Zeitschriftenartikel: „Threshold increment (fTI)“

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Chen, Yue, Harold E. Bedell und Laura J. Frishman. „Temporal-Contrast Discrimination and its Neural Correlates“. Perception 25, Nr. 5 (Mai 1996): 505–22. http://dx.doi.org/10.1068/p250505.

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Reported differences in neuronal contrast processing between the parallel magnocellular (M) and parvocellular (P) visual pathways invite the hypothesis that contrast discrimination in the human visual system is more sensitive at low contrasts and less sensitive at high contrasts, for stimuli modulated at high compared with low temporal frequencies. In the present study, an edgeless temporally modulated uniform field was selected as the stimulus for psychophysical contrast discrimination, and contrast-increment thresholds for pedestal contrasts ranging from 5.5% to 78.2% were determined with a temporal two-alternative forced-choice staircase procedure. The increment thresholds for five normal subjects were adequately fit by power functions with exponents that shifted continuously from about 0.5 (square-root-law behavior) to about 1.0 (Weber's-law behavior) as stimulus temporal frequency increased from 1 to 30 Hz. A neural simulation, with the use of published contrast-response functions of magnocellular and parvocellular neurons, adjusted with an estimate of response variance, produced two distinct ‘neural increment-threshold functions’ that were similar to the psychophysical results obtained at the highest and the lowest temporal frequencies, respectively. A shift from a relatively more noise-limited neural mechanism to one whose response is predominantly determined by gain is suggested to account for the change of the contrast-increment-threshold function with increasing temporal frequency.

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Barrett, J., F. Cerny, J. A. Hirsch und B. Bishop. „Control of breathing patterns and abdominal muscles during graded loads and tilt“. Journal of Applied Physiology 76, Nr. 6 (01.06.1994): 2473–80. http://dx.doi.org/10.1152/jappl.1994.76.6.2473.

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Tilting from supine to upright purportedly enhances both segmental and pulmonary proprioceptive feedback, whereas an expiratory threshold load (ETL) preferentially enhances pulmonary feedback. To test this we studied 13 adults when supine and 60 degrees and 90 degrees head up. We measured tidal volume, inspiratory duration (TI), and expiratory duration (TE) from flow; estimated end-expiratory lung volume from inspiratory capacity; and determined burst amplitudes and durations from abdominal electromyograms (EMGs). ETLs were incremented from 0 (control) to 25 cmH2O in 5-cmH2O steps. Tidal volume was significantly increased by ETL but was unaffected by body position. Every load prolonged TE, whereas TI remained unchanged. When subjects were supine, abdominal EMGs were silent but became tonically active when subjects were upright. During ETL, abdominal activity became rhythmical and phase locked to expiration. Bursts amplitudes were enhanced with each increment in ETL, but burst durations did not change even though TE was prolonged. The altered breathing pattern and active expiration augmented inspiratory flow and decreased end-tidal PCO2. Responses were greatest when subjects were 90 degrees head up. The load-related increments in abdominal recruitment, with no change in burst durations, fit the concept of two central pattern generators: one controlling pattern and the other controlling rhythm of the central respiratory drive.

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Workman, Daniel, und Donald L. Fisher. „A Threshold Model of Visual Search“. Proceedings of the Human Factors Society Annual Meeting 32, Nr. 19 (Oktober 1988): 1316–19. http://dx.doi.org/10.1177/154193128803201901.

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A new model of visual search is proposed. It is suggested that in searching for a target among distractors, there is some threshold level of similarity between the target and the distractors. When the similarity of the target to a given distractor is below this threshold the distractor can be quickly rejected. When the distractor is above the threshold level of similarity it will take additional time to reject the distractor. Several models of visual search, including threshold and non-threshold models, are simulated on a computer and compared to the results obtained by Geiselman, Landee & Christen (1982) in a visual search task. A threshold search model in which the time to reject distractors over the similarity threshold is a function of the increment above the threshold (where similarity is defined as proposed in Workman & Fisher, 1987), is shown to provide the best fit to the data. Implications for the selection of symbols for graphic displays are briefly discussed.

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Dobner Jr., Mário, und Rudi Arno Seitz. „INTENSIDADE ÓTIMA DE PODA EM Eucalyptus dunnii PARA A PRODUÇÃO DE MADEIRA LIVRE DE NÓS“. FLORESTA 45, Nr. 4 (12.08.2015): 791. http://dx.doi.org/10.5380/rf.v45i4.39474.

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Eucalytpus dunnii é uma espécie subtropical e tem seu cultivo indicado para regiões onde há ocorrência de geadas. Apesar de ser atualmente utilizada para a produção de papel, carvão e chapas, o uso sólido da madeira para fins mais nobres é conhecido, desde que práticas silviculturais como podas e desbastes sejam consideradas. O presente estudo teve como objetivo analisar o crescimento de indivíduos dominantes de E. dunnii submetidos a diferentes intensidades de poda. Foram testadas quatro diferentes intensidades de poda, mantendo uma copa remanescente de 100, 80, 50 e 20% da altura total de árvores dominantes. Foi utilizado um delineamento inteiramente casualizado com 10 indivíduos por tratamento. Passados 20 meses da realização da poda, a manutenção de até 50% da copa foi suficiente para manter um crescimento em diâmetro considerado normal. Mais importante que a proporção de copa remanescente, é o comprimento absoluto das mesmas. Conclui-se que são necessários, no mínimo, 4 m de copa remanescente para que as árvores mantenham um incremento periódico anual acima de 4 cm (média anual durante o período de 17 a 37 meses). Ao ultrapassar este limite, perdas na ordem de 50% do incremento em diâmetro são esperadas.AbstractOptimum pruning intensity in Eucalytpus dunnii for clear wood producing. Eucalyptus dunnii is a subtropical species, indicated for areas where frosts occur. Besides its current utilization for paper, coal and boards production, the potential for nobler solid-uses are recognized, provided that silvicultural practices such as pruning and thinning are regarded. The objective of this study was to analyze the growth of dominant E. dunnii trees subjected to four different pruning intensities: 100, 80, 50 and 20% of the total tree height of remained canopy. Experimental design was fully randomized, with 10 replications per treatment. After 20 months of pruning, maintaining 50% of canopy was sufficient to allow a normal diameter growth. More important than the proportion, was the absolute length of remained canopy. It was concluded that it is necessary to keep, at least, 4 m of remained canopy in order to maintain a periodic annual increment over 4 cm (average during the 17-37 months period). When this threshold is exceeded, lost in the order of 50% in diameter increment are expected.Keywords: Forest Management; Multiple-uses.

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Cross, Amanda J., Kate Wooldrage, Emma C. Robbins, Ines Kralj-Hans, Eilidh MacRae, Carolyn Piggott, Iain Stenson et al. „Faecal immunochemical tests (FIT) versus colonoscopy for surveillance after screening and polypectomy: a diagnostic accuracy and cost-effectiveness study“. Gut 68, Nr. 9 (11.12.2018): 1642–52. http://dx.doi.org/10.1136/gutjnl-2018-317297.

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ObjectiveThe English Bowel Cancer Screening Programme (BCSP) recommends 3 yearly colonoscopy surveillance for patients at intermediate risk of colorectal cancer (CRC) postpolypectomy (those with three to four small adenomas or one ≥10 mm). We investigated whether faecal immunochemical tests (FITs) could reduce surveillance burden on patients and endoscopy services.DesignIntermediate-risk patients (60–72 years) recommended 3 yearly surveillance were recruited within the BCSP (January 2012–December 2013). FITs were offered at 1, 2 and 3 years postpolypectomy. Invitees consenting and returning a year 1 FIT were included. Participants testing positive (haemoglobin ≥40 µg/g) at years one or two were offered colonoscopy early; all others were offered colonoscopy at 3 years. Diagnostic accuracy for CRC and advanced adenomas (AAs) was estimated considering multiple tests and thresholds. We calculated incremental costs per additional AA and CRC detected by colonoscopy versus FIT surveillance.Results74% (5938/8009) of invitees were included in our study having participated at year 1. Of these, 97% returned FITs at years 2 and 3. Three-year cumulative positivity was 13% at the 40 µg/g haemoglobin threshold and 29% at 10 µg/g. 29 participants were diagnosed with CRC and 446 with AAs. Three-year programme sensitivities for CRC and AAs were, respectively, 59% and 33% at 40 µg/g, and 72% and 57% at 10 µg/g. Incremental costs per additional AA and CRC detected by colonoscopy versus FIT (40 µg/g) surveillance were £7354 and £180 778, respectively.ConclusionsReplacing 3 yearly colonoscopy surveillance in intermediate-risk patients with annual FIT could reduce colonoscopies by 71%, significantly cut costs but could miss 30%–40% of CRCs and 40%–70% of AAs.Trial registration numberISRCTN18040196; Results.

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Benamouzig, Robert, Stéphanie Barré, Jean-Christophe Saurin, Henri Leleu, Alexandre Vimont, Sabrine Taleb und Frédéric De Bels. „Cost-effectiveness analysis of alternative colorectal cancer screening strategies in high-risk individuals“. Therapeutic Advances in Gastroenterology 14 (Januar 2021): 175628482110023. http://dx.doi.org/10.1177/17562848211002359.

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Background and aims: Current guidelines recommend colonoscopy every 3–5 years for colorectal cancer (CRC) screening of individuals with a familial history of CRC. The objective of this study was to compare the cost effectiveness of screening alternatives in this population. Methods: Eight screening strategies were compared with no screening: fecal immunochemical test (FIT), Stool DNA and blood-based screening every 2 years, colonoscopy, computed tomography colonography, colon capsules, and sigmoidoscopy every 5 years, and colonoscopy at 45 years followed, if negative, by FIT every 2 years. Screening test and procedures performance were obtained from the literature. A microsimulation model reproducing the natural history of CRC was used to estimate the cost (€2018) and effectiveness [quality-adjusted life-years (QALYs)] of each strategy. A lifetime horizon was used. Costs and effectiveness were discounted at 3.5% annually. Results: Compared with no screening, colonoscopy and sigmoidoscopy at a 30% uptake were the most effective strategy (46.3 and 43.9 QALY/1000). FIT at a 30 µg/g threshold with 30% uptake was only half as effective (25.7 QALY). Colonoscopy was associated with a cost of €484,000 per 1000 individuals whereas sigmoidoscopy and FIT were associated with much lower costs (€123,610 and €66,860). Incremental cost-effectiveness rate for FIT and sigmoidoscopy were €2600/QALY ( versus no screening) and €3100/QALY ( versus FIT), respectively, whereas it was €150,000/QALY for colonoscopy ( versus sigmoidoscopy). With a lower threshold (10 µg/g) and a higher uptake of 45%, FIT was more effective and less costly than colonoscopy at a 30% uptake and was associated with an incremental cost–effectiveness ratio (ICER) of €4240/QALY versus no screening. Conclusion: At 30% uptake, current screening is the most effective screening strategy for high-risk individuals but is associated with a high ICER. Sigmoidoscopy and FIT at lower thresholds (10 µg/g) and a higher uptake should be given consideration as cost-effective alternatives. Plain Language Summary Cost-effectiveness analysis of colorectal cancer screening strategies in high-risk individuals Fecal occult blood testing with an immunochemical test (FIT) is generally considered as the most cost-effective alternative in colorectal cancer screening programs for average risk individuals without family history. Current screening guidelines for high-risk individuals with familial history recommend colonoscopy every 3–5 years. Colonoscopy every 3–5 years for individuals with familial history is the most effective strategy but is associated with a high incremental cost–effectiveness ratio. Compared with colonoscopy, if screening based on FIT is associated with a higher participation rate, it can achieve a similar effectiveness at a lower cost.

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Lotgering, F. K., P. C. Struijk, M. B. van Doorn, W. E. Spinnewijn und H. C. Wallenburg. „Anaerobic threshold and respiratory compensation in pregnant women“. Journal of Applied Physiology 78, Nr. 5 (01.05.1995): 1772–77. http://dx.doi.org/10.1152/jappl.1995.78.5.1772.

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In an effort to explore why CO2 output (VCO2) at peak exercise is lower during pregnancy than postpartum despite little change in the peak O2 uptake (VO2), we determined the VCO2/VO2 relationship during rapidly incremental exercise and estimated the anaerobic threshold (AT) and the respiratory compensation (RC) point. We measured heart rate, VO2, VCO2, and minute ventilation (VE) at rest and during cycle exercise tests with rapidly increasing exercise intensities until maximal effort in 33 volunteers at 16-, 25-, and 35-wk gestation and postpartum. Through modification of the V-slope method, we estimated the AT and RC point for each test by nonlinear regression analysis in a three-dimensional space (defined by VE, VO2, and VCO2) for a line assumed to have two breakpoints; we found a good fit for all tests. The AT and RC points were found at exercise intensities of approximately 50 and 80% peak VO2, respectively, with no significant differences between test periods. VE was significantly higher during pregnancy than during postpartum at rest and throughout incremental exercise. A lower peak VCO2 relative to peak VO2 during pregnancy compared with postpartum was reflected by a more shallow slope of VCO2 vs. VO2 above the AT point. This suggests that during pregnancy the buffering of lactic acid is reduced.

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Atkin, Wendy, Amanda J. Cross, Ines Kralj-Hans, Eilidh MacRae, Carolyn Piggott, Sheena Pearson, Kate Wooldrage et al. „Faecal immunochemical tests versus colonoscopy for post-polypectomy surveillance: an accuracy, acceptability and economic study“. Health Technology Assessment 23, Nr. 1 (Januar 2019): 1–84. http://dx.doi.org/10.3310/hta23010.

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Background In the UK, patients with one or two adenomas, of which at least one is ≥ 10 mm in size, or three or four small adenomas, are deemed to be at intermediate risk of colorectal cancer (CRC) and referred for surveillance colonoscopy 3 years post polypectomy. However, colonoscopy is costly, can cause discomfort and carries a small risk of complications. Objectives To determine whether or not annual faecal immunochemical tests (FITs) are effective, acceptable and cost saving compared with colonoscopy surveillance for detecting CRC and advanced adenomas (AAs). Design Diagnostic accuracy study with health psychology assessment and economic evaluation. Setting Participants were recruited from 30 January 2012 to 30 December 2013 within the Bowel Cancer Screening Programme in England. Participants Men and women, aged 60–72 years, deemed to be at intermediate risk of CRC following adenoma removal after a positive guaiac faecal occult blood test were invited to participate. Invitees who consented and returned an analysable FIT were included. Intervention We offered participants quantitative FITs at 1, 2 and 3 years post polypectomy. Participants testing positive with any FIT were referred for colonoscopy and not offered further FITs. Participants testing negative were offered colonoscopy at 3 years post polypectomy. Acceptibility of FIT was assessed using discussion groups, questionnaires and interviews. Main outcome measures The primary outcome was 3-year sensitivity of an annual FIT versus colonoscopy at 3 years for detecting advanced colorectal neoplasia (ACN) (CRC and/or AA). Secondary outcomes included participants’ surveillance preferences, and the incremental costs and cost-effectiveness of FIT versus colonoscopy surveillance. Results Of 8008 invitees, 5946 (74.3%) consented and returned a round 1 FIT. FIT uptake in rounds 2 and 3 was 97.2% and 96.9%, respectively. With a threshold of 40 µg of haemoglobin (Hb)/g faeces (hereafter referred to as µg/g), positivity was 5.8% in round 1, declining to 4.1% in round 3. Over three rounds, 69.2% (18/26) of participants with CRC, 34.3% (152/443) with AAs and 35.6% (165/463) with ACN tested positive at 40 µg/g. Sensitivity for CRC and AAs increased, whereas specificity decreased, with lower thresholds and multiple rounds. At 40 µg/g, sensitivity and specificity of the first FIT for CRC were 30.8% and 93.9%, respectively. The programme sensitivity and specificity of three rounds at 10 µg/g were 84.6% and 70.8%, respectively. Participants’ preferred surveillance strategy was 3-yearly colonoscopy plus annual FITs (57.9%), followed by annual FITs with colonoscopy in positive cases (31.5%). FIT with colonoscopy in positive cases was cheaper than 3-yearly colonoscopy (£2,633,382), varying from £485,236 (40 µg/g) to £956,602 (10 µg/g). Over 3 years, FIT surveillance could miss 291 AAs and eight CRCs using a threshold of 40 µg/g, or 189 AAs and four CRCs using a threshold of 10 µg/g. Conclusions Annual low-threshold FIT with colonoscopy in positive cases achieved high sensitivity for CRC and would be cost saving compared with 3-yearly colonoscopy. However, at higher thresholds, this strategy could miss 15–30% of CRCs and 40–70% of AAs. Most participants preferred annual FITs plus 3-yearly colonoscopy. Further research is needed to define a clear role for FITs in surveillance. Future work Evaluate the impact of ACN missed by FITs on quality-adjusted life-years. Trial registration Current Controlled Trials ISRCTN18040196. Funding National Institute for Health Research (NIHR) Health Technology Assessment programme, NIHR Imperial Biomedical Research Centre and the Bobby Moore Fund for Cancer Research UK. MAST Group Ltd provided FIT kits.

