Salvage Regimen With Autologous Stem Cell Transplantation With Or Without Rituximab Maintenance For Relapsed Diffuse Large B-Cell Lymphoma (Dlbcl): Coral Final Report

Times Cited: 0 References: 0 Citation MapAbstract : Background: Chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard treatment for relapsed DLBCL. No study has compared salvage therapies and evaluated maintenance post ASCT.Methods: DLBCL CD 20+ in first relapse or pts refractory after first therapy were randomized between R ICE (rituximab, ifosfamide, etoposide, carboplatinum) or R DHAP (rituximab dexamethasone cytarabine cisplatinum). Responding patients received BEAM and ASCT then randomized between observation or maintenance with rituximab every 2 m for 1 yr (Gisselbrecht J Clin Oncol; 2010).Results: Analysis was made on 477 pts (R ICE: 243 pts; R DHAP: 234 pts): 255 relapses >12m, 213 refractory/early relapses; 306 pts had prior rituximab; secondary(s) IPI 0-1: 281 pts; s IPI 2-3:181pts. There was no difference in response rate between R ICE 63.6% and R DHAP 64.3%. There was no difference between R ICE and R DHAP at 4 yrs for EFS (26% vs 37% p=0.2) and OS (43% vs 51%, p=0.3). Factors affecting 4 yrs EFS, PFS and OS were: prior treatment with rituximab; early relapse< 12 m; s IPI 2-3. ASCT was performed in 255 pts and 242 randomized for maintenance: 122 pts rituximab (R), 120 pts observation (O). Distribution between R/O arms were respectively: median age 54 /53 yrs, Male 76/83; female 46/37; secondary IPI 0-1: 84/81; sIPI 2-3: 36/36. 89/76 relapses >12m., 33/41 refractory/early relapses. Median follow up was 44 m with 111 events. 4 yrs EFS was 52.8 % (CI 46-59) with 63% (CI 56-69) OS. There was no difference in EFS, PFS and OS between R and O arms. In multivariate analysis, sIPI2-3 significantly affected EFS, PFS, OS (p=0.0004). Women (83pts) had a better 4 yrs EFS 63% than male (159pts) 37% (p=0.01). The difference was only in the R arm (p=0.004). Gender was an independent prognostic factor in the R arm. Toxicity was mild with 12% SAE versus 4% for R /O respectively.Conclusions: There was no difference between R ICE and R DHAP and between post ASCT maintenance with R or O. Women did significantly better after ASCT with rituximab. Early relapses to upfront rituximab-based chemotherapy have a poor prognosis.

Governance mode vs. governance fit: Performance implications of make-or-ally choices for product innovation in the worldwide aircraft industry, 1942-2000

We examine the impact of governance mode and governance fit on performance in make-or-ally decisions. We argue that while horizontal collaboration and autonomous governance have direct and countervailing performance implications, the alignment of make-or-ally choices with the focal firm's resource endowment and the activity's resource requirements leads to better performance. Data on the aircraft industry show that relative to aircraft developed autonomously, collaborative aircraft exhibit greater sales but require longer time-to-market. However, governance fit increases unit sales and reduces time-to-market. We contribute to the alliance and economic organization literatures. (Copyright © 2013 John Wiley & Sons, Ltd.)

Turnaround across diverse global supply chains using shared metrics and change methodology: The Case of Amer Sports Corporation

