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Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1-18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)-Berlin-Frankfurt- Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement. © 2013 Macmillan Publishers Limited.

Background-Combined analysis of 2 genome-wide association studies in cases enriched for family history recently identified 7 loci (on 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21, 10q11.21, and 15q22.33) that may affect risk of coronary artery disease (CAD). Apart from the 9p21 locus, the other loci await substantive replication. Furthermore, the effect of these loci on CAD risk in a broader range of individuals remains to be determined.Methods and Results-We undertook association analysis of single nucleotide polymorphisms at each locus with CAD risk in 11 550 cases and 11 205 controls from 9 European studies. The 9p21.3 locus showed unequivocal association (rs1333049, combined odds ratio [OR]=1.20, 95% CI [1.16 to 1.25], probability value=2.81x10(-21)). We also confirmed association signals at 1p13.3 (rs599839, OR=1.13 [1.08 to 1.19], P=1.44x10(-7)), 1q41 (rs3008621, OR=1.10 [1.04 to 1.17], P=1.02x10(-3)), and 10q11.21 (rs501120, OR=1.11 [1.05 to 1.18], P=4.34x10(-4)). The associations with 6q25.1 (rs6922269, P=0.020) and 2q36.3 (rs2943634, P=0.032) were borderline and not statistically significant after correction for multiple testing. The 15q22.33 locus did not replicate. The 10q11.21 locus showed a possible sex interaction (P = 0.015), with a significant effect in women (OR=1.29 [1.15 to 1.45], P=1.86x10(-5)) but not men (OR=1.03 [0.96 to 1.11], P=0.387). There were no other strong interactions of any of the loci with other traditional risk factors. The loci at 9p21, 1p13.3, 2q36.3, and 10q11.21 acted independently and cumulatively increased CAD risk by 15% (12% to 18%), per additional risk allele. ConclusionsThe findings provide strong evidence for association between at least 4 genetic loci and CAD risk. Cumulatively, these novel loci have a significant impact on risk of CAD at least in European populations. (Arterioscler Thromb Vasc Biol. 2009; 29: 774-780.)

Background-Combined analysis of 2 genome-wide association studies in cases enriched for family history recently identified 7 loci (on 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21, 10q11.21, and 15q22.33) that may affect risk of coronary artery disease (CAD). Apart from the 9p21 locus, the other loci await substantive replication. Furthermore, the effect of these loci on CAD risk in a broader range of individuals remains to be determined.Methods and Results-We undertook association analysis of single nucleotide polymorphisms at each locus with CAD risk in 11 550 cases and 11 205 controls from 9 European studies. The 9p21.3 locus showed unequivocal association (rs1333049, combined odds ratio [OR]=1.20, 95% CI [1.16 to 1.25], probability value=2.81x10(-21)). We also confirmed association signals at 1p13.3 (rs599839, OR=1.13 [1.08 to 1.19], P=1.44x10(-7)), 1q41 (rs3008621, OR=1.10 [1.04 to 1.17], P=1.02x10(-3)), and 10q11.21 (rs501120, OR=1.11 [1.05 to 1.18], P=4.34x10(-4)). The associations with 6q25.1 (rs6922269, P=0.020) and 2q36.3 (rs2943634, P=0.032) were borderline and not statistically significant after correction for multiple testing. The 15q22.33 locus did not replicate. The 10q11.21 locus showed a possible sex interaction (P = 0.015), with a significant effect in women (OR=1.29 [1.15 to 1.45], P=1.86x10(-5)) but not men (OR=1.03 [0.96 to 1.11], P=0.387). There were no other strong interactions of any of the loci with other traditional risk factors. The loci at 9p21, 1p13.3, 2q36.3, and 10q11.21 acted independently and cumulatively increased CAD risk by 15% (12% to 18%), per additional risk allele. ConclusionsThe findings provide strong evidence for association between at least 4 genetic loci and CAD risk. Cumulatively, these novel loci have a significant impact on risk of CAD at least in European populations. (Arterioscler Thromb Vasc Biol. 2009; 29: 774-780.)

