Drug use problems with self-injected low-molecular-weight heparins in primary care

Purpose: Outpatient subcutaneous therapies are becoming increasingly common. A literature search failed to find produced any studies on application problems pertaining to the self-injection of low-molecular-weight heparins (LMWH) in a heterogeneous outpatient population under daily-life conditions. We therefore designed a study with the aim of recording drug use problems, patient satisfaction, compliance, problems arising from the injection site (abdomen vs. thigh), and residual drug volumes in pre-filled syringes used in self-injection therapy. Methods: Patients were recruited in community pharmacies by 95 trained Master's students in pharmacy. Data were collected during recruitment and by means of structured questionnaire-based telephone interviews that were carried out at the beginning and the end of the LMWH treatment. Results: The median age of the 213 patients enrolled in the study was 54years [interquartile range (IQR) 39-70 years]; of these, 15.5% had their injections administered by a third person. The rate of self-reported non-compliance was 17.1%. At least one relevant problem was recorded in 85.0% of the cases. At the end of the treatment, 38.9% of the patients stated self-administration of the injections required some effort. The preferred injection site was the thigh (68.5%). An overall mean residual drug volume ≥10.0% was detected for 3.9% of the patients. If residual drug was present, a median of 11.2% (IQR 8.6-17.6%) of the total drug volume had not been injected. Patients injecting into the thigh showed a higher risk of leaving residual medication (odds ratio 2.16, 95% confidence interval 1.04-4.51). Conclusions: Most patients had drug use problems, whereas no clear factors were associated with non-compliance, the injection site (apart from residual drug), and discomfort or effort required (apart from prior injection use

Antiretroviral Therapy Reduces Markers of Endothelial and Coagulation Activation in Patients Infected with Human Immunodeficiency Virus Type 1

We investigated the effect of antiretroviral therapy on vascular activation in 41 human immunodeficiency (HIV)—infected patients receiving a regimen that included either at least 1 protease inhibitor (PI; n = 21) or a nonnucleoside reverse-transcriptase inhibitor (NNRTI; n = 20). Acontrol group of 21 healthy subjectswas included for comparison. Levels of endothelialmarkers (soluble vascular cell adhesion molecule [sVCAM]-1, soluble intercellular adhesionmolecule-1, and vonWillebrand factor) were higher in HIV-infected persons before treatment than in control subjects anddecreasedsignificantlyafter 5-13 months of treatment. Levels of sVCAM-1 and vonWillebrand factor correlated significantly with initial virus load. D-dimer concentrations also decreased significantly after initiation of treatment. PI- and NNRTI-containing regimens had similar effects. Therapy did not reduce levels of the soluble platelet (sP) activation markers sP-selectin and CD40 ligand. The inhibition of markers of vascular activation may counterbalance sequelae of therapy-induced dyslipidemia and potentially prevent development of atherosclerosis in HIVinfected patient

Endogenous Immunosuppression and the Effect of Blood Transfusion on Cell Mediated Immunity in Haemodialysis Patients

