

Sporting performance is undoubtedly one of the key aspects of the way in which professional clubs operate. Insufficient results often result in coach turnover. The initial motivation to replace the coach suggests that improvement should come after the change. This paper aims at determining how the rotation on the coach position influences football clubs’ short-term sporting performance. The material for analysis consists of ten games before and ten games after each coach replacement in Premier League and La Liga in the past three seasons from 2018 to 2021. A statistical analysis is conducted to determine and highlight the difference in performance in respective time frames before and after the turnover. The analysis helped to understand that coach replacement does in fact come with a performance booster in most cases – the teams generally benefit short-term. Drawing conclusions from the analysis, it needs to be noted that this positive effect quickly wears off. Eventually, however, accumulated data is an indicator that the shock-therapy, which coach turnover is, works. When the performance regresses, rotation on coaches’ chair should be considered as a possible solution.

Identification of maternal depression risk from natural language collected in a mobile health app

Depression is one of the most common pregnancy complications, affecting approximately 15% of pregnant people. While valid psychometric measures of depression risk exist, they are not consistently administered at routine prenatal care, exacerbating the problem of adequate detection. The language we use in daily life offers a window into our psychological wellbeing. In this longitudinal observational cohort study of prenatal patients using a prenatal care mobile health app, we examine how features of app-entered natural language and other app-entered patient-reported data may be used as indicators for validated depression risk measures. Patient participants (n=1091) were prescribed a prenatal care app as part of a quality improvement initiative in the UPMC healthcare system from September 2019 – May 2022. Natural language from open-ended writing prompts in the app and self-reported daily mood, were entered by patients using the tool. Participants also completed a validated measure of depression risk - the Edinburgh Postnatal Depression Scale (EPDS) - at least once in their pregnancy. A variety of natural language processing tools were used to score sentiment, categorize topics, and capture other semantic and syntactic information from text entries. LASSO was used to model the relationship between the natural language features and depression risk. Open-ended text within a 30-day and 60-day timeframe of completing an EPDS was found to be moderately predictive of moderate to severe depression risk (AUROC=0.66 and 0.67, for each respective timeframe). When combined with average daily reported mood, open-ended text showed good predictive power (AUROC=0.87). Consistently predictive language features across all models included themes of “money” and “sadness.” The combination of natural language and other user-reported data collected through a mobile health app offers an opportunity for identifying depression risk among a pregnant population.

Real-world treatment patterns and overall survival in previously treated advanced renal cell carcinoma patients receiving nivolumab in the UK.

e16561 Background: CheckMate 025 demonstrated favorable efficacy and safety results for nivolumab monotherapy in previously treated advanced or metastatic renal cell carcinoma (aRCC). However, real-world evidence on treatment patterns and clinical outcomes is limited. Methods: This multi-centre, retrospective cohort study examined treatment patterns and overall survival (OS) in aRCC patients treated with nivolumab monotherapy. Eligible patients who initiated nivolumab at second-line (2L) or beyond (index) between 01 March 2016 and 30 June 2018 were sampled from four UK centers. Data were extracted using an electronic case report form from index to earliest of: most recent visit; death; end of follow up (31 May 2019). Results: Overall , 151 patients were included in analyses (mean age at index 66.9 years, 72.2% male, median follow-up from index 15.2 months), with 109 (72.2%) and 42 (27.8%) receiving nivolumab at 2L and ≥ third-line (3L+), respectively. Key clinical characteristics are outlined in Table 1. All 2L nivolumab patients had received first-line (1L) tyrosine kinase inhibitors (TKI), pazopanib (57.8%), sunitinib (30.3%), or both in sequence (10.1%). After 2L nivolumab, 3L cabozantinib (36/52, 69.2%) was most common. Most 3L nivolumab patients received 2L TKI (31/36, 86.1%) - commonly axitinib (70.9%). After 3L nivolumab, most patients received fourth-line cabozantinib (8/12, 66.7%). Median time on line of therapy (LOT) decreased with LOT progression: from 7.8 months at 1L to 4.6 months at fifth-line (5L). The proportion of patients who discontinued treatment due to adverse events decreased by LOT, (28.6%, 22.7%, 16.0% and 0%, and 34.7%, 28.1%, 0% and 0% from 2L to 5L, overall and for nivolumab treatment, respectively). Overall, median OS from nivolumab initiation was 19.2 months [95% CI, 16.9-27.0]. Patients who received 2L nivolumab had longest median OS (23.0 months [95% CI, 17.2, not reached]), comparable to CheckMate 025 (25.8 months [95% CI, 22.2-29.8]). Median OS for 3L+ nivolumab patients was 12.4 months [95% CI, 8.8, 23.2]. Among 2L nivolumab patients, 73.9%, 46.2%, and 33.6% survived 12, 24, and 36 months, respectively. For the same respective timeframes, 52.4%, 24.7%, and 18.6% of 3L+ nivolumab patients survived. Conclusions: This study provides real-world evidence on the characteristics, treatment patterns and effectiveness of 2L or ≥ 3L nivolumab monotherapy in previously treated aRCC patients. OS results from UK routine clinical care were comparable to those found in CheckMate 025.[Table: see text]

