Hypertrophic cardiomyopathy (HCM) is a relatively common inherited myocardial disorder, once regarded as largely untreatable with ominous prognosis and most visibly as a common cause of sudden death ...(SD) in the young. Over the last several years, HCM has been transformed into a contemporary treatable disease with management options that significantly alter clinical course. With the use of implantable cardioverter-defibrillators (ICDs) in the HCM patient population, a new paradigm has emerged, with primary prevention device therapy reliably terminating potentially lethal ventricular tachyarrhythmias (3%–4% per year) and being largely responsible for a >10-fold decrease in disease-related mortality (to 0.5% per year), independent of age.
An evidenced-based and guideline directed clinical risk stratification algorithm has evolved, including variables identified with cardiac magnetic resonance. One or more risk markers judged major and relevant within a patient’s clinical profile can be considered sufficient to recommend a primary prevention implant (associated with a measure of physician judgment and shared decision-making). ICD decisions using the prospective individual risk marker strategy have been associated with 95% sensitivity for identifying patients who subsequently experienced appropriate ICD therapy, (albeit often delayed substantially for >5 or >10 years after implant), but without heart failure deterioration or HCM death following device intervention. A rigid mathematically derived statistical risk model proposed by the European Society of Cardiology is associated with low sensitivity (ie, 33%) for predicting SD events.
Introduction of prophylactically inserted ICDs to HCM 20 years ago has significantly altered the clinical course and landscape of this disease. SD prevention has reduced HCM mortality significantly, making preservation of life and the potential for normal longevity a reality for most patients.
This randomized, open-label, phase 2b study (NCT01565668) evaluated the efficacy and safety of 2 dosing regimens of quizartinib monotherapy in patients with relapsed/refractory (R/R) FLT3-internal ...tandem duplication (ITD)–mutated acute myeloid leukemia (AML) who previously underwent transplant or 1 second-line salvage therapy. Patients (N = 76) were randomly assigned to 30- or 60-mg/day doses (escalations to 60 or 90 mg/day, respectively, permitted for lack/loss of response) of single-agent oral quizartinib dihydrochloride. Allelic frequency of at least 10% was defined as FLT3-ITD–mutated disease. Coprimary endpoints were composite complete remission (CRc) rates and incidence of QT interval corrected by Fridericia's formula (QTcF) of more than 480 ms (grade 2 or greater). Secondary endpoints included overall survival (OS), duration of CRc, bridge to transplant, and safety. CRc rates were 47% in both groups, similar to earlier reports with higher quizartinib doses. Incidence of QTcF above 480 ms was 11% and 17%, and QTcF above 500 ms was 5% and 3% in the 30- and 60-mg groups, respectively, which is less than earlier reports with higher doses of quizartinib. Median OS (20.9 and 27.3 weeks), duration of CRc (4.2 and 9.1 weeks), and bridge to transplant rates (32% and 42%) were higher in the 60-mg groups than in the 30-mg group. Dose escalation occurred in 61% and 14% of patients in the 30- and 60-mg groups, respectively. This high clinical activity of quizartinib at the evaluated doses is consistent with previous reports with an improved safety profile. Need to dose-escalate more than half of patients who received quizartinib 30 mg also supports further investigation of treatment with quizartinib 60 mg/day.
•Quizartinib at 60 mg/day (vs 30 mg/day) was associated with higher overall response, survival, and bridge to transplant.•The benefit-risk profile of quizartinib in relapsed or refractory FLT3-ITD–mutated AML warrants further evaluation of 60-mg once-daily dose.
Display omitted
Polyamines have been implicated in skin tumorigenesis; however, their role in epidermal homeostasis remains obscure. In a new article in the Journal of Investigative Dermatology, Rahim et al. (2021) ...report that keratinocyte differentiation requires a shift in polyamine ratios that is mediated by AMD1. Results suggest that targeting polyamine availability might be useful in the treatment of hyperproliferative skin disorders.
Cyclic products can be obtained through the intramolecular version of the Nicholas reaction, which requires having the nucleophile connected to the alkyne unit. Here, we report the synthesis of ...1-oxa-3-cyclooctynes starting from commercially available (1
,3
)-camphoric acid. The strategy is based on the initial preparation of propargylic alcohols, complexation of the triple bond with Co
(CO)
, and treatment with BF
·Et
O to induce an intramolecular Nicholas reaction with the free hydroxyl group as nucleophile. Finally, oxidative deprotection of the alkyne afforded the cyclooctynes in good yields. Notably, large-sized R substituents at the chiral center connected to the O atom were oriented in such a way that steric interactions were minimized in the cyclization, allowing the formation of cyclooctynes exclusively with
configuration, in good agreement with theoretical predictions. Moreover, preliminary studies demonstrated that these cyclooctynes were reactive in the presence of azides yielding substituted triazoles.
Understanding the Great Recession Christiano, Lawrence J.; Eichenbaum, Martin S.; Trabandt, Mathias
American economic journal. Macroeconomics,
01/2015, Volume:
7, Issue:
1
Journal Article
Peer reviewed
Open access
We argue that the vast bulk of movements in aggregate real economic activity during the Great Recession were due to financial frictions. We reach this conclusion by looking through the lens of an ...estimated New Keynesian model in which firms face moderate degrees of price rigidities, no nominal rigidities in wages, and a binding zero lower bound constraint on the nominal interest rate. Our model does a good job of accounting for the joint behavior of labor and goods markets, as well as inflation, during the Great Recession. According to the model the observed fall in total factor productivity and the rise in the cost of working capital played critical roles in accounting for the small drop in inflation that occurred during the Great Recession.