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Cabrera, M. E., und H. J. Chizeck. „On the existence of a lactate threshold during incremental exercise: a systems analysis“. Journal of Applied Physiology 80, Nr. 5 (01.05.1996): 1819–28. http://dx.doi.org/10.1152/jappl.1996.80.5.1819.

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The relationship between blood lactate concentration ([La]) and O2 uptake (VO2) during incremental exercise remains controversial: does [La] increase smoothly as a function of VO2 (continuous model), or does it begin to increase abruptly above a particular metabolic rate (threshold model)? The dynamic characteristics of the underlying physiological system are investigated using system identification analysis techniques. A multivariate deterministic time series model of the [La] and VO2 response to incremental changes in work rate was fitted to simulated and experimental data. Time-varying system response parameters were determined through the application of a weighted recursive least squares algorithm. The model, using the identified time-varying parameters, provided a good fit to the data. The variation of these parameters over time was then examined. Two major transitions in the parameters were found to occur at intensity levels equivalent to 53 +/- 8% and 77 +/- 9% maximal VO2 (experimental data). These changes in the model parameters indicate that the best linear dynamic model that fits the observed system behavior has changed. This implies that the system has changed its operation in some way, by altering its structure or by moving to a different operating region. The identified parameter changes over time suggest that the exercise intensity range (from rest to maximal VO2) is divided into three main intensity domains, each with distinct dynamics. Further study of this three-phase system may help in the understanding of the underlying physiological mechanisms that affect the dynamics of [La] and VO2 during exercise.

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Nabetani, Teru, Takeshi Ueda und Keisuke Teramoto. „Measurement of Ventilatory Threshold by Respiratory Frequency“. Perceptual and Motor Skills 94, Nr. 3 (Juni 2002): 851–59. http://dx.doi.org/10.2466/pms.2002.94.3.851.

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This study was conducted to assess whether respiratory frequency can be used as a valid parameter for estimating ventilatory threshold and for examining differences in exercise modes such as a cycle ergometer and a treadmill. 24 men and 12 women performed an incremental exercise test to exhaustion on a cycle ergometer and on a treadmill. Oxygen uptake, carbon dioxide output, pulmonary ventilation, ventilatory frequency, and heart rate were measured continuously every 30 sec. during the test. Three different and independent reviewers detected the ventilatory threshold point and break point of respiratory rate, which were then compared. Analysis indicated that (1) ventilatory threshold was well correlated with break point of respiratory rate for both cycle ( r = .88, p<.001) and treadmill exercise ( r = .96, p<.001). However, on the average, ventilatory threshold was only 71% (cycle) or 88% (treadmill) of break point of respiratory rare. (2) The regression equation for treadmill exercise was more accurate than that for cycling, but the detected data samples were smaller. The break point of respiratory rate was more easily detected for the cycle ergometer test (33 of 36 subjects) than for the treadmill test (only 15 of 36). The cycle ergometer test identified the break point of respiratory rate more easily than did the treadmill test. (3) There was an association between physical fitness and whether the break point of respiratory rate was detectable, and the more fit the subject (above average), the more likely the break point was to be undetected. Our study demonstrates that the break point of respiratory rate is closely associated with ventilatory threshold and that the cycle ergometer test is more conducive than the treadmill test to the detectability of break point of respiratory rate.

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Deruelle, Fabien, Cédric Nourry, Patrick Mucci, Frédéric Bart, Jean-Marie Grosbois, Ghislaine Lensel und Claudine Fabre. „Incremental Exercise Tests in Master Athletes and Untrained Older Adults“. Journal of Aging and Physical Activity 13, Nr. 3 (Juli 2005): 254–65. http://dx.doi.org/10.1123/japa.13.3.254.

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This study aimed to analyze the impact of step-duration protocols, 1-min vs. 3-min, on cardiorespiratory responses to exercise, whatever the aerobic-fitness level of sedentary (65.5 ± 2.3 years,n= 8) or highly fit (63.1 ± 3.2 years,n= 19) participants. Heart rate and VO2at the first and second ventilatory thresholds (VT1, VT2) and maximal exercise were not significantly different between the two protocols. In master athletes, the 3-min protocol elicited significantly lower ventilation at VT2and maximal exercise (p< .01). In the latter, breathlessness was also lower at maximal exercise (p< .05) than in sedentary participants. In trained or sedentary older adults, VT1, VT2, and VO2maxwere not influenced by stage duration. According to the lower breathlessness and ventilation, however, the 3-min step protocol could be more appropriate in master athletes. In untrained participants, because the cardiorespiratory responses were similar with the two incremental exercise tests, either of them could be used.

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Wong, John, Stephanie Anne Co, Joy Bagas, Ma Sophia Graciela Reyes, Hadrian Lim und Nel Jason Haw. „PP137 Colorectal Cancer Screening In The Philippines: Cost-Utility Analysis“. International Journal of Technology Assessment in Health Care 34, S1 (2018): 120. http://dx.doi.org/10.1017/s0266462318002714.

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Introduction:Colorectal cancer (CRC) is the fourth leading cause of cancer deaths in the Philippines. In 2014, the Philippine Health Insurance Corporation (PhilHealth) created a CRC treatment package. The study aimed to determine the cost-utility and budget impact of CRC screening strategies.Methods:A discrete-event microsimulation model was used to simulate four screening modalities: (i) guaiac-fecal occult blood test (gFOBT) followed by colonoscopy every 10 years; (ii) fecal immunochemical test (FIT) followed by colonoscopy every 10 years; (iii) FIT followed by flexible sigmoidoscopy; and (iv) colonoscopy screening every 10 years. These interventions were all compared to no screening. Parameter values were taken from a rapid review of the medical literature and primary data collection from a nationally representative sample of tertiary hospitals.Results:All screening modalities were very cost effective considering that the incremental cost-effective ratios (ICERs) were lower than the gross domestic product per capita threshold suggested by the World Health Organization. Sensitivity analysis showed that the ICERs of all screening modalities evaluated remained below this threshold. The strategy of using FIT followed by colonoscopy every 10 years had an ICER of USD 6,025, with an annual budget impact of USD 6.5 million, assuming low compliance. With moderate compliance this could increase to USD 18.7 million annually.Conclusions:PhilHealth may introduce a benefit package for outpatient screening of colorectal cancer using the screening modality of annual FIT followed by colonoscopy every 10 years.

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Beaver, W. L., K. Wasserman und B. J. Whipp. „Bicarbonate buffering of lactic acid generated during exercise“. Journal of Applied Physiology 60, Nr. 2 (01.02.1986): 472–78. http://dx.doi.org/10.1152/jappl.1986.60.2.472.

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The pattern of decrease in arterial bicarbonate concentration ([HCO3-]) during progressive incremental exercise was compared with that of the rise in arterial lactate ([La-]) to determine the degree of buffering of lactic acid by bicarbonate. A mathematical model was derived for the change in [HCO3-] beyond the lactate threshold. This was based on a log-log transformation of the data, a model previously found to provide a very good fit to the [La-]-O2 consumption (VO2) relationship. The results of the analysis of incremental exercise data from 10 subjects show that the decrease in [HCO3-] very nearly matches the increase in [La-]. However, it was found by comparing regression models that the correspondence between [HCO3-] and [La-] could be improved by assuming that the [HCO3-] decrease was delayed until the arterial lactate level had increased by approximately 0.4 meq/l. This result is compatible with the existence of buffering mechanisms in the cell which buffer the initial increase of lactic acid. Beyond this initial buffering, lactic acid appears to be buffered almost entirely by the bicarbonate buffer system.

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Frequete da Silva, Livia, Ana Paula Dos Santos Silva, Fernanda Ceresine Caporal, José Eduardo Pachioni de Souza, Larissa Carvalho Pozzato, Letícia Constâncio da Rocha Luccas, Mauro César de Mello Filho et al. „TREINAMENTO DE FORÇA E RESISTÊNCIA MUSCULAR RESPIRATÓRIA NA DISTROFIA MUSCULAR DE DUCHENNE: REVISÃO NARRATIVA DA LITERATURA“. RECIMA21 - Revista Científica Multidisciplinar - ISSN 2675-6218 1, Nr. 1 (24.09.2021): e28703. http://dx.doi.org/10.47820/recima21.v1i1.703.

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A distrofia muscular de Duchenne (DMD) é uma doença progressiva hereditária que causa degradação musculoesquelético decorrente da falta e/ou diminuição da proteína distrofina, devido a deficiência do gene DMD localizado na região Xp21apresentando os primeiros sinais entre o terceiro e quinto ano de vida com progressivo enfraquecimento muscular, evoluindo para a musculatura respiratória e falência cardíaca. Neste contexto, a fisioterapia minimiza o comprometimento musculoesquelético, auxilia na manutenção das funções cardiovascular e respiratória e em conjunto com o treinamento muscular respiratório (TMR) precoce, auxilia no incremento de força e endurance respiratória. Assim sendo, o objetivo deste estudo foi discorrer sobre a DMD e os efeitos do TMR com enfoque no uso do dispositivo PowerBreathe® (PB), além de enriquecer a literatura relacionada ao tema, por meio de uma revisão narrativa da literatura. A revisão foi feita nas bases de dados científicos Scielo, Pubmed, Lilacs, BVS e Google Acadêmico utilizando descritores: distrofia muscular de Duchenne, PowerBreathe®, Threshold® IMT, treinamento muscular respiratório e endurance nas línguas portuguesa e inglesa entre os anos de 2001 a 2019. Esta revisão evidenciou a efetividade da fisioterapia nos pacientes com DMD e do tratamento precoce, que visa manter a função motora e respiratória; e que o equipamento mais utilizado para o TMR de um modo geral é o Threshold® IMT. Além disso, aponta para a escassez de estudos específicos sobre uso do PB na DMD; sugerindo mais pesquisas que possam elucidar os benefícios diretos desse dispositivo aos pacientes com DMD.

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Simon, J., J. L. Young, D. K. Blood, K. R. Segal, R. B. Case und B. Gutin. „Plasma lactate and ventilation thresholds in trained and untrained cyclists“. Journal of Applied Physiology 60, Nr. 3 (01.03.1986): 777–81. http://dx.doi.org/10.1152/jappl.1986.60.3.777.

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Six trained male cyclists and six untrained sedentary men were studied to determine whether the plasma lactate threshold (PLT) and ventilation threshold (VT) occur at the same work rate in both fit and unfit populations. The PLT was determined from a marked increase in plasma lactate concentration ([La]) and VT from a nonlinear increase in expired minute ventilation (VE) during incremental leg-cycling tests; work rate was increased 30 W every 2 min until volitional exhaustion. The trained subjects' mean VO2 max (63.8 ml O2 X kg-1 X min-1) and VT (65.8% VO2 max) were significantly higher (P less than 0.05) than the untrained subjects' mean VO2max (35.5 ml O2 X kg-1 X min-1) and VT (51.4% VO2 max). The trained subjects' mean PLT (68.8% VO2 max) and VT did not differ significantly, but the untrained subjects' mean PLT (61.6% VO2 max) was significantly higher than their VT. The trained subjects' mean peak [La] (10.5 mmol X l-1) did not differ significantly from the untrained subjects' mean peak [La] (11.5 mmol X l-1). However, the time of appearance of the peak [La] during passive recovery was inversely related to VO2 max. These results suggest that variance in lactate diffusion and/or removal processes between the trained and untrained subjects may account in part for the different relationships between the VT and PLT in each population.

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Filingeri, Davide, Damien Fournet, Simon Hodder und George Havenith. „Tactile cues significantly modulate the perception of sweat-induced skin wetness independently of the level of physical skin wetness“. Journal of Neurophysiology 113, Nr. 10 (Juni 2015): 3462–73. http://dx.doi.org/10.1152/jn.00141.2015.

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Humans sense the wetness of a wet surface through the somatosensory integration of thermal and tactile inputs generated by the interaction between skin and moisture. However, little is known on how wetness is sensed when moisture is produced via sweating. We tested the hypothesis that, in the absence of skin cooling, intermittent tactile cues, as coded by low-threshold skin mechanoreceptors, modulate the perception of sweat-induced skin wetness, independently of the level of physical wetness. Ten males (22 yr old) performed an incremental exercise protocol during two trials designed to induce the same physical skin wetness but to induce lower (TIGHT-FIT) and higher (LOOSE-FIT) wetness perception. In the TIGHT-FIT, a tight-fitting clothing ensemble limited intermittent skin-sweat-clothing tactile interactions. In the LOOSE-FIT, a loose-fitting ensemble allowed free skin-sweat-clothing interactions. Heart rate, core and skin temperature, galvanic skin conductance (GSC), and physical ( wbody) and perceived skin wetness were recorded. Exercise-induced sweat production and physical wetness increased significantly [GSC: 3.1 μS, SD 0.3 to 18.8 μS, SD 1.3, P < 0.01; wbody: 0.26 no-dimension units (nd), SD 0.02, to 0.92 nd, SD 0.01, P < 0.01], with no differences between TIGHT-FIT and LOOSE-FIT ( P > 0.05). However, the limited intermittent tactile inputs generated by the TIGHT-FIT ensemble reduced significantly whole-body and regional wetness perception ( P < 0.01). This reduction was more pronounced when between 40 and 80% of the body was covered in sweat. We conclude that the central integration of intermittent mechanical interactions between skin, sweat, and clothing, as coded by low-threshold skin mechanoreceptors, significantly contributes to the ability to sense sweat-induced skin wetness.

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Nepal, Reecha, Joanna Spencer, Guneet Bhogal, Amulya Nedunuri, Thomas Poelman, Thejas Kamath, Edwin Chung, Katherine Kantardjieff, Andrea Gottlieb und Brooke Lustig. „Logistic regression models to predict solvent accessible residues using sequence- and homology-based qualitative and quantitative descriptors applied to a domain-complete X-ray structure learning set“. Journal of Applied Crystallography 48, Nr. 6 (10.11.2015): 1976–84. http://dx.doi.org/10.1107/s1600576715018531.

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A working example of relative solvent accessibility (RSA) prediction for proteins is presented. Novel logistic regression models with various qualitative descriptors that include amino acid type and quantitative descriptors that include 20- and six-term sequence entropy have been built and validated. A domain-complete learning set of over 1300 proteins is used to fit initial models with various sequence homology descriptors as well as query residue qualitative descriptors. Homology descriptors are derived from BLASTp sequence alignments, whereas the RSA values are determined directly from the crystal structure. The logistic regression models are fitted using dichotomous responses indicating buried or accessible solvent, with binary classifications obtained from the RSA values. The fitted models determine binary predictions of residue solvent accessibility with accuracies comparable to other less computationally intensive methods using the standard RSA threshold criteria 20 and 25% as solvent accessible. When an additional non-homology descriptor describing Lobanov–Galzitskaya residue disorder propensity is included, incremental improvements in accuracy are achieved with 25% threshold accuracies of 76.12 and 74.79% for the Manesh-215 and CASP(8+9) test sets, respectively. Moreover, the described software and the accompanying learning and validation sets allow students and researchers to explore the utility of RSA prediction with simple, physically intuitive models in any number of related applications.

