Three problems of hemophilia B : a study of abnormal factor IX molecules with an inhibitor neutralization assay

Hemophilia is a sex linked, recessive, hereditary disorder characterizedby excessive bleeding. This bleeding tendency manifestsitself in spontaneous hemorrhages in the joint cavities and muscles,and in excessive bleeding after trauma or surgical procedures.The first written references to the disease can be found in theBabylonian Talmud, in which it can be read that Rabbi Judah thePatriarch exempted the third son from circumcision if his motherhad already lost two sons because they had bled to death afterthis operation ( 1 ) . Rabbi Simon hen Gamaliel even forbade a boyto be circumcised whien sons of his mother's three elder sisters haddied from bleeding after circumcision ( 2).In the 19th century Wardrop discovered the prolonged clottingtime of hemophilic blood. For a long time lack of prothrombin washeld responsible for the clotting defect until in 1935 Quick foundthat the prothrombin time of hemophilic plasma was normal ( 2) .Patek and Taylor reported in 1937 that the prolonged clottingtime of hemophilic plasma could be normalized by the addition ofa globulin fraction of normal blood. For this reason the lackingclotting component was called antihemophilic globulin; later, byinternational agreement, it was named clotting factor VIII (2).In 1944 Pavlovsky observed that a mixture of the blood of twohemophiliacs known to him had a normal clotting time ( 3, 4). Theright interpretation of this finding was given only in 1952 and notby Pavlovsky himself. In that year reports from New York, SanFrancisco, and Oxford described a disease which was clinically andgenetically undistinguishable from hemophilia, but the lackingclotting component was not factor VIII ( 5-7). The missing factorin this new disorder, PTC-deficiency, Christmas disease or hemophiliaB, was later called factor IX.Financial support was obtained from the "Hippocrates Studiefonds"LUMC / Geneeskund

Temporal correlation between malaria and rainfall in Sri Lanka

<p>Abstract</p> <p>Background</p> <p>Rainfall data have potential use for malaria prediction. However, the relationship between rainfall and the number of malaria cases is indirect and complex.</p> <p>Methods</p> <p>The statistical relationships between monthly malaria case count data series and monthly mean rainfall series (extracted from interpolated station data) over the period 1972 – 2005 in districts in Sri Lanka was explored in four analyses: cross-correlation; cross-correlation with pre-whitening; inter-annual; and seasonal inter-annual regression.</p> <p>Results</p> <p>For most districts, strong positive correlations were found for malaria time series lagging zero to three months behind rainfall, and negative correlations were found for malaria time series lagging four to nine months behind rainfall. However, analysis with pre-whitening showed that most of these correlations were spurious. Only for a few districts, weak positive (at lags zero and one) or weak negative (at lags two to six) correlations were found in pre-whitened series. Inter-annual analysis showed strong negative correlations between malaria and rainfall for a group of districts in the centre-west of the country. Seasonal inter-annual analysis showed that the effect of rainfall on malaria varied according to the season and geography.</p> <p>Conclusion</p> <p>Seasonally varying effects of rainfall on malaria case counts may explain weak overall cross-correlations found in pre-whitened series, and should be taken into account in malaria predictive models making use of rainfall as a covariate.</p

Incidence and consequences of damage to insecticide-treated mosquito nets in Kenya

BACKGROUND: Efforts to improve the impact of long-lasting insecticidal nets (LLINs) should be informed by understanding of the causes of decay in effect. Holes in LLINs have been estimated to account for 7-11% of loss in effect on vectorial capacity for Plasmodium falciparum malaria in an analysis of repeated cross-sectional surveys of LLINs in Kenya. This does not account for the effect of holes as a cause of net attrition or non-use, which cannot be measured using only cross-sectional data. There is a need for estimates of how much these indirect effects of physical damage on use and attrition contribute to decay in effectiveness of LLINs. METHODS: Use, physical integrity, and survival were assessed in a cohort of 4514 LLINs followed for up to 4 years in Kenya. Flow diagrams were used to illustrate how the status of nets, in terms of categories of use, physical integrity, and attrition, changed between surveys carried out at 6-month intervals. A compartment model defined in terms of ordinary differential equations (ODEs) was used to estimate the transition rates between the categories. Effects of physical damage to LLINs on use and attrition were quantified by simulating counterfactuals in which there was no damage. RESULTS: Allowing for the direct effect of holes, the effect on use, and the effect on attrition, 18% of the impact on vectorial capacity was estimated to be lost because of damage. The estimated median lifetime of the LLINs was 2.9 years, but this was extended to 5.7 years in the counterfactual without physical damage. Nets that were in use were more likely to be in a damaged state than unused nets but use made little direct difference to LLIN lifetimes. Damage was reported as the reason for attrition for almost half of attrited nets, but the model estimated that almost all attrited nets had suffered some damage before attrition. CONCLUSIONS: Full quantification of the effects of damage will require measurement of the supply of new nets and of household stocks of unused nets, and also of their impacts on both net use and retention. The timing of mass distribution campaigns is less important than ensuring sufficient supply. In the Kenyan setting, nets acquired damage rapidly once use began and the damage led to rapid attrition. Increasing the robustness of nets could substantially increase their lifetime and impact but the impact of LLIN programmes on malaria transmission is ultimately limited by levels of use. Longitudinal analyses of net integrity data from different settings are needed to determine the importance of physical damage to nets as a driver of attrition and non-use, and the importance of frequent use as a cause of physical damage in different contexts

