In this reply to commentaries on the Kirschner, Sweller, and
Clark (2006)
paper, we not only reemphasize the importance of randomized, controlled experimental tests of competing instructional ...procedures, but also indicate that altering one variable at a time is an essential feature of a properly controlled experiment. Furthermore, we also emphasize that variable must be relevant to the issue at hand with its effects explainable by our knowledge of human cognitive architecture. We reject the view that the presentation of relevant information should be reduced in favor of teaching learners how to find information. Lastly, we indicate that we believe a new educational psychology has been developed that has the potential to rapidly change our field.
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We pose that an age-related increase in the metabolic cost of walking arises in part from a redistribution of joint power where muscles spanning the hip compensate for insufficient ankle push-off and ...smaller peak propulsive forces (F
P
). Young adults elicit a similar redistribution when walking with smaller F
P
via biofeedback. We used targeted F
P
biofeedback and musculoskeletal models to estimate the metabolic costs of operating lower limb muscles in young adults walking across a range of F
P
. Our simulations support the theory of distal-to-proximal redistribution of joint power as a determinant of increased metabolic cost in older adults during walking.
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Summary
The prognosis for younger patients with relapsed acute myeloid leukaemia (AML) is generally dismal. Allogeneic stem cell transplantation is the preferred therapy for these patients. As part ...of the UK NCRI AML17 trial, daunorubicin/clofarabine (DClo) was compared with fludarabine, cytarabine, granulocyte colony‐stimulating factor with idarubicin (FLAG‐Ida) in 311 patients designated high‐risk following course one of induction therapy, which has previously been reported. We now report the results of the same randomisation in patients who were refractory to two induction courses or subsequently relapsed. A total of 94 relapsed or refractory AML patients, usually less than 60 years of age and with mainly favourable or intermediate‐risk cytogenetics, were randomised to receive up to three courses of DClo or FLAG‐Ida, with the aim of proceeding to transplant. Complete remission was achieved in 74% of patients with no difference between the arms. Overall, 57% of patients received a transplant with no difference between the arms, likewise overall survival at five years showed no significant difference (21% for DClo vs. 22% for FLAG‐Ida). No patient who did not receive a transplant survived beyond 21months. A stratified analysis including the 311 post course 1 high‐risk patients who underwent the same randomisation showed a consistent treatment benefit for FLAG‐Ida.
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Febrile infants in the first 90 days may have life-threatening serious bacterial infection (SBI). Well-appearing febrile infants with SBI cannot be distinguished from those without by examination ...alone. Variation in care resulting in both undertreatment and overtreatment is common.
We developed and implemented an evidence-based care process model (EB-CPM) for the management of well-appearing febrile infants in the Intermountain Healthcare System. We report an observational study describing changes in (1) care delivery, (2) outcomes of febrile infants, and (3) costs before and after implementation of the EB-CPM in a children's hospital and in regional medical centers.
From 2004 through 2009, 8044 infants had 8431 febrile episodes, resulting in medical evaluation. After implementation of the EB-CPM in 2008, infants in all facilities were more likely to receive evidence-based care including appropriate diagnostic testing, determination of risk for SBI, antibiotic selection, decreased antibiotic duration, and shorter hospital stays (P < .001 for all). In addition, more infants had a definitive diagnosis of urinary tract infection or viral illness (P < .001 for both). Infant outcomes improved with more admitted infants positive for SBI (P = .011), and infants at low risk for SBI were more often managed without antibiotics (P < .001). Although hospital admissions were shortened by 27%, there were no cases of missed SBI. Health Care costs were also reduced, with the mean cost per admitted infant decreasing from $7178 in 2007 to $5979 in 2009 (-17%, P < .001).
The EB-CPM increased evidence-based care in all facilities. Infant outcomes improved and costs were reduced, substantially improving value.
Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four ...baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.
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Introduction
Tyrosine kinase inhibitors (TKIs) have become the mainstay of treatment for chronic myeloid leukaemia (CML), but cardiovascular (CV) risk and exacerbation of underlying risk factors ...associated with TKIs have become widely debated. Real‐world evidence reveals little application of CV risk factor screening or continued monitoring within UK CML management. This consensus paper presents practical recommendations to assist healthcare professionals in conducting CV screening/comorbidity management for patients receiving TKIs.
Methods
We conducted a multidisciplinary panel meeting and two iterative surveys involving 10 CML specialists: five haematologists, two cardio‐oncologists, one vascular surgeon, one haemato‐oncology pharmacist and one specialist nurse practitioner.
