Personalized prophylaxis COLLINS, P. W.
Haemophilia : the official journal of the World Federation of Hemophilia,
July 2012, Letnik:
18, Številka:
s4
Journal Article
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Prophylaxis is the recommended treatment for people with severe haemophilia. It is unlikely that a single prophylactic regimen, for example based on weight, would be optimal for all patients and ...therefore each individual should have a personalized regimen, agreed between themselves and their haemophilia centre. This regimen should take into account the individual’s bleeding pattern, the condition of their musculoskeletal system, level and timing of physical activity and measurement of coagulation factor in their blood. It is important to recognize that prophylactic regimens are likely to need to change with time as the circumstances of an individual change. For example, activity may change with age or with the season and an individual’s factor VIII pharmacokinetics vary with age. Knowledge of a patient’s pharmacokinetics is likely to help personalize prophylaxis when combined with other information. Factor VIII pharmacokinetics are simple to measure in routine clinical practice and can be adequately calculated from 2 to 3 blood samples combined with a simple to use computer program. Prophylaxis is expensive and, in countries with a limited health care budget, ways to improve its cost effectiveness need to be considered to allow increased access to this treatment. For example, increasing the frequency of prophylaxis can dramatically reduce the amount of treatment required to sustain measureable factor levels and hence reduce cost. The introduction of longer‐acting coagulation factors may necessitate a change in concepts about prophylaxis because whilst these agents may sustain an apparently adequate trough level with fewer infusions, the length of time a person spends at a low level will be increased and this could increase the risk of bleeding, especially at the time of increased physical activity. There is convincing evidence that prophylaxis is the optimal therapy for severe haemophilia, optimizing treatment for each individual and increasing access to this treatment modality are important goals for the future.
Acquired haemophilia A is an auto-immune disease caused by an inhibitory antibody to factor VIII. The pattern of bleeding varies but patients remain at risk of life threatening bleeding until the ...inhibitor has been eradicated. The cornerstones of management are; rapid and accurate diagnosis, control of bleeding, investigation for an underlying cause and eradication of the inhibitor by immunosuppression. Patients should always be managed jointly with a specialist centre even if they present without significant bleeding. Despite an extensive literature, few controlled data are available and treatment guidelines are based on expert opinion. To treat bleeds recombinant factor VIIa and activated prothrombin complex concentrate are equally efficacious but both are superior to factor VIII or desmopressin. Immunosuppression should be started as soon as the diagnosis is made. Commonly used regimens are steroids alone or combined with cytotoxic agents. Rituximab is being used more widely but current evidence does not suggest that it improves outcomes or reduces side effects.
Summary
The haemostatic management of major obstetric haemorrhage remains challenging, and current published guidance relies heavily on experience from the non‐pregnant population and expert opinion. ...In recent years, an interest in the implications of relative hypofibrinogenaemia, point‐of‐care monitoring of coagulation abnormalities, and the potential to give goal‐directed therapy to correct coagulopathies, have created the possibility of significantly challenging and changing guidance. There is evidence that the haemostatic impairment in the pregnant population is different from trauma‐induced bleeding, and the type and rate of onset of coagulopathies differ depending on the underlying cause. This review examines areas such as possible intervention points, describes evidence for over‐transfusion of fresh frozen plasma in some situations and challenges conventional thinking on formulaic management. It also examines the rationale for other therapeutic options, including fibrinogen concentrate and tranexamic acid.
Heart failure is a global public health problem, affecting a large number of individuals from low-income and middle-income countries. REPORT-HF is, to our knowledge, the first prospective global ...registry collecting information on patient characteristics, management, and prognosis of acute heart failure using a single protocol. The aim of this study was to investigate differences in 1-year post-discharge mortality according to region, country income, and income inequality.
Patients were enrolled during hospitalisation for acute heart failure from 358 centres in 44 countries on six continents. We stratified countries according to a modified WHO regional classification (Latin America, North America, western Europe, eastern Europe, eastern Mediterranean and Africa, southeast Asia, and western Pacific), country income (low, middle, high) and income inequality (according to tertiles of Gini index). Risk factors were identified on the basis of expert opinion and knowledge of the literature.