Purpose - The purpose of this paper is to document the outcome of a global three-year long supply chain improvement initiative at a multi-national producer of branded sporting goods that is transforming from a holding structure to an integrated company. The case company is comprised of seven internationally well-known sport brands, which form a diverse set of independent sub-cases, on which the same supply chain metrics and change project approach was applied to improve supply chain performance. Design/methodology/approach - By using in-depth case study and statistical analysis the paper analyzes across the brands how supply chain complexity (SKU count), supply chain type (make or buy) and seasonality affect completeness and punctuality of deliveries, and inventory as the change project progresses. Findings - Results show that reduction in supply chain complexity improves delivery performance, but has no impact on inventory. Supply chain type has no impact on service level, but brands with in-house production are better in improving inventory than those with outsourced production. Non-seasonal business units improve service faster than seasonal ones, yet there is no impact on inventory. Research limitations/implications - The longitudinal data used for the analysis is biased with the general business trend, yet the rich data from different cases and three-years of data collection enables generalizations to a certain level. Practical implications - The in-depth case study serves as an example for other companies on how to initiate a supply chain improvement project across business units with tangible results. Originality/value - The seven sub-cases with their different characteristics on which the same improvement initiative was applied sets a unique ground for longitudinal analysis to study supply chain complexity, type and seasonality.

Cultural Biases in Public Service Delivery : Evidence from a Regression Discontinuity Approach

What determines the share of public employment, at a given size of the State, in countries of similar levels of economic development? While the theoretical and empirical literature on this issue has mostly considered technical dimensions (efficiency and political considerations), this paper emphasizes the role of culture and quantifies it. We build a representative database for contracting choices of municipalities in Switzerland and exploit the discontinuity at the Swiss language border at identical actual set of policies and institutions to analyze the causal e↵ect of culture on the choice of how public services are provided. We find that French-speaking border municipalities are 50% less likely to contract with the private sector than their German-speaking adjacent municipalities. Technical dimensions are much smaller by comparison. This result points out that culture is a source of a potential bias that distorts the optimal choice for public service delivery. Systematic differences in the level of confidence in public administration and private companies potentially explain this discrepancy in private sector participation in public services provision.

When do we dare to stop biological or immunomodulatory therapy for Crohn's disease? Results of a multidisciplinary European expert panel.

BACKGROUND: Safety and economic issues have increasingly raised concerns about the long term use of immunomodulators or biologics as maintenance therapies for Crohn's disease (CD). Despite emerging evidence suggesting that stopping therapy might be an option for low risk patients, criteria identifying target groups for this strategy are missing, and there is a lack of recommendations regarding this question. METHODS: Multidisciplinary European expert panel (EPACT-II Update) rated the appropriateness of stopping therapy in CD patients in remission. We used the RAND/UCLA Appropriateness Method, and included the following variables: presence of clinical and/or endoscopic remission, CRP level, fecal calprotectin level, prior surgery for CD, and duration of remission (1, 2 or 4 years). RESULTS: Before considering withdrawing therapy, the prerequisites of a C-reactive protein (CRP) and fecal calprotectin measurement were rated as "appropriate" by the panellists, whereas a radiological evaluation was considered as being of "uncertain" appropriateness. Ileo-colonoscopy was considered appropriate 1 year after surgery or after 4 years in the absence of prior surgery. Stopping azathioprine, 6-mercaptopurine or methotrexate mono-therapy was judged appropriate after 4 years of clinical remission. Withdrawing anti-TNF mono-therapy was judged appropriate after 2 years in case of clinical and endoscopic remission, and after 4 years of clinical remission. In case of combined therapy, anti-TNF withdrawal, while continuing the immunomodulator, was considered appropriate after two years of clinical remission. CONCLUSION: A multidisciplinary European expert panel proposed for the first time treatment stopping rules for patients in clinical and/or endoscopic remission, with normal CRP and fecal calprotectin levels.

Role of NINJA in root jasmonate signaling.