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Ascensão, Antônio Alexandre, Paulo Santos, José Magalhães, José Oliveira, José Maia und José Soares. „Blood lactate concentrations during a constant load at an intensity corresponding to the aerobic-an aerobic threshold in young athletes“. Revista Paulista de Educação Física 15, Nr. 2 (20.12.2001): 186. http://dx.doi.org/10.11606/issn.2594-5904.rpef.2001.139900.

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Tem sido assumido que a carga correspondente a uma concentração sangüínea de lactato (CSL) de 4 mmol/1, determinada a partir do limiar aeróbio-anaeróbio, pode ser mantida em adultos durante o teste constante de 30 min (“steady-state” CSL). A escassez de estudos que confirmem se tal fenômeno ocorre em jovens atletas, poderá justificar a possibilidade de considerar CSL diferentes para avaliação e desenvolvimento da capacidade aeróbia nesta população. Os objetivos do presente estudo foram: a) investigar a existência de um “steady-state” das CSL durante uma carga constante de 30 min (realizada a uma intensidade correspondente a 4 mmo/1) em jovens atletas; e b) verificar a existência de possíveis diferenças intra-individuais nas CSL durante o teste. Treze jovens atletas (idade: 16,07 ± 1,38 anos; massa: 61,0 ± 6,69 kg; 171,0 ± 5,6 cm) realizaram um teste incrementai e um teste de carga constante. O teste incrementai foi utilizado para determinar a carga correspondente a uma CSL de 4 mmol/1 ( V 4). Três dias depois os sujeitos realizaram um teste de carga constante de 30 min a uma intensidade correspondente à V 4 previamente determinada. No decorrer de ambos os testes foram recolhidas amostras de sangue capilar do lóbulo da orelha e imediatamente analisadas num analisador sangüíneo enzimático (YSI 1500 L - Sport) para determinação das CSL. Durante o teste constante, as amostras sangüíneas foram recolhidas aos 5o., 10o., 15o., 20o., 25o. e 30o. min. Como procedimentos estatísticos foram utilizados, para além das medidas descritivas, (média e desvio padrão), a análise de variância de medidas repetidas. O valor médio da V4 foi 3,9 ± 0,28 m/s. Dois dos 13 sujeitos foram incapazes de terminar o teste de 30 min (CSL finais de 9,82 e 7,25 mmol/1, respectivamente). De acordo com o critério de Heck et alli (1985c) os restantes sujeitos completaram o teste com CSL médias de 4,15 ± 1,11 mmol/1. As CSL médias nos diferentes momentos (5o., 10o., 15o., 20o., 25o. e 30o. min) do teste constante foram, respectivamente: 4,21; 4,50; 4,67; 4,57; 4,87 e 4,25 mmo/1. Não foram observadas diferenças significativas nas observações repetidas (F(5, 6) = 1,035; p = 0,474), indicando a inexistência de diferenças intra-individuais nas CSL durante o teste de 30 min. Deste modo, concluímos que a carga correspondente a uma CSL de 4 mmol/1 pode ser suportada, por jovens atletas, em condições de “steady-state” Os resultados sugerem que o referencial láctico a adotar na avaliação e treino da capacidade aeróbia em jovens não parece diferir do utilizado em adultos.

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Elman, Ilana, Ana Paula Gines Geraldo, Cristiane Karcher und Maria Elisabeth Machado Pinto e. Silva. „Characterization of umami taste sensitivity in children With and without cancer“. Journal of Human Growth and Development 23, Nr. 2 (23.08.2013): 136. http://dx.doi.org/10.7322/jhgd.61277.

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Resumo Introdução: O gosto umami é proveniente de glutamato e 5 ribonucleotídeos, incluindo inosinato e guanilato, os quais aparecem naturalmente em muitos alimentos. Pode ser identificado pelo glutamato monossódico, sendo considerado como gosto sutil, mas misturando-se bem com outros gostos, expande e incrementa o sabor. Objetivo: Identificar os limiares de detecção do gosto umami em crianças com Leucemia Lonfóide Aguda ou Linfoma não-Hodgkin e em escolares saudáveis, e correlacionar a sensibilidade ao gosto com o estado nutricional, idade e sexo. Método: Foi aplicado teste de sensibilidade de Threshold para determinar o limiar do gosto umami, com 6 concentrações crescentes de água deionizada e glutamato monossódico. Os indivíduos foram pesados e medidos, e calculado o IMC para determinar o estado nutricional. Para as análises estatísticas foram utilizadas versão 2.6.6 do software estatístico R e testes de Mann-Whitney e Kruskal-Wallis com níveis descritivos (p = 0,05). Resultados: a amostra foi contituida de 102 pacientes e 42 escolares, sendo que 74 do sexo masculino (53,9% e 54,8%), 93 eutróficos (63,7% e 69,0%) e 43 na faixa etária de 6 a 9 anos (58,8% e 52,4%), respectivamente. A maioria dos pacientes (92,0%) e escolares (97,4%) eram sensíveis ao gosto umami e tiveram valores de limiar de sensibilidade semelhantes ao gosto umami. Não foi encontrada diferença estatisticamente significante entre os limiares do gosto umami de pacientes sensíveis e escolares, IMC, sexo. Conclusões: a percepção ao gosto umami foi independente do sexo, idade, estado nutricional ou presença de doença.

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Ma, Yonggang, Yue Huang und Tie Liu. „Change and Climatic Linkage for Extreme Flows in Typical Catchments of Middle Tianshan Mountain, Northwest China“. Water 10, Nr. 8 (10.08.2018): 1061. http://dx.doi.org/10.3390/w10081061.

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Due to an absence of an essential daily data set, changing characteristics, and cause of flow extremes in the Tianshan Mountains are rarely explored in depth. In this study, daily based long-term meteorological and hydrological observation data were collected in four typical watersheds in the middle Tianshan Mountains; Manne-Kendall trend analysis and Pettit’s test were used to detect the trends and alterations of extreme flow series; Generalized Extreme Value distribution (GEV) and General Pareto distribution (GDP) models were used to describe the probability distributions of annual maximum (AM) and peaks over threshold (POT) series based on daily discharge; and the relationship between extreme flow and climate indices, were also investigated. The findings indicated that, change of the AM series at five hydrological stations experienced positive trends; the POT series generally showed no significant trends, while the peaks over threshold number (POTN) present a positive trend at the five stations. Change points exist in the POT and occurrence time of maximum daily discharge in spring (AM-SPR) series at the Kensiwate (KSWT) station in Manas watershed; the mean extreme flow decreased after 1986, and the occurrence time the annual maximum daily flow in spring significant forward after 1978. The AM series can well fit the GEV distribution, while the POT series fit the GDP distribution better; the GEV model performed worse in estimating flood events with high return period than low return period events. Moreover, acceleration of glacier melting lead to the magnitude and frequency increments of flood in the north slope; intensifying and frequent precipitation extremes are dominate factors of extreme flow variations in south slope watersheds which without large amount of glacier coverage; and continually temperature rising in spring and increased precipitation in winter lead to the change on magnitude and timing of spring extreme floods.

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Gravelle, Braden M. R., Juan M. Murias, Matthew D. Spencer, Donald H. Paterson und John M. Kowalchuk. „Adjustments of pulmonary O2 uptake and muscle deoxygenation during ramp incremental exercise and constant-load moderate-intensity exercise in young and older adults“. Journal of Applied Physiology 113, Nr. 9 (01.11.2012): 1466–75. http://dx.doi.org/10.1152/japplphysiol.00884.2011.

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The matching of muscle O2 delivery to O2 utilization can be inferred from the adjustments in muscle deoxygenation (Δ[HHb]) and pulmonary O2 uptake (V̇o2p). This study examined the adjustments of V̇o2p and Δ[HHb] during ramp incremental (RI) and constant-load (CL) exercise in adult males. Ten young adults (YA; age: 25 ± 5 yr) and nine older adults (OA; age: 70 ± 3 yr) completed two RI tests and six CL step transitions to a work rate (WR) corresponding to 1) 80% of the estimated lactate threshold (same relative WR) and 2) 50 W (same absolute WR). V̇o2p was measured breath by breath, and Δ[HHb] of the vastus lateralis was measured using near-infrared spectroscopy. Δ[HHb]-WR profiles were normalized from baseline (0%) to peak Δ[HHb] (100%) and fit using a sigmoid function. The sigmoid slope ( d) was greater ( P < 0.05) in OA (0.027 ± 0.01%/W) compared with YA (0.017 ± 0.01%/W), and the c/ d value (a value corresponding to 50% of the amplitude) was smaller ( P < 0.05) for OA (133 ± 40 W) than for YA (195 ± 51 W). No age-related differences in the sigmoid parameters were reported when WR was expressed as a percentage of peak WR. V̇o2p kinetics compared with Δ[HHb] kinetics for the 50-W transition were similar between YA and OA; however, Δ[HHb] kinetics during the transition to 80% of the lactate threshold were faster than V̇o2p kinetics in both groups. The greater reliance on O2 extraction displayed in OA during RI exercise suggests a lower O2 delivery-to-O2 utilization relationship at a given absolute WR compared with YA.

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Hughson, R. L., K. H. Weisiger und G. D. Swanson. „Blood lactate concentration increases as a continuous function in progressive exercise“. Journal of Applied Physiology 62, Nr. 5 (01.05.1987): 1975–81. http://dx.doi.org/10.1152/jappl.1987.62.5.1975.

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The relationship between arterialized blood lactate concentration [( La-]) and O2 uptake (VO2) was examined during a total of 23 tests by eight subjects. Exercise was on a cycle ergometer with work rate incremented from loadless pedaling to exhaustion as a 50-W/min ramp function. Two different mathematical models were studied. One model employed a log-log transformation of [La-] and VO2 to yield [La-] threshold as proposed by Beaver et al. (J. Appl. Physiol. 59: 1936–1940, 1985). The other model was a continuous exponential plus constant of the form La- = a + b[exp(cVO2)]. In 21 of 23 data sets, the mean square error (MSE) of the continuous model was less than that of the log-log model (P less than 0.001). The MSE was on average 3.5 times greater in the log-log model than in the continuous model. The residuals were randomly distributed about the line of best fit for the continuous model. In contrast, the log-log model showed a nonrandom pattern indicating an inappropriate model. As an index of the position of the [La-]-VO2 continuous model, the VO2 at which the rate of increase of [La-] equaled the rate of increase of VO2 (d[La-]/dVO2 = 1) was determined. This VO2 was 2.241 +/- 0.081 l/min, which averaged 64.6% of maximal VO2. It is proposed that this lactate slope index could be used as a relative indicator of fitness instead of the previously applied threshold concept. The change in [La-] could be better described mathematically by a continuous model rather than the threshold model of Beaver et al.

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Pichon-Riviere, Andres, Osvaldo Ulises Garay, Federico Augustovski, Carlos Vallejos, Leandro Huayanay, Maria del Pilar Navia Bueno, Alarico Rodriguez, Carlos José Coelho de Andrade, Jefferson Antonio Buendía und Michael Drummond. „IMPLICATIONS OF GLOBAL PRICING POLICIES ON ACCESS TO INNOVATIVE DRUGS: THE CASE OF TRASTUZUMAB IN SEVEN LATIN AMERICAN COUNTRIES“. International Journal of Technology Assessment in Health Care 31, Nr. 1-2 (2015): 2–11. http://dx.doi.org/10.1017/s0266462315000094.

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Objectives:Differential pricing, based on countries’ purchasing power, is recommended by the World Health Organization to secure affordable medicines. However, in developing countries innovative drugs often have similar or even higher prices than in high-income countries. We evaluated the potential implications of trastuzumab global pricing policies in terms of cost-effectiveness (CE), coverage, and accessibility for patients with breast cancer in Latin America (LA).Methods:A Markov model was designed to estimate life-years (LYs), quality-adjusted life-years (QALYs), and costs from a healthcare perspective. To better fit local cancer prognosis, a base case scenario using transition probabilities from clinical trials was complemented with two alternative scenarios with transition probabilities adjusted to reflect breast cancer epidemiology in each country.Results:Incremental discounted benefits ranged from 0.87 to 1.00 LY and 0.51 to 0.60 QALY and incremental CE ratios from USD 42,104 to USD 110,283 per QALY (2012 U.S. dollars), equivalent to 3.6 gross domestic product per capita (GDPPC) per QALY in Uruguay and to 35.5 GDPPC in Bolivia. Probabilistic sensitivity analysis showed 0 percent probability that trastuzumab is CE if the willingness-to-pay threshold is one GDPPC per QALY, and remained so at three GDPPC threshold except for Chile and Uruguay (4.3 percent and 26.6 percent, respectively). Trastuzumab price would need to decrease between 69.6 percent to 94.9 percent to became CE in LA.Conclusions:Although CE in other settings, trastuzumab was not CE in LA. The use of health technology assessment to prioritize resource allocation and support price negotiations is critical to making innovative drugs available and affordable in developing countries.

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Levi-Mourao, Alexandre, Filipe Madeira, Roberto Meseguer, Addy García und Xavier Pons. „Effects of Temperature and Relative Humidity on the Embryonic Development of Hypera postica Gyllenhal (Col.: Curculionidae)“. Insects 12, Nr. 3 (16.03.2021): 250. http://dx.doi.org/10.3390/insects12030250.

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The combined effect of the temperature and relative humidity on the survival and development time of the eggs of Spanish populations of the weevil Hypera postica, a key pest of alfalfa around the world, was evaluated under laboratory conditions. The experimental temperatures ranged from 8 to 36 °C, in 4 °C increments. Three relative humidity ranges were defined: high, medium, and low. Eggs of the alfalfa weevil successfully developed until larval emergence at all of the 24 conditions tested. However, the temperature and relative humidity affected the survival of the eggs. The egg developmental time decreased as the temperature increased from 8 to 32 °C, and the longest time was recorded at a low relative humidity (RH). The relationship between the development rate and temperature fit well to the lineal model for relative humidity. The minimum development threshold (T0) and the thermal requirement for egg development (K) ranged between 3 and 4 °C and 209 and 246 degree-days, respectively. According to these values and the occurrence of eggs and larvae (in winter) and adults (in autumn) in field samplings, the period of oviposition was determined. The results of the study contribute to better understanding the annual cycle and phenology of H. postica in the Iberian Peninsula and southern Europe.

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Schønning, Kristian, Ole Lund, Ole Søgaard Lund und John-Erik Stig Hansen. „Stoichiometry of Monoclonal Antibody Neutralization of T-Cell Line-Adapted Human Immunodeficiency Virus Type 1“. Journal of Virology 73, Nr. 10 (01.10.1999): 8364–70. http://dx.doi.org/10.1128/jvi.73.10.8364-8370.1999.

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ABSTRACT In order to study the stoichiometry of monoclonal antibody (MAb) neutralization of T-cell line-adapted human immunodeficiency virus type 1 (HIV-1) in antibody excess and under equilibrium conditions, we exploited the ability of HIV-1 to generate mixed oligomers when different env genes are coexpressed. By the coexpression of Env glycoproteins that either can or cannot bind a neutralizing MAb in an env transcomplementation assay, virions were generated in which the proportion of MAb binding sites could be regulated. As the proportion of MAb binding sites in Env chimeric virus increased, MAb neutralization gradually increased. Virus neutralization by virion aggregation was minimal, as MAb binding to HIV-1 Env did not interfere with an AMLV Env-mediated infection by HIV-1(AMLV/HIV-1) pseudotypes of CD4− HEK293 cells. MAb neutralization of chimeric virions could be described as a third-order function of the proportion of Env antigen refractory to MAb binding. This scenario is consistent with the Env oligomer constituting the minimal functional unit and neutralization occurring incrementally as each Env oligomer binds MAb. Alternatively, the data could be fit to a sigmoid function. Thus, these data could not exclude the existence of a threshold for neutralization. However, results from MAb neutralization of chimeric virus containing wild-type Env and Env defective in CD4 binding was readily explained by a model of incremental MAb neutralization. In summary, the data indicate that MAb neutralization of T-cell line-adapted HIV-1 is incremental rather than all or none and that each MAb binding an Env oligomer reduces the likelihood of infection.