Of 18 102 patients discharged, 3461 (20%) died within 1 year. Important predictors of 1-year mortality were old age, anaemia, chronic kidney disease, presence of valvular heart disease, left ventricular ejection fraction phenotype (heart failure with reduced ejection fraction HFrEF vs preserved ejection fraction HFpEF), and being on guideline-directed medical treatment (GDMT) at discharge (p<0·0001 for all). Patients from eastern Europe had the lowest 1-year mortality (16%) and patients from eastern Mediterranean and Africa (22%) and Latin America (22%) the highest. Patients from lower-income countries (ie, ≤US$3955 per capita; hazard ratio 1·58, 95% CI 1·41–1·77), or with greater income inequality (ie, from the highest Gini tertile; 1·25, 1·13–1·38) had a higher 1-year mortality compared with patients from regions with higher income (ie, >$12 235 per capita) or lower income inequality (ie, from the lowest Gini tertile). Compared with patients with HFrEF, patients with HFpEF had a lower 1-year mortality with little variation by income level (pinteraction for HFrEF vs HFpEF <0·0001).
Acute heart failure is associated with a high post-discharge mortality, particularly in patients with HFrEF from low-income regions with high income inequality. Regional differences exist in the proportion of eligible patients discharged on GDMT, which was strongly associated with mortality and might reflect lack of access to post-discharge care and prescribing of GDMT.
Novartis Pharma.
Reports of malformed amphibians and global amphibian declines have led to public concern, particularly because amphibians are thought to be indicator species of overall environmental health. The ...topic also draws scientific attention because there is no obvious, simple answer to the question of what is causing amphibian declines? Complex interactions of several anthropogenic factors are probably at work, and understanding amphibian declines may thus serve as a model for understanding species declines in general. While we have fewer answers than we would like, there are six leading hypotheses that we sort into two classes. For class I hypotheses, alien species, over-exploitation and land use change, we have a good understanding of the ecological mechanisms underlying declines; these causes have affected amphibian populations negatively for more than a century. However, the question remains as to whether the magnitude of these negative effects increased in the 1980s, as scientists began to notice a global decline of amphibians. Further, remedies for these problems are not simple. For class II hypotheses, global change (including UV radiation and global climate change), contaminants and emerging infectious diseases we have a poor, but improving understanding of how each might cause declines. Class II factors involve complex and subtle mechanistic underpinnings, with probable interactions among multiple ecological and evolutionary variables. They may also interact with class I hypotheses. Suspected mechanisms associated with class II hypotheses are relatively recent, dating from at least the middle of the 20th century. Did these causes act independently or in concert with preexisting negative forces of class I hypotheses to increase the rate of amphibian declines to a level that drew global attention? We need more studies that connect the suspected mechanisms underlying both classes of hypotheses with quantitative changes in amphibian population sizes and species numbers. An important step forward in this task is clarifying the hypotheses and conditions under which the various causes operate alone or together.
The low temperature pyrolysis of organic material produces biochar, a charcoal like substance. Biochar is being promoted as a soil amendment to enhance soil quality, it is also seen as a mechanism of ...long-term sequestration of carbon. Our experiments tested the hypothesis that biochar is inert in soil. However, we measured an increase in CO
2 production from soils after biochar amendment which increased with increasing rates of biochar. The ∂
13C signature of the CO
2 evolved in the first several days of the incubation was the same as the ∂
13C signature of the biochar, confirming that biochar contributed to the CO
2 flux. This effect diminished by day 6 of the incubation suggesting that most of the biochar C is slowly decomposing. Thus, aside from this short-term mineralization increasing soil C with young biochar may indeed be a long-term C storage mechanism.
