AML1, the Target of Multiple Chromosomal Translocations in Human Leukemia, Is Essential for Normal Fetal Liver Hematopoiesis

AbstractThe AML1–CBFβ transcription factor is the most frequent target of chromosomal rearrangements in human leukemia. To investigate its normal function, we generated mice lacking AML1. Embryos with homozygous mutations in AML1 showed normal morphogenesis and yolk sac–derived erythropoiesis, but lacked fetal liver hematopoiesis and died around E12.5. Sequentially targeted AML1−/− ES cells retained their capacity to differentiate into primitive erythroid cells in vitro; however, no myeloid or erythroid progenitors of definitive hematopoietic origin were detected in either the yolk sac or fetal livers of mutant embryos. Moreover, this hematopoietic defect was intrinsic to the stem cells in that AML1−/− ES cells failed to contribute to hematopoiesis in chimeric animals. These results suggest that AML1-regulated target genes are essential for definitive hematopoiesis of all lineages

Mutation Testing as a Safety Net for Test Code Refactoring

Refactoring is an activity that improves the internal structure of the code without altering its external behavior. When performed on the production code, the tests can be used to verify that the external behavior of the production code is preserved. However, when the refactoring is performed on test code, there is no safety net that assures that the external behavior of the test code is preserved. In this paper, we propose to adopt mutation testing as a means to verify if the behavior of the test code is preserved after refactoring. Moreover, we also show how this approach can be used to identify the part of the test code which is improperly refactored

Fermi Surface Properties of Low Concentration Cex_{x}La1−x_{1-x}B6_{6}: dHvA

The de Haas-van Alphen effect is used to study angular dependent extremal areas of the Fermi Surfaces (FS) and effective masses of Ce$_{x}$La$_{1-x}$B$_{6}$ alloys for $x$ between 0 and 0.05. The FS of these alloys was previously observed to be spin polarized at low Ce concentration ($x$ = 0.05). This work gives the details of the initial development of the topology and spin polarization of the FS from that of unpolarized metallic LaB$_{6}$ to that of spin polarized heavy Fermion CeB$_{6}$ .Comment: 7 pages, 9 figures, submitted to PR

Economisch perspectief van de PAS. Baten en kosten van de Programmatische Aanpak Stikstof in Natura 2000-gebieden

De Programmatische Aanpak Stikstof (PAS), onderdeel van Natura 2000, is economisch voordelig voor ons land. Van 2013 tot 2020 zijn de economische baten zo'n 100-200 mln. euro/jaar hoger dan de kosten. De baten van de PAS voor de sectoren landbouw, industrie en verkeer en vervoer bedragen in die periode naar schatting 200 tot 300 mln. euro/jaar, terwijl de economische kosten op een kleine 100 mln. euro/jaar worden geschat. De PAS leidt tot duidelijkheid voor ondernemers. Die duidelijkheid levert economisch voordeel op. De veehouderij bij de stikstofgevoelige Natura 2000-gebieden kan zich blijven ontwikkelen, wat met name gunstig is voor de rundveehouderij. De PAS is daarnaast voor ondernemers gunstig, omdat ze minder on-derzoekskosten voor het verkrijgen van een Natuurbeschermingswetvergunning hoeven te maken. Andere baten van de PAS, die ontstaan bij de aanleg van wegen en in de industrie, blijken moeilijk te kwantificeren vanwege het ontbreken van voldoende gegevens

Randomized controlled trial of vacuum therapy for intermittent claudication

OBJECTIVE: The "gold standard" treatment of intermittent claudication (IC) is supervised exercise therapy (SET). Intermittent vacuum therapy (IVT) has recently been promoted as an additional treatment of IC. During IVT, negative pressure and atmospheric pressure are alternatingly applied to the lower extremities, possibly resulting in improved circulation. The aim of this study was to determine a potential additional effect of IVT in IC patients undergoing a standardized SET program. METHODS: IC patients were recruited from three Dutch general hospitals between December 2015 and July 2017. They received a standardized SET program but were also randomly assigned to an intervention group receiving an IVT treatment (-50 mBar negative pressure) or a control group receiving a sham treatment (-5 mBar negative pressure). IVT was provided in a dedicated clinic during 12 sessions of 30 minutes during a 6-week period. The primary outcome measure was a change in maximal treadmill walking distance. Secondary outcome measures were a change in functional treadmill walking distance, 6-minute walk test, ambulatory ability, and quality of life. RESULTS: A total of 78 patients were randomized, of whom 70 were available for intention-to-treat analysis (control, n = 34; intervention, n = 36). At 6 and 12 weeks, increases in walking distance were of equal magnitude. Median (interquartile range) change in maximal treadmill walking distance during 12 weeks was +335 (205-756) meters in control patients and +250 (77-466) meters in intervention patients (P = .109), whereas functional treadmill walking distance increased +230 (135-480) meters and +188 (83-389) meters (P = .233), respectively. Mean ± standard deviation change in the 6-minute walk test was +36 ± 48 meters and +55 ± 63 meters (P = .823), respectively. Ambulatory ability and quality of life improved equally in both groups. CONCLUSIONS: IVT does not confer any additional beneficial effects in IC patients undergoing a standardized SET program

Footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in patients with diabetes: a systematic review

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Evaluating the usability of a visual feature modeling notation