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Khaki, Ali Raza, Leonidas Nikolaos Diamantopoulos, Marita Zimmerman, Louis P. Garrison und Petros Grivas. „Assessing the potential cost-effectiveness of the addition of atezolizumab to first-line platinum chemotherapy in advanced urothelial cancer: Implications for value-based pricing.“ Journal of Clinical Oncology 38, Nr. 15_suppl (20.05.2020): 5031. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.5031.

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5031 Background: Data from interim analysis of IMvigor130 trial showed that 1st line treatment of advanced urothelial cancer (aUC) with atezolizumab (Atezo) + platinum-based chemotherapy (PBC) significantly improved progression-free survival (PFS), but not overall survival (OS), vs PBC. Switch maintenance anti-PD(L)1 after completion of PBC as 1st line therapy is an alternate strategy, recently reported to significantly prolong OS. We aimed to compare cost-effectiveness of combined treatment (Atezo+PBC) vs PBC based on IMvigor130. Methods: We used a partitioned-survival model to evaluate the potential cost-effectiveness of treatment with A) Atezo+PBC (gemcitabine with cisplatin or carboplatin) or B) PBC alone with checkpoint inhibitor pembrolizumab at progression (standard-of-care). PFS and OS curves were extracted from IMvigor 130 and parametric models were fit to approximate outcomes with Atezo+PBC with the hazard ratio (HR) from the trial used to project outcomes for PBC alone. We used a health-care payer perspective with a two-year time horizon. Model outputs — costs, life-years, quality-adjusted life years (QALYs) — were used to calculate an incremental cost-effectiveness ratio (ICER). A scenario analysis evaluated the “value-based price” needed for Atezo+PBC to be cost-effective; a one-way sensitivity analysis was also performed. Results: Results of the cost-effectiveness analysis are summarized in the table. The mean projected incremental cost of Atezo+PBC compared to PBC was $59,604 for a mean incremental gain of 0.09 life-years and 0.07 QALYs. This resulted in an ICER of $629,755/life-year and $895,800/QALY, respectively. A 33% reduction would be needed in the price of atezolizumab to make Atezo+PBC cost-effective at an ICER of $150,000/QALY. Results were sensitive to cost of pembrolizumab at progression, the cost of Atezo+PBC, and the OS HR between Atezo+PBC and PBC. Conclusions: Combined chemoimmunotherapy with atezolizumab and PBC would likely not be cost-effective for the first-line treatment of aUC. However, with a price rebate of 33%, it would approach being cost-effective at a widely used cost-effectiveness threshold. [Table: see text]

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Modesto, Francisco José Nunes, Maria Ângela Cruz Macêdo Dos Santos, Tales Miler Soares und Ellen Paula Menezes Dos Santos. „CRESCIMENTO, PRODUÇÃO E CONSUMO HÍDRICO DO QUIABEIRO SUBMETIDO À SALINIDADE EM CONDIÇÕES HIDROPÔNICAS“. IRRIGA 24, Nr. 1 (29.03.2019): 86–97. http://dx.doi.org/10.15809/irriga.2019v24n1p86-97.

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CRESCIMENTO, PRODUÇÃO E CONSUMO HÍDRICO DO QUIABEIRO SUBMETIDO À SALINIDADE EM CONDIÇÕES HIDROPÔNICAS FRANCISCO JOSÉ NUNES MODESTO1; MARIA ÂNGELA CRUZ MACÊDO DOS SANTOS1; TALES MILER SOARES2 E ELLEN PAULA MENEZES DOS SANTOS3 1 Engenheiro Agrônomo, Mestre em Engenharia Agrícola, Universidade Federal do Recôncavo da Bahia, Núcleo de Engenharia de Água e Solo, Rua Rui Barbosa, S/N, Cruz das Almas-BA, CEP 44.380-000, e-mail: fjmodesto@gmail.com; angela_macedo.08@hotmail.com 2 Engenheiro Agrônomo, Prof. Doutor, Universidade Federal do Recôncavo da Bahia, Núcleo de Engenharia de Água e Solo, Rua Rui Barbosa, S/N, Cruz das Almas-BA, CEP 44.380-000, e-mail: talesmiler@gmail.com 3 Graduanda em Engenharia Agronômica na Universidade Federal do Recôncavo da Bahia, Núcleo de Engenharia de Água e Solo, Rua Rui Barbosa, S/N, Cruz das Almas-BA, CEP 44.380-000, e-mail: ellenpaulamenezes@gmail.com 1 RESUMO Pesquisas têm sido conduzidas com uso de águas salobras em cultivos hidropônicos e são estratégicas para o aproveitamento racional dessas águas. Nesse contexto surge o interesse em se pesquisar culturas que estão na demanda dos consumidores, como é o caso do quiabeiro. Objetivou-se com o presente trabalho analisar o consumo hídrico, o crescimento, a produção e a qualidade do quiabeiro, submetido a diferentes níveis de condutividade elétrica em sistema hidropônico. O quiabeiro foi submetido a sete níveis de condutividade elétrica da solução nutritiva (CEsol 2,08; 4,47; 7,90; 9,46; 12,84; 14,82; 18,61 dS m-1). Aos 85 dias após o transplantio foi avaliado o consumo hídrico, eficiência do uso da água (EUA), o crescimento vegetativo, a produção, a qualidade do fruto e o índice de tolerância do quiabeiro. Para a determinação da tolerância à salinidade foi utilizado, dentre outros, o modelo de platô com redução exponencial. A área foliar e o número de folhas foram as variáveis do crescimento mais afetadas com o incremento da CEsol. A EUA teve seu máximo de 7,81 Kg m-3 para a CEsol de 7,08 dS m-1. A salinidade limiar encontrada foi de 5,43 dS m-1. O aumento da CEsol até 18,61 dS m-1 não afetou a qualidade do fruto. PALAVRAS CHAVE: Condutividade elétrica, Abelmoschus esculentus L. (Moench), qualidade da água, cultivo hidropônico. MODESTO, F. J. N.; SANTOS, M. A. C. M. dos; SOARES, T. M.; SANTOS, E. P. M. dos GROWTH, PRODUCTION AND WATER CONSUMPTION OF OKRA SUBJECTED TO SALINITY UNDER HYDROPONIC CONDITIONS 2 ABSTRACT Researches have been conducted using brackish water in hydroponic crops and are strategic for the rational use of these waters. In this context the interest arises in researching cultures that are in the demand of the consumers as it is the case of the okra. The objective of this work was to analyze water consumption, growth, production and quality of okra submitted to different levels of electrical conductivity in a hydroponic system. Okra trees were submitted to seven levels of electrical conductivity of the nutrient solution (ECsol 2.08, 4.47, 7.90, 9.46, 12.84, 14.82, 18.61 dS m-1). At 85 days after transplanting, water consumption, water use efficiency (WUE), vegetative growth, yield, fruit quality and tolerance index of okra were evaluated. For determination of tolerance to salinity was used, among models, the plateau model with exponential reduction. Leaf area and number of leaves were the growth variables most affected with the increment of ECsol. WUE had its maximum of 7.81 kg m-3 for ECsol of 7.08 dS m-1. Threshold salinity found was 5.43 dS m-1. ECsol increase up to 18.61 dS m-1 did not affect fruit quality. Keywords: Eletrical conductivity, Abelmoschus esculentus L. (Moench), water quality, soilless cultivation.

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Idowu, Sunday O. „Computational Antioxidant Capacity Simulation (CAOCS): A Novel Framework of Antioxidant Capacity Profiling“. Chemical Product and Process Modeling 9, Nr. 1 (01.06.2014): 25–43. http://dx.doi.org/10.1515/cppm-2013-0041.

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Abstract Inconsistent ranking is a well-known drawback of antioxidant capacity (AOC) profiling methodologies that use free-radical species as oxidant. This problem leads to assay results that are not biorelevant. Linear free energy relationships (LFER) theory predicts proton transfer (PT) kinetics as a surrogate for biorelevant hydrogen atom transfer (HAT) kinetics. Computational antioxidant capacity simulation (CAOCS), based on real-time proton transfer kinetics modeling (PTKM) of polyphenols and phenol-like small molecules, inspired a novel AOC profiling methodology. Kinetic data acquired by incremental addition of resorcinol to an oxidized probe (phenol red), was fitted to mono-exponential decay equation (MED). Absorbance decay data from strongly antioxidant phenol-like molecules (e.g. ascorbic acid) and a new chromogenic probe (phenolphthalein) was fitted to MED and bi-exponential decay equation. The preferred model and corresponding best-fit rate constant (Kptt) was identified by comparison of fits, using Akaike’s Information Criterion (AICc). Photometric phenolphthalein assay (PPA)-derived metric was normalized with photometric phenol red assay (PPRA) results by using a function developed from proton concentration differential between phenolphthalein and phenol red, with respect to decay threshold to plateau (assay endpoint) interval. pKa dependence of the CAOCS’ metric is a signature of structure–function relationships, and hence, biorelevance. It is shown, unambiguously, that a combination of two phenolic probe molecules, an analytical system devoid of free radicals, and statistical identification of preferred exponential decay fit to PT kinetics data, constitutes a novel algorithm for AOC profiling of polyphenols and phenol-like molecules. This methodology holds a promise of utility in quality assurance of dietary supplements.

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Schurgers, Leon J., Martin J. Shearer, Karly Hamulyák, Elisabeth Stöcklin und Cees Vermeer. „Effect of vitamin K intake on the stability of oral anticoagulant treatment: dose-response relationships in healthy subjects“. Blood 104, Nr. 9 (01.11.2004): 2682–89. http://dx.doi.org/10.1182/blood-2004-04-1525.

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Abstract Oral anticoagulants exert their effect by blocking the utilization of vitamin K, yet little is known about competitive aspects of their interaction with dietary vitamin K. We carried out systematic dose-response studies in healthy volunteers who had been stably anticoagulated and maintained on their individualized doses for 13 weeks. First, we studied the response to weekly incremental doses (50 μg-500 μg) of vitamin K1 supplements (K1) taken daily for 7 days. The threshold K1 dose causing a statistically significant lowering of the INR was 150 μg/day. In 25% of the participants the INR change was regarded as clinically relevant at a vitamin K intake of 150 μg/day. Circulating undercarboxylated osteocalcin did not decrease until 300 μg K1/day compared with 100 μg K1/day for undercarboxylated FII, suggesting differential antidotal effects on bone and hepatic γ-carboxylation. Next, we tested the response to vitamin K-rich food items. The short-lived response after meals of spinach and broccoli suggested an inefficient bioavailability from these 2 sources. We conclude that short-term variability in intake of K1 is less important to fluctuations in the international normalized ratio (INR) than has been commonly assumed and that food supplements providing 100 μg/day of vitamin K1 do not significantly interfere with oral anticoagulant therapy. (Blood. 2004;104:2682-2689)

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Feldman, Tatyana, Denise Zou, Mayvis Rebeira, Joseph Lee, Mack Harris, Wenkang Ma, Michelle A. Fanale et al. „Cost-Effectiveness of brentuximab vedotin with chemotherapy in frontline treatment of CD30-expressing peripheral T-cell lymphoma.“ Journal of Clinical Oncology 37, Nr. 15_suppl (20.05.2019): e19060-e19060. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e19060.

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e19060 Background: The most common frontline treatment for peripheral T-cell lymphoma (PTCL) is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or a CHOP-like regimen. In the recently reported phase 3 ECHELON-2 trial, brentuximab vedotin (BV) in combination with CHP (A+CHP) demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS) compared to CHOP, with a manageable safety profile. The objective of this analysis was to evaluate the cost-effectiveness of A+CHP in the frontline setting for CD30-expressing PTCL. Methods: A partitioned survival model consisting of 3 health states (PFS, post progression survival, and death), was constructed using clinical and quality of life data from ECHELON-2 from a US payer perspective over a lifetime time horizon. PFS and OS observed from ECHELON-2 were extrapolated using standard parametric distributions. The best-fitting distributions (log-normal for both arms) were selected based on statistical goodness of fit and clinical plausibility of the long-term projections. Health utilities were derived from the European Quality of Life 5-Dimensions (EQ-5D) data collected in ECHELON-2. The average utility scores for the pre- and post-progression periods were estimated via a repeated-measures mixed-effects model. Medical resource use and costs were from literature. Results: The model predicted A+CHP extended undiscounted PFS by 2.92 and OS by 3.38 years over CHOP. These survival gains drive the value in the model. After adjusting for quality of life and discounting, A+CHP was associated with 1.79 quality-adjusted life years (QALYs) gained at an incremental cost of $176,842, yielding an incremental cost-effectiveness ratio (ICER) of $98,987. Sensitivity analyses of alternative model assumptions provided ICERs from $64,000 to $154,000. The estimated probability that A+CHP is cost-effective compared with CHOP was 75% at a willingness-to-pay threshold of $150,000. Conclusions: Based on the ECHELON-2 trial data, this analysis showed for patients with previously untreated CD30-expressing PTCL, treatment with BV in combination with CHP is likely to be cost-effective in comparison to CHOP.

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Ferreira, Paulo Afonso, Giovani De Oliveira Garcia, Glauco Vieira Miranda, Flávio Gonçalves de Oliveira und Delfran Batista dos Santos. „TOLERÂNCIA DA VARIEDADE MILHO UFVM 100 À SALINIDADE AVALIADA POR TRÊS MÉTODOS“. IRRIGA 12, Nr. 4 (06.12.2007): 544–56. http://dx.doi.org/10.15809/irriga.2007v12n4p544-556.

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TOLERÂNCIA DA VARIEDADE MILHO UFVM 100 À SALINIDADE AVALIADA POR TRÊS MÉTODOS Paulo Afonso Ferreira 1, Giovanni de Oliveira Garcia 2, Glauco Vieira Miranda3, Flávio Gonçalves de Oliveira4, Delfran Batista dos Santos51 Departamento de Engenharia Agrícola, Universidade Federal de Viçosa, Viçosa, MG, pafonso@ufv.br2 Departamento de Engenharia Rural, Centro de Ciências Agrárias da Universidade Federal do Espírito Santo, Alegre, ES.3 Departamento de Fitotecnia, Universidade Federal de Viçosa, Viçosa, MG.4 Núcleo de Ciências Agrárias, Universidade Federal de Minas Gerais, Montes Claros, MG.5 Escola Agrotécnica Federal do Senhor do Bonfin, Senhor do Bonfin, BA. 1 RESUMO Com objetivo de avaliar a produção relativa e a tolerância à salinidade da variedade de milho UFVM 100 por meio de três métodos de classificação, foi conduzido um experimento em lisímetros de drenagem, sob casa de vegetação, montado no delineamento inteiramente casualizado com sete tratamentos constituído de um irrigado com água doce (sem lixiviação) e seis irrigados com água salina de 1,2 dS m-1, com frações de lixiviação de 40, 30, 20, 15, 10 e 5% da lâmina de irrigação aplicada e três repetições. Os três métodos de classificação da tolerância da cultura à salinidade baseados na condutividade elétrica do extrato da pasta saturada do solo (CEes), déficit relativo de evapotranspiração (fator de sensibilidade ky) e índice diário de estresse hídrico (WSDI), conduzem a resultados diferentes. A produção relativa da variedade de milho UFVM 100 decresce 6,85% e 15,68% , respectivamente, com incrementos unitários do WSDI e da CEes além da salinidade limiar de 1,20 dS m-1. UNITERMOS: Índice diário de estresse hídrico, lisímetro de drenagem, água salina FERREIRA, P.A.; GARCIA, G.O. de; MIRANDA, G.V.; OLIVEIRA, F.G.de; SANTOS, D.B.dos. UFVM 100 MAIZE TOLERANCE TO SALINITY EVALUATED BY THREE METHODS 2 ABSTRACT Relative yield and UFVM 100 maize tolerance to salinity were evaluated by three classification methods. The experiment was carried out in drainage lysimeters under greenhouse conditions. The entirely randomized experimental design was used with seven treatments, being the first one irrigated with non saline water (without leaching) and the other ones irrigated with saline water of 1.20 dS m-1 and leaching fractions of 40, 30, 20, 15, 10 and 5% of the applied irrigation depth and three replicates. Those three classification methods for UFVM 100 maize tolerance to salinity, based on electric conductivity of the saturated soil paste extract (CEes), relative evapotranspiration deficit (sensibility factor- ky) and water stress daily index (WSDI) led to different results. The relative yield of the UFVM 100 maize decreases down to 6.85% and 15.68%, respectively, with unitary increments in WSDI and CEes beyond the salinity threshold of 1.20 dS m-1;KEYWORDS: Water stress daily index, drainage lysimeter, saline water

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Zhou, Zheng-Yi, Kejal Parikh, Xinglei Chai, Ariel Rokito, Chuka Udeze, Jipan Xie und Amit Agarwal. „Cost-Effectiveness Analysis of Lenalidomide for Maintenance Therapy after Autologous Stem Cell Transplant (ASCT) in Newly Diagnosed Multiple Myeloma (NDMM) Patients: A United States Payer Perspective“. Blood 132, Supplement 1 (29.11.2018): 3535. http://dx.doi.org/10.1182/blood-2018-99-112942.

