Ética e investigación en la historia de la malaria

Resumen La investigacion cientifica en clinica es absolutamente necesaria para el desarrollo del saber medico. No obstante, no siempre el gran progreso alcanzado por la Medicina se ha obtenido respetando la persona humana. En particular, a partir de 1880, cuando Laveran constato por primera vez la naturaleza protozoaria de la malaria, el desarrollo del conocimiento sobre el paludismo ha sido muy notable, pero hasta la mitad del siglo XX estos logros fueron, en muchos casos, fruto de experimentos que hoy resultan en extremo discutibles desde el punto de vista etico, tanto los dedicados al estudio de la biologia y de la fisiopatologia, como especialmente los ensayos de caracter farmacologi-co efectuados en individuos sanos para probar scrapbookpages.com/dachauscrapbook/Dachau Trials/Klaus moleculas con accion antimalarica real o presunta. Schilling.html Referencias 1.- Zakon S J. Alexander Samoilovitch Rosenblium. His contri-His contri-bution to fever therapy. Arch Derm Syph 1943; 48: 52-9. 2.- Codell Carter, K. The rise of causal concepts of disease: case histories. Ashgate Publishing Ltd, UK 2003; 165-6. 3.- Marchiafava E, Celli A. Nuove ricerche sulla infezione malarica. Annali di Agricoltura 1885; 96: 1-33. 4.- Massani, M. Le molte vite dell'Ospedale di S. Spirito dalle sue origini ai nostri giorni. Giornale di Medizina Militare 1983; 103 (1): 54-66.5.- Snowden F M. La conquista della malaria. Una moderniz-zazione italiana 1900-1962. Giulio Einaudi editore, Torino 2000; 46.6.- Columella. Los doce libros de agricultura que escribiera en latin Lucio Junio Moderato Columela, traducidos al castellano por D. Juan Maria Alvarez de Sotomayor y Rubio. Imprenta de D. Miguel de Burgos, Madrid 1824; I (5): 22. 7.- Fantini B. Uno zoologo e la malaria : Battista Grassi e la scoperta del ciclo di trasmissione della malaria. En: Grassi B. Studi di uno zoologo sulla malaria. Giunti Gruppo Edito-riale, Firenze 1998; 22. 8.- Grassi B. Studi di uno zoologo sulla malaria. Biblioteca del-la scienza italiana. Giunti Gruppo Editoriale, Firenze 1998; 89-276.9.- Consejo de Organizaciones Internacionales de las Ciencias Medicas (CIOMS). Pautas eticas internacionales para la investigacion biomedica en seres humanos. Ginebra 2002.10.- Verhage D F, Telgt D S C, Bousema J T, Hermsen C C, van Gemert G J A, van der Meer J W M, et al. Clinical outcome of experimental human malaria induced b

Charge carrier transfer in the gas electron multiplier at low gas gains

Connected to the Linear Collider project TESLA at DESY, studies on the readout of TPCs based on the GEM-technology are ongoing. For particle identication via dE/dx - measurement, a good energy resolution is indispensable, and therefore losses of primary electrons have to be avoided. It turned out, that in the GEM transverse diffusion inside or close to the holes is a not negligible reason for these losses. For Ar-CH4 90:10 and TPC-like field configurations it was found, that when operated in normal amplification mode, the Standard Geometry GEM should not lose primaries, whereas for low gains, also when operated in magnetic fields up to 5T, a GEM with larger pitch and hole diameter would be necessary

Weighted complex projective 2-designs from bases: optimal state determination by orthogonal measurements

We introduce the problem of constructing weighted complex projective 2-designs from the union of a family of orthonormal bases. If the weight remains constant across elements of the same basis, then such designs can be interpreted as generalizations of complete sets of mutually unbiased bases, being equivalent whenever the design is composed of d+1 bases in dimension d. We show that, for the purpose of quantum state determination, these designs specify an optimal collection of orthogonal measurements. Using highly nonlinear functions on abelian groups, we construct explicit examples from d+2 orthonormal bases whenever d+1 is a prime power, covering dimensions d=6, 10, and 12, for example, where no complete sets of mutually unbiased bases have thus far been found.Comment: 28 pages, to appear in J. Math. Phy