Monthly entomological inoculation rate data for studying the seasoanality of malaria transmission in Africa

A comprehensive literature review was conducted to create a new database of 197 field surveys of monthly malaria Entomological Inoculation Rates (EIR), a metric of malaria transmission intensity. All field studies provide data at a monthly temporal resolution and have a duration of at least one year in order to study the seasonality of the disease. For inclusion, data collection methodologies adhered to a specific standard and the location and timing of the measurements were documented. Auxiliary information on the population and hydrological setting were also included. The database includes measurements that cover West and Central Africa and the period from 1945 to 2011, and hence facilitates analysis of interannual transmission variability over broad regions

Optimal intensity of oral anticoagulant therapy after myocardial infarction

AbstractObjectives.This study attempted to determine the optimal intensity of anticoagulant therapy in patients after myocardial infarction.Background.Treatment with oral anticoagulant therapy entails a delicate balance between over- (risk of bleeding) and under-anticoagulant (risk of thromboemboli). The optimal intensity required to prevent the occurrence of either event (bleeding or thromboembolic) is not known.Methods.A method was used to determine the optimal intensity of anticoagulant therapy by calculating incidence rates for either event associated with a specific international normalized ratio. The numerator included events occurring at given international normalized ratios, and the denominator comprised the total observation time.Results.The study population included 3,404 myocardial infarction patients enrolled in the ASPECT (anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis) trial. Total treatment was 6,918 patient-years. Major bleeding occurred in 57 patients (0.8/100 patient-years), and thromboembolic complications in 397 (5.7/100 patient-years). The incidence of the combined outcome (bleeding or thromboembolic complications) with international normalized ratio < 2 was 8.0/100 patient-years (283 events in 3,559 patient-years), with international normalized ratios between 2 and 3, 3.9/100 patient-years (33 events in 838 patient-years); 3.2/100 patient-years (57 events in 1,775 patient-years) for international normalized ratios between 3 and 4; 6.6/100 patient-years (37 events in 564 patient-years) for international normalized ratios between 4 and 5; and 7.7/100 patient-years (14 events in 182 patient-years) for international normalized ratios >5. After adjustment for achieved international normalized ratio levels, significant predictors were higher levels of systolic blood pressure and age.Conclusions.If equal weight is given to hemorrhagic and thromboembolic complications, these results suggest that the optimal intensity of long-term anticoagulant therapy for myocardial infarction patients lies between 2.0 and 4.0 international normalized ratio, with a trend to suggest an optimal intensity of 3.0 to 4.0

Experimental estimation of the dimension of classical and quantum systems

An overwhelming majority of experiments in classical and quantum physics make a priori assumptions about the dimension of the system under consideration. However, would it be possible to assess the dimension of a completely unknown system only from the results of measurements performed on it, without any extra assumption? The concept of a dimension witness answers this question, as it allows one to bound the dimension of an unknown classical or quantum system in a device-independent manner, that is, only from the statistics of measurements performed on it. Here, we report on the experimental demonstration of dimension witnesses in a prepare and measure scenario. We use pairs of photons entangled in both polarization and orbital angular momentum to generate ensembles of classical and quantum states of dimensions up to 4. We then use a dimension witness to certify their dimensionality as well as their quantum nature. Our results open new avenues for the device-independent estimation of unknown quantum systems and for applications in quantum information science.Comment: See also similar, independent and jointly submitted work of J. Ahrens et al., quant-ph/1111.127

