Targeting fertility and female participation through the income tax

We evaluate the effect of a 2003 reform in the Spanish income tax on fertility and the employment of mothers with small children. The reform introduced a tax credit for working mothers with children under the age of three, while also increasing child deductions for all households with children. Theoretically, given the interplay of these two components, the expected effect of the reform is ambiguous on both outcomes. We find that the combined reforms significantly increased both fertility (by almost five percent) and the employment rate of mothers with children under three (by two percent). These effects were more pronounced among less-educated women. In addition, to disentangle the impact of the two reform components, we use an earlier reform that increased child deductions in 1999. We find that the child deductions affect mothers employment negatively, which implies that the 2003 tax credit would have increased employment even more (up to five percent) in the absence of the change in child deductions.

Management of patient dose and image noise in routine pediatric CT abdominal examinations.

The aim was to propose a strategy for finding reasonable compromises between image noise and dose as a function of patient weight. Weighted CT dose index (CTDI(w)) was measured on a multidetector-row CT unit using CTDI test objects of 16, 24 and 32 cm in diameter at 80, 100, 120 and 140 kV. These test objects were then scanned in helical mode using a wide range of tube currents and voltages with a reconstructed slice thickness of 5 mm. For each set of acquisition parameter image noise was measured and the Rose model observer was used to test two strategies for proposing a reasonable compromise between dose and low-contrast detection performance: (1) the use of a unique noise level for all test object diameters, and (2) the use of a unique dose efficacy level defined as the noise reduction per unit dose. Published data were used to define four weight classes and an acquisition protocol was proposed for each class. The protocols have been applied in clinical routine for more than one year. CTDI(vol) values of 6.7, 9.4, 15.9 and 24.5 mGy were proposed for the following weight classes: 2.5-5, 5-15, 15-30 and 30-50 kg with image noise levels in the range of 10-15 HU. The proposed method allows patient dose and image noise to be controlled in such a way that dose reduction does not impair the detection of low-contrast lesions. The proposed values correspond to high- quality images and can be reduced if only high-contrast organs are assessed.

In vivo targeting of an anti-tumor antibody coupled to antigenic MHC class I complexes induces specific growth inhibition and regression of established syngeneic tumor grafts.

The concept of antibody-mediated targeting of antigenic MHC/peptide complexes on tumor cells in order to sensitize them to T-lymphocyte cytotoxicity represents an attractive new immunotherapy strategy. In vitro experiments have shown that an antibody chemically conjugated or fused to monomeric MHC/peptide can be oligomerized on the surface of tumor cells, rendering them susceptible to efficient lysis by MHC-peptide restricted specific T-cell clones. However, this strategy has not yet been tested entirely in vivo in immunocompetent animals. To this aim, we took advantage of OT-1 mice which have a transgenic T-cell receptor specific for the ovalbumin (ova) immunodominant peptide (257-264) expressed in the context of the MHC class I H-2K(b). We prepared and characterized conjugates between the Fab' fragment from a high-affinity monoclonal antibody to carcinoembryonic antigen (CEA) and the H-2K(b) /ova peptide complex. First, we showed in OT-1 mice that the grafting and growth of a syngeneic colon carcinoma line transfected with CEA could be specifically inhibited by systemic injections of the conjugate. Next, using CEA transgenic C57BL/6 mice adoptively transferred with OT-1 spleen cells and immunized with ovalbumin, we demonstrated that systemic injections of the anti-CEA-H-2K(b) /ova conjugate could induce specific growth inhibition and regression of well-established, palpable subcutaneous grafts from the syngeneic CEA-transfected colon carcinoma line. These results, obtained in a well-characterized syngeneic carcinoma model, demonstrate that the antibody-MHC/peptide strategy can function in vivo. Further preclinical experimental studies, using an anti-viral T-cell response, will be performed before this new form of immunotherapy can be considered for clinical use.

Diagnostic de la maladie coronarienne stable par FFR non invasive, mythe ou réalité [Diagnosis of stable coronary artery disease with non-invasive FFR: myth or reality?].