Stepwise Projection: Toward Brane Setups for Generic Orbifold Singularities

The construction of brane setups for the exceptional series E6,E7,E8 of SU(2) orbifolds remains an ever-haunting conundrum. Motivated by techniques in some works by Muto on non-Abelian SU(3) orbifolds, we here provide an algorithmic outlook, a method which we call stepwise projection, that may shed some light on this puzzle. We exemplify this method, consisting of transformation rules for obtaining complex quivers and brane setups from more elementary ones, to the cases of the D-series and E6 finite subgroups of SU(2). Furthermore, we demonstrate the generality of the stepwise procedure by appealing to Frobenius' theory of Induced Representations. Our algorithm suggests the existence of generalisations of the orientifold plane in string theory.Comment: 22 pages, 3 figure

Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy

BACKGROUND: In Study 19, maintenance monotherapy with olaparib significantly prolonged progression-free survival vs placebo in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer. METHODS: Study 19 was a randomised, placebo-controlled, Phase II trial enrolling 265 patients who had received at least two platinum-based chemotherapy regimens and were in complete or partial response to their most recent regimen. Patients were randomised to olaparib (capsules; 400 mg bid) or placebo. We present long-term safety and final mature overall survival (OS; 79% maturity) data, from the last data cut-off (9 May 2016). RESULTS: Thirty-two patients (24%) received maintenance olaparib for over 2 years; 15 (11%) did so for over 6 years. No new tolerability signals were identified with long-term treatment and adverse events were generally low grade. The incidence of discontinuations due to adverse events was low (6%). An apparent OS advantage was observed with olaparib vs placebo (hazard ratio 0.73, 95% confidence interval 0.55‒0.95, P = 0.02138) irrespective of BRCA1/2 mutation status, although the predefined threshold for statistical significance was not met. CONCLUSIONS: Study 19 showed a favourable final OS result irrespective of BRCA1/2 mutation status and unprecedented long-term benefit with maintenance olaparib for a subset of platinum-sensitive, recurrent ovarian cancer patients

Mainstreamed Genetic Testing in Ovarian Cancer: Patient Experience of the Testing Process

Objective: Pathogenic BRCA variants account for between 5.8-24.8% of ovarian cancers. The identification of such a variant can have a significant impact on the affected individual and their relatives – determining eligibility for targeted therapies, predicting treatment response and granting access to disease prevention strategies. Cancer services are responding to the increased demand for genetic testing with the introduction of mainstreamed genetic testing via oncology clinics. The study aimed to evaluate patient experience of the mainstreamed genetic testing pathway at a tertiary referral centre in London. / Methods: Study participants were patients diagnosed with high-grade non-mucinous ovarian cancer, tested via a mainstreamed genetic testing pathway at the tertiary referral centre between February 2015 and June 2017. Eligible participants were invited to complete the retrospective study questionnaire. Five quantitative measures with additional free-text items evaluated the patient experience of mainstreamed genetic testing. / Results: The tertiary referral centre tested 170 ovarian cancer patients. Twenty-three pathogenic BRCA mutations were identified (23/170, 13.5%). One-hundred and six patients (106/170, 62.4%) met the study inclusion criteria. Twenty-nine of those invited (29/106, 27.4%) to participate returned the retrospective study questionnaire. Pathogenic BRCA1/2 variants were identified within four respondents (4/29, 13.8%). Motivations for genetic testing related to improved medical management, and the ability to provide relatives with genetic information. Participants did not appear to be adversely affected by result disclosure post mainstreamed genetic testing. Two individuals with a pathogenic variant reported that the support provided by the tertiary referral centre post-result disclosure could have been improved. / Conclusion: Results of the current study support further psychosocial research into the expansion of the mainstreamed genetic testing pathway. The results although promising have also highlighted the importance of genetic awareness within the multidisciplinary team and the provision of timely psychological support from genetic specialists

