Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of Sulfasalazine for the treatment of progressing malignant gliomas in adults

BACKGROUND: Sulfasalazine, a NF-kappaB and x(c)-cystine/glutamate antiport inhibitor, has demonstrated a strong antitumoral potential in preclinical models of malignant gliomas. As it presents an excellent safety profile, we initiated a phase 1/2 clinical study of this anti-inflammatory drug for the treatment of recurrent WHO grade 3 and 4 astrocytic gliomas in adults. METHODS: 10 patients with advanced recurrent anaplastic astrocytoma (n = 2) or glioblastoma (n = 8) aged 32-62 years were recruited prior to the planned interim analysis of the study. Subjects were randomly assigned to daily doses of 1.5, 3, 4.5, or 6 grams of oral sulfasalazine, and treated until clinical or radiological evidence of disease progression or the development of serious or unbearable side effects. Primary endpoints were the evaluation of toxicities according to the CTCAE v.3.0, and the observation of radiological tumor responses based on MacDonald criteria. RESULTS: No clinical response was observed. One tumor remained stable for 2 months with sulfasalazine treatment, at the lowest daily dose of the drug. The median progression-free survival was 32 days. Side effects were common, as all patients developed grade 1-3 adverse events (mean: 7.2/patient), four patients developed grade 4 toxicity. Two patients died while on treatment or shortly after its discontinuation. CONCLUSION: Although the proper influence of sulfasalazine treatment on patient outcome was difficult to ascertain in these debilitated patients with a large tumor burden (median KPS = 50), ISRCTN45828668 was terminated after its interim analysis. This study urges to exert cautiousness in future trials of Sulfasalazine for the treatment of malignant gliomas. TRIAL REGISTRATION: Current Controlled Trials ISRCTN45828668

Disaggregation of SMOS soil moisture over West Africa using the Temperature and Vegetation Dryness Index based on SEVIRI land surface parameters

The overarching objective of this study was to produce a disaggregated SMOS Soil Moisture (SM) product using land surface parameters from a geostationary satellite in a region covering a diverse range of ecosystem types. SEVIRI data at 15 minute temporal resolution were used to derive the Temperature and Vegetation Dryness Index (TVDI) that served as SM proxy within the disaggregation process. West Africa (3 N, 26 W; 28 N, 26 E) was selected as a case study as it presents both an important North-South climate gradient and a diverse range of ecosystem types. The main challenge was to set up a methodology applicable over a large area that overcomes the constraints of SMOS (low spatial resolution) and TVDI (requires similar atmospheric forcing and triangular shape formed when plotting morning rise temperature versus fraction of vegetation cover) in order to produce a 0.05 degree resolution disaggregated SMOS SM product at sub-continental scale. Consistent cloud cover appeared as one of the main constraints for deriving TVDI, especially during the rainy season and in the southern parts of the region and a large adjustment window (105x105 SEVIRI pixels) was therefore deemed necessary. Both the original and the disaggregated SMOS SM products described well the seasonal dynamics observed at six locations of in situ observations. However, there was an overestimation in both products for sites in the humid southern regions; most likely caused by the presence of forest. Both TVDI and the associated disaggregated SM product was found to be highly sensitive to algorithm input parameters; especially of conditions of high fraction of vegetation cover. Additionally, seasonal dynamics in TVDI did not follow the seasonal patters of SM. Still, its spatial heterogeneity was found to be a good proxy for disaggregating SMOS SM data; main river networks and spatial patterns of SM extremes (i.e. droughts and floods) not seen in the original SMOS SM product were revealed in the disaggregated SM product for a test case of July-September 2012. The disaggregation methodology thereby successfully increased the spatial resolution of SMOS SM, with potential application for local drought/flood monitoring of importance for the livelihood of the population of West Africa

