Safety and efficacy of recombinant human erythropoietin treatment of anaemia associated with multiple myeloma in haemodialysed patients

Recombinant human erythropoietin (rHuEpo) was used to treat the anaemia of four haemodialysed patients (3 males, 1 female) with advanced multiple myeloma; the type of serum M component was IgG kappa in all cases. During the 6-month period preceding rHuEpo therapy the patients received multiple blood transfusions (range 4-22 units of packed red cells per patient). After the first month of treatment haematocrit increased from 23±3 (SD) to 32±4% and during the last 3 months the maintenance dose of rHuEpo was 143±37 U/kg per week to achieve a mean haematocrit of 35±1%. After introduction of rHuEpo, blood transfusions were no longer required and the patients reported an improvement in wellbeing. No apparent worsening of multiple myeloma has been observed over the treatment period ranging from 5 to 34 months (cumulative duration of treatment 55 months). Anti-hypertensive therapy was started in one case and increased in two patients. We conclude that rHuEpo appears to be effective and safe in treating anaemia associated with multiple myeloma in patients requiring haemodialysi

EPR optical detection of F centre pairs in alkali halides. - I : Pumping cycle kinetics and characteristics of the resonances

The EPR of F centres in the ground and excited states was optically detected in the following alkali halide crystals: NaCl, KF, KCl, KBr, KI, RbBr, and RbI. A decrease of the radiative quantum efficiency of the F centre luminescence was observed when microwave transitions were induced between the spin levels. The mechanism responsible for this effect was an electronic tunnelling through the crystal field potential; the electron in the relaxed excited state of an F centre (F~*) is transferred nonradiatively to another nearby F centre in its ground state (F0), and leads to the momentary formation of an ƒ¿ and an F\u27 centre. Such a process is a function of the total spin of the F~*-F0 pair. The role played by the paired centres was confirmed by measurements at different F centre concentration. Moreover, at high optical excitation pumping rates, the population of the intermediate complexes (F\u27-ƒ¿) is large enough to allow an estimation of the rate of the reverse process F\u27 + ƒ¿ \u27¨ F0 + F0

Effect of altered loading conditions during haemodialysis on left ventricular filling pattern

Changes in the circulating volume associated with haemodialysis result in modification of left ventricular loading conditions. To determine the influence of haemodialysis on Doppler indices of left ventricular filling, 12 patients (mean age 40.8 ±2.7 (SEM) years) with renal insufficiency but without overt heart disease were studied by Doppler-echocardiography immediately before and after haemodialysis. Haemodialysis resulted in a decrease in body weight from 68.0±3.8 kg to 65.0 ±3.7 kg (P< 0.01). Heart rate and blood pressure did not change significantly during haemodialysis. Left ventricular diastolic dimension (M-mode) decreased from 53.5±1.1 mm to 49.5±1.9 mm (P < 0.05), whereas the shortening fraction did not change. Haemodialysis elicited marked changes in the early diastolic rapid filling wave (E wave) recorded by pulsed Doppler at the level of the mitral annulus. Peak velocity of the early rapid filling phase (peak E) decreased significantly from 95.3 ± 8.2 cm .s−1 to 63.0 ±5.7cm .s−1 (P< 0.001) and mid-diastolic deceleration of transmitral velocity decreased from 437.3 ±54.2 cm . s−2 to 239.7 ±54.4 cm . s−2 (P<0.01). The peak filling velocity during atrial contraction (peak A) did not change (79.7 ±6.3 cm .s−1 vs 74.1±4.7 cm.s−1;P=NS). The ratio peak E/peak A decreasedfrom 1.19±0.06 to 0.85 ± 0.04 (P < 0.01) during haemodialysis. The results provide further evidence for the pronounced preload-dependence of Doppler indices of left ventricular diastolic functio

Highly potent bispecific sybodies neutralize SARS-CoV-2

The ongoing COVID-19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair (Sb#15 and Sb#68) that can bind simultaneously to the SARS-CoV-2 spike-RBD and efficiently neutralize pseudotyped and live-viruses by interfering with ACE2 interaction. Two spatially-discrete epitopes identified by cryo-EM translated into the rational design of bispecific and tri-bispecific fusions constructs, exhibiting up to 100- and 1000-fold increase in neutralization potency. Cryo-EM of the sybody-spike complex further revealed a novel up-out RBD conformation. While resistant viruses emerged rapidly in the presence of single binders, no escape variants were observed in presence of the bispecific sybody. The multivalent bispecific constructs further increased the neutralization potency against globally-circulating SARS-CoV-2 variants of concern. Our study illustrates the power of multivalency and biparatopic nanobody fusions for the development of clinically relevant therapeutic strategies that mitigate the emergence of new SARS-CoV-2 escape mutants