Finite covers of random 3-manifolds

A 3-manifold is Haken if it contains a topologically essential surface. The Virtual Haken Conjecture posits that every irreducible 3-manifold with infinite fundamental group has a finite cover which is Haken. In this paper, we study random 3-manifolds and their finite covers in an attempt to shed light on this difficult question. In particular, we consider random Heegaard splittings by gluing two handlebodies by the result of a random walk in the mapping class group of a surface. For this model of random 3-manifold, we are able to compute the probabilities that the resulting manifolds have finite covers of particular kinds. Our results contrast with the analogous probabilities for groups coming from random balanced presentations, giving quantitative theorems to the effect that 3-manifold groups have many more finite quotients than random groups. The next natural question is whether these covers have positive betti number. For abelian covers of a fixed type over 3-manifolds of Heegaard genus 2, we show that the probability of positive betti number is 0. In fact, many of these questions boil down to questions about the mapping class group. We are lead to consider the action of mapping class group of a surface S on the set of quotients pi_1(S) -> Q. If Q is a simple group, we show that if the genus of S is large, then this action is very mixing. In particular, the action factors through the alternating group of each orbit. This is analogous to Goldman's theorem that the action of the mapping class group on the SU(2) character variety is ergodic.Comment: 60 pages; v2: minor changes. v3: minor changes; final versio

Hypervitaminosis A is prevalent in children with CKD and contributes to hypercalcemia.

Vitamin A accumulates in renal failure, but the prevalence of hypervitaminosis A in children with predialysis chronic kidney disease (CKD) is not known. Hypervitaminosis A has been associated with hypercalcemia. In this study we compared dietary vitamin A intake with serum retinoid levels and their associations with hypercalcemia

Impact of retrospective data verification to prepare the ICON6 trial for use in a marketing authorization application

Background: The ICON6 trial (ISRCTN68510403) is a phase III academic-led, international, randomized, three-arm, double-blind, placebo-controlled trial of the addition of cediranib to chemotherapy in recurrent ovarian cancer. It investigated the use of placebo during chemotherapy and maintenance (arm A), cediranib alongside chemotherapy followed by placebo maintenance (arm B) and cediranib throughout both periods (arm C). Results of the primary comparison showed a meaningful gain in progression-free survival (time to progression or death from any cause) when comparing arm A (placebo) with arm C (cediranib). As a consequence of the positive results, AstraZeneca was engaged with the Medical Research Council trials unit to discuss regulatory submission using ICON6 as the single pivotal trial. / Methods: A relatively limited level of on-site monitoring, single data entry and investigator’s local evaluation of progression were used on trial. In order to submit a license application, it was decided that (a) extensive retrospective source data verification of medical records against case report forms should be performed, (b) further quality control checks for accuracy of data entry should be performed and (c) blinded independent central review of images used to define progression should be undertaken. To assess the value of these extra activities, we summarize the impact on both efficacy and safety outcomes. / Results: Data point changes were minimal; those key to the primary results had a 0.47% error rate (36/7686), and supporting data points had a 0.18% error rate (109/59,261). The impact of the source data verification and quality control processes were analyzed jointly. The conclusion drawn for the primary outcome measure of progression-free survival between arm A and arm C was unchanged. The log-rank test p-value changed only at the sixth decimal place, the hazard ratio does not change from 0.57 with the exception of a marginal change in its upper bound (0.74–0.73) and the median progression-free survival benefit from arm C remained at 2.4 months. Separately, the blinded independent central review of progression scans was performed as a sensitivity analysis. Estimates and p values varied slightly but overall demonstrated a difference in arms, which is consistent with the initial result. Some increases in toxicity were observed, though these were generally minor, with the exception of hypertension. However, none of these increases were systematically biased toward one arm. / Conclusion: The conduct of this pragmatic, academic-sponsored trial was sufficient given the robustness of the results, shown by the results remaining largely unchanged following retrospective verification despite not being designed for use in a marketing authorization. The burden of such comprehensive retrospective effort required to ensure the results of ICON6 were acceptable to regulators is difficult to justify