Wound responses in plants have to be coordinated between organs so that locally reduced growth in a wounded tissue is balanced by appropriate growth elsewhere in the body. We used a JASMONATE ZIM DOMAIN 10 (JAZ10) reporter to screen for mutants affected in the organ-specific activation of jasmonate (JA) signaling in Arabidopsis thaliana seedlings. Wounding one cotyledon activated the reporter in both aerial and root tissues, and this was either disrupted or restricted to certain organs in mutant alleles of core components of the JA pathway including COI1, OPR3, and JAR1. In contrast, three other mutants showed constitutive activation of the reporter in the roots and hypocotyls of unwounded seedlings. All three lines harbored mutations in Novel Interactor of JAZ (NINJA), which encodes part of a repressor complex that negatively regulates JA signaling. These ninja mutants displayed shorter roots mimicking JA-mediated growth inhibition, and this was due to reduced cell elongation. Remarkably, this phenotype and the constitutive JAZ10 expression were still observed in backgrounds lacking the ability to synthesize JA or the key transcriptional activator MYC2. Therefore, JA-like responses can be recapitulated in specific tissues without changing a plant's ability to make or perceive JA, and MYC2 either has no role or is not the only derepressed transcription factor in ninja mutants. Our results show that the role of NINJA in the root is to repress JA signaling and allow normal cell elongation. Furthermore, the regulation of the JA pathway differs between roots and aerial tissues at all levels, from JA biosynthesis to transcriptional activation.

Comparative short-term response and remission rates for tacrolimus, cyclosporine, and infliximab for steroid-refractory ulcerative colitis

BACKGROUND: Calcineurin inhibitors (cyclosporine (CsA) and tacrolimus (Tcl)) and the anti-TNF-antibody infliximab (IFX) are established therapeutic options in steroid-refractory ulcerative colitis (UC). In acute severe UC failing steroids, a randomized trial showed an 85% short term response to CsA or IFX, with avoidance of colectomy. Comparative responses to the three drugs in outpatients with steroid-refractory UC are unknown. METHOD: Response to treatment in patients with steroid-refractory moderate to severe UC was retrospectively studied in three cohorts of patients: Cohort A (n=24) treated with oral Tcl (initially 0.05mg/kg twice daily, aiming for serum trough levels of 5-10 ng/mL); Cohort B (n=19) treated with intravenous CsA 2mg/kg/daily and then oral CsA 5mg/kg/daily; Cohort C. (n= 41) treated with IFX (5mg/kg intravenously at week 0, 2, 6 and then every 8 weeks). After successful rescue therapy with Tcl or CsA, thiopurine maintenance therapy was introduced. The endpoint was evaluation of clinical remission or response at week 6, on the basis of modified Truelove-Witts severity index (MTWSI). RESULTS: After 6 weeks, 42% (10/24) of patients treated with Tcl achieved remission (MTWSI score ≤4) compared to 47% (9/ 19) on CsA and 66% (27/41) of patients treated with IFX (Tcl & CsA vs IFX p=0.127). Clinical response (decrease of MTWSI score of more than 4 points) at week 6 was reached in 25% (6/24) patients on Tcl, compared to 11% (2/19) on CsA and 20% (8/41) given IFX (p=0.484). Subgroup analysis showed the highest rates of remission in those with moderate steroid-refractory UC treated with IFX: 29% (2/7) in Tcl group compared to 50% (2/4) in CsA group and 76 % (19/25) in IFX group (Tcl &CsA vs IFX p= 0.058) Patients with severe colitis showed similar rates of remission in all three groups: 47% (8/17) on Tcl, 47% (7/ 15) on CsA and 50% (8/16) on IFX (p= 0.700). Colectomy within 6 weeks occurred in 4% (1/24) after Tcl, 5% (1/19) after CsA and 0% (0/41) after IFX. Adverse effects in the first 6 weeks were observed in 13% (3/24) on Tcl, 26% (5/19) on CsA, and 10% (4/41) on IFX (p=0.224) CONCLUSION: No significant differences in response, remission, colectomy rate or adverse events between the three agents were found, although the study is too small for definitive conclusions. There are intriguing differences, with potentially greater response to IFX in moderate, steroid-refractory UC.

Consequences of genetic erosion on fitness and phenotypic plasticity in European tree frog populations (Hyla arborea).