Implementation of 5G NR Primary and Secondary Synchronization

The 5th generation cellular communication system (5G) is oriented towards a new generation of cell conversation device. Similar to all cellular broadband for highly reliable communique with networks consisting of very low latency, synchronization within the respective time frame and frequency domain plays an essential role by allowing the user devices (UE) to acquire data accordingly and transfer it. The paper gives an overview of the 5G signal receiving systems framework required to obtain a physical mobile identification. The physical alerts anticipated with the aid of the 3GPP (third Generation Partnership Project) 5G New Radio specification for synchronization and cellular seek in 5th-era Wi-Fi broadband get entry to structures is provided in this paper. The statistics required to determine the 5G NR physical layer that is carried with the aid of. Secondary Synchronization Signal (SSS) and Primary Synchronization Signal. Subsequently, this paper affords implementation of low power, High speed Synchronization signal detection in Xilinx Kintex FPGA. An excessive-Performance Synchronization Signal detection is derived.

Dose-dependent and time-dependent metabolic, hemodynamic, and redox disturbances in dexamethasone-treated Wistar rats.

Dexamethasone is used experimentally to induce insulin resistance and type 2 diabetes. However, data concerning the dose, the duration of treatment, and the associated comorbidities are inconsistent. The aim of this study was to compare the effects of different doses of dexamethasone and the duration of treatment necessary for the development of a model of insulin resistance thatmimics the clinical condition with the associated comorbidities. Dexamethasone was administered intramuscularly to male Wistar rats, at doses of 500 and 1,000µg/kg/day for the subchronic treatment (eight consecutive days) and at doses of 5, 25, 50, and 100µg/kg/day in chronic treatment (28 consecutive days). Effects on body weight, metabolism, hemodynamics, renal function, and redox status were evaluated. Both treatments induced a progressive body weight loss that was drastic in subchronic treatment, improved glucose tolerance without affecting fasting glycemia. Doses of 1,000 and 100µg/kg were associated with hypertriglyceridemia, hypertension, and increased heart rate, cardiac and renal hypertrophy. Increased creatinemia associated with reduced creatinuria were observed in sub-chronic treatment while increased proteinuria and reduced creatinuria were noticed in chronic treatment. 1,000µg/kg dexamethasone caused an increase in hepatic, and renal malondialdehyde (MDA) and glutathione (GSH) coupled with a reduction in catalase activity. The dose of 100µg/kg induced a rise in GSH and catalase activity but reduced MDA levels in the kidney. Doses of 1,000µg/kg for subchronic and 100µg/kg for chronic treatment exhibited similar effects and are the best doses to respective time frames to induce the model.

Patterns of organizing pneumonia and microinfarcts as surrogate for endothelial disruption and microangiopathic thromboembolic events in patients with coronavirus disease 2019.