International audienceFeature modeling is a popular Software Product Line Engineering (SPLE) technique used to describe variability in a product family. A usable feature modeling tool environment should enable SPLE practitioners to produce good quality models, in particular, models that effectively communicate modeled information. FAMILIAR is a text-based environment for manipulating and composing Feature Models (FMs). In this paper we present extensions we made to FAMILIAR to enhance its usability. The extensions include a visualization of FMs, or more precisely , a feature diagram rendering mechanism that supports the use of a combination of text and graphics to describe FMs, their configurations, and the results of FM analyses. We also present the results of a preliminary evaluation of the environment's usability. The evaluation involves comparing the use of the extended environment with the previous text-based console-driven version. The preliminary experiment provides some evidence that use of the new environment results in increased cognitive effectiveness of novice users and improved quality of new FMs

Improvement in left ventricular ejection fraction after pharmacological up-titration in new-onset heart failure with reduced ejection fraction

OBJECTIVE: Recent studies have reported suboptimal up-titration of heart failure (HF) therapies in patients with heart failure and a reduced ejection fraction (HFrEF). Here, we report on the achieved doses after nurse-led up-titration, reasons for not achieving the target dose, subsequent changes in left ventricular ejection fraction (LVEF), and mortality. METHODS: From 2012 to 2018, 378 HFrEF patients with a recent (< 3 months) diagnosis of HF were referred to a specialised HF-nurse led clinic for protocolised up-titration of guideline-directed medical therapy (GDMT). The achieved doses of GDMT at 9 months were recorded, as well as reasons for not achieving the optimal dose in all patients. Echocardiography was performed at baseline and after up-titration in 278 patients. RESULTS: Of 345 HFrEF patients with a follow-up visit after 9 months, 69% reached ≥ 50% of the recommended dose of renin-angiotensin-system (RAS) inhibitors, 73% reached ≥ 50% of the recommended dose of beta-blockers and 77% reached ≥ 50% of the recommended dose of mineralocorticoid receptor antagonists. The main reasons for not reaching the target dose were hypotension (RAS inhibitors and beta-blockers), bradycardia (beta-blockers) and renal dysfunction (RAS inhibitors). During a median follow-up of 9 months, mean LVEF increased from 27.6% at baseline to 38.8% at follow-up. Each 5% increase in LVEF was associated with an adjusted hazard ratio of 0.84 (0.75–0.94, p = 0.002) for mortality and 0.85 (0.78–0.94, p = 0.001) for the combined endpoint of mortality and/or HF hospitalisation after a mean follow-up of 3.3 years. CONCLUSIONS: This study shows that protocolised up-titration in a nurse-led HF clinic leads to high doses of GDMT and improvement of LVEF in patients with new-onset HFrEF. SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s12471-021-01591-6) contains supplementary material, which is available to authorized users

Increased EEG gamma band activity in Alzheimer’s disease and mild cognitive impairment

High frequency (30–70 Hz) gamma band oscillations in the human electro-encephalogram (EEG) are thought to reflect perceptual and cognitive processes. It is therefore interesting to study these measures in cognitive impairment and dementia. To evaluate gamma band oscillations as a diagnostic biomarker in Alzheimer’s disease (AD) and mild cognitive impairment (MCI), 15 psychoactive drug naïve AD patients, 20 MCI patients and 20 healthy controls participated in this study. Gamma band power (GBP) was measured in four conditions viz. resting state, music listening, story listening and visual stimulation. To evaluate test–retest reliability (TRR), subjects underwent a similar assessment one week after the first. The overall TRR was high. Elevated GBP was observed in AD when compared to MCI and control subjects in all conditions. The results suggest that elevated GBP is a reproducible and sensitive measure for cognitive dysfunction in AD in comparison with MCI and controls

Costs and difficulties of recruiting patients to provide e-health support: pilot study in one primary care trust

<p>Abstract</p> <p>Background</p> <p>Better use of e-health services by patients could improve outcomes and reduce costs but there are concerns about inequalities of access. Previous research in outpatients suggested that anonymous personal email support may help patients with long term conditions to use e-health, but recruiting earlier in their 'journey' may benefit patients more. This pilot study explored the feasibility and cost of recruiting patients for an e-health intervention in one primary care trust.</p> <p>Methods</p> <p>The sample comprised 46 practices with total patient population of 250,000. We approached all practices using various methods, seeking collaboration to recruit patients via methods agreed with each practice. A detailed research diary was kept of time spent recruiting practices and patients. Researcher time was used to estimate costs. Patients who consented to participate were offered email support for their use of the Internet for health.</p> <p>Results</p> <p>Eighteen practices agreed to take part; we recruited 27 patients, most (23/27) from five practices. Practices agreed to recruit patients for an e-health intervention via waiting room leaflets (16), posters (16), practice nurses (15), doctors giving patients leaflets (5), a study website link (7), inclusion in planned mailshots (2), and a special mailshot to patients selected from practice computers (1). After low recruitment response we also recruited directly in five practices through research assistants giving leaflets to patients in waiting rooms. Ten practices recruited no patients. Those practices that were more difficult to recruit were less likely to recruit patients. Leaving leaflets for practice staff to distribute and placing posters in the practice were not effective in recruiting patients. Leaflets handed out by practice nurses and website links were more successful. The practice with lowest costs per patient recruited (£70) used a special mailshot to selected patients.</p> <p>Conclusion</p> <p>Recruitment via general practice was not successful and was therefore expensive. Direct to consumer methods and recruitment of patients in outpatients to offer email support may be more cost effective. If recruitment in general practice is required, contacting practices by letter and email, not following up non-responding practices, and recruiting patients with selected conditions by special mailshot may be the most cost-effective approach.</p