Background-Combined analysis of 2 genome-wide association studies in cases enriched for family history recently identified 7 loci (on 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21, 10q11.21, and 15q22.33) that may affect risk of coronary artery disease (CAD). Apart from the 9p21 locus, the other loci await substantive replication. Furthermore, the effect of these loci on CAD risk in a broader range of individuals remains to be determined.Methods and Results-We undertook association analysis of single nucleotide polymorphisms at each locus with CAD risk in 11 550 cases and 11 205 controls from 9 European studies. The 9p21.3 locus showed unequivocal association (rs1333049, combined odds ratio [OR]=1.20, 95% CI [1.16 to 1.25], probability value=2.81x10(-21)). We also confirmed association signals at 1p13.3 (rs599839, OR=1.13 [1.08 to 1.19], P=1.44x10(-7)), 1q41 (rs3008621, OR=1.10 [1.04 to 1.17], P=1.02x10(-3)), and 10q11.21 (rs501120, OR=1.11 [1.05 to 1.18], P=4.34x10(-4)). The associations with 6q25.1 (rs6922269, P=0.020) and 2q36.3 (rs2943634, P=0.032) were borderline and not statistically significant after correction for multiple testing. The 15q22.33 locus did not replicate. The 10q11.21 locus showed a possible sex interaction (P = 0.015), with a significant effect in women (OR=1.29 [1.15 to 1.45], P=1.86x10(-5)) but not men (OR=1.03 [0.96 to 1.11], P=0.387). There were no other strong interactions of any of the loci with other traditional risk factors. The loci at 9p21, 1p13.3, 2q36.3, and 10q11.21 acted independently and cumulatively increased CAD risk by 15% (12% to 18%), per additional risk allele. ConclusionsThe findings provide strong evidence for association between at least 4 genetic loci and CAD risk. Cumulatively, these novel loci have a significant impact on risk of CAD at least in European populations. (Arterioscler Thromb Vasc Biol. 2009; 29: 774-780.)

Background-Combined analysis of 2 genome-wide association studies in cases enriched for family history recently identified 7 loci (on 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21, 10q11.21, and 15q22.33) that may affect risk of coronary artery disease (CAD). Apart from the 9p21 locus, the other loci await substantive replication. Furthermore, the effect of these loci on CAD risk in a broader range of individuals remains to be determined.Methods and Results-We undertook association analysis of single nucleotide polymorphisms at each locus with CAD risk in 11 550 cases and 11 205 controls from 9 European studies. The 9p21.3 locus showed unequivocal association (rs1333049, combined odds ratio [OR]=1.20, 95% CI [1.16 to 1.25], probability value=2.81x10(-21)). We also confirmed association signals at 1p13.3 (rs599839, OR=1.13 [1.08 to 1.19], P=1.44x10(-7)), 1q41 (rs3008621, OR=1.10 [1.04 to 1.17], P=1.02x10(-3)), and 10q11.21 (rs501120, OR=1.11 [1.05 to 1.18], P=4.34x10(-4)). The associations with 6q25.1 (rs6922269, P=0.020) and 2q36.3 (rs2943634, P=0.032) were borderline and not statistically significant after correction for multiple testing. The 15q22.33 locus did not replicate. The 10q11.21 locus showed a possible sex interaction (P = 0.015), with a significant effect in women (OR=1.29 [1.15 to 1.45], P=1.86x10(-5)) but not men (OR=1.03 [0.96 to 1.11], P=0.387). There were no other strong interactions of any of the loci with other traditional risk factors. The loci at 9p21, 1p13.3, 2q36.3, and 10q11.21 acted independently and cumulatively increased CAD risk by 15% (12% to 18%), per additional risk allele. ConclusionsThe findings provide strong evidence for association between at least 4 genetic loci and CAD risk. Cumulatively, these novel loci have a significant impact on risk of CAD at least in European populations. (Arterioscler Thromb Vasc Biol. 2009; 29: 774-780.)