BackgroundTo evaluate chest-computed-tomography (CT) scans in coronavirus-disease-2019 (COVID-19) patients for signs of organizing pneumonia (OP) and microinfarction as surrogate for microscopic thromboembolic events.MethodsReal-time polymerase-chain-reaction (RT-PCR)-confirmed COVID-19 patients undergoing chest-CT (non-enhanced, enhanced, pulmonary-angiography [CT-PA]) from March-April 2020 were retrospectively included (COVID-19-cohort). As control-groups served 175 patients from 2020 (cohort-2020) and 157 patients from 2019 (cohort-2019) undergoing CT-PA for pulmonary embolism (PE) during the respective time frame at our institution. Two independent readers assessed for presence and location of PE in all three cohorts. In COVID-19 patients additionally parenchymal changes typical of COVID-19 pneumonia, infarct pneumonia and OP were assessed. Inter-reader agreement and prevalence of PE in different cohorts were calculated.ResultsFrom 68 COVID-19 patients (42 female [61.8%], median age 59 years [range 32–89]) undergoing chest-CT 38 obtained CT-PA. Inter-reader-agreement was good (k = 0.781). On CT-PA, 13.2% of COVID-19 patients presented with PE whereas in the control-groups prevalence of PE was 9.1% and 8.9%, respectively (p = 0.452). Up to 50% of COVID-19 patients showed changes typical for OP. 21.1% of COVID-19 patients suspected with PE showed subpleural wedge-shaped consolidation resembling infarct pneumonia, while only 13.2% showed visible filling defects of the pulmonary artery branches on CT-PA.ConclusionDespite the reported hypercoagulability in critically ill patients with COVID-19, we did not encounter higher prevalence of PE in our patient cohort compared to the control cohorts. However, patients with suspected PE showed a higher prevalence of lung changes, resembling patterns of infarct pneumonia or OP and CT-signs of pulmonary-artery hypertension.

Complications and mortality of cardiovascular emergency admissions during COVID-19 associated restrictive measures

While hospital admissions for myocardial infarction (MI) and pulmonary embolism (PE) are decreased during the COVID-19 pandemic, controversy remains about respective complication and mortality rates. This study evaluated admission rates, complications, and intrahospital mortality for selected life-threatening cardiovascular emergencies (MI, PE, and acute aortic dissection (AAD)) during COVID-19-associated restrictive social measures (RM) in Styria, Austria. By screening a patient information system for International Statistical Classification of Diseases and Related Health Problems (ICD) diagnosis codes covering more than 85% of acute hospital admissions in the state of Styria (~1.24 million inhabitants), we retrospectively identified patients with admission diagnoses for MI (I21, I22), PE (I26), and AAD (I71). Rates of complications such as cardiogenic shock and cardiopulmonary resuscitation, treatment escalations (thrombolysis for PE), and mortality were analyzed by patient chart review during 6 weeks following onset of COVID-19 associated RM, and during respective time frames in the years 2016 to 2019. 1,668 patients were included. Cumulative admissions for MI, PE and AAD decreased (RR 0.77; p<0.001) during RM compared to previous years. In contrast, intrahospital mortality increased by 65% (RR 1.65; p = 0.041), mainly driven by mortality following MI (RR 1.80; p = 0.042). PE patients received more frequently thrombolysis treatment (RR 3.63; p = 0.006), while rates of cardiogenic shock and cardiopulmonary resuscitation remained unchanged. Of 226 patients hospitalized during RM, 81 patients with suspected COVID-19 disease were screened for SARS-CoV-2 infection with only 5 testing positive. Thus, cumulative hospital admissions for cardiovascular emergencies decreased during COVID-19 associated RM while intrahospital mortality increased.

Assuring Adequate Treatment for Persons Diagnosed With Gonorrhea in New York State.

From November 2014 to May 2016, 57 local health departments in New York State (NYS) excluding New York City were offered a performance incentive (PI) to promote adherence to federally recommended treatment guidelines for gonorrhea. The rationale of the PI was to delay antibiotic resistance and disrupt transmission through attaining a high percentage of treatment adherence. Surveillance data from the NYS Communicable Disease Electronic Surveillance System were used for analysis. We evaluated adherence per Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines for persons 12 years and older reported with uncomplicated gonorrhea during 4 time frames: Pre-PI, PI One, PI Two, and Post-PI. We measured adherence per the Centers for Disease Control and Prevention sexually transmitted disease treatment guidelines during each respective time frame and conducted χ tests to test for the association between treatment adequacy and time frame. During the Pre-PI, treatment was adequate in 82.0% of persons diagnosed with gonorrhea. After program implementation, treatment adequacy increased significantly (92.1% of diagnosed persons during PI One, 90.4% during PI Two, and 90.5% during the Post-PI; P ≤ 0.0001). The most common reason for inadequate or missing treatment was patient lost to follow-up. Public health intervention by the NYS Department of Health improved local health department adherence to federally recommended gonorrhea treatment guidelines, and improvements were maintained after the completion of the PI.