The detrimental effects of genetic erosion on small isolated populations are widely recognized contrary to their interactions with environmental changes. The ability of genotypes to plastically respond to variability is probably essential for the persistence of these populations. Genetic erosion impact may be exacerbated if inbreeding affects plastic responses or if their maintenance were at higher phenotypic costs. To understand the interplay 'genetic erosion-fitness-phenotypic plasticity', we experimentally compared, in different environments, the larval performances and plastic responses to predation of European tree frogs (Hyla arborea) from isolated and connected populations. Tadpoles from isolated populations were less performant, but the traits affected were environmental dependant. Heterosis observed in crosses between isolated populations allowed attributing their low fitness to inbreeding. Phenotypic plasticity can be maintained in the face of genetic erosion as inducible defences in response to predator were identical in all populations. However, the higher survival and developmental costs for isolated populations in harsh conditions may lead to an additional fitness loss for isolated populations.

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In this chapter, we examine the multiple dimensions of declarations of fertility in-tention in order to provide a critical reading of currently used indicators of the childbearing decision-making process. Using a qualitative approach, we pay atten-tion to the complexity of the process through which individuals make (or fail to make) plans regarding their reproductive future. The data are a series of compara-ble in-depth interviews conducted in a number of European countries with varying fertility levels, and differing normative and institutional contexts. First, we ana-lyze the meanings that respondents attribute to their childbearing intentions, pay-ing particular attention to uncertain intentions that are often underanalyzed. Se-cond, we study the ways in which individuals vary in holding to their intentions over time, and consider why they might change their minds, even over relatively short periods of time. Third, we examine how several aspects of the larger social context (attitudes towards having children, family policy, norms related to the di-vision of labor, norms about the timing of children) shape fertility intentions.

Evolutionary Games in Networked Populations: Models and Experiments

Cooperation and coordination are desirable behaviors that are fundamental for the harmonious development of society. People need to rely on cooperation with other individuals in many aspects of everyday life, such as teamwork and economic exchange in anonymous markets. However, cooperation may easily fall prey to exploitation by selfish individuals who only care about short- term gain. For cooperation to evolve, specific conditions and mechanisms are required, such as kinship, direct and indirect reciprocity through repeated interactions, or external interventions such as punishment. In this dissertation we investigate the effect of the network structure of the population on the evolution of cooperation and coordination. We consider several kinds of static and dynamical network topologies, such as Baraba´si-Albert, social network models and spatial networks. We perform numerical simulations and laboratory experiments using the Prisoner's Dilemma and co- ordination games in order to contrast human behavior with theoretical results. We show by numerical simulations that even a moderate amount of random noise on the Baraba´si-Albert scale-free network links causes a significant loss of cooperation, to the point that cooperation almost vanishes altogether in the Prisoner's Dilemma when the noise rate is high enough. Moreover, when we consider fixed social-like networks we find that current models of social networks may allow cooperation to emerge and to be robust at least as much as in scale-free networks. In the framework of spatial networks, we investigate whether cooperation can evolve and be stable when agents move randomly or performing Le´vy flights in a continuous space. We also consider discrete space adopting purposeful mobility and binary birth-death process to dis- cover emergent cooperative patterns. The fundamental result is that cooperation may be enhanced when this migration is opportunistic or even when agents follow very simple heuristics. In the experimental laboratory, we investigate the issue of social coordination between indi- viduals located on networks of contacts. In contrast to simulations, we find that human players dynamics do not converge to the efficient outcome more often in a social-like network than in a random network. In another experiment, we study the behavior of people who play a pure co- ordination game in a spatial environment in which they can move around and when changing convention is costly. We find that each convention forms homogeneous clusters and is adopted by approximately half of the individuals. When we provide them with global information, i.e., the number of subjects currently adopting one of the conventions, global consensus is reached in most, but not all, cases. Our results allow us to extract the heuristics used by the participants and to build a numerical simulation model that agrees very well with the experiments. Our findings have important implications for policymakers intending to promote specific, desired behaviors in a mobile population. Furthermore, we carry out an experiment with human subjects playing the Prisoner's Dilemma game in a diluted grid where people are able to move around. In contrast to previous results on purposeful rewiring in relational networks, we find no noticeable effect of mobility in space on the level of cooperation. Clusters of cooperators form momentarily but in a few rounds they dissolve as cooperators at the boundaries stop tolerating being cheated upon. Our results highlight the difficulties that mobile agents have to establish a cooperative environment in a spatial setting without a device such as reputation or the possibility of retaliation. i.e. punishment. Finally, we test experimentally the evolution of cooperation in social networks taking into ac- count a setting where we allow people to make or break links at their will. In this work we give particular attention to whether information on an individual's actions is freely available to poten- tial partners or not. Studying the role of information is relevant as information on other people's actions is often not available for free: a recruiting firm may need to call a job candidate's refer- ences, a bank may need to find out about the credit history of a new client, etc. We find that people cooperate almost fully when information on their actions is freely available to their potential part- ners. Cooperation is less likely, however, if people have to pay about half of what they gain from cooperating with a cooperator. Cooperation declines even further if people have to pay a cost that is almost equivalent to the gain from cooperating with a cooperator. Thus, costly information on potential neighbors' actions can undermine the incentive to cooperate in dynamical networks.