Keuring van jonge competitieve sporters in de huisartsenpraktijk

Achtergrond E r lijkt een gebrek aan een uniforme aanpak bij het keuren van jonge, competitieve sporters en richtlijnen hieromtrent binnen de huisartsenpraktijk. D oel Nagaan wat de beste aanpak is van een gesystematiseerd keuringsonderzoek in een huisartsgeneeskundige setting ter voorkoming van plotse, cardiale dood bij jonge, competitieve sporters en een aanbeveling doen. Methode E r werd gezocht in MEDL INE, Tripdatabase TM, gevarieerde bronnen van klinische praktijkrichtlijnen, website van de European Society of Cardiology, de American Heart Association en de Vlaamse Gemeenschap (afdeling Medisch Verantwoord Sporten). De gebruikte zoektermen waren “Death, Sudden, Cardiac”, “Mass Screening” en “Sports”. Andere artikels werden aangereikt door een expert of via de referentielijst van reeds gevonden artikels. R esultaten Anamnese en klinisch onderzoek worden doorgaans aanbevolen. Over de nood aan een stelselmatige afname van een elektrocardiogram (ECG ) in rust bestaat geen eensgezindheid. Bij afwijkende bevindingen verwijst men de sporter door naar een specialist. Sportmedische keuring dient te worden uitgevoerd vanaf de start van competitie en minstens tweejaarlijks te worden herhaald. Enkele auteurs raden aan om de sportmedische keuring te koppelen aan of zelfs te vervangen door een cardiovasculaire voorlichting. Besprekin g E r bestaan grote en kleine inhoudelijke verschillen tussen de verschillende aanbevelingen. Een driedelig protocol met anamnese, klinisch onderzoek en ECG is bewezen (kosten)effectief. Voldoende kennis van de artsen is wel noodzakelijk. De Vlaamse Gemeenschap zal moeten uitzoeken hoe en door wie de sportmedische keuring van jonge, competitieve sporters in de toekomst dient te gebeuren. Keuringsprotocollen verschillend per geslacht, leeftijd, ras en type en/of niveau van de sportbeoefening lijken een nuttig instrument. Besluit P lotse, cardiale overlijdens van jonge, competitieve sporters kunnen worden voorkomen door een gestandaardiseerd, herhaaldelijk keuringsonderzoek bestaande uit anamnese, klinisch onderzoek en ECG .status: publishe

Prediction of the voluntary intake of low quality roughages by sheep from chemical composition and ruminal degradation characteristics

Six cereal straws and two traditional hays were used to study the relationship between voluntary dry matter (DM) intake and chemical composition and ruminal degradation characteristics. The voluntary DM intake was measured during 60 days using Barbarin adult ewes given food individually in four groups of six animals. The forages were offered to the ewes twice daily and were supplemented with 10 g DM of soya-bean meal per kg M(0.75) per day and 30 g per ewe per day of a commercial mixture of minerals and vitamins. The chemical composition and the leaf/stem (LIS) ratio of forages were determined. Their ruminal degradation characteristics were measured by using the nylon bag technique according to the exponenfini model Dg = a + b (1 - e(-ct)). Crude protein contents of straws ranged from 22 to 35 g/kg DM and that of hays from 35 to 57 g/kg DM. The corresponding values of L/S ratio varied from 0 . 68 to 0 . 88. The voltintauy DM intake was highly variable and the hays were ingested at greater amounts than the straws, although their degradable (b) and their rate of digestion (c) were not significantly different (P > 0 . 05). Significant relationships were established between voluntary DM intake and the neutral-detergent fibre (R(2) = -0 . 72; P < 0 . 001), acid-detergent fibre (R(2) = -0 . 75; P < 0 . 001) and a values (R(2) = 0 . 83; P < 0 . 001). The precision of the prediction was significantly improved using ruminal degradation characteristics (S-yx = 4 . 42)compared with the chemical composition (S-yx = 5 . 60)