Decision to revascularize a patient with stable coronary artery disease should be based on the detection of myocardial ischemia. If this decision can be straightforward with significant stenosis or in non-significant stenosis, the decision with intermediate stenosis is far more difficult and require invasive measures of functional impact of coronary stenosis on maximal blood (flow fractional flow reserve=FFR). A recent computer based method has been developed and is able to measure FFR with data acquired during a standard coronary CT-scan (FFRcT). Two recent clinical studies (DeFACTO and DISCOVER-FLOW) show that diagnostic performance of FFRcT was associated with improved diagnostic accuracy versus standard coronary CT-scan for the detection of myocardial ischemia although FFRcT need further development.

Protection from lethal gram-negative bacterial sepsis by targeting Toll-like receptor 4.

Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor complex, plays a fundamental role in the sensing of LPS from gram-negative bacteria. Activation of TLR4 signaling pathways by LPS is a critical upstream event in the pathogenesis of gram-negative sepsis, making TLR4 an attractive target for novel antisepsis therapy. To validate the concept of TLR4-targeted treatment strategies in gram-negative sepsis, we first showed that TLR4(-/-) and myeloid differentiation primary response gene 88 (MyD88)(-/-) mice were fully resistant to Escherichia coli-induced septic shock, whereas TLR2(-/-) and wild-type mice rapidly died of fulminant sepsis. Neutralizing anti-TLR4 antibodies were then generated using a soluble chimeric fusion protein composed of the N-terminal domain of mouse TLR4 (amino acids 1-334) and the Fc portion of human IgG1. Anti-TLR4 antibodies inhibited intracellular signaling, markedly reduced cytokine production, and protected mice from lethal endotoxic shock and E. coli sepsis when administered in a prophylactic and therapeutic manner up to 13 h after the onset of bacterial sepsis. These experimental data provide strong support for the concept of TLR4-targeted therapy for gram-negative sepsis.

Onde não há médico: questões de tradução e de adaptação à realidade cabo-verdiana

A presente dissertação visa, numa primeira parte, o estudo de questões de tradução científico-técnicas integradas em dimensões culturais e, fundamentalmente, de adaptação de uma obra científico-técnico em inglês, na área da medicina, Where there is no doctor (1977) para português Onde não há médico, em adequação, segundo prefácio do autor, ao ambiente ecológico de Moçambique e dos restantes países africanos de expressão oficial portuguesa, o que será objeto de crítica. Assim, na segunda parte do trabalho, propõe-se, partindo de um enfoque significado-experiência de índole cognitiva, uma adaptação do texto à realidade cabo-verdiana, tendo em conta as diferenças ambientais e socioculturais entre Moçambique e Cabo Verde, essencialmente no que diz respeito aos recursos naturais, nomeadamente a água, e doenças que lhes estão associadas, bem como as diferenças socioculturais e de desenvolvimento relativamente ao papel das curandeiras locais versus o papel dos agentes de saúde.

Retinal degeneration progression changes lentiviral vector cell targeting in the retina