Results
The panel recommended that patients commencing second‐/third‐generation TKIs undergo formal CV risk assessment at baseline, with additional investigations and involvement of cardiologists/vascular surgeons for those with high CV risk. During treatment, patients should undergo CV monitoring, with the nature and frequency of testing dependent on TKI and baseline CV risk. For patients who develop CV adverse events, decision‐making around TKI interruption, cessation or change should be multidisciplinary and balance CV and haematological risk.
Conclusion
The panel anticipates these recommendations will support healthcare professionals in implementing CV risk screening and monitoring, broadly and consistently, and thereby help optimise TKI treatment for CML.
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Purpose
To evaluate whether total FSH dose was negatively correlated with number of oocytes retrieved in a large data set where previously, a negative correlation between FSH dose and live birth rate ...was identified.
Methods
Data from 650,637 fresh autologous in vitro fertilization (IVF) cycles reported to the Society for Assisted Reproductive Technology between 2004 and 2012 were included. Logistic regression analysis was performed to determine if the relationship between total FSH dose used during ART with number of oocytes retrieved was impacted by the patient’s health prognosis, age, BMI, ovarian stimulation protocol, or infertility diagnosis.
Results
The number of oocytes retrieved was negatively correlated with FSH dose (
P
< 0.0001). Regardless of patient prognosis, age, BMI, ovarian stimulation protocol, and infertility diagnosis, the highest number of oocytes retrieved was in the 1001–2000 IU FSH group, and was 36–51% lower in the > 5000 IU compared with the optimal, 1001–2000 IU, FSH groups. Overall, ~80% of patients received FSH doses outside of the optimal FSH dose. Moreover, 61% of good prognosis patients (excludes individuals likely prescribed higher FSH doses) received doses exceeding the optimal dose range.
Conclusion
The inverse relationship between FSH dose and the number of oocytes retrieved independent of patient age or health implies that excessive FSH doses during ART may be detrimental to oocyte retrieval.
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Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that inhibits the tumor suppressor PP2A-B56α. However,
mRNA variants remain uncharacterized. Here, we report the discovery of a
...splicing variant, novel CIP2A variant (
).
Characterization of CIP2A variants was performed by both 3' and 5' rapid amplification of cDNA ends from cancer cells. The function of NOCIVA was assessed by structural and molecular biology approaches. Its clinical relevance was studied in an acute myeloid leukemia (AML) patient cohort and two independent chronic myeloid leukemia (CML) cohorts.
contains
exons 1 to 13 fused to 349 nucleotides from
intron 13. Intriguingly, the first 39 nucleotides of the
-specific sequence are in the coding frame with exon 13 of
and code for a 13-amino acid peptide tail nonhomologous to any known human protein sequence. Therefore, NOCIVA translates to a unique human protein. NOCIVA retains the capacity to bind to B56α, but, whereas CIP2A is predominantly a cytoplasmic protein, NOCIVA translocates to the nucleus. Indicative of prevalent alternative splicing from
to
in myeloid malignancies, AML and CML patient samples overexpress
, but not
mRNA. In AML, a high
mRNA expression ratio is a marker for adverse overall survival. In CML, high
expression is associated with inferior event-free survival among imatinib-treated patients, but not among patients treated with dasatinib or nilotinib.
We discovered a novel variant of the oncoprotein CIP2A and its clinical relevance in predicting tyrosine kinase inhibitor therapy resistance in myeloid leukemias.
Many populations live in environments subject to frequent biotic and abiotic changes. Nonetheless, it is interesting to ask whether an evolving population's mean fitness can increase indefinitely, ...and potentially without any limit, even in a constant environment. A recent study showed that fitness trajectories of Escherichia coli populations over 50 000 generations were better described by a power-law model than by a hyperbolic model. According to the power-law model, the rate of fitness gain declines over time but fitness has no upper limit, whereas the hyperbolic model implies a hard limit. Here, we examine whether the previously estimated power-law model predicts the fitness trajectory for an additional 10 000 generations. To that end, we conducted more than 1100 new competitive fitness assays. Consistent with the previous study, the power-law model fits the new data better than the hyperbolic model. We also analysed the variability in fitness among populations, finding subtle, but significant, heterogeneity in mean fitness. Some, but not all, of this variation reflects differences in mutation rate that evolved over time. Taken together, our results imply that both adaptation and divergence can continue indefinitely—or at least for a long time—even in a constant environment.
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