Prostate cancer (PCa) is the most common type of cancer in men in the United States, which disproportionately affects African American descents. While metastasis is the most common cause of death ...among PCa patients, no specific markers have been assigned to severity and ethnic biasness of the disease. MicroRNAs represent a promising new class of biomarkers owing to their inherent stability and resilience. In the present study, we investigated potential miRNAs that can be used as biomarkers and/or therapeutic targets and can provide insight into the severity and ethnic biasness of PCa. PCR array was performed in FFPE PCa tissues (5 Caucasian American and 5 African American) and selected differentially expressed miRNAs were validated by qRT-PCR, in 40 (15 CA and 25 AA) paired PCa and adjacent normal tissues. Significantly deregulated miRNAs were also analyzed in urine samples to explore their potential as non-invasive biomarker for PCa. Out of 8 miRNAs selected for validation from PCR array data, miR-205 (p<0.0001), mir-214 (p<0.0001), miR-221(p<0.001) and miR-99b (p<0.0001) were significantly downregulated in PCa tissues. ROC curve shows that all four miRNAs successfully discriminated between PCa and adjacent normal tissues. MiR-99b showed significant down regulation (p<0.01) in AA PCa tissues as compared to CA PCa tissues and might be related to the aggressiveness associated with AA population. In urine, miR-205 (p<0.05) and miR-214 (p<0.05) were significantly downregulated in PCa patients and can discriminate PCa patients from healthy individuals with 89% sensitivity and 80% specificity. In conclusion, present study showed that miR-205 and miR-214 are downregulated in PCa and may serve as potential non-invasive molecular biomarker for PCa.
Gene drives are systems of biased inheritance that enhance the likelihood a sequence of DNA passes between generations through sexual reproduction and potentially throughout a local population and ...ultimately all connected populations of a species. Gaps in our knowledge of gene drive systems prompted the US National Institutes of Health (NIH) and the Foundation for the NIH to ask the US National Academies of Sciences, Engineering, and Medicine (NASEM) to convene an expert panel to provide an independent, objective examination of what we know about gene drive systems. The report, "Gene drives on the horizon: Advancing science, navigating uncertainty, and aligning research with public values," outlines our understanding of the science, ethics, public engagement, governance, and risk assessment pertaining to gene drive research. Researchers have studied naturally occurring gene drive systems for more than a century. While CRISPR/Cas9 was not the first molecular tool considered to create an engineered gene drive, the advent of the CRISPR/Cas9 technology for gene editing gave a renewed impetus to developing gene drives in the laboratory for eventual release in the field. Recent experiments demonstrate that a CRISPR/Cas9-based gene drive can spread a targeted gene throughout nearly all of laboratory populations of yeast, fruit flies, or mosquitoes. Applying this basic science, there are proposals to use gene drive modified organisms to address such things as eradication of insect-borne infectious diseases and conservation of threatened and endangered species. Gene drives could potentially support agriculture by reversing pesticide and herbicide resistance in insects and weeds, and by control of damaging, invasive species. A major recommendation of the NASEM report is that there is insufficient evidence at this time to support release of gene-drive modified organisms into the environment. Importantly, the committee also recognized that the potential benefits of gene drives for basic and applied research are significant and justify proceeding with laboratory research and controlled field trials. This review summarizes highlights of the NASEM report with its focus on using the CRISPR/Cas9 genome-editing technology to develop gene drive modified organisms.
Carbon nanotubes display either metallic or semiconducting properties. Both large, multiwalled nanotubes (MWNTs), with many concentric carbon shells, and bundles or "ropes" of aligned single-walled ...nanotubes (SWNTs), are complex composite conductors that incorporate many weakly coupled nanotubes that each have a different electronic structure. Here we demonstrate a simple and reliable method for selectively removing single carbon shells from MWNTs and SWNT ropes to tailor the properties of these composite nanotubes. We can remove shells of MWNTs stepwise and individually characterize the different shells. By choosing among the shells, we can convert a MWNT into either a metallic or a semiconducting conductor, as well as directly address the issue of multiple-shell transport. With SWNT ropes, similar selectivity allows us to generate entire arrays of nanoscale field-effect transistors based solely on the fraction of semiconducting SWNTs.
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