The Job Demands-Resources Model:Overview and Suggestions for Future Research

Several job characteristics have been suggested to influence workers’ well-being. For example, Herzberg (1968) differentiated job characteristics that offset dissatisfaction such as social relations from job aspects that foster job satisfaction such as opportunities for advancement. While Hackman and Oldham (1976) focused on the motivational potential of job characteristics such as task identity and feedback, Karasek (1979) accentuated time pressure as a pivotal job demand. Together these models point out that various job characteristics may influence workers’ functioning

Large variability in clinical judgement and definitions of left bundle branch block to identify candidates for cardiac resynchronisation therapy

BACKGROUND: Left bundle branch block (LBBB) morphology is associated with improved outcome of cardiac resynchronisation therapy (CRT) and is an important criterion for patient selection. There are, however, multiple definitions for LBBB. Moreover, applying these definitions seems subjective. We investigated the inter- and intraobserver agreement in the determination of LBBB using available definitions, and clinicians' judgement of LBBB. METHODS: Observers were provided with 12‑lead ECGs of 100 randomly selected CRT patients. Four observers judged the ECGs based on different LBBB-definitions (ESC, AHA/ACC/HRS, MADIT, and Strauss). Additionally, four implanting cardiologists scored the same 100 ECGs based on their clinical judgement. Observer agreement was summarized through the proportion of agreement (P) and kappa coefficient (k). RESULTS: Relative intra-observer agreement using different LBBB definitions, and within clinical judgement was moderate (range k 0.47-0.74 and k = 0.76 (0.14), respectively). The inter-observer agreement between observers using LBBB definitions as well as between clinical observers was minimal to weak (range k 0.19-0.44 and k = 0.35 (0.20), respectively). The probability of classifying an ECG as LBBB by available definitions varied considerably (range 0.20-0.76). The agreement between different definitions of LBBB ranged from good (P = 0.95 (0.07)) to weak (P = 0.40 (0.22)). Furthermore, correlation between the different LBBB definitions and clinical judgement was poor (range phi 0.30-0.55). CONCLUSION: Significant variation in the probability of classifying LBBB is present in using different definitions and clinical judgement. Considerable intra- and inter-observer variability adds to this variation. Interdefinition agreement varies significantly and correlation of clinical judgement with LBBB classification by definitions is modest at best

Large variability in clinical judgement and definitions of left bundle branch block to identify candidates for cardiac resynchronisation therapy

Background: Left bundle branch block (LBBB) morphology is associated with improved outcome of cardiac resynchronisation therapy (CRT) and is an important criterion for patient selection. There are, however, multiple definitions for LBBB. Moreover, applying these definitions seems subjective. We investigated the inter- and intraobserver agreement in the determination of LBBB using available definitions, and clinicians' judgement of LBBB. Methods: Observers were provided with 12-lead ECGs of 100 randomly selected CRT patients. Four observers judged the ECGs based on different LBBB-definitions (ESC, AHA/ACC/HRS, MADIT, and Strauss). Additionally, four implanting cardiologists scored the same 100 ECGs based on their clinical judgement. Observer agreement was summarized through the proportion of agreement (P) and kappa coefficient (k). Results: Relative intra-observer agreement using different LBBB definitions, and within clinical judgement was moderate (range k 0.47-0.74 and k = 0.76 (0.14), respectively). The inter-observer agreement between observers using LBBB definitions as well as between clinical observers was minimal to weak (range k 0.19-0.44 and k = 0.35 (0.20), respectively). The probability of classifying an ECG as LBBB by available definitions varied considerably (range 0.20-0.76). The agreement between different definitions of LBBB ranged from good (P = 0.95 (0.07)) to weak (P = 0.40 (0.22)). Furthermore, correlation between the different LBBB definitions and clinical judgement was poor (range phi 0.30-0.55). Conclusion: Significant variation in the probability of classifying LBBB is present in using different definitions and clinical judgement. Considerable intra-and inter-observer variability adds to this variation. Interdefinition agreement varies significantly and correlation of clinical judgement with LBBB classification by definitions is modest at best. (C) 2019 Elsevier B.V. All rights reserved