Composing Monads for a Musical Performance

Music is a testing challenge for formal information systems. Here we apply the full power of category theory to the challenge, involving the topos for data structuring and the monad for process. The topos handles many aspects of the data for a performance including the score and variants, the orchestral players, the conductor and the supporting infrastructure such as funding bodies. The monad as process controls the adjointness between the functors representing articulation and intonation, based on perceived activity in the brain in professional musicians. We present a musical performance as a categorical composition over time signatures that proceed in successive adjoint steps with the monad looking back and its associated comonad looking forward. The physical complexity of each musical sound operates in its respective time-frame, represented by a limit, as a colimit. The formalism can be implemented in a functional programming language such as Haskell.

Validity and reproducibility of self-reported working hours among Japanese male employees.

Working long hours is a potential health hazard. Although self-reporting of working hours in various time frames has been used in epidemiologic studies, its validity is unclear. The objective of this study was to examine the validity and reproducibility of self-reported working hours among Japanese male employees. The participants were 164 male employees of four large-scale companies in Japan. For validity, the Spearman correlation between self-reported working hours in the second survey and the working hours recorded by the company was calculated for the following four time frames: daily working hours, monthly overtime working hours in the last month, average overtime working hours in the last 3 months, and the frequency of long working months (≥45 h/month) within the last 12 months. For reproducibility, the intraclass correlation between the first (September 2013) and second surveys (December 2013) was calculated for each of the four time frames. The Spearman correlations between self-reported working hours and those based on company records were 0.74, 0.81, 0.85, and 0.89 for daily, monthly, 3-monthly, and yearly time periods, respectively. The intraclass correlations for self-reported working hours between the two questionnaire surveys were 0.63, 0.66, 0.73, and 0.87 for the respective time frames. The results of the present study among Japanese male employees suggest that the validity of self-reported working hours is high for all four time frames, whereas the reproducibility is moderate to high.

Time-course evaluation of survival and treatment in FIRE-3 (AIO KRK0306, first-line therapy of KRAS wild-type metastatic colorectal cancer with FOLFIRI plus cetuximab or bevacizumab).

617 Background: FIRE-3 reported overall survival (OS) difference in favour of arm A (FOLFIRI plus cetuximab, N= 297 pts.) compared to arm B (FOLFIRI plus bevacizumab, N= 295 pts.) in the absence of significant differences in progression-free survival and response rate. Methods: We subdivided the study into six-month time intervals, starting at the time point of randomisation and evaluated OS in a time-wise fashion. Within each interval, OS was analyzed by Cox regression. Furthermore, systemic treatment and local interventions were investigated in the respective time-frames. Results: The time-course hazard ratios of OS are summarized in the Table. Pronounced differences in overall survival by time-interval analysis are observed between 24 and 30 months and between 30 and 36 months. Within the interval of 24-30 months, 24.6% (73/297) of pts in arm A and 25.1% (74/295) of pts in arm B received systemic therapy (any treatment-line). In the subsequent interval of 30-36 months, systemic anti-tumor treatment decreased to 18.9% (56/297) of pts in arm A and 16.3% (48/295) of pts in arm B. Median time on treatment was less than 2 months in the intervals of 24-30 months and 30-36 months. Updated data including RAS wild-type population will be presented at the meeting. Conclusions: The differences in OS observed in FIRE-3 are pronounced in time intervals between 24-30 months as well as 30-36 months after randomisation into the study. A small number of patients received rather short courses of anti-tumor therapy in these observation units. The significant difference in OS that manifests in time-frames between 24 and 30 months as well as between 30 and 36 months suggests that underlying effects on OS in FIRE-3 may include multiple factors and cannot be explained by the number of patients on active treatment alone. Clinical trial information: NCT00433927. [Table: see text]

ET-27 * REPLICATION AND SPREAD OF ONCOLYTIC HERPES VIRUS IN GLIOMA STEM CELLS CAN BE ENHANCED BY SPECIFIC INHIBITION OF HISTONE DEACETYLASE 6