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Abstract Introduction: ASCT in multiple myeloma (MM) is associated with prolonged progression-free survival (PFS) compared with chemotherapy alone. Studies have shown that lenalidomide maintenance therapy after ASCT significantly improves PFS and overall survival (OS) in patients (pts) with NDMM. Although post-ASCT lenalidomide maintenance therapy is approved by the US FDA and the EMA for pts with MM, a small percentage of pts either use bortezomib or no maintenance in this setting. The current study aimed to assess the cost-effectiveness of lenalidomide maintenance versus no treatment or bortezomib maintenance after ASCT in pts with NDMM from a US third-party payer perspective. Methods: A partitioned survival model with a 28-day cycle was developed to estimate costs and outcomes of lenalidomide maintenance versus either no treatment or bortezomib maintenance therapy after ASCT among pts with NDMM over a lifetime time horizon. The model included four health states: PFS on treatment, PFS off treatment, progressed disease, and death. The OS and PFS for lenalidomide and no treatment arms were estimated using observed data from the phase 3 CALGB trial. Crossover adjustment was implemented to adjust for the potential diluting effects introduced by pts crossing over to lenalidomide from the no treatment arm before progression in the CALGB trial. Time on treatment for lenalidomide was estimated using the observed data in the pooled phase 3 trials (CALGB, IFM, GIMEMA). Efficacy inputs for bortezomib maintenance were estimated based on published literature. Standard parametric models were fitted to extrapolate OS and PFS for each treatment, and best fit was determined based on Akaike or Bayesian information criterion and clinical judgement. OS was adjusted using natural mortality rates in the USA. Treatment costs (including drug and drug administration costs), post-progression treatment costs, adverse event (AE) costs, and medical costs associated with health states were obtained from publicly available databases, literature, and real-world data. All costs were inflated to 2018 US dollars. Utilities for each health state and disutilities associated with AEs were obtained from the literature. Incremental costs per quality-adjusted life year (QALY) and life year (LY) gained were estimated comparing lenalidomide maintenance therapy with each comparator. Deterministic sensitivity analyses (DSAs) were performed to test the robustness of the results. Results: Over a lifetime time horizon, lenalidomide maintenance was associated with an increase of 3.64 and 2.76 in LYs compared with no treatment and bortezomib maintenance, respectively; and an increase of 2.99 and 2.42 in QALYs, respectively. Pts in the lenalidomide maintenance arm incurred higher total direct costs with an incremental cost of $476,690 and $412,872 versus no treatment and bortezomib maintenance, respectively. Initial and post-progression treatment costs comprised the majority of direct costs. The annual treatment costs for lenalidomide maintenance decreased by 49% and 86%, 3 years and 5 years after treatment initiation, respectively. Incremental cost per LY gained for lenalidomide maintenance versus no treatment and bortezomib maintenance was $130,817 and $149,411, respectively, and incremental cost per QALY gained was $159,240 and $170,408, respectively. The base-case results suggest that lenalidomide is cost-effective at a willingness-to-pay threshold of $200,000. Results from the DSA generally supported the base-case findings, with the largest variation observed when time horizon and treatment costs for lenalidomide were varied. Longer time horizons yielded greater cost-effectiveness for lenalidomide because of the reduction in treatment costs and increased effectiveness benefits. Lower initial treatment costs also yielded greater cost-effectiveness for lenalidomide. Conclusions: Over a lifetime time horizon, compared to no treatment and treatment with bortezomib, lenalidomide maintenance resulted in better effectiveness with incremental QALYs of 2.99 and 2.42, respectively, favorable incremental cost-effectiveness ratios, and an OS advantage. Annual treatment costs for lenalidomide decrease with incremental effectiveness increasing over time. Lenalidomide maintenance after ASCT offers a cost-effective strategy in the treatment of pts with NDMM from a US third-party payer perspective. Disclosures Zhou: Celgene Corporation: Research Funding; Analysis Group, Inc.: Employment. Parikh:Celgene Corporation: Employment, Equity Ownership. Chai:Celgene Corporation: Research Funding; Analysis Group, Inc.: Employment. Rokito:Analysis Group, Inc.: Employment; Celgene Corporation: Research Funding. Udeze:Celgene Corporation: Employment. Xie:Celgene Corporation: Research Funding; Analysis Group, Inc.: Employment. Agarwal:Celgene Corporation: Employment.

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Westwood, Marie, Isaac Corro Ramos, Shona Lang, Marianne Luyendijk, Remziye Zaim, Lisa Stirk, Maiwenn Al, Nigel Armstrong und Jos Kleijnen. „Faecal immunochemical tests to triage patients with lower abdominal symptoms for suspected colorectal cancer referrals in primary care: a systematic review and cost-effectiveness analysis“. Health Technology Assessment 21, Nr. 33 (Mai 2017): 1–234. http://dx.doi.org/10.3310/hta21330.

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BackgroundColorectal cancer (CRC) is the third most common cancer in the UK. Presenting symptoms that can be associated with CRC usually have another explanation. Faecal immunochemical tests (FITs) detect blood that is not visible to the naked eye and may help to select patients who are likely to benefit from further investigation.ObjectivesTo assess the effectiveness of FITs [OC-Sensor (Eiken Chemical Co./MAST Diagnostics, Tokyo, Japan), HM-JACKarc (Kyowa Medex/Alpha Laboratories Ltd, Tokyo, Japan), FOB Gold (Sentinel/Sysmex, Sentinel Diagnostics, Milan, Italy), RIDASCREEN Hb or RIDASCREEN Hb/Hp complex (R-Biopharm, Darmstadt, Germany)] for primary care triage of people with low-risk symptoms.MethodsTwenty-four resources were searched to March 2016. Review methods followed published guidelines. Summary estimates were calculated using a bivariate model or a random-effects logistic regression model. The cost-effectiveness analysis considered long-term costs and quality-adjusted life-years (QALYs) that were associated with different faecal occult blood tests and direct colonoscopy referral. Modelling comprised a diagnostic decision model, a Markov model for long-term costs and QALYs that were associated with CRC treatment and progression, and a Markov model for QALYs that were associated with no CRC.ResultsWe included 10 studies. Using a single sample and 10 µg Hb/g faeces threshold, sensitivity estimates for OC-Sensor [92.1%, 95% confidence interval (CI) 86.9% to 95.3%] and HM-JACKarc (100%, 95% CI 71.5% to 100%) indicated that both may be useful to rule out CRC. Specificity estimates were 85.8% (95% CI 78.3% to 91.0%) and 76.6% (95% CI 72.6% to 80.3%). Triage using FITs could rule out CRC and avoid colonoscopy in approximately 75% of symptomatic patients. Data from our systematic review suggest that 22.5–93% of patients with a positive FIT and no CRC have other significant bowel pathologies. The results of the base-case analysis suggested minimal difference in QALYs between all of the strategies; no triage (referral straight to colonoscopy) is the most expensive. Faecal immunochemical testing was cost-effective (cheaper and more, or only slightly less, effective) compared with no triage. Faecal immunochemical testing was more effective and costly than guaiac faecal occult blood testing, but remained cost-effective at a threshold incremental cost-effectiveness ratio of £30,000. The results of scenario analyses did not differ substantively from the base-case. Results were better for faecal immunochemical testing when accuracy of the guaiac faecal occult blood test (gFOBT) was based on studies that were more representative of the correct population.LimitationsOnly one included study evaluated faecal immunochemical testing in primary care; however, all of the other studies evaluated faecal immunochemical testing at the point of referral. Further, validation data for the Faecal haemoglobin, Age and Sex Test (FAST) score, which includes faecal immunochemical testing, showed no significant difference in performance between primary and secondary care. There were insufficient data to adequately assess FOB Gold, RIDASCREEN Hb or RIDASCREEN Hb/Hp complex. No study compared FIT assays, or FIT assays versus gFOBT; all of the data included in this assessment refer to the clinical effectiveness of individual FIT methods andnottheir comparative effectiveness.ConclusionsFaecal immunochemical testing is likely to be a clinically effective and cost-effective strategy for triaging people who are presenting, in primary care settings, with lower abdominal symptoms and who are at low risk for CRC. Further research is required to confirm the effectiveness of faecal immunochemical testing in primary care practice and to compare the performance of different FIT assays.Study registrationThis study is registered as PROSPERO CRD42016037723.FundingThe National Institute for Health Research Health Technology Assessment programme.

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Gandjour, Afschin, Nadja Chernyak, Andrea Icks und Amiram Gafni. „Public acceptance of different approaches to determine drug reimbursement prices and whether it is influenced by framing“. International Journal of Public Sector Management 27, Nr. 6 (05.08.2014): 501–11. http://dx.doi.org/10.1108/ijpsm-06-2013-0083.

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Purpose – In Germany, the Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG)) makes recommendations for reimbursement prices of drugs based on an evaluation of the relationship between incremental costs and effects. In 2009, the German government (“Koalitionsvertrag”) announced its intention to evaluate the transparency and acceptability of IQWiG's work. The purpose of this paper is to conduct a survey of a sample of the German population: to check the acceptance of the IQWiG's decision rule compared to a decision rule used in countries such as England and Wales; and to test if the way the IQWiG's decision rule is presented affects its acceptance. Design/methodology/approach – A questionnaire was developed eliciting acceptability of IQWiG's decision rule and a single cost-effectiveness threshold applying to all diseases (i.e. absolute rule (AR)). To check for a framing effect IQWiG's decision rule was presented in two ways. One version presented it, based on IQWiG's official publication, as a constant ratio between incremental costs and effects within a therapeutic area (proportional rule (PR), Version 1). The other version presented it in terms of a proportional relationship between costs and effects within a therapeutic area (PR, Version 2). χ 2 goodness of fit test and two-proportion z-test tested for differences between acceptance rates of decision rules. Findings – A sample of 108 persons from the general public (average age: 41 years, 48 per cent male) filled out the questionnaire. Acceptance rates for AR, PR Version 1, and PR Version 2 were 33, 48, and 39 per cent, respectively. Direct comparisons show that acceptance of PR Version 1 was significantly higher than acceptance of AR (p=0.026) and that there was a clear trend towards higher acceptance of PR Version 1 compared to Version 2 (p=0.22). The difference between PR Version 2 and AR was not significant (p=0.32). Research limitations/implications – In our study, different presentations of the IQWiG decision rule did not significantly alter its acceptance, although there was a clear trend towards accepting IQWiG's official version. Furthermore, the acceptance of the IQWiG's official version was significantly higher than AR. Because of the relevance of the research question we recommend additional research for confirmation and explanation of the choices made. Originality/value – This is one of the few studies on the impact of framing on allocation preferences in health care.

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Papadakis, Konstantinos, David Oscier, Emma SC Carr, Gavin Lewis und Rick Aultman. „A UK Cost-Effectiveness Analysis Comparing First Line Treatment with Rituximab in Combination with Fludarabine and Cyclophosphamide Versus Fludarabine and Cyclophosphamide Alone in Chronic Lymphocytic Leukemia (CLL) Patients“. Blood 112, Nr. 11 (16.11.2008): 2392. http://dx.doi.org/10.1182/blood.v112.11.2392.2392.

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Abstract Introduction: This analysis assesses whether Rituximab added to a Fludarabine Cyclophosphamide regimen (R-FC) is a cost-effective first-line treatment option for previously untreated CLL patients, using evidence from the phase III randomised controlled trial, ML17102 (CLL8) (Hallek et al., ASH 2008). In this trial, R-FC significantly prolonged the primary endpoint of progression–free survival (PFS) compared to FC alone and was well tolerated with no unexpected safety signals. Methods: A cost-effectiveness model was developed to evaluate the life-time health outcomes and direct costs of R-FC compared to FC as first-line treatment for CLL patients in the UK. Patients were modelled to be in one of three health states; PFS, Progressed or Death. The best parametric fit (Weibull) was used to extrapolate PFS beyond the end of the CLL8 trial follow-up period to a 15 year life-time horizon. The number of patients in each treatment arm that died while in PFS was based on the maximum of either the observed rate of death or background mortality. Because median overall survival had not been reached in CLL-8, a Markov process was used to model the transition from the progressed health state to death. Given the non significant difference in post progression survival by treatment (R-FC or FC), patients transitioning from progression to death were modelled as a single population with mean time to death (Kaplan-Meier) converted to a monthly probability of dying. This approach is conservative in that treatment benefit is exclusively a function of time spent in PFS. This Markovian approach is conservative in that treatment benefit is exclusively a function of time spent in PFS. Predicted time in each health state was weighted using CLL utility scores (Hancock et. al. 2002) to account for patient quality of life and estimate the Quality Adjusted Life Years (QALYs). Drug administration, patient monitoring and pharmacy costs were taken from the NHS schedule of reference costs 2006 and the published literature. Blood transfusions, bone marrow transplants, stem cell therapy and second line CLL treatments collected prospectively in CLL8 were included in monitoring costs. The cost of treatment related grade 3 or 4 infections were not included in the analysis as the incidence between the two treatment arms was comparable (Hallek et al., ASH 2008). Both costs and outcomes were discounted by 3.5%. RESULTS: R-FC improves mean life expectancy by 1.33 years compared to FC alone. After adjusting for quality of life, the incremental quality-adjusted life expectancy estimated was 1.06 years. Improvements in health outcomes were attributed to an increase in the time R-FC patients spent in the PFS health state (1.17 years).Total direct costs were higher for R-FC by £13,081 per patient, however, this was partially offset by a reduction in medication and monitoring costs incurred in the progressed health state. The incremental cost-effectiveness ratios (ICERs) were estimated to be £9558 per Life Year Gained with R-FC. When health-related quality of life was taken into account, the ICER was £12,387 per QALY gained for R-FC, well below commonly accepted thresholds in the UK. Although there is uncertainty associated with the progression of CLL and relapse treatment costs, the ICER did not exceed £22,458 per QALY despite a wide variation in each parameter value used in the probabilistic sensitivity analysis. CONCLUSIONS: Based on the significant prolongation of PFS demonstrated in CLL8, first-line R-FC substantially increases quality-adjusted life expectancy for CLL patients and is well within the UK threshold of cost-effectiveness. The sensitivity analysis provides adequate reassurance that the cost-effectiveness of R-FC held under most plausible scenarios.

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Flowers, C. R., J. C. Sambrook, A. Briggs, K. Osenenko, H. Wang und M. R. Dalal. „Cost-effectiveness of tositumomab and iodine I-131 tositumomab (Bexxar therapeutic regimen (BTR)), in treatment of non- Hodgkin lymphoma (NHL)“. Journal of Clinical Oncology 25, Nr. 18_suppl (20.06.2007): 8089. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.8089.