Imported malaria in children in Madrid, Spain, 2007–2013 Sánchez, Beatriz Soto; Tato, L.M. Prieto; Martín, S. Guillén ...
Enfermedades infecciosas y microbiologia clinica (English ed.),
June-July 2017, 2017-06-00, Volume:
35, Issue:
6
Journal Article
Peer reviewed
The majority of malaria cases diagnosed in Europe in the last few years have occurred in people living in non-endemic areas travelling back to their home country to visit friends and relatives ...(VFRs). Children account for 15–20% of imported malaria, with known higher risk of severe disease.
A retrospective multicentre study was conducted in 24 hospitals in Madrid (Spain) including patients under 16 years diagnosed with malaria (2007–2013).
A total of 149 episodes in 147 children were reported. Plasmodium falciparum was the species most commonly isolated. Twenty-five patients developed severe malaria and there was one death related to malaria. VFR accounted for 45.8% of our children. Only 17 VFRs had received prophylaxis, and 4 of them taken appropriately. They presented more frequently with fever (98% vs. 69%), a longer time with fever (55 vs. 26%), delay in diagnosis of more than three days (62 vs. 37%), and more thrombocytopenia (65 vs. 33%) than non-VFRs, and with significant differences (p<0.05).
VFRs represent a large proportion of imported malaria cases in our study. They seldom took adequate prophylaxis, and delayed the visit to the physician, increasing the length of fever and subsequent delaying in diagnosis. Appropriate preventive measures, such as education and pre-travel advices should be taken in this population.
En los últimos años la mayoría de los casos de malaria en Europa se han producido en personas asentadas en zonas no endémicas que viajan a su país de origen para visitar a amigos y familiares (VFR). Los niños representan el 15-20% de la malaria importada, con el conocido alto riesgo de enfermedad grave.
Estudio multicéntrico retrospectivo en 24 hospitales en Madrid, que incluyó pacientes menores de 16años con diagnóstico de malaria (2007-2013).
Se registraron 149 episodios en 147 niños. Plasmodium falciparum fue la especie más frecuentemente aislada. Veinticinco niños padecieron paludismo grave y hubo una muerte relacionada con la malaria. Los pacientes VFR representaron el 45,8% de nuestros niños estudiados. Solo 17 de los VFR habían recibido profilaxis y en solo 4 casos la tomaron apropiadamente. Estos pacientes presentaron con más frecuencia fiebre (98% vs 69%), retraso en el diagnóstico más de 3 días (62 vs 37%) y trombocitopenia (65 vs 33%).
Los niños VFR representaron una gran proporción de casos de paludismo importado en nuestro estudio. Rara vez tomaron la profilaxis de forma adecuada. Además estos niños presentaron un mayor retraso en la consulta al médico tras la aparición de síntomas, con el subsiguiente retraso en el diagnóstico. Es necesario tomar las medidas preventivas adecuadas, como la educación o el consejo pre-viaje, en esta población.
Familial Hypercholesterolemia (FH) is an inherited disorder leading to increased risk of premature atherosclerotic cardiovascular disease. This risk can be ameliorated through adherence to ...pharmacological treatment and salient lifestyle behaviors (e.g., physical activity participation, healthy eating). Identifying theory-based, modifiable determinants of these behaviors may inform behavioral interventions promoting participation in FH self-management behaviors. We aimed to identify the belief-based social cognition constructs uniquely associated with intentions to perform, and actual participation in, FH self-management behaviors in the extant research.
A systematic database search identified studies (k = 9, N = 1394) reporting relations between social cognition theory constructs and intention toward, or actual participation in, self-management behaviors in FH patients. As no studies examining prospectively-measured behaviors were identified, we tested relations among social cognition constructs, intentions, and past FH-self-management behavior using random effects multi-level meta-analysis and meta-analytic structural equation modelling.
We found non-zero averaged correlations among the key social cognition constructs (attitudes, norms, risk perceptions, self-efficacy), intentions, and past behavior. A meta-analytic structural equation model indicated non-zero averaged direct effects of attitudes, norms, self-efficacy, and past behavior on FH self-management behavioral intentions. There were also non-zero averaged indirect effects of past behavior on intentions mediated by the social cognition constructs.
Findings provide evidence to support the proposed model and highlight the importance of personal, normative, and capacity related beliefs and past experience as unique correlates of intentions to perform FH self-management behaviors. The model may signal potential constructs that could be targeted in behavioral interventions to promote participation in FH self-management behaviors.
•Social cognition correlates of self-management intentions in familial hypercholesterolemia (FH) patients were meta-analyzed.•Studies reporting correlations among social cognition constructs and FH self-management behavioral intentions were identified.•Meta-Analysis identified attitudes, norms, and self-efficacy as key correlates of intentions.•Associations between risk perceptions and self-management behavioral intentions was no different from zero.•Findings may inform development of interventions to promote FH patients' self-management behaviors.
PDF