Invasive meningococcal disease epidemiology and control measures: a framework for evaluation

<p>Abstract</p> <p>Background</p> <p>Meningococcal disease can have devastating consequences. As new vaccines emerge, it is necessary to assess their impact on public health. In the absence of long-term real world data, modeling the effects of different vaccination strategies is required. Discrete event simulation provides a flexible platform with which to conduct such evaluations.</p> <p>Methods</p> <p>A discrete event simulation of the epidemiology of invasive meningococcal disease was developed to quantify the potential impact of implementing routine vaccination of adolescents in the United States with a quadrivalent conjugate vaccine protecting against serogroups A, C, Y, and W-135. The impact of vaccination is assessed including both the direct effects on individuals vaccinated and the indirect effects resulting from herd immunity. The simulation integrates a variety of epidemiologic and demographic data, with core information on the incidence of invasive meningococcal disease and outbreak frequency derived from data available through the Centers for Disease Control and Prevention. Simulation of the potential indirect benefits of vaccination resulting from herd immunity draw on data from the United Kingdom, where routine vaccination with a conjugate vaccine has been in place for a number of years. Cases of disease are modeled along with their health consequences, as are the occurrence of disease outbreaks.</p> <p>Results</p> <p>When run without a strategy of routine immunization, the simulation accurately predicts the age-specific incidence of invasive meningococcal disease and the site-specific frequency of outbreaks in the Unite States. 2,807 cases are predicted annually, resulting in over 14,000 potential life years lost due to invasive disease. In base case analyses of routine vaccination, life years lost due to infection are reduced by over 45% (to 7,600) when routinely vaccinating adolescents 12 years of age at 70% coverage. Sensitivity analyses indicate that herd immunity plays an important role when this population is targeted for vaccination. While 1,100 cases are avoided annually when herd immunity effects are included, in the absence of any herd immunity, the number of cases avoided with routine vaccination falls to 380 annually. The duration of vaccine protection also strongly influences results.</p> <p>Conclusion</p> <p>In the absence of appropriate real world data on outcomes associated with large-scale vaccination programs, decisions on optimal immunization strategies can be aided by discrete events simulations such as the one described here. Given the importance of herd immunity on outcomes associated with routine vaccination, published estimates of the economic efficiency of routine vaccination with a quadrivalent conjugate vaccine in the United States may have considerably underestimated the benefits associated with a policy of routine immunization of adolescents.</p

Cost effectiveness of pediatric pneumococcal conjugate vaccines: a comparative assessment of decision-making tools

BACKGROUND: Several decision support tools have been developed to aid policymaking regarding the adoption of pneumococcal conjugate vaccine (PCV) into national pediatric immunization programs. The lack of critical appraisal of these tools makes it difficult for decision makers to understand and choose between them. With the aim to guide policymakers on their optimal use, we compared publicly available decision-making tools in relation to their methods, influential parameters and results. METHODS: The World Health Organization (WHO) requested access to several publicly available cost-effectiveness (CE) tools for PCV from both public and private provenance. All tools were critically assessed according to the WHO's guide for economic evaluations of immunization programs. Key attributes and characteristics were compared and a series of sensitivity analyses was performed to determine the main drivers of the results. The results were compared based on a standardized set of input parameters and assumptions. RESULTS: Three cost-effectiveness modeling tools were provided, including two cohort-based (Pan-American Health Organization (PAHO) ProVac Initiative TriVac, and PneumoADIP) and one population-based model (GlaxoSmithKline's SUPREMES). They all compared the introduction of PCV into national pediatric immunization program with no PCV use. The models were different in terms of model attributes, structure, and data requirement, but captured a similar range of diseases. Herd effects were estimated using different approaches in each model. The main driving parameters were vaccine efficacy against pneumococcal pneumonia, vaccine price, vaccine coverage, serotype coverage and disease burden. With a standardized set of input parameters developed for cohort modeling, TriVac and PneumoADIP produced similar incremental costs and health outcomes, and incremental cost-effectiveness ratios. CONCLUSIONS: Vaccine cost (dose price and number of doses), vaccine efficacy and epidemiology of critical endpoint (for example, incidence of pneumonia, distribution of serotypes causing pneumonia) were influential parameters in the models we compared. Understanding the differences and similarities of such CE tools through regular comparisons could render decision-making processes in different countries more efficient, as well as providing guiding information for further clinical and epidemiological research. A tool comparison exercise using standardized data sets can help model developers to be more transparent about their model structure and assumptions and provide analysts and decision makers with a more in-depth view behind the disease dynamics. Adherence to the WHO guide of economic evaluations of immunization programs may also facilitate this process. Please see related article: http://www.biomedcentral.com/1741-7007/9/55