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8089 Background: BTR has demonstrated efficacy in NHL patients and it has potential to prolong time to progression (TTP) in relapsed/refractory, low grade, follicular, or transformed NHL. This study assessed effectiveness and cost-effectiveness of BTR compared to alternative therapies in first, second, and third line NHL therapy. Methods: Time-to-event models were constructed with 2 events: progression and death. Patient data from 8 BTR clinical trials were combined to fit Weibull models for TTP and overall survival (OS) by including FLIPI covariates. Estimates for BTR were compared with estimates for alternatives from Weibull models fitted to published TTP and BTR OS data by lines of therapy and measured in life-years (LY). Estimated pre-progression costs included drug costs, lab tests, monitoring, and adverse events; post progression costs included NHL costs until death, all valued in 2006 $US and discounted at 3%. Indirect comparisons yielded incremental cost-effectiveness ratios (ICER=Δ cost/Δ LYs) in each line of therapy. Results: As observed in the table , cost of care estimates in BTR were often comparable with alternative therapies, but typically LY gain favored BTR. Mostly in first and third line, a BTR strategy had an ICER less than the cost-effectiveness threshold of $50,000 per LY gained. Conclusion: Overall, a BTR strategy has a favorable cost-effectiveness profile to alternative strategies including rituximab maintenance (RXM) in first, second, and third line NHL therapy. Results imply both a possible survival gain with early BTR use, and the cost-effectiveness of BTR. This modeling approach can aid in clinical decision making regarding the sequence and timing of therapy for patients with follicular NHL. No significant financial relationships to disclose. [Table: see text]

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Imredy, John P., Jacob R. Penniman, Spencer J. Dech, Winston D. Irving und Joseph J. Salata. „Modeling of the adrenergic response of the human IKs current (hKCNQ1/hKCNE1) stably expressed in HEK-293 cells“. American Journal of Physiology-Heart and Circulatory Physiology 295, Nr. 5 (November 2008): H1867—H1881. http://dx.doi.org/10.1152/ajpheart.433.2008.

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Stable coexpression of human (h)KCNQ1 and hKCNE1 in human embryonic kidney (HEK)-293 cells reconstitutes a nativelike slowly activating delayed rectifier K+ current (HEK- IKs), allowing β-adrenergic modulation of the current by stimulation of endogenous receptors in the host cell line. HEK- IKs was enhanced two- to fourfold by isoproterenol (EC50 = 13 nM), forskolin (10 μM), or 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate (50 μM), indicating an intact cAMP-dependent ion channel-regulating pathway analogous to the PKA-dependent regulation observed in native cardiac myocytes. Activation kinetics of HEK- IKs were accurately fit with a novel modified second-order Hodgkin-Huxley (H-H) gating model incorporating a fast and a slow gate, each independent of each other in scale and adrenergic response, or a “heterodimer” model. Macroscopically, β-adrenergic enhancement shifted the current activation threshold to more negative potentials and accelerated activation kinetics while leaving deactivation kinetics relatively unaffected. Modeling of the current response using the H-H model indicated that observed changes in gating could be explained by modulation of the opening rate of the fast gate. Under control conditions at nearly physiological temperatures (35°C), rate-dependent accumulation of HEK- IKs was observed only at pulse frequencies exceeding 3 Hz. Rate-dependent accumulation of IKs at high pulsing rate had two phases, an initial staircaselike effect followed by a slower, incremental accumulation phase. These phases are readily interpreted in the context of a heterodimeric H-H model with two independent gates with differing closing rates. In the presence of isoproterenol after normalizing for its tonic effects, rate-dependent accumulation of HEK- IKs appeared at lower pulse frequencies and was slightly enhanced (∼25%) over control.

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Lee, H. S., L. Hannes, M. Vancamelbeke, V. Ballet, M. Ferrante, S. Vermeire und I. Cleynen. „DOP46 Impact of a genetic burden on familial aggregation of inflammatory bowel disease“. Journal of Crohn's and Colitis 14, Supplement_1 (Januar 2020): S085. http://dx.doi.org/10.1093/ecco-jcc/jjz203.085.

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Abstract Background Family history of inflammatory bowel disease (IBD) is the strongest risk factor for IBD. There currently, however, is limited understanding of the contribution of genetic risk to familial aggregation of IBD. We aimed to evaluate the association between the IBD polygenic risk score (PRS) and familial IBD, and determine its contribution to familial IBD. Methods We included 54 multiple-affected families (≥3 first-degree relatives affected) of European ancestry, including 189 affected IBD patients (156 Crohn’s disease; 33 ulcerative colitis), and 133 unaffected relatives. For all individuals, Immunochip genotypes were available. Weighted PRSs with estimates derived from literature were calculated using PRSice-2.0, including clumping and different p-value thresholds (pT) to select which variants to include in the score. Explained variance (Nagelkerke pseudo-R²) was calculated across different pTs. To account for possible intra-familial correlations, the association between PRS and familial IBD was evaluated in age- and sex-adjusted generalised mixed regression models including family as random effects. Sporadic cases (n = 1768) and non-IBD controls (n = 868) with Immunochip genotypes were used for comparison. Results Using pT = 0.05 for PRS calculation, we found that affected relatives had a higher PRS than unaffected relatives (p = 1.00 × 10−2), sporadic cases (p = 4.58 × 10−2), and non-IBD controls (p < 2.20 × 10−16) (Figure 1a and b). The risk of disease in families increased by 1.23-fold (95% confidence interval (CI) 1.21–1.24) for every incremental standard deviation in PRS. Individuals in the highest quartile had a 3.45 times higher risk of IBD (95% CI 1.77–6.72) than those in the lowest quartile. However, the proportion of the explained variance between affected and unaffected family members was smaller than that of sporadic IBD and non-IBD controls; and the best pT was different for familial or sporadic IBD. In familial IBD, the best-fit PRS was at pT = 6.90 × 10−3 and explained 5.3% (Figure 1c, p = 3.07 × 10−4) of variance, whereas, in sporadic IBD, the best-fit PRS was at pT = 0.08 and explained 16.7% (Figure 1d, p = 8.48 × 10−63). For sporadic IBD, a typical increase in the proportion of variance explained was seen with more liberal p-value thresholds and levelling off at ~pT = 0.1 (Figure 1d). What was striking, however, was that in familial IBD this additive genetic variance was only observed until pT = 0.01, after which explained variance dropped dramatically (Figure 1c). Conclusion Higher IBD polygenic risk increases the risk for familial IBD as it does for sporadic IBD. In sporadic IBD, the increased risk is defined by variants of all p-value levels (until ~pT = 0.1). In familial IBD, the difference between those affected or not is in the higher-effect variants (p < 0.01).

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Mezzani, Alessandro, Bruno Grassi, Andrea Giordano, Ugo Corrà, Silvia Colombo und Pantaleo Giannuzzi. „Age-related prolongation of phase I of V̇o2 on-kinetics in healthy humans“. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 299, Nr. 3 (September 2010): R968—R976. http://dx.doi.org/10.1152/ajpregu.00739.2009.

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Data are lacking regarding age-related modifications of phase I (PhI) of pulmonary V̇o2 on-kinetics during moderate-intensity exercise. We studied three groups (aged 20–30, 40–50, and 60–70 years) of 10 normal subjects, who underwent one incremental and four below-gas exchange threshold constant-power cardiopulmonary exercise tests. Data from constant-power tests were time-aligned and averaged, and the PhI-phase II transition (PhI-IItr) determined when a sharp decrease from baseline of respiratory exchange ratio occurred. The V̇o2 phase II time constant (τ) was obtained by an exponential fitting starting 1) from PhI-IItr (“experimental” fitting strategy) and 2) after 20 s from exercise onset (“fixed-duration” fitting strategy). Assuming estimated arterial-venous O2 concentration difference not to change with respect to resting value, cardiac output (CO) values at rest and PhI-IItr were obtained according to Fick's principle. Average pulmonary flow acceleration (AFA) during PhI was calculated as the ratio between CO increase during PhI and PhI duration. PhI duration was related to age ( r = 0.74, P < 0.0001), increasing from 21 ± 3 s to 27 ± 3 s to 32 ± 4 s in the 20–30, 40–50, and 60–70 age groups, respectively, and to AFA ( r = −0.60, P < 0.001), but not to CO increase during PhI. With respect to the experimental fitting strategy, the fixed-duration strategy overestimated V̇o2 phase II τ the more the higher the subject's age, with a lower goodness of fit in the 60–70 group (SE 0.035 vs. 0.056, P < 0.01). In conclusion, PhI duration is related to age in healthy male humans and is linked to CO acceleration—rather than to increase—during PhI. A significant overestimation of phase II τ thus may occur in healthy elderly subjects and patients with a pathologically induced longer PhI duration when fitting data where the PhI-PhIItr was not experimentally determined but assumed to be a set value (i.e., 20 s).

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Gottermeier, Linda, und Carol De Filippo. „Patterns of Aided Loudness Growth in Experienced Adult Listeners with Early-Onset Severe–Profound Hearing Loss“. Journal of the American Academy of Audiology 29, Nr. 06 (Juni 2018): 457–76. http://dx.doi.org/10.3766/jaaa.16060.

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AbstractIndividuals with early-onset severe–profound bilateral hearing loss (S/PHL) manifest diverse levels of benefit and satisfaction with hearing aids (HAs), even with prescriptive HA fitting. Such fittings incorporate normal loudness values, but little is known about aided loudness outcomes in this population and how those outcomes affect benefit or satisfaction.To describe aided loudness growth and satisfaction with aided listening in experienced adult HA users with S/PHL.The Contour Test of loudness perception was administered to listeners with S/PHL in the aided sound field using broadband speech, band-limited speech, and warble tones. Patterns and slopes of resultant loudness growth functions were referenced to sound field results from listeners with normal hearing (NH). S/PHL listeners also rated their aided listening satisfaction. It was expected that (1) most S/PHL listeners would demonstrate steeper than normal aided loudness growth, (2) loudness normalization would be associated with better high-frequency detection thresholds and speech recognition, and (3) closer approximation to normal would yield greater satisfaction.Participants were paid college-student volunteers: 23 with S/PHL, long-term aided listening experience, and new HAs; 15 with NH.Participants rated loudness on four ascending runs per stimulus (5-dB increments) using categories defined in 1997 by Cox and colleagues. The region between the 10th and 90th percentiles of the NH distribution constituted local norms against which location and slope of the S/PHL functions were examined over the range from Quiet to Loud-but-OK. S/PHL functions were categorized on the basis of their configurations (locations/slopes) relative to the norms.Pattern of aided loudness was normalized or within 5 dB of the normal region on 37% of trials with sufficient data for analysis. Only one of the 23 S/PHL listeners did not demonstrate Normal/Near-normal loudness on any trials. Four nonnormal patterns were identified: Steep (recruitment-like; 38% of trials); Shifted right, with normal growth rate (10%); Hypersensitive, with most intensities louder than normal (10%); and Shallow, with decreasing growth rate (7%). Listeners with high-frequency average thresholds above 100 dB hearing loss or no phonemic-based speech-discrimination skill were less likely to display normalized loudness. Slope was within norms for 52% of S/PHL trials, most also having a Normal/Near-normal growth pattern. Regardless of measured loudness results, all but four listeners with S/PHL reported satisfactory hearing almost always or most of the time with their HAs in designated priority need areas.The variety of aided loudness growth patterns identified reflects the diversity known to characterize individuals with early-onset S/PHL. Loudness rating at the validation stage of HA fit with these listeners is likely to reveal nonnormal loudness, signaling need for further HA adjustment. High satisfaction, however, despite nonnormal loudness growth, suggests that listeners with poor auditory speech recognition may benefit more from aided loudness that supports pattern perception (via the time-intensity waveform of speech), different from most current-day prescription fits.

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lo Storto, Corrado. „Benchmarking operational efficiency in the integrated water service provision“. Benchmarking: An International Journal 21, Nr. 6 (30.09.2014): 917–43. http://dx.doi.org/10.1108/bij-11-2012-0076.

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Purpose – This is a benchmarking study and the purpose of this paper is to investigate if there is any association between operational efficiency in the integrated water management industry in Italy and the typology of service providers, and as a consequence, the nature of concession contract. Design/methodology/approach – The study is focussed on 38 optimal territorial areas (ATOs), e.g. a circumscribed geographical area where the provision of integrated water services is considered efficient. It uses Data Envelopment Analysis (DEA) to calculate ATO efficiency and a stepwise regression procedure performed to investigate the effect of contract type on the operational efficiency rate of the ATO. Findings – This study shows that there are some inefficiencies in the water service supply industry in Italy. The estimated average pure technical and scale efficiency of ATOs are 92.62 and 93.91 percent, respectively, while the average technical efficiency is 87.61 percent and the lowest is slightly higher than 13 percent. Operational inefficiencies might not be determined by size only. In fact, results show that the water service provider and contract agreement typologies are associated with efficiency. In particular, operational efficiency is higher in those ATOs where the water service supply concession contracts that fit the schemes of the new legislative framework prevail or where the service is mostly provided by a private equity owned or by mixed public-private companies. Research limitations/implications – It was assumed that any incremental level of water quality beyond the minimum acceptable threshold as required by law is not important to increase the operation efficiency score; henceforth, no variables measuring the water quality were introduced in the DEA model. The result of the study may be not fully representative of the Italian water service sector, because the unavailability of accurate and consistent public databank in Italy did not allowed to have a larger sample. Practical implications – This paper is one of the first in Italy to investigate the association between the operational efficiency of the ATOs and the nature of water service providers and contract agreements used. Originality/value – This paper is one of the first in Italy to investigate the association between the operational efficiency of the ATOs and the nature of water service providers and contract agreements used.

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Langsetmo, I., G. E. Weigle, M. R. Fedde, H. H. Erickson, T. J. Barstow und D. C. Poole. „V˙o 2 kinetics in the horse during moderate and heavy exercise“. Journal of Applied Physiology 83, Nr. 4 (01.10.1997): 1235–41. http://dx.doi.org/10.1152/jappl.1997.83.4.1235.

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Langsetmo, I., G. E. Weigle, M. R. Fedde, H. H. Erickson, T. J. Barstow, and D. C. Poole.V˙o 2 kinetics in the horse during moderate and heavy exercise. J. Appl. Physiol. 83(4): 1235–1241, 1997.—The horse is a superb athlete, achieving a maximal O2 uptake (∼160 ml ⋅ min−1 ⋅ kg−1) approaching twice that of the fittest humans. Although equine O2 uptake (V˙o 2) kinetics are reportedly fast, they have not been precisely characterized, nor has their exercise intensity dependence been elucidated. To address these issues, adult male horses underwent incremental treadmill testing to determine their lactate threshold (Tlac) and peakV˙o 2(V˙o 2 peak), and kinetic features of theirV˙o 2 response to “square-wave” work forcings were resolved using exercise transitions from 3 m/s to a below-Tlac speed of 7 m/s or an above-Tlac speed of 12.3 ± 0.7 m/s (i.e., between Tlac andV˙o 2 peak) sustained for 6 min. V˙o 2 and CO2 output were measured using an open-flow system: pulmonary artery temperature was monitored, and mixed venous blood was sampled for plasma lactate.V˙o 2 kinetics at work levels below Tlac were well fit by a two-phase exponential model, with a phase 2 time constant (τ1 = 10.0 ± 0.9 s) that followed a time delay (TD1 = 18.9 ± 1.9 s). TD1 was similar to that found in humans performing leg cycling exercise, but the time constant was substantially faster. For speeds above Tlac, TD1 was unchanged (20.3 ± 1.2 s); however, the phase 2 time constant was significantly slower (τ1 = 20.7 ± 3.4 s, P < 0.05) than for exercise below Tlac. Furthermore, in four of five horses, a secondary, delayed increase inV˙o 2 became evident 135.7 ± 28.5 s after the exercise transition. This “slow component” accounted for ∼12% (5.8 ± 2.7 l/min) of the net increase in exercise V˙o 2. We conclude that, at exercise intensities below and above Tlac, qualitative features ofV˙o 2 kinetics in the horse are similar to those in humans. However, at speeds below Tlac the fast component of the response is more rapid than that reported for humans, likely reflecting different energetics of O2utilization within equine muscle fibers.