Ce travail de thèse a été réalisé au sein de l'Unité de Thérapie Génique et Biologie des Cellules Souches de l'Hôpital Jules- Gonin dans le Service d'Ophtalmologie de l'Université de Lausanne. Ce laboratoire recherche des solutions thérapeutiques pour des maladies dégénératives et incurables de la rétine comme les rétinites pigmentaires (RP). Ayant déjà montré certains résultats dans le domaine, la thérapie génique a été notre outil pour ce travail. Cette méthode se base sur le principe de remplacer un gène déficient par sa copie normale, en transportant celle-ci au coeur même du noyau par un vecteur. Il existe à l'heure actuelle différents vecteurs. Un des plus efficaces est un vecteur viral non-réplicatif : le lentivirus, dérivé de HIV-1. Celui-ci a la capacité d'intégrer le génome de la cellule cible, lui conférant ainsi un nouveau matériel génétique. Notre but a été d'établir le tropisme du lentivirus dans une rétine en dégénérescence. Ce lentivirus est connu pour transduire efficacement les cellules de l'épithélium pigmentaire rétinien dans l'oeil adulte sain, ainsi que celles de la neurorétine, mais ce, uniquement durant le développement. On sait aussi que le vecteur lentiviral présente un tropisme différent selon les enveloppes dont il est muni ; par exemple, le lentivirus avec une enveloppe Mokola est connu pour transduire les cellules gliales du système nerveux central. La rétine qui dégénère montre quant à elle des changements de sa structure qui pourraient influencer la diffusion du vecteur et/ou son tropisme. Le postulat de base a été le suivant : chez l'adulte, la transduction des neurones de la rétine via le lentivirus pourrait être facilitée par l'altération de la membrane limitante externe induite par la dégénérescence (meilleure pénétrance du virus). D'un point de vue technique, nous avons utilisé deux types distincts de modèles murins de dégénérescence rétinienne : des souris Balb/C soumises à une dose toxique de lumière et les souris Rhodopsin knockout, animaux génétiquement modifiés. Comme vecteur viral, nous avons employé deux différents pseudotypes de lentivirus (caractérisés par les enveloppes virales) avec différents promoteurs (séquence d'ADN qui initie la transduction et confère la spécificité d'expression d'un gène). En changeant l'enveloppe et le promoteur, nous avons essayé de trouver la meilleure combinaison pour augmenter l'affinité du vecteur vis-à-vis des photorécepteurs d'abord, puis vis-à-vis d'autres cellules de la rétine. Nos résultats ont montré que la membrane limitante externe est effectivement altérée chez les deux modèles de dégénérescence, mais que cette modification ne favorise pas la transduction des photorécepteurs lorsqu'on utilise un vecteur lentiviral contenant une enveloppe VSVG et un promoteur photorécepteur-spécifique ou ubiquitaire. En effet, une forte réaction gliale a été observée. Par contre, en utilisant le lentivirus avec une enveloppe Mokola et un promoteur ubiquitaire, nous avons constaté une très bonne transduction au niveau des cellules de Millier dans la rétine en dégénérescence, phénomène non observé chez les souris sauvages. Ce travail a donc permis de trouver un vecteur viral efficace pour atteindre et transduire les cellules de Miiller, ceci seulement pendant la dégénérescence de la rétine. Ces cellules, une fois transduites, pourraient être utilisées pour sécréter dans la rétine des agents thérapeutiques tels que des facteurs neurotrophiques pour soutenir la survie des photorécepteurs ou des facteurs anti-angiogéniques pour prévenir la néo-vascularisation lors de diabète ou de dégénérescence maculaire liée à l'âge. - In normal mice, the lentiviral vector (LV) is very efficient to target the RPE cells, but transduces retinal neurons well only during development. In the present study, the tropism of LV has been investigated in the degenerating retina of mice, knowing that the retina structure changes during degeneration. We postulated that the viral transduction would be increased by the alteration of the iuter limiting membrane (OLM). Two different LV pseudotypes were tested using the VSVG arid the Mokola envelopes, as well as two animal models of retinal degeneration: light-damaged Balb-C and Rhodopsin knockout (Rho-/-) mice. After light damage, the OLM is altered and no significant increase of the number of transduced photoreceptors can be obtained with a LV-VSVG-Rhop-GFP vector. In the Rho-/- mice, an altération of the OLM was also observed, but the possibility of transducing photoreceptors was decreased, probably by ongoing gliosis. The use of a ubiquitous promoter allows better photoreceptor transduction, suggesting that photoreceptór-specific promoter activity change during late stages of photoreceptor degeneration. However, the number of targeted photoreceptors remains low. In contrast, LV pseudotyped with the tfokola envelope allows a wide dispersion of the ctor into the retina (corresponding to the injection bleb) with preferential targeting of Muller cells, a situation Mc\ does ot occur in the wild- type retina. Mokola-pseudotyped lentiviral vectors may serve to engineer these glial cells to deliver secreted therapeutic factors to a diseased area of the retina.