Aim. This paper contrasts structural and managerial characteristics of low- and high-turnover hospitals, and describes the organizational configuration of attractive hospitals. Background. In countries facing nurse shortages and turnover, some hospitals succeed in recruiting and retaining nurses. In Magnet Hospitals, managerial practices and environmental characteristics increase nurses' job satisfaction and their commitment to the organization, which in turn decreases nurse turnover. Such an approach suggests that organizations are best understood as clusters of interconnected structures and practices, i.e. organizational configurations rather than entities whose components can be understood in isolation. Method. From a sample of 12 hospitals whose nurse turnover was studied for 1 year, structural and organizational features of hospitals in the first and fourth quartiles, i.e. attractive (turnover <3.1%) vs. conventional (turnover >11.8%) were contrasted. A questionnaire, including perceptions of health-related factors, job demands, stressors, work schedules, organizational climate, and work adjustments antecedent to turnover, was received from 401 nurses working in attractive hospitals (response rate = 53.8%) and 774 nurses in conventional hospitals (response rate = 54.5%). Findings. Structural characteristics did not differentiate attractive and conventional hospitals, but employee perceptions towards the organization differed strikingly. Differences were observed for risk exposure, emotional demands, role ambiguity and conflicts, work-family conflicts, effort-reward imbalance and the meaning of work, all in favour of attractive hospitals (P < 0.001). Relationships with nursing management, work ability and satisfaction with working time, handover shifts and schedules were also better in attractive hospitals (P < 0.001). Job satisfaction and commitment were higher in attractive hospitals, whereas burnout and intention to leave were lower (P < 0.0

Aim. This paper contrasts structural and managerial characteristics of low- and high-turnover hospitals, and describes the organizational configuration of attractive hospitals. Background. In countries facing nurse shortages and turnover, some hospitals succeed in recruiting and retaining nurses. In Magnet Hospitals, managerial practices and environmental characteristics increase nurses' job satisfaction and their commitment to the organization, which in turn decreases nurse turnover. Such an approach suggests that organizations are best understood as clusters of interconnected structures and practices, i.e. organizational configurations rather than entities whose components can be understood in isolation. Method. From a sample of 12 hospitals whose nurse turnover was studied for 1 year, structural and organizational features of hospitals in the first and fourth quartiles, i.e. attractive (turnover <3.1%) vs. conventional (turnover >11.8%) were contrasted. A questionnaire, including perceptions of health-related factors, job demands, stressors, work schedules, organizational climate, and work adjustments antecedent to turnover, was received from 401 nurses working in attractive hospitals (response rate = 53.8%) and 774 nurses in conventional hospitals (response rate = 54.5%). Findings. Structural characteristics did not differentiate attractive and conventional hospitals, but employee perceptions towards the organization differed strikingly. Differences were observed for risk exposure, emotional demands, role ambiguity and conflicts, work-family conflicts, effort-reward imbalance and the meaning of work, all in favour of attractive hospitals (P < 0.001). Relationships with nursing management, work ability and satisfaction with working time, handover shifts and schedules were also better in attractive hospitals (P < 0.001). Job satisfaction and commitment were higher in attractive hospitals, whereas burnout and intention to leave were lower (P < 0.0

Aim. This paper contrasts structural and managerial characteristics of low- and high-turnover hospitals, and describes the organizational configuration of attractive hospitals. Background. In countries facing nurse shortages and turnover, some hospitals succeed in recruiting and retaining nurses. In Magnet Hospitals, managerial practices and environmental characteristics increase nurses' job satisfaction and their commitment to the organization, which in turn decreases nurse turnover. Such an approach suggests that organizations are best understood as clusters of interconnected structures and practices, i.e. organizational configurations rather than entities whose components can be understood in isolation. Method. From a sample of 12 hospitals whose nurse turnover was studied for 1 year, structural and organizational features of hospitals in the first and fourth quartiles, i.e. attractive (turnover <3.1%) vs. conventional (turnover >11.8%) were contrasted. A questionnaire, including perceptions of health-related factors, job demands, stressors, work schedules, organizational climate, and work adjustments antecedent to turnover, was received from 401 nurses working in attractive hospitals (response rate = 53.8%) and 774 nurses in conventional hospitals (response rate = 54.5%). Findings. Structural characteristics did not differentiate attractive and conventional hospitals, but employee perceptions towards the organization differed strikingly. Differences were observed for risk exposure, emotional demands, role ambiguity and conflicts, work-family conflicts, effort-reward imbalance and the meaning of work, all in favour of attractive hospitals (P < 0.001). Relationships with nursing management, work ability and satisfaction with working time, handover shifts and schedules were also better in attractive hospitals (P < 0.001). Job satisfaction and commitment were higher in attractive hospitals, whereas burnout and intention to leave were lower (P < 0.0