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Delea, Thomas, Nicholas Despiegel, Diana Boyko, Jordan Amdahl, Ze Cong und Jerald Radich. „Cost-Effectiveness of Blinatumomab Versus Standard of Care in Adult Patients with Philadelphia-Chromosome-Negative B-Precursor Acute Lymphoblastic Leukemia in First Hematological Complete Remission (CR) with Minimal Residual Disease (MRD) from a US Payer Perspective“. Blood 132, Supplement 1 (29.11.2018): 4746. http://dx.doi.org/10.1182/blood-2018-99-115230.

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Abstract INTRODUCTION: Blinatumomab is a bispecific CD19 directed CD3 T cell engager indicated for the treatment of adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission (CR) with minimal residual disease (MRD) greater than or equal to 0.1%. In BLAST (NCT01207388), an open-label, multicenter, single-arm, phase 2 study of blinatumomab in patients with MRD positive B-precursor ALL in hematological CR, blinatumomab resulted in complete MRD response in cycle 1 in 78% of patients. Overall survival (OS) was significantly better in those with MRD vs those without MRD. The objective of this study is to evaluate the cost-effectiveness of blinatumomab vs. standard of care (SOC) therapy in patients with Ph- B-cell precursor ALL in first hematological CR with MRD based on the BLAST study from a US healthcare payer perspective. METHODS: A partitioned survival model was used to estimate the incremental cost-effectiveness ratio (ICER) of blinatumomab vs. SOC maintenance. A 50-year lifetime horizon and US payer perspective were employed. Costs and outcomes were discounted at 3% annually. Probabilities of complete MRD response, relapse-free survival (RFS), OS, numbers of cycles of blinatumomab and SOC, and transplant rates were estimated from BLAST and a historical cohort comparator study using propensity score analyses. RFS and OS were based on parametric survival distributions fit to individual patient failure-time data. Utility values were based from a generalized linear model/generalized estimating equation (GLM/GEE) model fitted to EQ-5D data collected in BLAST applying US tariffs. Inpatient and outpatient healthcare use by MRD status was from an observational study which evaluated treatment patterns and healthcare resource utilization in adult B-cell precursor ALL in first hematological CR with and without MRD. Deterministic and probabilistic sensitivity analyses were conducted to assess the effects of changes in model assumptions and uncertainty around key parameters. RESULTS: The unrestricted Gompertz distribution for RFS and lognormal mixture cure model distribution for OS were selected. In the base case, blinatumomab was projected to yield 3.52 additional life years and 2.93 additional quality-adjusted life years (QALYs) compared with SOC. Blinatumomab is associated with higher drug and administration costs and transplant costs, which were partially offset by lower post-relapse costs. The ICER for blinatumomab vs. SOC maintenance therapy was estimated to be $81,807/QALY gained (table). The main cost drivers were the drug acquisition costs and the additional hematopoietic stem cell transplant costs with blinatumomab. Cost-effectiveness was mostly sensitive to the uncertainty around the cure fraction (proportion of patients whose survival pattern is similar to the general cancer-free population) and transplant rates. Assumptions that most affected cost-effectiveness were the duration of benefit of blinatumomab and the long-term mortality estimation. The cost-effectiveness remained below the willingness-to-pay threshold value of $150,000/QALY gained in all scenarios tested. In the probabilistic sensitivity analyses, the estimated probability that blinatumomab is cost-effective was 87% at a willingness-to-pay threshold of $150,000/QALY. CONCLUSIONS: Blinatumomab is a cost effective treatment option vs. SOC for adults with Ph - B-precursor ALL in first hematological CR with MRD from the US healthcare perspective with an ICER well below the threshold of $150,000 per QALY gained. The value of blinatumomab is derived from its high complete MRD response rate, prolonged RFS, and OS. Disclosures Delea: Seattle Genetics: Research Funding; Takeda: Research Funding; Sanofi: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Policy Analysis Inc.: Employment. Despiegel:Amgen, Inc.: Employment, Equity Ownership. Boyko:Amgen: Research Funding. Amdahl:Amgen: Research Funding. Cong:Amgen, Inc.: Employment, Equity Ownership.

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Castillo, Jorge J., Keri Yang, Rongzhe Liu, Yu Wang, Aileen Cohen, Todd M. Zimmerman, Qian Zhao, Gijs van de Wetering, Xin Gao und Boxiong Tang. „Cost-effectiveness of zanubrutinib versus ibrutinib in adult patients with Waldenström macroglobulinemia in the United States.“ Journal of Clinical Oncology 39, Nr. 15_suppl (20.05.2021): e18856-e18856. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e18856.

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e18856 Background: The efficacy of zanubrutinib and ibrutinib was examined in the randomized ASPEN trial (NCT03053440) in adult patients with Waldenström macroglobulinemia (WM). This analysis assessed the cost-effectiveness (CE) of zanubrutinib vs ibrutinib in this population from a US payer perspective. Methods: A 3-state (pre-progression, post-progression, and death) partitioned survival model was used to estimate the life years (LYs), quality-adjusted life years (QALYs), and costs for each treatment over a 30-year lifetime horizon. Overall survival (OS), progression-free survival (PFS), and time-to-discontinuation (TTD) curves were fitted using parametric distributions to extrapolate long-term outcomes. Selection of the parametric models for each outcome and treatment was based on assessments of 1) the proportional hazard assumption, 2) goodness-of-fit, and 3) clinical plausibility of extrapolated mean OS and associated hazard patterns (based on literature and US clinical expert input) and the alignment between PFS and TTD. Background US mortality was accounted for in the model. Utilities were based on the ASPEN EQ-5D data and literature. Costs (2020 US$) included drug (wholesale acquisition cost from RED BOOK) and adverse event management (Healthcare Cost and Utilization Project) for zanubrutinib and ibrutinib, routine care, and terminal care. Sensitivity analyses were conducted to evaluate the impact of parameter uncertainty. All outcomes were discounted at 3% annually. Results: In the base case analyses using the dependent exponential model for all outcomes over a 30-year time horizon, zanubrutinib led to 0.94 LY and 0.84 QALY gained with an additional total drug cost of $11,132. This additional cost was primarily driven by patients staying on zanubrutinib treatment longer as zanubrutinib has longer time to treatment failure. However, this is partially offset by zanubrutinib’s lower monthly drug acquisition, reduced cost of routine care (–$2,935) and terminal care (–$2,964) than ibrutinib. The incremental cost-effectiveness ratio (ICER) of zanubrutinib is $13,205 per QALY gained. The deterministic sensitivity analyses showed that ICER was most sensitive to the monthly costs of routine care. The probabilistic sensitivity analyses showed that the mean probabilistic ICER was $16,804, and that the probability of zanubrutinib being cost-effective was 61% at a willingness-to-pay threshold of $100,000 per QALY gained. Varying the time horizon to 5, 10, or 15 years consistently led to zanubrutinib being dominant (i.e., greater QALYs but lower costs). Conclusions: Zanubrutinib appears to be cost-effective compared with ibrutinib for the treatment of patients with WM in the US.[Table: see text]

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Guzauskas, Gregory F., Anthony Masaquel, Carolina Reyes, Kenneth Wilhelm, Tania Krivasi und David L. Veenstra. „What Is the Cost-Effectiveness of Obinutuzumab Plus Bendamustine Followed By Obinutuzumab Monotherapy for the Treatment of Follicular Lymphoma Patients Who Relapse after or Are Refractory to a Rituximab-Containing Regimen in the US?“ Blood 128, Nr. 22 (02.12.2016): 3605. http://dx.doi.org/10.1182/blood.v128.22.3605.3605.

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Abstract Background. Obinutuzumab (G) was recently approved for the treatment of follicular lymphoma (FL) in patients who relapsed after or are refractory to a rituximab (R)-containing regimen. In the phase III open label GADOLIN study of patients with rituximab-refractory iNHL, patients received either bendamustine (B, 120 mg/m2, d1+2, c1-6) alone, or obinutuzumab (G 1000 mg (d1, 8, 15 c1, d1 c2-6) for up to six 28d cycles) plus B (90 mg/m2, d1+2, c1-6) followed by G monotherapy (100 mg every 2 mo for up to 2 years). The net clinical benefit and economic value of G+B vs. B in R-refractory patients and the larger relapse patient population have not been formally evaluated. The objective of this study was to estimate the cost-effectiveness of G plus B followed by G monotherapy vs. B monotherapy based on results of the phase III GADOLIN trial in rituximab-refractory FL patients as well as model results for a refractory/relapse population. Methods. We developed a Markov model that utilized the GADOLIN trial's progression-free (PFS), and pooled G+B and B post-progression survival (PPS) through 4.5 years to model long-term patient PFS, progression, and death. We fit parametric curves to trial PFS and PPS data; PPS was used in lieu of immature overall survival (OS) data to model transitions to death from the progressed state. We used a U.S. registry of FL patients to inform the PFS and OS curves beyond the trial follow-up time to reflect a refractory/relapse patient population. The National LymphoCare Study is a disease-specific, prospective registry that enrolled more than 2,700 patients with newly diagnosed FL from 2004 to 2007 from more than 200 practice sites in the U.S. Drug utilization and adverse events were based on trial data, and costs were based on Medicare reimbursements and drug wholesale acquisition costs in 2016. Utility estimates were derived from the literature. Sensitivity analyses were conducted to assess uncertainty in the results. Results. Treatment with G+B followed by G monotherapy led to an increase in quality-adjusted life years (QALYs) relative to B-mono (1.23, 95% CR: -0.01, 2.38). The total cost of G+B was $114,815 and B-mono was $62,034, resulting in an incremental cost of $52,781. The average total cost was greater for G+B due primarily to increased drug and administration costs ($106,053 for G+B vs. $50,104 for B-mono), however this was offset by cost-savings for disease progression of -$4268 ($5,558 for G+B vs. $9,826 for B-mono). Adverse event costs were higher for G+B ($3,204) vs. B-mono ($2,103). The incremental cost-effectiveness ratio was $43,000 per QALY gained. In probabilistic sensitivity analyses, there was a 89% probability that G+B followed by G monotherapy was cost-effective versus B-mono at the $100,000 per QALY threshold. Conclusions. Our US-based analysis suggests that treatment with G+B followed by G monotherapy compared to B-mono is cost-effective in patients with FL who relapsed/refractory to a rituximab containing regimen. These findings are driven by the improvement in PFS with G+B treatment that lead to a projected increase in survival and decreased cost of treating disease progression. There was a high probability G+B was cost effective even when all parameters in the model were varied. In conclusion, G+B vs. B monotherapy in follicular lymphoma patients who relapse after or are refractory to a R-containing regimen is very likely cost effective in the US. Disclosures Guzauskas: Genentech, Inc.: Consultancy. Masaquel:Roche: Equity Ownership; Genentech: Employment. Reyes:Genentech: Employment; Roche: Equity Ownership. Wilhelm:Genentech: Employment; Roche: Equity Ownership. Krivasi:F. Hoffman-La Roche Ltd.: Employment. Veenstra:Genentech, Inc.: Consultancy.

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Uyl-de Groot, Carin A., Rachel Ramsden, Janneke Boersma, Sonja Zweegman und Sujith Dhanasiri. „Lenalidomide As Maintenance Treatment for Patients with Newly Diagnosed Multiple Myeloma Post-Autologous Stem Cell Transplantation: A Pharmacoeconomic Assessment in the Netherlands“. Blood 132, Supplement 1 (29.11.2018): 3555. http://dx.doi.org/10.1182/blood-2018-99-112826.

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Abstract Background: Standard of care for patients with newly diagnosed multiple myeloma (NDMM) who are ≤ 70 years of age and who are fit is induction therapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT). However, this approach is not curative, and residual disease leads to disease relapse. Sustaining response and postponing relapse following ASCT is an important clinical goal, as early progression is associated with an increased risk of death. Lenalidomide (LEN) maintenance therapy has emerged as an important standard of care post-ASCT. Several clinical studies have shown that patients who received LEN maintenance therapy after ASCT had significantly longer progression-free survival (PFS) and overall survival (OS) in comparison with those who did not receive maintenance therapy. Other studies have indicated that active LEN maintenance treatment does not impair quality of life (Tay J, et al. Blood. 2017;130:abstract 2150). A recent EU5 cost-impact analysis suggested that LEN maintenance is potentially cost saving on direct medical costs by 24% over a 5-year period (Jackson G, et al. Blood. 2017;130:abstract 3405). To date, no study has specifically assessed the cost-effectiveness of LEN as maintenance treatment. Aims: To assess the cost-effectiveness of LEN treatment versus no maintenance treatment in transplant-eligible NDMM patients from a Dutch healthcare service perspective. Methods: A partitioned survival model structure was selected to provide a good fit to the supporting efficacy and safety data. The model was structured around 3 primary health states relevant to an NDMM patient's treatment trajectory: pre-progression state (encompassing on- and off-treatment periods), post-progression state (encompassing periods just prior to second-line treatment, on second-line treatment, and post-second-line treatment), and death. Efficacy and safety data were taken from a pooled meta-analysis of the CALGB 100104, GIMEMA RV-MM-PI-209, and IFM 2005-02 studies. Parametric models were used to estimate long-term survival. Utility data were applied from a real-world setting captured in the Connect® MM Disease Registry, which was used to calculate the progression-free (LEN), progression-free (no treatment), progressive disease (treatment-free), and progressive disease (second-line treatment) utilities. A 21 out of 28-day cycles dosing regimen for LEN was applied as recommended in the Dutch HOVON clinical guidelines. Costs (2016) and subsequent therapy data were derived from published literature and sources appropriate for the Dutch market. All drug costs are presented at list price. Healthcare resource utilization was informed from a EU5 (France, Germany, Italy, Spain, and the UK) real-world study (Ashcroft J, et al. Int J Hematol Oncol. 2018;Epub ahead of print). The total costs, life years gained (LYG) and quality-adjusted life years (QALYs) were estimated over a lifetime horizon. Multiple scenario and sensitivity analyses were conducted to test the robustness of the model results to key assumptions and data inputs. Results: The cost-effectiveness model predicted a QALY gain of 2.26 and a LYG of 2.79 for LEN in the base case analysis (Table). First-line drug costs of LEN contributed to an increase of EUR 147,707 in total costs versus no maintenance treatment. However, this was partially offset by savings of EUR 77,462 in subsequent treatment costs. LEN was shown to represent a cost-effective use of resources when compared with the Dutch willingness-to-pay (WTP) threshold for NDMM of EUR 50,000/QALY. Scenario analyses showed LEN remained cost-effective in settings representative of Dutch clinical practice. For instance, use of only the Dutch recommended dose (10 mg with dose reductions if needed) of LEN for NDMM gave an incremental cost-effectiveness ratio (ICER) of EUR 30,709. Scenario ICERs evaluating the key assumptions, aligning the subsequent therapy data as per in-trial use (EUR 49,059) and up to 83.9% of patients receiving 28 out of 28-day dosing, also remained below the WTP threshold. Conclusions: Introducing LEN as a maintenance therapy post-ASCT delays progression, improves survival, and reduces subsequent treatment-line costs. The use of LEN post-ASCT is cost-effective in comparison with no maintenance therapy in the Netherlands. Disclosures Uyl-de Groot: Merck: Research Funding; Janssen- Cilag: Research Funding; Gilead: Research Funding; Genzyme: Research Funding; Celgene Corp.: Research Funding; Boehringer Ingelheim: Research Funding; Bayer: Research Funding; AstraZeneca: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Roche: Research Funding; Sanofi: Research Funding. Ramsden:Celgene Corp.: Consultancy; BresMed: Employment. Boersma:Celgene BV: Employment, Equity Ownership. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dhanasiri:Celgene International: Employment, Equity Ownership.

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Sebag, Michael, Julie Stakiw, Thomas J. Stephens, Amie Padhiar, Tony Kim, Jane Shum, Sujith Dhanasiri und Suzanne Trudel. „Lenalidomide Plus Bortezomib and Dexamethasone in the Treatment of Newly Diagnosed Multiple Myeloma: Results from a Canadian Cost-Effectiveness Analysis“. Blood 134, Supplement_1 (13.11.2019): 70. http://dx.doi.org/10.1182/blood-2019-123636.