In order to clarify the effect of blood transfusion in uraemic patients, 48 dialysis patients who had not received previous blood transfusion were randomly allocated to receive 5 or 10 units of third-party packed cells at two week intervals. Twelve dialysis patients and 12 healthy subjects who had not received previous blood transfusion were also studied as control groups. The cell-mediated immunity (CMI) of the transfused patients was measured by skin testing with DNCB and four recall antigens before the first transfusion and 14 days after the last unit of blood. In addition, prior to the first and 14 days after each transfusion patients were screened for a) haematological and biochemistry results, b) cytotoxic antibodies, c) complement levels, d) titres of IgG secreting cells (PFC) in the peripheral blood both spontaneously and after stimulation with PWM and SAC, using a protein A plaque assay, and e) prostaglandin E (PGE) production in supernatants from both Con A-stimulated PBMC cultures and unstimulated ones. The two control groups were screened for these parameters on 3-4 occasions over a period of 3 months. The methods and results from this randomised controlled study are described in detail in the first 8 chapters of this thesis. In Chapter 9, I describe results from a large number of patients with regard to factors determining the response to DNCB and its value as a means of predicting renal allograft survival. This retrospective analysis was done from an angle and evidence provided by the prospective study. The aim of the study was, a) to assess the effect of blood transfusion in uraemic patients, b) to see whether patients with strong or weak reaction to DNCB differ in their response to transfusion, and try to define the optimum number of transfusions for each group to achieve a beneficial effect, c) to see whether blood transfusion-induced alterations in immune responses could be monitored with simple skin tests and d) to define possible factors determining the response to DNCB and assess the predictive value of the skin test regarding graft survival. In the group of the previously non-transfused dialysis patients more than half were strong DNCB responders. This proportion was two fold higher compared to that of the overall dialysis population. There was a progressive decline in strong responders as patients received more blood, and in multi-transfused patients CMI was profoundly suppressed. Multivariate analysis revealed that the most significant factor associated with the response to DNCB was blood transfusion. A number of factors did not show any association, namely age, sex, primary renal disease, type of dialysis, parity, ABO and rhesus blood groups, interval between last transfusion and test, cytotoxic antibodies and a number of haematological and biochemical parameters. HLA-DRW6 positive patients were more likely to be strong responders when tested prior to any blood transfusion, but the DRW6 effect was not observed in patients sensitised after one or more transfusions. This suggests that HLA-DRW6 is a marker of strong CMI, but this strong response can be modified by transfusion. Sequential skin testing with DNCB and recall antigens did not reflect changes induced by transfusion, as repeated immunisation resulted in stronger anamnestic responses, regardless of the amount of blood or whether they were transfused at all. Follow-up DNCB skin testing showed that blood transfusion at the time of sensitisation to DNCB was a crucial event for secondary responses to DNCB. Patients eliciting a strong primary response retained and gave even stronger responses on subsequent tests regardless of transfusion status at the time of sensitisation to DNCB. Contrary to that, weak responders who were sensitised after transfusion showed a further depression in their secondary responses, while weak responders sensitised prior to any transfusion were more likely to show increased secondary responses. As a result of this, approximately one third of the latter patients changed to strong responders in follow-up tests. (Abstract shortened by ProQuest.)

A finite element method for non-linear hyperelasticity applied for the simulation of octopus ARM motions

An implicit non-linear finite element (FE) numerical procedure for the simulation of biological muscular tissues is presented. The method has been developed for studying the motion of muscular hydrostats, such as squid and octopus arms and its general framework is applicable to other muscular tissues. The FE framework considered is suitable for the dynamic numerical simulations of three-dimensional non-linear nearly incompressible hyperelastic materials that undergo large displacements and deformations. Human and animal muscles, consisting of fibers and connective tissues, belong to this class of materials. The stress distribution inside the muscular FE model is considered as the superposition of stresses along the muscular fibers and the connective tissues. The stresses along the fibers are modeled as the sum of active and passive stresses, according to the muscular model of Van Leeuwen and Kier (1997) Philos. Trans. R. Soc. London, 352: 551-571. Passive stress distribution is an experimentally-defined function of fibers’ deformation; while active stress distribution is the product of an activation level time function, a force-stretch function and a force-stretch ratio function. The mechanical behavior of the surrounding tissues is determined adopting a Mooney-Rivlin constitutive model. The incompressibility criterion is met by enforcing large bulk modulus and by introducing modified deformation measures. Due to the non-linear nature of the problem, approximate determination of the Jacobian matrix is performed, in order to utilize the full Newton-Raphson iterative procedure within each time-step. In addition, time discretization is performed via the implicit Newmark method. We developed an open-source finite element code that is capable of simulating large deflection maneuvers of muscular hydrostats. The proposed methodology is validated by comparing the numerical results with existing measurements for the squid arm extension. The efficiency and robustness of the proposed numerical method is demonstrated through a series of octopus arm maneuvers, such as extension, compression and bending

Hemostasis and complement in allogeneic hematopoietic stem cell transplantation: clinical significance of two interactive systems.