The main purpose of this study is to illustrate how, within the nursing profession, work ability can be deteriorated by a job alienation mechanism which acts differently according to age. From the total number of nurses participating in the NEXT Study, a sample of 27,146 nurses was selected. In addition to age, "Job demands", "Job control" and "Harassment at work" were considered as determinants of job alienation. "Overcommitment", "Uncertainty about patients' treatment" and "Work meaning" were used as symptoms of job alienation. Finally, "Work Ability Index" (WAI) was employed as the outcome variable. A structural equation model was used to test the job alienation hypothesis. The model demonstrated a good fit with the data. Overcommitment, uncertainty about patients' treatment and work meaning had a direct effect on WAI. High job demands, high harassment at work, low job control and age had both direct and indirect effects (via overcommitment, uncertainty about patients' treatment and work meaning) on WAI. Low work ability in older nurses is due to ageing and to an increase in overcommitment yielded by perceived high demands, low job control and high harassment at work. On the contrary, among the nurses under 50 years old, decrease of WAI turned out to be more associated with higher uncertainty about patients' treatment and lower work meaning, which both affect the possibility to reach more professional competence and develop occupational expertise.

The main purpose of this study is to illustrate how, within the nursing profession, work ability can be deteriorated by a job alienation mechanism which acts differently according to age. From the total number of nurses participating in the NEXT Study, a sample of 27,146 nurses was selected. In addition to age, "Job demands", "Job control" and "Harassment at work" were considered as determinants of job alienation. "Overcommitment", "Uncertainty about patients' treatment" and "Work meaning" were used as symptoms of job alienation. Finally, "Work Ability Index" (WAI) was employed as the outcome variable. A structural equation model was used to test the job alienation hypothesis. The model demonstrated a good fit with the data. Overcommitment, uncertainty about patients' treatment and work meaning had a direct effect on WAI. High job demands, high harassment at work, low job control and age had both direct and indirect effects (via overcommitment, uncertainty about patients' treatment and work meaning) on WAI. Low work ability in older nurses is due to ageing and to an increase in overcommitment yielded by perceived high demands, low job control and high harassment at work. On the contrary, among the nurses under 50 years old, decrease of WAI turned out to be more associated with higher uncertainty about patients' treatment and lower work meaning, which both affect the possibility to reach more professional competence and develop occupational expertise.

The main purpose of this study is to illustrate how, within the nursing profession, work ability can be deteriorated by a job alienation mechanism which acts differently according to age. From the total number of nurses participating in the NEXT Study, a sample of 27,146 nurses was selected. In addition to age, "Job demands", "Job control" and "Harassment at work" were considered as determinants of job alienation. "Overcommitment", "Uncertainty about patients' treatment" and "Work meaning" were used as symptoms of job alienation. Finally, "Work Ability Index" (WAI) was employed as the outcome variable. A structural equation model was used to test the job alienation hypothesis. The model demonstrated a good fit with the data. Overcommitment, uncertainty about patients' treatment and work meaning had a direct effect on WAI. High job demands, high harassment at work, low job control and age had both direct and indirect effects (via overcommitment, uncertainty about patients' treatment and work meaning) on WAI. Low work ability in older nurses is due to ageing and to an increase in overcommitment yielded by perceived high demands, low job control and high harassment at work. On the contrary, among the nurses under 50 years old, decrease of WAI turned out to be more associated with higher uncertainty about patients' treatment and lower work meaning, which both affect the possibility to reach more professional competence and develop occupational expertise.