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Introduction: In the Southwest Oncology Group trial SWOG S0777 (NCT00644228), lenalidomide (LEN), bortezomib (BORT), and dexamethasone (DEX; RVd) demonstrated superior median progression-free survival (PFS; 43 months vs. 30 months, P = 0.002) and overall survival (OS; 75 months vs. 64 months, P = 0.025) compared with Rd in patients with newly diagnosed multiple myeloma (NDMM) not eligible for immediate autologous stem cell transplantation (ASCT). This analysis compared the cost-effectiveness of RVd with existing treatment options for Canadian patients with NDMM not intended for ASCT (including LEN and DEX (Rd); and BORT, melphalan, and prednisone [VMP]), and regimens such as daratumumab plus VMP [D-VMP], which is currently under review by the pan-Canadian Oncology Drug Review (pCODR). Methods: The natural history of disease was modelled using a partitioned survival analysis and comprised of 3 health states (pre-progression, post-progression, and death). PFS and OS for RVd and Rd were estimated based on analysis of the SWOG S0777 trial data. Survival estimates for VMP and D-VMP were informed by a previously published network meta-analysis (NMA). Although cyclophosphamide, BORT, and DEX (CyBorD) is a commonly used therapy for MM patients in Canada, due to the lack of randomized trial data on its efficacy VMP was used as a proxy. Given the non-proportional hazards for PFS observed between regimens with a fixed duration (e.g. VMP) and those used until progression (e.g. Rd), a piecewise model was fit to the PFS data from the MM-020 trial comparing melphalan, prednisone, and thalidomide (MPT) and Rd, and hazard ratios (HR) from the NMA for VMP and D-VMP were applied to MPT. The OS curve for VMP was generated by applying the published HR to the modelled Rd arm. Given the paucity of OS data for D-VMP, this was assumed to be equivalent to RVd, based on feedback from clinical experts. A threshold analysis was also conducted to estimate the OS HR needed for D-VMP to be cost-effective at a threshold of Canadian dollars (CAD)100,000 compared with RVd. Quality-of-life estimates were obtained from data collected from transplant-ineligible patients in the MM-020 trial. Costs included drug acquisition and administration, supportive care and monitoring, adverse events, subsequent treatment, and end-of-life care. The analysis was conducted from the perspective of the Canadian public payer over a 30-year time horizon. Cost-effectiveness results were presented in terms of the incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY). Costs and outcomes were discounted at a rate of 1.5% per year. The robustness of the results and the impact of the model's assumptions were tested in sensitivity and scenario analyses. Results: In the reference case, RVd was associated with the highest total number of life years gained and QALYs. ICERs for RVd were CAD 43,632 per QALY gained versus Rd, CAD 70,488 per QALY gained versus VMP, and RVd was superior to D-VMP (more QALYs and lower costs). Scenario analyses showed that the most sensitive factors were the use of the second-best fitting model for extrapolating OS (RVd vs. VMP ICER increased by CAD 13,007) and the assumption of no drug wastage (RVd vs. Rd ICER decreased by CAD 7,236). Age of patients at baseline was associated with substantial variation in ICER across all comparators, with older patients having larger ICERs. For D-VMP to be cost effective over RVd at the threshold of CAD 100,000, the required HR for OS will have to be 0.18 or better versus VMP in the ALCYONE (NCT02195479) trial; for comparison, the current PFS and time to second progression (PFS2) HRs have been reported as 0.43 and 0.59 in the ALCYONE trial. Conclusions: This cost-effectiveness analysis demonstrated that RVd is associated with both survival and QALY gains compared with treatments that are currently available or pending approval and is a cost-effective strategy in the management of patients with NDMM not intended for ASCT in Canada, a setting with a high unmet need in terms of patient survival. Disclosures Sebag: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Stakiw:Janssen: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Roche: Research Funding; BMS: Honoraria; Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Lundbeck: Honoraria; Sanofi: Honoraria. Stephens:Amaris Consulting: Employment; Celgene Corporation: Consultancy. Padhiar:Amaris Consulting: Employment. Kim:Celgene Corporation: Employment, Equity Ownership. Shum:Celgene Corporation: Employment, Equity Ownership. Dhanasiri:Celgene Corporation: Employment, Equity Ownership. Trudel:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria; Astellas: Research Funding; Genentech: Research Funding; Sanofi: Honoraria; Janssen: Honoraria, Research Funding; Pfizer: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Soares, Tales Miler, Sergio Nascimento Duarte, Cristiano Nascimento Duarte, Christiano César Dibbern Graf, Marcelo Zanetti und Silvio Sandoval Zocchi. „IRRIGAÇÃO DE PORTA-ENXERTOS CÍTRICOS COM ÁGUAS SALINAS“. IRRIGA 11, Nr. 3 (14.09.2006): 428–40. http://dx.doi.org/10.15809/irriga.2006v11n3p428-440.

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IRRIGAÇÃO DE PORTA-ENXERTOS CÍTRICOS COM ÁGUAS SALINAS Tales Miler Soares1; Sergio Nascimento Duarte1; Christiano César Dibbern Graf2; Marcelo Zanetti2; Silvio Sandoval Zocchi31Departamento de Engenharia Rural, Escola Superior de Agricultura Luiz de Queiroz, Universidade de São Paulo, Piracicaba, SP, talesmiler@bol.com.br2Citrograf Mudas, Conchal, SP3Departamento de Ciências Exatas, Escola Superior de Agricultura Luiz de Queiroz, Universidade de São Paulo, Piracicaba, SP 1 RESUMO Avaliar o desenvolvimento dos porta-enxertos limoeiro ‘Cravo’, tangerineira ‘Cleópatra’ e citrumeleiro ‘Swingle’, irrigados com águas salinas, mensurando se a aplicação de Ca(NO3)2 mitiga eventuais efeitos de íons fitotóxicos, foi objetivo do presente trabalho, conduzido sob ambiente protegido, em Rio Claro-SP. Investigou-se três qualidades de água: água natural (CEa= 1,19 dS m-1), explorada de poço tubular profundo, água dessalinizada (CEa= 0,02 dS m-1), obtida mediante osmose reversa da água natural, e água residual (CEa= 2,11 dS m-1), sub-produto da dessalinização. Os níveis de Ca(NO3)2 avaliados foram 0 e 2,105 g L-1. Averiguando-se os parâmetros usuais do crescimento vegetal, não foram observadas diferenças estatísticas, entre os tratamentos, decorrentes da qualidade da água, embora se tenha registrado que esta contribuiu para o aumento da salinização do substrato, ultrapassando, inclusive, o valor da salinidade limiar (CEes= 1,4 dS m-1) reconhecido para os citros. A adição de Ca(NO3)2 não incrementou o desenvolvimento, atuando negativamente no crescimento inicial das raízes e do caule. O curto período necessário ao crescimento dos porta-enxertos, proporcionado pelo atual sistema de produção, associado às irrigações freqüentes e suas frações de lixiviação podem ter restringido efeitos negativos das águas salinas investigadas. UNITERMOS: Citrus, salinidade, condutividade elétrica, substrato. SOARES, T.M.; DUARTE, S.N.; GRAF, C.C.D.; ZANETTI, M.; ZOCCHI, S.S. CITRUS ROOTSTOCKS IRRIGATION WITH SALINE WATER 2 ABSTRACT This research aimed to evaluate the growth of three citrus rootstocks (‘Rangpur’ lime, ‘Cleopatra’ mandarin and ‘Swingle’ citrumelo) irrigated with saline waters, under greenhouse conditions, in order to measure if calcium nitrate mitigates their toxic effects. Three water qualities were investigated: natural water (ECw= 1,19 dS m-1), obtained from a deep tubular well, desalinated water (ECw= 0,02 dS m-1), obtained by reverse osmosis from the natural water, and reject water (ECw= 2,11 dS m-1), resultant from the desalination process. Two Ca(NO3)2 levels were evaluated: 0 and 2,105 g L-1. Usual parameters for plant growth analysis were measured. According to Tukey’s test (5% probability), water quality did not affect rootstocks development, although the water type have contributed to increase the electrical conductivity of substrate saturation extract (ECs) along the experimental period, surpassing the salinity threshold value (ECs = 1,4 dS m-1) reported for citrus. The Ca(NO3)2 addition did not increase the plant growth, but negatively affected the first evaluations of root and stem diameter development. The short time necessary to rootstocks growth provided by new production system, associated to the frequent irrigations and its leaching fractions possible may have restricted the negative effects of saline waters. KEYWORDS: Citrus, salinity, electrical conductivity, substrate.

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Virga, Thais, und Humberto Miranda do Nascimento. „EXPANSÃO DO CAPITAL E AÇÕES DOS ESTADOS NACIONAIS NA GRAN AMAZONÍA (2000-2019): impactos e impasses“. InterEspaço: Revista de Geografia e Interdisciplinaridade 7, Nr. 20 (25.03.2021): 202101. http://dx.doi.org/10.18764/2446-6549.e202101.

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CAPITAL EXPANSION AND ACTIONS BY NATIONAL STATES IN THE GRAND AMAZONIA (2000-2019): impacts and impassesEXPANSIÓN DE CAPITAL Y ACCIONES DE LOS ESTADOS NACIONALES EN LA GRAN AMAZONÍA (2000-2019): impactos e impassesRESUMOA emergência da China como ator econômico global no limiar do século XXI impactou diretamente na consolidação e ampliação de novos e velhos centros de extração e produção agromineral em grande parte da América Latina. Objetiva-se, neste artigo, discutir sobre relevantes impactos dos investimentos chineses na Gran Amazonía no período 2000-2019 e mostrar como os Estados nacionais sul-americanos contribuíram para incrementar as frentes de expansão neste imenso espaço subcontinental. Como metodologia, apresenta-se o levantamento mais recente sobre as principais frentes de expansão do capital nos países da Gran Amazonía, com base em dados de pesquisa de campo, consultas a instituições governamentais, não governamentais, empresariais e outras organizações civis, além de bibliografia atualizada. Conclui-se que a expansão do capital chinês sobre toda a Gran Amazonía foi produto de uma relação consensual com os Estados Nacionais, gerando oportunidades econômicas, porém, com importantes implicações socioambientais.Palavras-chave: Expansão do Capital (China); Gran Amazonía; Ação dos Países Sul-americanos.ABSTRACTThe emergence of China as a global economic actor on the threshold of the 21st century had a direct impact on the consolidation and expansion of new and old centers of extraction and agromineral production in much of Latin America. The aim of this article is to discuss the relevant impacts of Chinese investments in Gran Amazonía in the period 2000-2019 and to show how the South American national states contributed to the expansion fronts in this immense subcontinental space. As a methodology, the most recent survey on the main fronts of capital expansion in the countries of Gran Amazonía is presented, based on data from field research, consultations with governmental, non-governmental, business and other civil organizations, in addition to updated bibliography. It is concluded that the expansion of Chinese capital over the whole of Gran Amazonía was the product of a consensual relationship with the National States, generating economic opportunities, however, with important socio-environmental implications.Keywords: Capital Expansion (China); Gran Amazonía; Action by South American Countries.RESUMENEl surgimiento de China como actor económico global en el umbral del siglo XXI tuvo un impacto directo en la consolidación y expansión de nuevos y viejos centros de extracción y producción agromineral en gran parte de América Latina. El objetivo de este artículo es discutir los impactos relevantes de las inversiones chinas en la Gran Amazonía en el período 2000-2019 y mostrar cómo los estados nacionales sudamericanos contribuyeron a los frentes de expansión en este inmenso espacio subcontinental. Como metodología se presenta la encuesta más reciente sobre los principales frentes de expansión de capital en los países de la Gran Amazonía, con base en datos de investigaciones de campo, consultas con organizaciones gubernamentales, no gubernamentales, empresariales y otras organizaciones civiles, además de bibliografía actualizada. Se concluye que la expansión del capital chino por toda la Gran Amazonía fue producto de una relación consensuada con los Estados Nacionales, generando oportunidades económicas, sin embargo, con importantes implicaciones socioambientales.Palabras clave: Expansión de Capital (China); Gran Amazonía; Acción de Países Sudamericanos.

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Robak, Tadeusz, Monika Szkultecka-Dêbek, Rick Aultman, Emma S. Carr und P. Kawalec. „Long-Term Health Outcomes and Costs Associated with the Use of Rituximab in Combination with fludarabine and Cyclophosphamide (R-FC) in the Treatment of relapsed or Refractory Chronic Lymphocytic Leukaemia (CLL) in Poland.“ Blood 114, Nr. 22 (20.11.2009): 4528. http://dx.doi.org/10.1182/blood.v114.22.4528.4528.

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Abstract Abstract 4528 Objective Results from the REACH (Robak et al, 2008) randomised clinical trial showed that patients with relapsed or refractory CLL who received rituximab in combination with fludarabine-cyclophosphamide (R-FC) experienced an additional ten months (median) without disease progression compared to those receiving FC alone (30.6 vs. 20.6 months). With the pressure on healthcare budgets, it has become increasingly important for decision makers to consider the value for money for treatments they reimburse. This analysis evaluated the life-time health outcomes and direct costs of R-FC compared to FC for relapsed /refractory CLL patients in Poland, using evidence from the REACH trial and the public payer perspective. Methods A cost-effectiveness analysis was conducted with patients modeled while in and transitioning through the health states; PFS, Disease Progression and Death. The best fit parametric function was used to extrapolate PFS beyond the end of the trial follow-up period (2.1 years) to a life-time horizon (15 years). The number of patients transitioning from PFS to death was based on the maximum of either the observed rate of death or background mortality. At the time of this analysis median overall survival had not been reached, thus a Markov process was used to model the transition from the progressed health state to death. Transitions from the progressive health state to death was based on a constant probability of dying calculated from the clinical data. Patients experiencing at least 1 day of progression were modeled using KM stratified by protocol-specified treatments to determine if the two populations were significantly different. No significant difference (p = 0.5596) was observed between the two population's progression to death and so the two populations were combined and modeled as a single population. The log of the survival was linearly regressed against time, with the estimated parameter serving as the statistic for the rate of death with respect to the exponential distribution. This rate of death was converted to a monthly probability of dying and applied to both arms. Predicted time in each health state was weighted using CLL utility scores based on expert opinion to account for patient quality of life. Adverse events (≥grade 3), blood transfusions, bone marrow transplants, and subsequent CLL treatments collected prospectively in REACH were included in monitoring costs. Cost data were collected in 4 reference oncology centers and derived from the National Health Fund. According to Polish Health Technology Appraisal guidelines the costs were discounted by 5% and results by 3,5%. Results When R-FC is compared to FC alone over a 15 year timeframe, the average benefit to the patient is 0.670 life years gained (LYG) and 0.585 quality-adjusted life years gained (QALY). For patients treated with FC alone their mean time to progression was 2.19 years compared with 3.11 years for R-FC treated patients. The main cost drivers for FC treated patients was cost of supportive care in progression. The total average per-patient cost is higher with R-FC when compared with FC alone, but partially offset by the lower mean supportive care cost of progression, bone marrow transplants and blood transfusions. Use of R-FC in place of FC alone is predicted to result in additional cost per extra LYG of 80 942 PLN (1EUR=4,1PLN), and cost per extra QALY of 91 283 PLN, on average. These incremental cost-effectiveness ratio (ICER) values were below the assumed willingness to pay threshold of 100 000 PLN, which is 3 times the Polish Gross Domestic Product (per capita, 2008). ICER values were found to be robust given the uncertainty associated with various parameters used to describe the disease progression of CLL. Conclusion R-FC is a clinically effective in the treatment of relapsed/ refractory CLL patients and demonstrates a strong case for being cost-effective compared to other treatments funded in Poland. Disclosures: Robak: F Hoffmann-La Roche: Honoraria. Szkultecka-Dêbek:F.Hoffmann La Roche: Employment. Aultman:F Hoffmann-La Roche: Employment. Carr:F. Hoffmann La Roche: Employment.

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