Parallelizing remote sensing image geometric correction

Remote sensing spatial, spectral, and temporal resolutions of images, acquired over a reasonably sized image extent, result in imagery that can be processed to represent land cover over large areas with an amount of spatial detail that is very attractive for monitoring, management, and scienti c activities. With Moore's Law alive and well, more and more parallelism is introduced into all computing platforms, at all levels of integration and programming to achieve higher performance and energy e ciency. Being the geometric calibration process one of the most time consuming processes when using remote sensing images, the aim of this work is to accelerate this process by taking advantage of new computing architectures and technologies, specially focusing in exploiting computation over shared memory multi-threading hardware. A parallel implementation of the most time consuming process in the remote sensing geometric correction has been implemented using OpenMP directives. This work compares the performance of the original serial binary versus the parallelized implementation, using several multi-threaded modern CPU architectures, discussing about the approach to nd the optimum hardware for a cost-e ective execution.

Reliability of the image evaluation system PGMI

Purpose: Many countries used the PGMI (P=perfect, G=good, M=moderate, I=inadequate) classification system for assessing the quality of mammograms. Limits inherent to the subjectivity of this classification have been shown. Prior to introducing this system in Switzerland, we wanted to better understand the origin of this subjectivity in order to minimize it. Our study aimed at identifying the main determinants of the variability of the PGMI system and which criteria are the most subjected to subjectivity. Methods and Materials: A focus group composed of 2 experienced radiographers and 2 radiologists specified each PGMI criterion. Ten raters (6 radiographers and 4 radiologists) evaluated twice a panel of 40 randomly selected mammograms (20 analogic and 20 digital) according to these specified PGMI criteria. The PGMI classification was assessed and the intra- and inter-rater reliability was tested for each professional group (radiographer vs radiologist), image technology (analogic vs digital) and PGMI criterion. Results: Some 3,200 images were assessed. The intra-rater reliability appears to be weak, particularly in respect to inter-rater variability. Subjectivity appears to be largely independent of the professional group and image technology. Aspects of the PGMI classification criteria most subjected to variability were identified. Conclusion: Post-test discussions enabled to specify more precisely some criteria. This should reduce subjectivity when applying the PGMI classification system. A concomitant, important effort in training radiographers is also necessary.

Access to a simulator is not enough: the benefits of virtual reality training based on peer-group-derived benchmarks--a randomized controlled trial.

BACKGROUND: Virtual reality (VR) simulators are widely used to familiarize surgical novices with laparoscopy, but VR training methods differ in efficacy. In the present trial, self-controlled basic VR training (SC-training) was tested against training based on peer-group-derived benchmarks (PGD-training). METHODS: First, novice laparoscopic residents were randomized into a SC group (n = 34), and a group using PGD-benchmarks (n = 34) for basic laparoscopic training. After completing basic training, both groups performed 60 VR laparoscopic cholecystectomies for performance analysis. Primary endpoints were simulator metrics; secondary endpoints were program adherence, trainee motivation, and training efficacy. RESULTS: Altogether, 66 residents completed basic training, and 3,837 of 3,960 (96.8 %) cholecystectomies were available for analysis. Course adherence was good, with only two dropouts, both in the SC-group. The PGD-group spent more time and repetitions in basic training until the benchmarks were reached and subsequently showed better performance in the readout cholecystectomies: Median time (gallbladder extraction) showed significant differences of 520 s (IQR 354-738 s) in SC-training versus 390 s (IQR 278-536 s) in the PGD-group (p < 0.001) and 215 s (IQR 175-276 s) in experts, respectively. Path length of the right instrument also showed significant differences, again with the PGD-training group being more efficient. CONCLUSIONS: Basic VR laparoscopic training based on PGD benchmarks with external assessment is superior to SC training, resulting in higher trainee motivation and better performance in simulated laparoscopic cholecystectomies. We recommend such a basic course based on PGD benchmarks before advancing to more elaborate VR training.