Hematopoietic stem cell transplantation (HCT) represents a curative treatment option for certain malignant and nonmalignant hematological diseases. Conditioning regimens before HCT, the development of graft-versus-host disease (GVHD) in the allogeneic setting, and delayed immune reconstitution contribute to early and late complications by inducing tissue damage or humoral alterations. Hemostasis and/or the complement system are biological regulatory defense systems involving humoral and cellular reactions and are variably involved in these complications after allogeneic HCT. The hemostasis and complement systems have multiple interactions, which have been described both under physiological and pathological conditions. They share common tissue targets, such as the endothelium, which suggests interactions in the pathogenesis of several serious complications in the early or late phase after HCT. Complications in which both systems interfere with each other and thus contribute to disease pathogenesis include transplant-associated thrombotic microangiopathy (HSCT-TMA), sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), and GVHD. Here, we review the current knowledge on changes in hemostasis and complement after allogeneic HCT and how these changes may define clinical impact

Long-term observation reveals high-frequency engraftment of human acute myeloid leukemia in immunodeficient mice

Repopulation of immunodeficient mice remains the primary method for functional assessment of human acute myeloid leukemia. Published data report engraftment in ~40-66% of cases, mostly of intermediate- or poor-risk subtypes. Here we report that extending follow-up beyond the standard analysis endpoints of 10 to 16 weeks after transplantation permitted leukemic engraftment from nearly every case of xenotransplanted acute myeloid leukemia (18/19, ~95%). Xenogeneic leukemic cells showed conserved immune pheno-types and genetic signatures when compared to corresponding pre-transplant cells and, furthermore, were able to induce leukemia in re-transplantation assays. Importantly, bone marrow biopsies taken at standardized time points failed to detect leukemic cells in 11/18 of cases that later showed robust engraftment (61%, termed "long-latency engrafters"), indicating that leukemic cells can persist over months at undetectable levels without losing disease-initiating properties. Cells from favorable-risk leukemia subtypes required longer to become detectable in NOD/SCID/IL2Rγ; null; mice (27.5±9.4 weeks) than did cells from intermediate-risk (21.9±9.4 weeks,; P; <0.01) or adverse-risk (17±7.6 weeks;; P; <0.0001) subtypes, explaining why the engraftment of the first was missed with previous protocols. Mechanistically, leukemic cells engrafting after a prolonged latency showed inferior homing to the bone marrow. Finally, we applied our model to favorable-risk acute myeloid leukemia with inv(16); here, we showed that CD34; +; (but not CD34; -; ) blasts induced robust, long-latency engraftment and expressed enhanced levels of stem cell genes. In conclusion, we provide a model that allows; in vivo; mouse studies with a wide range of molecular subtypes of acute myeloid leukemia subtypes which were previously considered not able to engraft, thus enabling novel insights into leukemogenesis

Safety of intravenous ferric carboxymaltose versus oral iron in patients with nondialysis-dependent CKD: an analysis of the 1-year FIND-CKD trial.

Background: The evidence base regarding the safety of intravenous (IV) iron therapy in patients with chronic kidney disease (CKD) is incomplete and largely based on small studies of relatively short duration. Methods: FIND-CKD (ClinicalTrials.gov number NCT00994318) was a 1-year, open-label, multicenter, prospective study of patients with nondialysis-dependent CKD, anemia and iron deficiency randomized (1:1:2) to IV ferric carboxymaltose (FCM), targeting higher (400-600 µg/L) or lower (100-200 µg/L) ferritin, or oral iron. A post hoc analysis of adverse event rates per 100 patient-years was performed to assess the safety of FCM versus oral iron over an extended period. Results: The safety population included 616 patients. The incidence of one or more adverse events was 91.0, 100.0 and 105.0 per 100 patient-years in the high ferritin FCM, low ferritin FCM and oral iron groups, respectively. The incidence of adverse events with a suspected relation to study drug was 15.9, 17.8 and 36.7 per 100 patient-years in the three groups; for serious adverse events, the incidence was 28.2, 27.9 and 24.3 per 100 patient-years. The incidence of cardiac disorders and infections was similar between groups. At least one ferritin level ≥800 µg/L occurred in 26.6% of high ferritin FCM patients, with no associated increase in adverse events. No patient with ferritin ≥800 µg/L discontinued the study drug due to adverse events. Estimated glomerular filtration rate remained the stable in all groups. Conclusions: These results further support the conclusion that correction of iron deficiency anemia with IV FCM is safe in patients with nondialysis-dependent CKD

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this populatio