Models of effectiveness of interventions against malaria transmitted by Anopheles albimanus

Most impact prediction of malaria vector control interventions has been based on African vectors. Anopheles albimanus, the main vector in Central America and the Caribbean, has higher intrinsic mortality, is more zoophilic and less likely to rest indoors. Therefore, relative impact among interventions may be different. Prioritizing interventions, in particular for eliminating Plasmodium falciparum from Haiti, should consider local vector characteristics.; Field bionomics data of An. albimanus from Hispaniola and intervention effect data from southern Mexico were used to parameterize mathematical malaria models. Indoor residual spraying (IRS), insecticide-treated nets (ITNs), and house-screening were analysed by inferring their impact on the vectorial capacity in a difference-equation model. Impact of larval source management (LSM) was assumed linear with coverage. Case management, mass drug administration and vaccination were evaluated by estimating their effects on transmission in a susceptible-infected-susceptible model. Analogous analyses were done for Anopheles gambiae parameterized with data from Tanzania, Benin and Nigeria.; While LSM was equally effective against both vectors, impact of ITNs on transmission by An. albimanus was much lower than for An. gambiae. Assuming that people are outside until bedtime, this was similar for the impact of IRS with dichlorodiphenyltrichloroethane (DDT) or bendiocarb, and impact of IRS was less than that of ITNs. However, assuming people go inside when biting starts, IRS had more impact on An. albimanus than ITNs. While house-screening had less impact than ITNs or IRS on An. gambiae, it had more impact on An. albimanus than ITNs or IRS. The impacts of chemoprevention and chemotherapy were comparable in magnitude to those of strategies against An. albimanus. Chemo-prevention impact increased steeply as coverage approached 100%, whilst clinical-case management impact saturated because of remaining asymptomatic infections.; House-screening and repellent IRS are potentially highly effective against An. albimanus if people are indoors during the evening. This is consistent with historical impacts of IRS with DDT, which can be largely attributed to excito-repellency. It also supports the idea that housing improvements have played a critical role in malaria control in North America. For elimination planning, impact estimates need to be combined with feasibility and cost-analysis

The effect of malaria control on <i>Plasmodium falciparum</i> in Africa between 2000 and 2015

Since the year 2000, a concerted campaign against malaria has led to unprecedented levels of intervention coverage across sub-Saharan Africa. Understanding the effect of this control effort is vital to inform future control planning. However, the effect of malaria interventions across the varied epidemiological settings of Africa remains poorly understood owing to the absence of reliable surveillance data and the simplistic approaches underlying current disease estimates. Here we link a large database of malaria field surveys with detailed reconstructions of changing intervention coverage to directly evaluate trends from 2000 to 2015, and quantify the attributable effect of malaria disease control efforts. We found that Plasmodium falciparum infection prevalence in endemic Africa halved and the incidence of clinical disease fell by 40% between 2000 and 2015. We estimate that interventions have averted 663 (542-753 credible interval) million clinical cases since 2000. Insecticide-treated nets, the most widespread intervention, were by far the largest contributor (68% of cases averted). Although still below target levels, current malaria interventions have substantially reduced malaria disease incidence across the continent. Increasing access to these interventions, and maintaining their effectiveness in the face of insecticide and drug resistance, should form a cornerstone of post-2015 control strategies.</p

The Hilbertian Tensor Norm and Entangled Two-Prover Games

We study tensor norms over Banach spaces and their relations to quantum information theory, in particular their connection with two-prover games. We consider a version of the Hilbertian tensor norm $\gamma_2$ and its dual $\gamma_2^*$ that allow us to consider games with arbitrary output alphabet sizes. We establish direct-product theorems and prove a generalized Grothendieck inequality for these tensor norms. Furthermore, we investigate the connection between the Hilbertian tensor norm and the set of quantum probability distributions, and show two applications to quantum information theory: firstly, we give an alternative proof of the perfect parallel repetition theorem for entangled XOR games; and secondly, we prove a new upper bound on the ratio between the entangled and the classical value of two-prover games.Comment: 33 pages, some of the results have been obtained independently in arXiv:1007.3043v2, v2: an error in Theorem 4 has been corrected; Section 6 rewritten, v3: completely rewritten in order to improve readability; title changed; references added; published versio