The Effect of Two Speed Endurance Training Regimes on Performance of Soccer Players.

In order to better understand the specificity of training adaptations, we compared the effects of two different anaerobic training regimes on various types of soccer-related exercise performances. During the last 3 weeks of the competitive season, thirteen young male professional soccer players (age 18.5±1 yr, height 179.5±6.5 cm, body mass 74.3±6.5 kg) reduced the training volume by ~20% and replaced their habitual fitness conditioning work with either speed endurance production (SEP; n = 6) or speed endurance maintenance (SEM; n = 7) training, three times per wk. SEP training consisted of 6-8 reps of 20-s all-out running bouts followed by 2 min of passive recovery, whereas SEM training was characterized by 6-8 x 20-s all-out efforts interspersed with 40 s of passive recovery. SEP training reduced (p<0.01) the total time in a repeated sprint ability test (RSAt) by 2.5%. SEM training improved the 200-m sprint performance (from 26.59±0.70 to 26.02±0.62 s, p<0.01) and had a likely beneficial impact on the percentage decrement score of the RSA test (from 4.07±1.28 to 3.55±1.01%) but induced a very likely impairment in RSAt (from 83.81±2.37 to 84.65±2.27 s). The distance covered in the Yo-Yo Intermittent Recovery test level 2 was 10.1% (p<0.001) and 3.8% (p<0.05) higher after SEP and SEM training, respectively, with possibly greater improvements following SEP compared to SEM. No differences were observed in the 20- and 40-m sprint performances. In conclusion, these two training strategies target different determinants of soccer-related physical performance. SEP improved repeated sprint and high-intensity intermittent exercise performance, whereas SEM increased muscles' ability to maximize fatigue tolerance and maintain speed development during both repeated all-out and continuous short-duration maximal exercises. These results provide new insight into the precise nature of a stimulus necessary to improve specific types of athletic performance in trained young soccer players.

Methadone maintenance treatment (MMT) in general practice or in specialized centers: profile of patients in the Swiss Canton of Vaud.

We studied profile of patients (n=1782) treated in specialized centers and general practice (GP) enrolled in methadone maintenance treatment (MMT) programs during 2001 in the Swiss Canton of Vaud. We found that GPs treated the majority of patients (76%). Specialized centers treated a higher proportion of patients with uncontrolled intravenous use of cocaine and heroin, and prescribed neuroleptics as concomitant medication three times more frequently than GPs. Patients treated in specialized centers were more likely to undergo screening for HIV, HBV, HCV, and receive complete HBV immunization. In conclusion, specialized centers are more likely to treat severely addicted patients and patients with a poor global assessment (physical, psychiatric, and social).