High-grade gliomas remain clinically challenging and under current therapies the prognosis is generally dismal. Intratumoral heterogeneity, therapy resistance, and tumor recurrence likely caused by glioma stem cells (GSCs) still represent major challenges, which need to be addresses by novel, multimodal therapies. We attempted to combine rQnestin34.5, an oncolytic herpes simplex virus expressing its ICP34.5 virulence gene under the glioma-specific nestin promoter, with specific inhibition of histone deacetylase 6 (HDAC6). We have previously reported that pan-HDAC inhibition using valproic acid enhances rQnestin34.5's antitumor activity and our data obtained in established glioma cell lines indicate that sole inhibition of HDAC6 can at least in part be accounted for this effect. We now analyzed the influence of the specific HDAC6 inhibitor Tubacin on rQnestin34.5 replication in GSC lines originating from proneural, classic, and mesenchymal glioma subtypes. Time-lapse microscopy revealed that plaque formation and spread were accelerated within the first 48 hours after infection when cells were pre-treated with Tubacin, translating into significantly increased cytotoxicity in the respective time frame. Viral DNA replication was enhanced after combination treatment as increased viral copy numbers per cell were detected by qPCR. Furthermore, HDAC6 inhibition increased mRNA expression levels of immediate early and late genes. Importantly, the positive effect of Tubacin on rQnestin34.5 replication and spread in GSCs was critically dependent on drug pre-treatment regimens and very low infectious titers. We also noted that the benefit of rQnestin34.5 oncolysis from HDAC6 inhibition varied quantitatively between GSCs. While responsiveness was not determined by glioma subtype or HDAC6 expression levels, we are currently investigating whether the choice of the exact viral entry mechanism can be used as a predictive marker. Future studies will also aim at establishing a therapeutic regimen demonstrating the potential benefit of HDAC6 inhibition in addition to herpes simplex oncolysis in a GSC-derived orthotopic glioma model.

The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis

Oncogenic stimuli trigger the DNA damage response (DDR) and induction of the alternative reading frame (ARF) tumor suppressor, both of which can activate the p53 pathway and provide intrinsic barriers to tumor progression. However, the respective timeframes and signal thresholds for ARF induction and DDR activation during tumorigenesis remain elusive. Here, these issues were addressed by analyses of mouse models of urinary bladder, colon, pancreatic and skin premalignant and malignant lesions. Consistently, ARF expression occurred at a later stage of tumor progression than activation of the DDR or p16(INK4A), a tumor-suppressor gene overlapping with ARF. Analogous results were obtained in several human clinical settings, including early and progressive lesions of the urinary bladder, head and neck, skin and pancreas. Mechanistic analyses of epithelial and fibroblast cell models exposed to various oncogenes showed that the delayed upregulation of ARF reflected a requirement for a higher, transcriptionally based threshold of oncogenic stress, elicited by at least two oncogenic 'hits', compared with lower activation threshold for DDR. We propose that relative to DDR activation, ARF provides a complementary and delayed barrier to tumor development, responding to more robust stimuli of escalating oncogenic overload.

Conceptual measurement framework for help-seeking for mental health problems.

BackgroundDespite a high level of research, policy, and practice interest in help-seeking for mental health problems and mental disorders, there is currently no agreed and commonly used definition or conceptual measurement framework for help-seeking.MethodsA systematic review of research activity in the field was undertaken to investigate how help-seeking has been conceptualized and measured. Common elements were used to develop a proposed conceptual measurement framework.ResultsThe database search revealed a very high level of research activity and confirmed that there is no commonly applied definition of help-seeking and no psychometrically sound measures that are routinely used. The most common element in the help-seeking research was a focus on formal help-seeking sources, rather than informal sources, although studies did not assess a consistent set of professional sources; rather, each study addressed an idiosyncratic range of sources of professional health and community care. Similarly, the studies considered help-seeking for a range of mental health problems and no consistent terminology was applied. The most common mental health problem investigated was depression, followed by use of generic terms, such as mental health problem, psychological distress, or emotional problem. Major gaps in the consistent measurement of help-seeking were identified.ConclusionIt is evident that an agreed definition that supports the comparable measurement of help-seeking is lacking. Therefore, a conceptual measurement framework is proposed to fill this gap. The framework maintains that the essential elements for measurement are: the part of the help-seeking process to be investigated and respective time frame, the source and type of assistance, and the type of mental health concern. It is argued that adopting this framework will facilitate progress in the field by providing much needed conceptual consistency. Results will then be able to be compared across studies and population groups, and this will significantly benefit understanding of policy and practice initiatives aimed at improving access to and engagement with services for people with mental health concerns.

O01 Meeting the needs of the Huntington's Disease community with allocated Individual Support Packages (ISP) located within the doctrine of the existing disability service system in the State of Victoria, Australia

BackgroundHuntington's Victoria (HV) is a non-government community service provider that receives funding from the Victorian State government body situated within a generalised disability service framework. HV is currently funded to...