Comprehensive Expression Analyses of Neural Cell-Type-Specific miRNAs Identify New Determinants of the Specification and Maintenance of Neuronal Phenotypes.

MicroRNAs (miRNAs) have been shown to play important roles in both brain development and the regulation of adult neural cell functions. However, a systematic analysis of brain miRNA functions has been hindered by a lack of comprehensive information regarding the distribution of miRNAs in neuronal versus glial cells. To address this issue, we performed microarray analyses of miRNA expression in the four principal cell types of the CNS (neurons, astrocytes, oligodendrocytes, and microglia) using primary cultures from postnatal d 1 rat cortex. These analyses revealed that neural miRNA expression is highly cell-type specific, with 116 of the 351 miRNAs examined being differentially expressed fivefold or more across the four cell types. We also demonstrate that individual neuron-enriched or neuron-diminished RNAs had a significant impact on the specification of neuronal phenotype: overexpression of the neuron-enriched miRNAs miR-376a and miR-434 increased the differentiation of neural stem cells into neurons, whereas the opposite effect was observed for the glia-enriched miRNAs miR-223, miR-146a, miR-19, and miR-32. In addition, glia-enriched miRNAs were shown to inhibit aberrant glial expression of neuronal proteins and phenotypes, as exemplified by miR-146a, which inhibited neuroligin 1-dependent synaptogenesis. This study identifies new nervous system functions of specific miRNAs, reveals the global extent to which the brain may use differential miRNA expression to regulate neural cell-type-specific phenotypes, and provides an important data resource that defines the compartmentalization of brain miRNAs across different cell types.

Associations of short-term particle and noise exposures with markers of cardiovascular and respiratory health among highway maintenance workers

BACKGROUND: Highway maintenance workers are constantly and simultaneously exposed to traffic-related particle and noise emissions, and both have been linked to increased cardiovascular morbidity and mortality in population-based epidemiology studies. OBJECTIVES: We aimed to investigate short-term health effects related to particle and noise exposure. METHODS: We monitored 18 maintenance workers, during as many as five 24-hour periods from a total of 50 observation days. We measured their exposure to fine particulate matter (PM2.5), ultrafine particles, noise, and the cardiopulmonary health endpoints: blood pressure, pro-inflammatory and pro-thrombotic markers in the blood, lung function and fractional exhaled nitric oxide (FeNO) measured approximately 15 hours post-work. Heart rate variability was assessed during a sleep period approximately 10 hours post-work. RESULTS: PM2.5 exposure was significantly associated with C-reactive protein and serum amyloid A, and negatively associated with tumor necrosis factor α. None of the particle metrics were significantly associated with von Willebrand factor or tissue factor expression. PM2.5 and work noise were associated with markers of increased heart rate variability, and with increased HF and LF power. Systolic and diastolic blood pressure on the following morning were significantly associated with noise exposure after work, and non-significantly associated with PM2.5. We observed no significant associations between any of the exposures and lung function or FeNO. CONCLUSIONS: Our findings suggest that exposure to particles and noise during highway maintenance work might pose a cardiovascular health risk. Actions to reduce these exposures could lead to better health for this population of workers.

Médecine sociate en 2013: quand la précarité précède la pauvrete [Social medicine: does it still make sense in 2013?].

Social medicine is a medicine that seeks to understand the impact of socio-economic conditions on human health and diseases in order to improve the health of a society and its individuals. In this field of medicine, determining the socio-economic status of individuals is generally not sufficient to explain and/or understand the underlying mechanisms leading to social inequalities in health. Other factors must be considered such as environmental, psychosocial, behavioral and biological factors that, together, can lead to more or less permanent damages to the health of the individuals in a society. In a time where considerable progresses have been made in the field of the biomedicine, does the practice of social medicine in a primary care setting still make sense?